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1. Concurrent Olaparib and Radiotherapy in Patients With Triple-Negative Breast Cancer: The Phase 1 Olaparib and Radiation Therapy for Triple-Negative Breast Cancer Trial

Author: Pierre Loap, Delphine Loirat, Frederique Berger, Manuel Rodrigues, Louis Bazire, Jean-Yves Pierga, Anne Vincent-Salomon, Fatima Laki, Latifa Boudali, Laurence Raizonville, Veronique Mosseri, Anne Jochem, Alexandre Eeckhoutte, Mamadou Diallo, Marc-Henri Stern, Alain Fourquet, and Youlia Kirova
Subjects: Cancer Research, Oncology
Abstract: ImportanceTriple-negative breast cancer (TNBC) cells are sensitive to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors used as radiosensitizers. Whether combining PARP inhibitors with radiotherapy in patients with TNBC would enhance the biological effectiveness of the irradiation and improve locoregional control is unclear.ObjectiveTo assess the safety and tolerability of PARP inhibition with olaparib used concurrently with radiotherapy in patients with TNBC with residual disease after neoadjuvant chemotherapy.Design, Setting, and ParticipantsThis phase 1 prospective dose-escalation trial (Olaparib and Radiation Therapy for TNBC [RadioPARP] trial) using a time-to-event continual reassessment method was performed from September 2017 to November 2019, with follow-up until November 2021. Participants had an incomplete pathologic response after neoadjuvant chemotherapy or unresectable TNBC despite previous neoadjuvant chemotherapy, an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, and adequate organ functions.InterventionsOlaparib was administered orally in the form of tablets and given at increasing doses (50 mg, 100 mg, 150 mg, or 200 mg twice daily). Olaparib therapy was started 1 week before radiotherapy and was continued concomitantly with radiotherapy. After breast-conserving surgery, a total dose of 50.4 Gy was delivered to the whole breast, with a 63-Gy simultaneously integrated boost to the tumor bed for patients younger than 60 years. After radical mastectomy or for unresectable tumors despite neoadjuvant chemotherapy, a total dose of 50.0 Gy was delivered to the chest wall (after mastectomy) or to the whole breast (for unresectable tumors). Regional lymph node stations could be treated with a total dose of 50.0 Gy to 50.4 Gy in cases of node-positive disease.Main Outcomes and MeasuresMain outcomes were the safety and tolerability of PARP inhibition with radiotherapy for early-stage, high-risk TNBC. Secondary outcomes included overall survival (OS) and event-free survival (EFS).ResultsAmong the 24 patients included in the trial (100% female; median age, 46 years [range, 25-74 years]), no dose-limiting toxic effects were observed, and olaparib was escalated to 200 mg twice daily without reaching the maximum tolerated dose. No late treatment-related grade 3 or greater toxic effect was observed, and the maximum observed treatment-related toxic effects at the 2-year follow-up were grade 2 breast pain, fibrosis, and deformity in 1 patient (4.2%). Three-year OS and EFS were 83% (95% CI, 70%-100%) and 65% (95% CI, 48%-88%), respectively. Homologous recombination status was not associated with OS or EFS.Conclusions and RelevanceThe findings of this phase 1 dose-escalation trial suggest that PARP inhibition with olaparib concurrently with radiotherapy for early-stage, high-risk TNBC is well tolerated and should continue to be evaluated in further clinical trials.Trial RegistrationClinicalTrials.gov Identifier: NCT03109080
Published: 2023

2. The place of the boost in the breast cancer treatment: State of art

Author: Arnaud, Beddok, Youlia, Kirova, Fatima, Laki, Fabien, Reyal, Anne, Vincent Salomon, Vincent, Servois, and Alain, Fourquet
Subjects: Observer Variation, Oncology, Radiotherapy Planning, Computer-Assisted, Humans, Reproducibility of Results, Breast Neoplasms, Female, Radiology, Nuclear Medicine and imaging, Hematology, Mastectomy, Segmental, Tomography, X-Ray Computed, Tumor Burden
Abstract: Several randomized controlled trials have demonstrated the benefit of a boost to the tumor bed (TB) to reduce the risk of ipsilateral breast tumor recurrence. Recent technological progress has facilitated improved conformation of isodoses around the target volume. The accuracy and reproducibility of TB delineation have become even more essential. The purpose of this study is to review the extant knowledge on the boost delineation in breast cancer, focusing on interobserver variability (IOV) and the influence of various factors, such as the presence of clips or different imaging modalities to improve IOV. Most studies investigating IOV for boost delineation have shown poor reproducibility (with comparison indices such as the dice similarity index around 0.5). Clips in the lumpectomy cavity (LC), postoperative fluid accumulation in the LC and/or high cavity visualization score appeared to be associated with improved IOV. Likewise, the use of preoperative imaging (CT and/or MRI) may also be useful in improving the accuracy of TB definition but without any real gain in terms of IOV. Moreover, the delineation of boost has become even more challenging since the development of oncoplastic surgery. To improve the reproducibility and the accuracy of boost delineation, this review suggests that within each center, a group of multidisciplinary experts, including surgeons, radiation oncologists, pathologists, and radiologists, should convene to develop local guidelines, which may include the choice of preoperative imaging, the number and location of surgical clips, pathological margins, and orientation. The elaboration of contouring atlas is certainly of great assistance.
Published: 2022
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3. Abstract P1-07-01: Real time detection of ESR1 mutation in blood by droplet digital PCR in the PADA-1 trial: Feasibility and cross-validation with NGS

Author: Céline Callens, François-Clément Bidard, Anais Curto-Taribo, Olfa Trabelsi-Grati, Samia Melaabi, Suzette Delaloge, Anne-Claire Hardy-Bessard, Thomas Bachelot, Florian Clatot, Thibault De La Motte Rouge, Jean-Luc Canon, Laurent Arnould, Fabrice André, Sandrine Marques, Marc-Henri Stern, Jean-Yves Pierga, Anne-Vincent Salomon, Emmanuelle Jeannot, Frederique Berger, Ivan Bieche, and Anne Pradines
Subjects: Cancer Research, Oncology
Abstract: Background: Mutations of ESR1 (ESR1mut), the gene encoding for Estrogen Receptor (ER) alpha, have been functionally characterized as driving resistance to aromatase inhibitors (AI) given to in ER+ HER2- metastatic breast cancer (mBC). In the randomized multicenter phase 3 PADA-1 trial (NCT03079011), ER+ HER2- mBC patients treated with first line AI+Palbociclib were screened every two months for ESR1mut in blood (bESR1mut), by subjecting cell-free circulating DNA (cfcDNA) to a droplet digital PCR (ddPCR) assay. Upon the onset of a rising (i.e., increasing or appearing) bESR1mut, patients with no concomitant disease progression were randomized between keeping the same regimen (AI-Palbociclib) or switching to Fulvestrant-Palbociclib. We report herein the sample flow of this first-in-its-class trial, from April 2017 to March 2021, and the cross-validation of ddPCR results with NGS. Methods: At each time point, 20 mL of blood were drawn into BCT Streck® tubes. cfcDNA was extracted from 4 mL of plasma. bESR1mut testing was centralized in 2 platforms using the same ddPCR assay, which combines a drop-off ddPCR, targeting the clustered hotspot L536, Y537 and D538 mutations found in exon 8, with an unconventional ddPCR interrogating specifically the E380Q mutation, located in exon 5 (Jeannot et al, Oncogene 2020). Results were expressed as the number of ESR1mut copies detected per mL of plasma together with the Mutant Allele Frequency (MAF). As a control, we submitted 200 ESR1mut+ (by ddPCR) left-over samples to an amplicon-based Next Generation Sequencing (NGS) assay covering all ESR1 exons - with a nominal sensitivity of >0.5% MAF. Results: From 03/2017 to 03/2021, 1,017 MBC patients have been included in 83 centers and 12,552 blood samples have been collected. The median time of delivery to central platforms was 1 day (range: [0-11]). A median volume of 9.5 mL [2-20] of plasma was obtained after 2 centrifugations. bESR1mut results were notified to investigators with a median turnaround time of 13 days [1-813] (32 days in 2017, 9 days in 2019, 8 days in 2021). Among the 12,525 available ddPCR results: N=77 ( Citation Format: Céline Callens, François-Clément Bidard, Anais Curto-Taribo, Olfa Trabelsi-Grati, Samia Melaabi, Suzette Delaloge, Anne-Claire Hardy-Bessard, Thomas Bachelot, Florian Clatot, Thibault De La Motte Rouge, Jean-Luc Canon, Laurent Arnould, Fabrice André, Sandrine Marques, Marc-Henri Stern, Jean-Yves Pierga, Anne-Vincent Salomon, Emmanuelle Jeannot, Frederique Berger, Ivan Bieche, Anne Pradines. Real time detection of ESR1 mutation in blood by droplet digital PCR in the PADA-1 trial: Feasibility and cross-validation with NGS [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-01.
Published: 2022
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4. Abstract PD11-04: A multi-feature AI-based solution for cancer diagnosis in breast biopsies: A prospective blinded multi-site clinical study

Author: Anne Vincent-Salomon, Guillaume Bataillon, Alona Nudelman, Judith Sandbank, Anat Albrecht Shach, Lucie Thibault, Lilach Bien, Rachel Mikulinsky, Ira Krasnitsky, Ronen Heled, Chaim Linhart, Manuela Vecsler, and Daphna Laifenfeld
Subjects: Cancer Research, Oncology, skin and connective tissue diseases
Abstract: Objective This study aimed to clinically validate the performance of a multi-feature AI-based solution on detection of invasive versus in situ carcinomas and in situ ductal carcinoma high grade from atypical ductal hyperplasia/low grade DCIS compared to rigorous ground truth (GT) established by multiple blinded expert pathologists in breast biopsies. Design Performance of the AI solution was prospectively tested on breast biopsies from two medical institutions in different geographies. AI results were compared against the ground truth (GT) established by consensus of two subspecialist breast pathologists. The study endpoints were detection of invasive carcinoma (IDC, ILC) and DCIS/ADH, including differentiating between different DCIS grades and ADH. ADH and DCIS Low Grade were pooled together because of similar clinical management when diagnosed on a biopsy. Results Six pathologists participated in the study and reported on 436 breast biopsies (841 H&E slides), including 156 invasive (including 31 rare subtypes), 135 DCIS/ADH and 145 benign diagnoses. The AI solution demonstrated high performance when compared with the GT with an AUC of 0.99 for the detection of invasive carcinoma (specificity and sensitivity of 93.6% and 95.5% respectively) and with AUC of 0.95 for the detection of DCIS/ADH. The AI solution differentiated well between subtypes/grades of invasive and in-situ cancers with an AUC of 0.97 for IDC vs. ILC and AUC of 0.92 for DCIS high grade vs. low grade/ADH, respectively. Only 11 (7%) cases had discrepancies on invasive diagnosis, 4 of these between invasive versus benign diagnosis encompassing one case on which the invasive component was only represented by rare lympho-vascular invasion, two cases of ILC (one with a diffuse pattern and the second in a case with granulomatous mastitis with multinucleated giant cells and hemosiderin-laden macrophages) and one rare case of tubular carcinoma surrounded by flat epithelial atypia and columnar cell lesions. Fifteen cases (11%) had discrepancies on DCIS/ADH diagnosis between the two specialist pathologists necessitating a third assessment by a specialist to establish GT. Six of these cases also necessitated a review on a multihead microscope to reach a consensus decision, since there was no majority even after 3 reviews. Conclusion This blinded multi-site study reports the successful clinical validation of a multi-feature AI-based solution in detecting and automatically imparting clinically relevant diagnostic parameters regarding invasive and in situ breast carcinoma, offering an important tool for computer-aided diagnosis in routine pathology practice. Citation Format: Anne Vincent-Salomon, Guillaume Bataillon, Alona Nudelman, Judith Sandbank, Anat Albrecht Shach, Lucie Thibault, Lilach Bien, Rachel Mikulinsky, Ira Krasnitsky, Ronen Heled, Chaim Linhart, Manuela Vecsler, Daphna Laifenfeld. A multi-feature AI-based solution for cancer diagnosis in breast biopsies: A prospective blinded multi-site clinical study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD11-04.
Published: 2022
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5. Validation and real-world clinical application of an artificial intelligence algorithm for breast cancer detection in biopsies

Author: Judith Sandbank, Guillaume Bataillon, Alona Nudelman, Ira Krasnitsky, Rachel Mikulinsky, Lilach Bien, Lucie Thibault, Anat Albrecht Shach, Geraldine Sebag, Douglas P. Clark, Daphna Laifenfeld, Stuart J. Schnitt, Chaim Linhart, Manuela Vecsler, and Anne Vincent-Salomon
Subjects: Oncology, Pharmacology (medical), Radiology, Nuclear Medicine and imaging
Abstract: Breast cancer is the most common malignant disease worldwide, with over 2.26 million new cases in 2020. Its diagnosis is determined by a histological review of breast biopsy specimens, which can be labor-intensive, subjective, and error-prone. Artificial Intelligence (AI)—based tools can support cancer detection and classification in breast biopsies ensuring rapid, accurate, and objective diagnosis. We present here the development, external clinical validation, and deployment in routine use of an AI-based quality control solution for breast biopsy review. The underlying AI algorithm is trained to identify 51 different types of clinical and morphological features, and it achieves very high accuracy in a large, multi-site validation study. Specifically, the area under the receiver operating characteristic curves (AUC) for the detection of invasive carcinoma and of ductal carcinoma in situ (DCIS) are 0.99 (specificity and sensitivity of 93.57 and 95.51%, respectively) and 0.98 (specificity and sensitivity of 93.79 and 93.20% respectively), respectively. The AI algorithm differentiates well between subtypes of invasive and different grades of in situ carcinomas with an AUC of 0.97 for invasive ductal carcinoma (IDC) vs. invasive lobular carcinoma (ILC) and AUC of 0.92 for DCIS high grade vs. low grade/atypical ductal hyperplasia, respectively, as well as accurately identifies stromal tumor-infiltrating lymphocytes (TILs) with an AUC of 0.965. Deployment of this AI solution as a real-time quality control solution in clinical routine leads to the identification of cancers initially missed by the reviewing pathologist, demonstrating both clinical utility and accuracy in real-world clinical application.
Published: 2022
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6. Association du double blocage de HER2 et radiothérapie dans la prise en charge du cancer du sein exprimant HER2

Author: Anne Vincent-Salomon, L. Escalup, Alain Fourquet, Y.M. Kirova, Pierre Loap, S. Ben Dhia, K.I. Cao, and Delphine Loirat
Subjects: Gynecology, medicine.medical_specialty, business.industry, medicine.medical_treatment, medicine.disease, Radiation therapy, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Oncology, 030220 oncology & carcinogenesis, medicine, Radiology, Nuclear Medicine and imaging, Pertuzumab, business, medicine.drug
Abstract: Resume Introduction et but de l’etude La tolerance de l’association d’une radiotherapie concomitante a un traitement par pertuzumab et trastuzumab ) est encore inconnue. L’objectif de ce travail etait d’evaluer la tolerance de cette association chez des patientes traitees pour un cancer du sein localement evolue ou metastatique surexprimant HER2 . Materiel et methodes Etude retrospective menee a l’institut Curie chez toutes les patientes traitees en concomitance par pertuzumab, trastuzumab et irradiation. La radiotherapie a ete delivree pendant un traitement par maintenance par pertuzumab et trastuzumab a respectivement 420 mg (dose totale) et 6 mg/kg toutes les trois semaines sans chimiotherapie. L’evaluation de la toxicite a ete faite selon la « National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 ». La fraction d’ejection ventriculaire gauche (FEVG) a ete evalue dans le bilan pre-therapeutique et puis tous les 3 a 4 mois. Resultats et analyse statistique Nous avons etudie 77 patientes traitees entre octobre 2013 et decembre 2019 avec un suivi median de 38 mois (extremes : 0–246 mois). L’âge median etait de 53 ans (extremes : 36–86 ans). Il y avait 50 patientes (64,9 %) atteintes de metastatses au moment du diagnostic et 27 patientes (35,1 %) en situation de recidive. Toutes les patientes ont recu comme premiere ligne therapeutique une chimiotherapie a base de taxanes suivie par pertuzumab et trastuzumab avec un nombre de cycle median de 34 (10–85). Toutes les patientes avaient une reponse partielle ou complete selon les criteres RECIST. Les volumes de radiotherapie etaient le sein (41 patientes, 53,2 %) et la paroi thoracique (29 patientes, 37,7 %) a la dose de 50 Gy avec une duree mediane de traitement de 39 jours. Une irradiation des aires ganglionnaires regionales a ete delivree chez 53 patientes (68,8 %) comme suit : irradiation sus/sous claviculaire axillaire chez 52 patientes (67,5 %) et mammaire interne chez 31 patientes (40,3 %). Pour 20 patientes, la radiotherapie etait a visee palliative : osseuse (12 patientes, 15,6 %), de encephale in toto (2 patientes, 2,6 %), de nodules metastatiques cerebraux (six patientes). Comme toxicite aigue, nous avons observe : une radioepitheliite de grade 1 chez 36 patientes (46,8 %), de grade 2 chez 17 patientes (22,1 %) et de grade 3 chez trois patientes (3,9 %). Une patiente a souffert d'une œsophagite de grade 2 et une d'une baisse asymptomatique de la FEVG en cours de traitement par pertuzumab, trastuzumab et irradiation. Comme toxicite tardive, nous avons observe des telangiectasies chez deux patientes, de grade 1 (1,3 %) et de grade 2 (1,3 %) ; il y a eu un cas de cardiotoxicite de grade 3 huit mois apres la fin de la radiotherapie. Conclusion Le traitement concomitant par irradiation, pertuzumab et trastuzumab semble avec un bon profil de tolerance ; une etude prospective plus large avec un suivi plus prolonge reste cependant necessaire pour confirmer ces resultats.
Published: 2021
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7. Invasive Lobular Carcinoma of the Breast: Toward Tailoring Therapy?

Author: Lounes Djerroudi, Luc Cabel, Francois-Clement Bidard, and Anne Vincent-Salomon
Subjects: Cancer Research, Carcinoma, Lobular, Oncology, Carcinoma, Ductal, Breast, Humans, Female, Breast Neoplasms, Breast
Published: 2022

8. Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer

Author: K. Van Baelen, T. Geukens, M. Maetens, V. Tjan-Heijnen, C.J. Lord, S. Linn, F.-C. Bidard, F. Richard, W.W. Yang, R.E. Steele, S.J. Pettitt, C. Van Ongeval, M. De Schepper, E. Isnaldi, I. Nevelsteen, A. Smeets, K. Punie, L. Voorwerk, H. Wildiers, G. Floris, A. Vincent-Salomon, P.W.B. Derksen, P. Neven, E. Senkus, E. Sawyer, M. Kok, and C. Desmedt
Subjects: invasive lobular breast cancer, Carcinoma, Ductal, Breast, imaging, Breast Neoplasms, Hematology, Cadherins, Prognosis, Carcinoma, Lobular, Oncology, treatment strategies, Proto-Oncogene Proteins, ongoing trials, clinical management, Humans, Female, ESCAT alterations
Abstract: BACKGROUND: Invasive lobular breast cancer (ILC) is the second most common type of breast cancer after invasive breast cancer of no special type (NST), representing up to 15% of all breast cancers. DESIGN: Latest data on ILC are presented, focusing on diagnosis, molecular make-up according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) guidelines, treatment in the early and metastatic setting and ILC-focused clinical trials. RESULTS: At the imaging level, magnetic resonance imaging-based and novel positron emission tomography/computed tomography-based techniques can overcome the limitations of currently used imaging techniques for diagnosing ILC. At the pathology level, E-cadherin immunohistochemistry could help improving inter-pathologist agreement. The majority of patients with ILC do not seem to benefit as much from (neo-)adjuvant chemotherapy as patients with NST, although chemotherapy might be required in a subset of high-risk patients. No differences in treatment efficacy are seen for anti-human epidermal growth factor receptor 2 (HER2) therapies in the adjuvant setting and cyclin-dependent kinases 4 and 6 inhibitors in the metastatic setting. The clinical utility of the commercially available prognostic gene expression-based tests is unclear for patients with ILC. Several ESCAT alterations differ in frequency between ILC and NST. Germline BRCA1 and PALB2 alterations are less frequent in patients with ILC, while germline CDH1 (gene coding for E-cadherin) alterations are more frequent in patients with ILC. Somatic HER2 mutations are more frequent in ILC, especially in metastases (15% ILC versus 5% NST). A high tumour mutational burden, relevant for immune checkpoint inhibition, is more frequent in ILC metastases (16%) than in NST metastases (5%). Tumours with somatic inactivating CDH1 mutations may be vulnerable for treatment with ROS1 inhibitors, a concept currently investigated in early and metastatic ILC. CONCLUSION: ILC is a unique malignancy based on its pathological and biological features leading to differences in diagnosis as well as in treatment response, resistance and targets as compared to NST. ispartof: ANNALS OF ONCOLOGY vol:33 issue:8 pages:769-785 ispartof: location:England status: published
Published: 2022

9. 131P Efficacy of neoadjuvant letrozole and palbociclib in HER2-low vs HER2 zero luminal breast cancer: An analysis of the Unicancer Neopal phase II study

Author: J.S. Frenel, A. Vincent-Salomon, J. Lemonnier, V. D'Hondt, I. Desmoulins, P.E. Heudel, F.P. Duhoux, G. Emile, M.A. Mouret Reynier, F. Dalenc, C. Jouannaud, L. Venat-Bouvet, S. Nguyen, J.M. Ferrero, J.L. Canon, L. Fuhrmann, J. Grenier, S. Delaloge, and P.H. Cottu
Subjects: Cancer Research, Oncology
Published: 2023
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10. 70P Invasive lobular breast cancer (ILC), an overlooked subtype in clinical trials

Author: K. Van Baelen, J. Van Cauwenberge, M. Maetens, A. Camden, M.C. Chase, V. Fraser, S. Freeney, L. Hutcheson, J.K. Levine, T. Lien, R. Terveer, C. Turner, V. Vandecaveye, P. Neven, H. Wildiers, E. Sawyer, A. Vincent-Salomon, P. Derksen, C. Desmedt, and G. Beck
Subjects: Cancer Research, Oncology
Published: 2023
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11. Abstract 4534: National Multidisciplinary Tumor Board improves diagnostic stratification and therapeutic management in Cancers of Unknown Primary: the French Experience

Author: Nicolas Jacquin, Maud Kamal, Ivan Bieche, Célia Dupain, Isabelle Guillou, Linda Larbi-Chérif, Etienne Rouleau, Julien Masliah Planchon, Isabelle Soubeyran, Christelle de la Fouchardière, Camille Tlemsani, Hélène Blons, Fabienne Escande, Michel Vidaud, Jennifer Wong, Pierre Saintigny, Sandrine Boyault, Adrien Buisson, Yves Allory, Anne Vincent-Salomon, Vincent Cockenpot, Janick Selves, Christophe Le Tourneau, and Sarah Watson
Subjects: Cancer Research, Oncology
Abstract: Introduction: With the increasing complexity of current diagnostic investigations, the integration of clinical, pathological and molecular characteristics is crucial for the management of patients (pts) with cancers of unknown primary (CUP). A national multidisciplinary tumor board (NatCUPMTB) was created 2 years ago in France to discuss the diagnostic and therapeutic management of CUP pts. The objective of this study was to evaluate its diagnostic, prognostic and therapeutic impact after 2 years of activity. Methods: This was a multicenter retrospective study with prospective follow-up. All pts discussed at least once in the NatCUPMTB between June 2020 and August 2022 were included. Pts and tumors characteristics, pathological and molecular analyses including WGS, WES and RNAseq performed on SEQOIA and AURAGEN national large-scale sequencing platforms, multidisciplinary tumor board (MTB) conclusions, and follow-up after MTB were collected. Results: 76 pts for whom a long-term follow-up was available were included. The median age at diagnosis was 57 yo, 54% were female, and the median number of metastatic sites at diagnosis was 2. The median time between diagnosis and first MTB presentation was 3.8 months (0.2-55). MTB investigations enabled to identify a likely primary origin in 44/76 (58%) pts, and the MTB recommended a personalized therapeutic strategy in 50/76 patients (66%). MTB recommendations were based on the combination of clinical, pathological and molecular investigations in 55% of pts. After a median follow-up of 6.2 months, the median overall survival (OS) was 17.7 months from diagnosis and 11.0 months from the 1st MTB presentation. Pts for which the MTB had a diagnostic impact, and having received a treatment following MTB recommendation (based on putative origin or targetable alteration) had increased OS compared to pts with no diagnostic orientation (median OS 18.4 months vs 5.6 months, p=0.003) or having received other treatments (median OS 18.4 vs 4.4 months, p=0.0001). Conclusion: NatCUPMTB provides significant diagnostic and therapeutic benefit in pts with CUP. Early presentation of pts at NatCUPMTB as soon as CUP diagnosis is suspected should be recommended. Citation Format: Nicolas Jacquin, Maud Kamal, Ivan Bieche, Célia Dupain, Isabelle Guillou, Linda Larbi-Chérif, Etienne Rouleau, Julien Masliah Planchon, Isabelle Soubeyran, Christelle de la Fouchardière, Camille Tlemsani, Hélène Blons, Fabienne Escande, Michel Vidaud, Jennifer Wong, Pierre Saintigny, Sandrine Boyault, Adrien Buisson, Yves Allory, Anne Vincent-Salomon, Vincent Cockenpot, Janick Selves, Christophe Le Tourneau, Sarah Watson. National Multidisciplinary Tumor Board improves diagnostic stratification and therapeutic management in Cancers of Unknown Primary: the French Experience. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4534.
Published: 2023
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12. Circulating tumor DNA as a dynamic biomarker of response to palbociclib and fulvestrant in metastatic breast cancer patients

Author: Marc Michel, Romain Geiss, Francesco Ricci, François-Clément Bidard, Luc Cabel, Paul Cottu, Charlotte Proudhon, Jean-Yves Pierga, Lauren Darrigues, Ivan Bièche, Anne Vincent-Salomon, Coraline Dubot, Amanda Bartolini Silveira, Alice Bernard-Tessier, and Delphine Loirat
Subjects: Oncology, medicine.medical_specialty, Pyridines, Estrogen receptor, Breast Neoplasms, Palbociclib, lcsh:RC254-282, Piperazines, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Surgical oncology, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Humans, Treatment follow-up, Neoplasm Metastasis, Fulvestrant, Aged, Neoplasm Staging, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, Circulating tumor DNA, business.industry, Precision medicine, Palbociclib-fulvestrant, Middle Aged, Prognosis, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Survival Analysis, Metastatic breast cancer, Treatment Outcome, Tumor progression, 030220 oncology & carcinogenesis, Mutation, Biomarker (medicine), Female, business, Research Article, medicine.drug
Abstract: Background Following the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with estrogen receptor-positive (ER+) HER2-negative (HER2−) metastatic breast cancer (MBC). Palbociclib has been shown to increase the progression-free survival (PFS) overall but no predictive biomarker of palbociclib efficacy has been validated so far. We thus evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency. Methods ER+ HER2− MBC patients were included in a prospective observational cohort before treatment initiation. Tumor response was assessed by radiological evaluation (RECIST v1.1) every 3 months. Plasma samples were collected before treatment (baseline), at day 15 (D15), at day 30 (D30), and at disease progression. We searched for somatic mutations from archived tumor tissues by targeted deep sequencing. For patients with somatic mutations identified, circulating tumor DNA (ctDNA) was tracked using digital droplet PCR. Ratios of ctDNA levels ([D15/baseline] and [D30/baseline]) were then correlated with prospectively registered patient characteristics and outcomes. Results Twenty-five of the 61 patients enrolled had a somatic mutation testable in plasma (NPIK3CA = 21, NTP53 = 2, NAKT1 = 2). At baseline, 84% of patients had detectable ctDNA levels but ctDNA levels had no prognostic impact on PFS (p = 0.10). Among those patients, ctDNA was still detected in 82% at D15 and 68% at D30. ctDNA clearance observed at day 30 was associated with longer PFS (HR = 7.2, 95% CI = 1.5–32.6, p = 0.004). On the contrary, a [D30/baseline] ctDNA ratio > 1 was associated with a shorter PFS (HR = 5.1, 95% CI = 1.4–18.3, p = 0.02) and all 5 patients with increased ctDNA levels at D30 showed disease progression after 3 months under palbociclib-fulvestrant. Finally, at the time of radiological tumor progression, ctDNA was detected in all patients tested. Conclusion Our study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS.
Published: 2021

13. Molecular features of untreated breast cancer and initial metastatic event inform clinical decision-making and predict outcome: long-term results of ESOPE, a single-arm prospective multicenter study

Author: Virginie Fourchotte, Céline Callens, Vincent Servois, Sylvie Giacchetti, Walid Chemlali, Patricia Legoix, Paul Cottu, Brigitte Sigal Zafrani, Frédérique Berger, Mahasti Saghatchian, Lisa Belin, Anais Boulai, Keltouma Driouch, Mario Campone, Zakia Tariq, Rosette Lidereau, Anne Vincent Salomon, Ivan Bièche, Etienne Brain, Virginie Bernard, Sylvain Baulande, aurelie comte, Thomas Bachelot, and François-Clément Bidard
Subjects: 0301 basic medicine, Oncology, lcsh:Medicine, Metastasis, Cohort Studies, 0302 clinical medicine, Breast cancer, CDKN2A, Prospective Studies, Neoplasm Metastasis, Prospective cohort study, Phylogeny, Genetics (clinical), Aged, 80 and over, Middle Aged, Targetable genes, Prognosis, Primary tumor, Metastatic breast cancer, Treatment Outcome, 030220 oncology & carcinogenesis, Molecular Medicine, Female, Adult, medicine.medical_specialty, lcsh:QH426-470, Clinical Decision-Making, Breast Neoplasms, 03 medical and health sciences, Internal medicine, Next generation sequencing, de novo metastases, Exome Sequencing, Genetics, medicine, Humans, Molecular Biology, Aged, business.industry, Research, lcsh:R, Cancer, medicine.disease, Survival Analysis, Clinical trial, lcsh:Genetics, 030104 developmental biology, Multivariate Analysis, Mutation, business
Abstract: Background Prognosis evaluation of advanced breast cancer and therapeutic strategy are mostly based on clinical features of advanced disease and molecular profiling of the primary tumor. Very few studies have evaluated the impact of metastatic subtyping during the initial metastatic event in a prospective study. The genomic landscape of metastatic breast cancer has mostly been described in very advanced, pretreated disease, limiting the findings transferability to clinical use. Methods We developed a multicenter, single-arm, prospective clinical trial in order to address these issues. Between November 2010 and September 2013, 123 eligible patients were included. Patients at the first, untreated metastatic event were eligible. All matched primary tumors and metastatic samples were centrally reviewed for pathological typing. Targeted and whole-exome sequencing was applied to matched pairs of frozen tissue. A multivariate overall survival analysis was performed (median follow-up 64 months). Results Per central review in 84 patients (out of 130), we show that luminal A breast tumors are more prone to subtype switching. By combining targeted sequencing of a 91 gene panel (n = 67) and whole-exome sequencing (n = 30), a slight excess of mutations is observed in the metastases. Luminal A breast cancer has the most heterogeneous mutational profile and the highest number of mutational signatures, when comparing primary tumor and the matched metastatic tissue. Tumors with a subtype change have more mutations that are private. The metastasis-specific mutation load is significantly higher in late than in de novo metastases. The most frequently mutated genes were TP53 and PIK3CA. The most frequent metastasis-specific druggable genes were PIK3CA, PTEN, KDR, ALK, CDKN2A, NOTCH4, POLE, SETD2, SF3B1, and TSC2. Long-term outcome is driven by a combination of tumor load and metastasis biology. Conclusions Profiling of the first, untreated, metastatic event of breast cancer reveals a profound heterogeneity mostly in luminal A tumors and in late metastases. Based on this profiling, we can derive information relevant to prognosis and therapeutic intervention, which support current guidelines recommending a biopsy at the first metastatic relapse. Trial registration The trial was registered at ClinicalTrials.gov (NCT01956552).
Published: 2021

14. Interobserver variability in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative invasive breast carcinoma influences the association with pathological complete response: the IVITA study

Author: Caroline Bouzin, Serdar Altinay, Gaëtan MacGrogan, Serena Wong, Anne Vincent-Salomon, Claudia Maria Stanciu-Pop, Laurent Arnould, Franceska Dedeurwaerdere, Delfyne Hastir, Alberto Ravarino, Stephen B. Fox, Valérie Duwel, Caterina Marchiò, Hannah Y Wen, Renata Sinke, Dieter Peeters, Clara Gerosa, Emily Reisenbichler, Benjamin F. Dessauvagie, Maschenka Balkenhol, Magali Lacroix-Triki, Aline François, Christine Galant, Carolien H.M. van Deurzen, S Sanati, Kathleen Lambein, Octavio Burguès, Eline Kurpershoek, Sharon Nofech-Mozes, Andoni Laka, Anne-Sophie Van Rompuy, Mieke R Van Bockstal, Abeer M Shaaban, Glenn Broeckx, Cecile Colpaert, Vera R. J. Schelfhout, Shabnam Jaffer, Anne Marie Schelfhout, Maria Dolores Martin Martinez, Koen Van de Vijver, Erika Resetkova, Giuseppe Floris, UCL - SSS/IREC/MORF - Pôle de Morphologie, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, UCL - (MGD) Service d'anatomie pathologique, and Pathology
Subjects: Oncology, Adult, medicine.medical_specialty, Pathology, interobserver variability, Intraclass correlation, Clinical Decision-Making, Triple Negative Breast Neoplasms, Article, Tumor-infiltrating lymphocytes, Pathology and Forensic Medicine, Breast cancer, Lymphocytes, Tumor-Infiltrating, SDG 3 - Good Health and Well-being, Predictive Value of Tests, Internal medicine, Biopsy, medicine, Tumor Microenvironment, Humans, Neoplasm Invasiveness, Stromal tumor, Pathological, Triple negative, Complete response, Mastectomy, Aged, Aged, 80 and over, Observer Variation, medicine.diagnostic_test, business.industry, Australia, Cancer, Reproducibility of Results, Middle Aged, medicine.disease, Neoadjuvant Therapy, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Europe, Treatment Outcome, Chemotherapy, Adjuvant, North America, triple-negative breast cancer, pathological complete response, Female, Human medicine, Stromal Cells, business, neoadjuvant chemotherapy
Abstract: Contains fulltext : 245198.pdf (Publisher’s version ) (Closed access) High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland-Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from -0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for eight participants (20%). Post hoc sTILs cutoffs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the 'ideal' sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions.
Published: 2021
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15. Concurrent Olaparib with Radiotherapy in Patients with Triple Negative Breast Cancer: Final Results of the RADIOPARP Phase 1 Trial

Author: P. Loap, D. Loirat, F. Berger, M. Rodrigues, L. Bazire, J.Y. Pierga, A. Vincent-Salomon, F. Laki, L. Boudali, L. Raizonville, V. Mosseri, A. Jochem, M. Diallo, M.H. Stern, A. Fourquet, and Y. Kirova
Subjects: Cancer Research, Radiation, Oncology, Radiology, Nuclear Medicine and imaging
Published: 2022
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16. Lipid-Associated Macrophages Are Induced by Cancer-Associated Fibroblasts and Mediate Immune Suppression in Breast Cancer

Author: Eleonora Timperi, Paul Gueguen, Martina Molgora, Ilaria Magagna, Yann Kieffer, Silvia Lopez-Lastra, Philemon Sirven, Laura G. Baudrin, Sylvain Baulande, André Nicolas, Gabriel Champenois, Didier Meseure, Anne Vincent-Salomon, Anne Tardivon, Enora Laas, Vassili Soumelis, Marco Colonna, Fatima Mechta-Grigoriou, Sebastian Amigorena, and Emanuela Romano
Subjects: Cancer Research, Cell Adhesion Molecules, Neuronal, Macrophages, Triple Negative Breast Neoplasms, Fibroblasts, Lipids, Mice, Oncology, Cancer-Associated Fibroblasts, Cell Line, Tumor, Tumor Microenvironment, Animals, Humans, Immune Checkpoint Inhibitors
Abstract: Tumor-associated macrophages (TAM) play a detrimental role in triple-negative breast cancer (TNBC). In-depth analysis of TAM characteristics and interactions with stromal cells, such as cancer-associated fibroblast (CAF), could provide important biological and therapeutic insights. Here we identify at the single-cell level a monocyte-derived STAB1+TREM2high lipid-associated macrophage (LAM) subpopulation with immune suppressive capacities that is expanded in patients resistant to immune checkpoint blockade (ICB). Genetic depletion of this LAM subset in mice suppressed TNBC tumor growth. Flow cytometry and bulk RNA sequencing data demonstrated that coculture with TNBC-derived CAFs led to reprogramming of blood monocytes towards immune suppressive STAB1+TREM2high LAMs, which inhibit T-cell activation and proliferation. Cell-to-cell interaction modeling and assays in vitro demonstrated the role of the inflammatory CXCL12–CXCR4 axis in CAF–myeloid cell cross-talk and recruitment of monocytes in tumor sites. Altogether, these data suggest an inflammation model whereby monocytes recruited to the tumor via the CAF-driven CXCL12–CXCR4 axis acquire protumorigenic LAM capacities to support an immunosuppressive microenvironment. Significance: This work identifies a novel lipid–associated macrophage subpopulation with immune suppressive functions, offering new leads for therapeutic interventions in triple-negative breast cancer.
Published: 2022

17. Innate lymphoid cells: NK and cytotoxic ILC3 subsets infiltrate metastatic breast cancer lymph nodes

Author: Louise Rethacker, Maxime Boy, Valeria Bisio, France Roussin, Jordan Denizeau, Anne Vincent-Salomon, Edith Borcoman, Christine Sedlik, Eliane Piaggio, Antoine Toubert, Nicolas Dulphy, and Anne Caignard
Subjects: Killer Cells, Natural, Oncology, Immunology, Tumor Microenvironment, Immunology and Allergy, Humans, Antineoplastic Agents, Breast Neoplasms, Female, Lymph Nodes, Immunity, Innate
Abstract: Innate lymphoid cells (ILCs) - which include cytotoxic Natural Killer (NK) cells and helper-type ILC - are important regulators of tissue immune homeostasis, with possible roles in tumor surveillance. We analyzed ILC and their functionality in human lymph nodes (LN). In LN, NK cells and ILC3 were the prominent subpopulations. Among the ILC3s, we identified a CD56
Published: 2022

18. Fine‐needle aspiration as an alternative to core needle biopsy for tumour molecular profiling in precision oncology: prospective comparative study of next‐generation sequencing in cancer patients included in the SHIVA02 trial

Author: Marie-Paule Sablin, Vincent Servois, Céline Gu, Edith Borcoman, Celia Dupain, Maud Kamal, Delphine Loirat, Elodie Girard, Ségolène Hescot, Diana Bello, Alexandre de Moura, Céline Callens, Charlotte Lecerf, Pierre Gestraud, Julien Masliah-Planchon, Maxime Frelaut, Odette Mariani, Samantha Antonio, Francesco Ricci, Pauline du Rusquec, Ivan Bièche, P. Tresca, Coralie Franck, Christophe Le Tourneau, and Anne Vincent-Salomon
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, DNA Copy Number Variations, precision medicine, tumour molecular profiling, Concordance, Biopsy, Fine-Needle, next‐generation sequencing, core biopsy, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Internal medicine, Biopsy, Genetics, medicine, Humans, SHIVA02 trial, Prospective Studies, Copy-number variation, fine‐needle aspiration, Research Articles, RC254-282, medicine.diagnostic_test, business.industry, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Reproducibility of Results, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, DNA, Neoplasm, General Medicine, Amplicon, Precision medicine, Gene Expression Regulation, Neoplastic, Clinical trial, 030104 developmental biology, medicine.anatomical_structure, Fine-needle aspiration, 030220 oncology & carcinogenesis, Molecular Medicine, Biopsy, Large-Core Needle, Pancreas, business, Research Article
Abstract: High‐throughput DNA analyses in cancers allow the detection of molecular abnormalities that can guide patients' treatment. The collection of a tumour DNA is mainly performed on a biopsy, an invasive procedure for the patients. Another less invasive method consists in using a fine needle. We showed that fine‐needle biopsies are as suitable as a classical biopsy for DNA analysis., High‐throughput molecular profiling of solid tumours using core needle biopsies (CNB) allows the identification of actionable molecular alterations, with around 70% success rate. Although several studies have demonstrated the utility of small biopsy specimens for molecular testing, there remains debate as to the sensitivity of the less invasive fine‐needle aspiration (FNA) compared to CNB to detect molecular alterations. We aimed to prospectively evaluate the potential of FNA to detect such alterations in various tumour types as compared to CNB in cancer patients included in the SHIVA02 trial. An in‐house amplicon‐based targeted sequencing panel (Illumina TSCA 99.3 kb panel covering 87 genes) was used to identify pathogenic variants and gene copy number variations (CNV) in concomitant CNB and FNA samples obtained from 61 patients enrolled in the SHIVA02 trial (NCT03084757). The main tumour types analysed were breast (38%), colon (15%), pancreas (11%), followed by cervix and stomach (7% each). We report 123 molecular alterations (85 variants, 23 amplifications and 15 homozygous deletions) among which 98 (80%) were concordant between CNB and FNA. The remaining discordances were mainly related to deletions status, yet undetected alterations were not exclusively specific to FNA. Comparative analysis of molecular alterations in CNB and FNA showed high concordance in terms of variants as well as CNVs identified. We conclude FNA could therefore be used in routine diagnostics workflow and clinical trials for tumour molecular profiling with the advantages of being minimally invasive and preserve tissue material needed for diagnostic, prognostic or theranostic purposes.
Published: 2020
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19. A Phase 1 dose-escalation study to evaluate safety, pharmacokinetics and pharmacodynamics of AsiDNA, a first-in-class DNA repair inhibitor, administered intravenously in patients with advanced solid tumours

Author: Christiane Jungels, Véronique Trochon-Joseph, Carlos Gomez-Roca, Jean-Pierre Delord, Anne Vincent-Salomon, Nuria Kotecki, Olga Adamiec, Wael Jdey, Philippe A. Cassier, Christophe Le Tourneau, Christelle Zandanel, Edith Borcoman, Hélène Toussaint, Audrey Mole, Lauriane Eberst, Vincent Cockenpot, Ségolène Hescot, Olivier de Beaumont, and Françoise Bono
Subjects: Adult, Male, Agonist, Cancer Research, DNA Repair, Maximum Tolerated Dose, DNA damage, DNA repair, medicine.drug_class, Pharmacology, Article, 03 medical and health sciences, chemistry.chemical_compound, Targeted therapies, 0302 clinical medicine, Belgium, Pharmacokinetics, Neoplasms, Humans, Medicine, Protein kinase A, Aged, 030304 developmental biology, 0303 health sciences, Dose-Response Relationship, Drug, business.industry, DNA, Middle Aged, Clinical trial, Adenosine diphosphate, Cholesterol, Oncology, chemistry, 030220 oncology & carcinogenesis, Pharmacodynamics, Disease Progression, Administration, Intravenous, Female, France, business
Abstract: BackgroundAsiDNA, a first-in-class oligonucleotide-mimicking double-stranded DNA breaks, acts as a decoy agonist to DNA damage response in tumour cells. It also activates DNA-dependent protein kinase and poly (adenosine diphosphate [ADP]-ribose) polymerase enzymes that induce phosphorylation of H2AX and protein PARylation.MethodsThe aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety and pharmacokinetics/pharmacodynamics of AsiDNA administered daily for 3 days in the first week then weekly thereafter. Twenty-two patients with advanced solid tumours were enrolled in 5 dose levels: 200, 400, 600, 900, and 1300 mg, using a 3 + 3 design.ResultsThe MTD was not reached. IV AsiDNA was safe. Two DLTs (grade 4 and grade 3 hepatic enzymes increased at 900 and 1300 mg), and two related SAE at 900 mg (grade 3 hypotension and grade 4 hepatic enzymes increased) were reported. AsiDNA PK increased proportionally with dose. A robust activation of DNA-PK by a significant posttreatment increase of γH2AX was evidenced in tumour biopsies.ConclusionThe dose of 600 mg was identified as the optimal dose for further clinical development.Clinical trial registrationClinical trial registration (NCT number): NCT03579628.
Published: 2020
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20. A subset of activated fibroblasts is associated with distant relapse in early luminal breast cancer

Author: Yann Kieffer, Fatima Mechta-Grigoriou, Jean Marc Guinebretière, Roman Rouzier, Delphine Hequet, Floriane Pelon, Sylvain Ladoire, Christophe Blanchet, Anne Vincent-Salomon, Antoine Elies, Claire Bonneau, Brigitte Bourachot, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut Curie [Paris], Risques cliniques et sécurité en santé des femmes et en santé périnatale (RISCQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut National de la SantÃ© et de la Recherche MÃ©dicale, Inserm ANR-10-EQPX-03, INCa-DGOS-Inserm-12554, STROMAE INCa-DGOS-9963 Institut National Du Cancer, INCa: INCa-11692, INCa-DGOS-4654, INCa-DGOS-9963 Fondation pour la Recherche MÃ©dicale, FRM Institut Curie: PIC3i CAFi Ligue Contre le Cancer: PC201317 Fondation Simone et Cino Del Duca, C.B. was supported by the Institut National de la Santé et de la Recherche Médicale (Inserm, Plan Cancer - Formation à la recherche translationnelle), A.E. by the association d’aide en Cancérologie de Saint-Cloud (ARCS), and Y.K. by the Institut National du Cancer, INCa (INCa-DGOS-9963, INCa-11692), SIRIC (INCa-DGOS-4654), and the Fondation pour la Recherche Medicale (FRM). The experimental work was supported by grants from the Ligue Nationale Contre le Cancer (Labelisation), Inserm (PC201317), Institut Curie (Incentive and Cooperative Program Tumor Micro-environment PIC TME/T-MEGA, PIC3i CAFi), ICGex (ANR-10-EQPX-03), SIRIC (INCa-DGOS-4654), and INCa (STROMAE INCa-DGOS-9963, CaLYS INCa-11692, INCa-DGOS-Inserm-12554). F.M-G acknowledges both the Association 'Le cancer du sein, Parlons-en' and the Simone and Cino del Duca Foundation for attribution of their 'Grand Prix'. F.M-G is very grateful to all her funders for providing support throughout the years., and F.M-G. received research support from Innate-Pharma, Roche and Bristol-Myers-Squibb (BMS). R. R received financial support for research (travel reimbursement) and speaker honoraria from Nanostring Technologies. Other authors declare no potential conflict of interest.
Subjects: Oncology, CDH11, Receptor, ErbB-2, Stroma, Metastases, 0302 clinical medicine, Luminal breast cancer, Surgical oncology, Tumor Microenvironment, Aged, 80 and over, 0303 health sciences, Carcinoma, Ductal, Breast, Middle Aged, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Combined Modality Therapy, 3. Good health, Tumor infiltrating lymphocytes, Survival Rate, Cadherin 11, Receptors, Estrogen, 030220 oncology & carcinogenesis, Immunohistochemistry, Female, Receptors, Progesterone, Research Article, Adult, medicine.medical_specialty, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, Breast cancer, Lymphocytes, Tumor-Infiltrating, Internal medicine, medicine, Biomarkers, Tumor, Humans, Clinical significance, TILs, Cancer-associated fibroblasts, 030304 developmental biology, Aged, business.industry, Tumor-infiltrating lymphocytes, medicine.disease, Carcinoma, Lobular, Tumor micro-environment, Case-Control Studies, Cancer cell, Cancer-Associated Fibroblasts, Neoplasm Recurrence, Local, business, Follow-Up Studies
Abstract: BackgroundEarly luminal breast cancer (BC) represents 70% of newly diagnosed BC cases. Among them, small (under 2 cm) BC without lymph node metastasis (classified as T1N0) have been rarely studied, as their prognosis is generally favorable. Nevertheless, up to 5% of luminal T1N0 BC patients relapse with distant metastases that ultimately prove fatal. The aim of our work was to identify the mechanisms involved in metastatic recurrence in these patients.MethodsOur study addresses the role that autonomous and non-autonomous tumor cell features play with regard to distant recurrence in early luminal BC patients. We created a cohort of T1N0 luminal BC patients (tumors between 0.5–2 cm without lymph node metastasis) with metastatic recurrence (“cases”) and corresponding “controls” (without relapse) matched 1:1 on main prognostic factors: age, grade, and proliferation. We deciphered different characteristics of cancer cells and their tumor micro-environment (TME) by deep analyses using immunohistochemistry. We performed in vitro functional assays and highlighted a new mechanism of cooperation between cancer cells and one particular subset of cancer-associated fibroblasts (CAF).ResultsWe found that specific TME features are indicative of relapse in early luminal BC. Indeed, quantitative histological analyses reveal that “cases” are characterized by significant accumulation of a particular CAF subset (CAF-S1) and decrease in CD4+T lymphocytes, without any other association with immune cells. In multivariate analysis, TME features, in particular CAF-S1 enrichment, remain significantly associated with recurrence, thereby demonstrating their clinical relevance. Finally, by performing functional analyses, we demonstrated that CAF-S1 pro-metastatic activity is mediated by the CDH11/osteoblast cadherin, consistent with bones being a major site of metastases in luminal BC patients.ConclusionsThis study shows that distant recurrence in T1N0 BC is strongly associated with the presence of CAF-S1 fibroblasts. Moreover, we identify CDH11 as a key player in CAF-S1-mediated pro-metastatic activity. This is independent of tumor cells and represents a new prognostic factor. These results could assist clinicians in identifying luminal BC patients with high risk of relapse. Targeted therapies against CAF-S1 using anti-FAP antibody or CDH11-targeting compounds might help in preventing relapse for such patients with activated stroma.
Published: 2020
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21. Abstract P2-08-21: Outcomes results of Prosigna® test in early breast cancer patients: Experience of Institut Curie, France

Author: Louise Maumy, Paul Cottu, Delphine Hequet, Jean-Marc Guinebretière, David Gentien, Céline Callens, Ivan Bièche, Anne Vincent-Salomon, Roman Rouzier, and Florence Lerebours
Subjects: Cancer Research, medicine.medical_specialty, education.field_of_study, Chemotherapy, business.industry, medicine.medical_treatment, Population, Cancer, medicine.disease, Gastroenterology, medicine.anatomical_structure, Breast cancer, Oncology, Internal medicine, medicine, Population study, Hormone therapy, education, business, Prospective cohort study, Lymph node
Abstract: Prosigna® tests are performed in Institut Curie to guide adjuvant chemotherapy decision in early estrogen receptor (ER) positive, Human Epidermal growth factor Receptor (HER2) negative breast cancer (BC) patients, with an intermediate risk of recurrence. The objective of this study was to check the absence of an early warning signal for therapeutic decisions guided by the use of genomic tests in terms of the occurrence of events during the follow-up. Methods: Follow-up analysis were made on 2 populations: Real-life population: ER positive, HER2 negative BC patients who had a Prosigna® test in clinical routine, were prospectively registered and their data collected. Prosigna® test was indicated for patients with an intermediate risk of recurrence defined by our regional guidelines (1): grade 1 T1cN1, grade 1 T2N0-1, grade 2 T1cN0 with pejorative prognosis parameters (Ki67>20% or lympho-vascular emboli), grade 2 T2N0, grade 3 T1cN0. Decision impact (DI) study (2): a prospective multicenter study evaluating the decision impact of Prosigna® tests on adjuvant chemotherapy treatment. All consecutive T1-T2 NO-N1(mic) ER positive, HER2 negative BC patients were included. Survival was estimated by Kaplan-Meier methods and compared between patients who received or not chemotherapy based on the tests results with a Log-rank test (chemotherapy was administered for patients with a 10-years distant recurrence probability >=10%). Results are given in % with 95% intervalley confidence. Results: 647 patients were included (124 from DI study and 523 from clinical routine). Median age was 59 years-old (28-83). The median size of the tumor was 17 mm, (3-75), with a majority of grade 2 tumors (n=473, 73%) and 14% of lymph node involvement (n=90). Prosigna® tests results showed: 54% of luminal A.; respectively 30% (n=195), 40% (n=257) and 30% (n=195) of high, intermediate and low risk categories. The median 10-years distant recurrence probability was 10% (2-45%). The median follow-up of the patients was 18 months (0-52). We did not observe death in our study population, and we registered 10 recurrences (4 distant-DMFS- and 6 locoregional-LDFS). Disease free survival (DFS) at respectively 12 and 24 months were 99.8% (98.9-100) and 98.6% (96.5-99.4). Locoregional DFS at 12 and 24 months were 99.8% (98.9-100) and 99.2% (97.4-99.8) and distant DFS at 12 and 24 months were 100% and 99.4% (97.5-99.8). We did not observe survival differences between patients treated by chemotherapy and hormone therapy (CT) and patients treated by hormone therapy alone (No CT). DFS were respectively for CT and no CT groups 99.6% (97.4-99.9) and 99.5% (96.8-99.9, p=0.8) at 12 months, and 98.9% (95.1-99.7) and 99% (96-99.7, p=0.8) at 24 months. Distant and locoregional DFS were also not different between CT and No CT groups. Discussion: The first results of this study, mainly composed of clinical routine patients, are totally reassuring. We did not identify early warning signal in terms of survival with the use of Prosigna® test to guide adjuvant chemotherapy decisions in early BC patients at intermediate risk of recurrence. Moreover, our results are in accordance with the TAILORx (3) and MINDACT (4) randomized prospective studies survivals. References: 1. https://www.gustaveroussy.fr/sites/default/files/referentiel-cancer-du-sein-gustaveroussy-curie-2016-2017.pdf 2. Hequet D, et al. PLoS One. 2017 Oct 18;12(10):e0185753 3. Sparano JA, et al. N Engl J Med. 2018 Jul 12;379(2):111-121 4. Cardoso F, et al; N Engl J Med. 2016 Aug 25;375(8):717-29 Citation Format: Delphine Hequet, Louise Maumy, Celine Callens, David Gentien, Ivan Bieche, Paul Cottu, Jean-Marc Guinebretiere, Anne Vincent-Salomon, Florence Lerebours, Roman Rouzier. Outcomes results of Prosigna® test in early breast cancer patients: Experience of Institut Curie, France [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-21.
Published: 2020
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22. Abstract P2-14-10: Prosigna® test in clinical routine: Impact on adjuvant chemotherapy decision and medico-economic considerations in France

Author: Delphine Hequet, Céline Callens, Roman Rouzier, Guillaume Harrissart, Jean-Marc Guinebretière, Florence Lerebours, Paul Cottu, Ivan Bièche, Anne Vincent-Salomon, and David Gentien
Subjects: Cancer Research, medicine.medical_specialty, Oncology, business.industry, Adjuvant chemotherapy, Medicine, Clinical routine, business, Intensive care medicine, Test (assessment)
Abstract: The Prosigna® test has been performed in Institut Curie, France, since 2016 in clinical routine with a financial support of the health ministry dedicated to innovative procedures. The genomic platform at the Institut Curie performs the Prosigna® test for patients cared for at the Curie Hospital and in other institutions. Our main objective was to evaluate the impact of Prosigna® tests on adjuvant chemotherapy decisions. The second objective was to assess the costs associated with implementation of the test for patient management. Methods: Early breast cancer patients with estrogen receptor positive and human epidermal growth factor receptor 2-negative tumors, who had a Prosigna® test in clinical routine, were prospectively registered and observed. The Prosigna® test was indicated for a population candidate for a chemotherapy, with an intermediate risk of recurrence defined by our regional guidelines (1): grade 1 T1cN1, grade 1 T2N0-1, grade 2 T1cN0 with risk factors (Ki67>20% or lympho-vascular emboli), grade 2 T2N0, grade 3 T1cN0. The French Health Authority (FHA) has also recently defined the population who are candidates for genomic testing: T1c/T2 and N0/N1(mic) and grade 2 without risk factors (age Results: Prosigna® test was performed for 831 patients in clinical practice from 2016 and 2019 at Institut Curie. Due to missing data, analyses have been performed on 735 patients. Median age was 57 years-old (28-80), and median size 18 mm (3-80). We observed a majority of grade 2 tumors (n=572, 78%), and 21% of lymph node involvement. Median Ki67 was 20 (0-100). Prosigna® tests classified respectively 234 (32%), 295 (40%) and 206 (28%) in high, intermediate and low risk categories. In the all real-life population (n=735), chemotherapy was avoided for 308 (42%) patients after Prosigna® test results, and in 192 (44%) cases in the population defined by the FHA (n=433). From a financial point of view, both the real-life data and the population defined by FHA demonstrated cost savings,1 739 614€ (n=735 patients). and 1 068 671€(n=433), respectively. Conclusion: This large real-life study showed a 40% decrease in adjuvant chemotherapy recommendations after introduction of the Prosigna® test in a population of chemotherapy candidates. Moreover, this therapeutic de-escalation demonstrated an overall cost savings for the health system despite the added cost of the test. References: 1. https://www.gustaveroussy.fr/sites/default/files/referentiel-cancer-du-sein-gustaveroussy-curie-2016-2017.pdf 2. Baffert S, et al. The patient-breast cancer care pathway: how could it be optimized? BMC Cancer. 2015 May 12;15:394 3. Héquet D, et al. Direct medical and non-medical costs of a one-year care pathway for early operable breast cancer: results of a French multicenter prospective study. Plosone 2019, accepted, in press. Citation Format: Delphine Hequet, Guillaume Harrissart, Celine Callens, David Gentien, Ivan Bieche, Paul Cottu, Jean-Marc Guinebretiere, Anne Vincent-Salomon, Florence Lerebours, Roman Rouzier. Prosigna® test in clinical routine: Impact on adjuvant chemotherapy decision and medico-economic considerations in France [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-10.
Published: 2020
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23. Oral Etoposide and Trastuzumab Use for HER2-Positive Metastatic Breast Cancer: A Retrospective Study from the Institut Curie Hospitals

Author: Clelia Chalumeau, Matthieu Carton, Alexandre Eeckhoutte, Stelly Ballet, Anne Vincent-Salomon, Perrine Vuagnat, Audrey Bellesoeur, Jean-Yves Pierga, Marc-Henri Stern, Francois-Clement Bidard, Florence Lerebours, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), and HAL UVSQ, Équipe
Subjects: trastuzumab, Cancer Research, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, oral etoposide, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, HER2 metastatic breast cancer, TOP2A/ERBB2 co-amplification, [SDV.CAN]Life Sciences [q-bio]/Cancer, skin and connective tissue diseases, neoplasms
Abstract: International audience; Background: The TOP2A and ERBB2 genes are co-amplified in about 40% of HER2 positive (HER2+) breast cancers. Oral etoposide (VP16), an inhibitor of topoisomerase-II (encoded by TOP2A), has demonstrated clinical activity in metastatic breast cancer (MBC). The benefit of oral VP16 combined with trastuzumab (VP16-T) in HER2+ MBC has not yet been evaluated.Methods: Patients treated at the Institut Curie Hospitals with VP16-T for HER2+ MBC were retrieved by an in silico search. Progression-free survival (PFS), overall survival (OS), response rate, prolonged PFS (defined as at least 6 months), clinical benefit, and toxicity were assessed. The co-amplification of ERBB2 and TOP2A was assessed by shallow whole genome sequencing on tumor tissue whenever available.Results: Forty-three patients received VP16-T after a median number of six prior treatment lines for HER2+ MBC. Median PFS and OS were 2.9 months (95% CI [2.4–4.7]) and 11.3 months (95% CI [8.3–25.0]), respectively. Three patients had a complete response, while 12/40 (30%) experienced clinical benefit. Only three patients stopped treatment for toxicity. Seven (35%) patients displayed a TOP2A/ERBB2 co-amplification. No statistically significant correlation was found between outcome and TOP2A/ERBB2 co-amplification.Conclusion: Our analysis suggests a favorable efficacy and toxicity profile for VP16-T in patients with heavily pretreated HER2+ MBC.
Published: 2022
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24. Value of the loss of heterozygosity to BRCA1 variant classification

Author: Elizabeth Santana dos Santos, Amanda B. Spurdle, Dirce M. Carraro, Adrien Briaux, Melissa Southey, Giovana Torrezan, Ambre Petitalot, Raphael Leman, Philippe Lafitte, kConFab Investigators, Didier Meseure, Keltouma Driouch, Lucy Side, Carole Brewer, Sarah Beck, Athalie Melville, Alison Callaway, Françoise Revillion, Maria A. A. Koike Folgueira, Michael T. Parsons, Heather Thorne, Anne Vincent-Salomon, Dominique Stoppa-Lyonnet, Ivan Bieche, Sandrine M. Caputo, and Etienne Rouleau
Subjects: endocrine system diseases, Oncology, Cancer genomics, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, skin and connective tissue diseases, Cancer genetics, Article, RC254-282
Abstract: At least 10% of the BRCA1/2 tests identify variants of uncertain significance (VUS) while the distinction between pathogenic variants (PV) and benign variants (BV) remains particularly challenging. As a typical tumor suppressor gene, the inactivation of the second wild-type (WT) BRCA1 allele is expected to trigger cancer initiation. Loss of heterozygosity (LOH) of the WT allele is the most frequent mechanism for the BRCA1 biallelic inactivation. To evaluate if LOH can be an effective predictor of BRCA1 variant pathogenicity, we carried out LOH analysis on DNA extracted from 90 breast and seven ovary tumors diagnosed in 27 benign and 55 pathogenic variant carriers. Further analyses were conducted in tumors with PVs yet without loss of the WT allele: BRCA1 promoter hypermethylation, next-generation sequencing (NGS) of BRCA1/2, and BRCAness score. Ninety-seven tumor samples were analyzed from 26 different BRCA1 variants. A relatively stable pattern of LOH (65.4%) of WT allele for PV tumors was observed, while the allelic balance (63%) or loss of variant allele (15%) was generally seen for carriers of BV. LOH data is a useful complementary argument for BRCA1 variant classification.
Published: 2022
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25. Assessment of the Molecular Heterogeneity of E-Cadherin Expression in Invasive Lobular Breast Cancer

Author: John Alexander, Odette Mariani, Celine Meaudre, Laetitia Fuhrmann, Hui Xiao, Kalnisha Naidoo, Andrea Gillespie, Ioannis Roxanis, Anne Vincent-Salomon, Syed Haider, and Rachael Natrajan
Subjects: Cancer Research, Oncology, invasive lobular breast cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, E-cadherin, heterogeneity, RC254-282, Article
Abstract: Simple Summary Invasive lobular breast cancers (ILCs) are histologically classified by their discohesive growth pattern, due to loss of the cell adhesion glycoprotein E-cadherin (CDH1), which arises via mutation in CDH1 in around half of these tumours. A subset of these tumours, however, show mixed levels of E-cadherin expression. Here, we sought to address whether the distinct parts of individual tumours showing heterogeneous E-cadherin expression harbour distinct driver alterations. Using whole genome sequencing and methylation profiling of nine such cases, we identified that these tumours are clonally related, suggesting that they are part of the spectrum of ILC tumours. CDH1 mutant tumours showed a higher mutational burden indicative of APOBEC-mediated mutagenesis. In some cases, known clinically actionable driver mutations, such as PIK3CA, were exclusive to one component. Together, these results highlight the heterogeneity underpinning this special histological breast cancer. Abstract Mutations and loss of E-cadherin protein expression define the vast majority of invasive lobular carcinomas. In a subset of these cases, the heterogeneous expression of E-cadherin is observed either as wild-type (strong membranous) expression or aberrant expression (cytoplasmic expression). However, it is unclear as to whether the two components would be driven by distinct genetic or epigenetic alterations. Here, we used whole genome DNA sequencing and methylation array profiling of two separately dissected components of nine invasive lobular carcinomas with heterogeneous E-cadherin expression. E-cadherin negative and aberrant/positive components of E-cadherin heterogeneous tumours showed a similar mutational, copy number and promoter methylation repertoire, suggesting they arise from a common ancestor, as opposed to the collision of two independent tumours. We found that the majority of E-cadherin heterogeneous tumours harboured CDH1 mutations in both the E-cadherin negative and aberrant/positive components together with somatic mutations in additional driver genes known to be enriched in both pure invasive carcinomas of no special type and invasive lobular breast cancers, whereas these were less commonly observed in CDH1 wild-type tumours. CDH1 mutant tumours also exhibited a higher mutation burden as well as increased presence of APOBEC-dependent mutational signatures 2 and 13 compared to CDH1 wild-type tumours. Together, our results suggest that regardless of E-cadherin protein expression, tumours showing heterogeneous expression of E-cadherin should be considered as part of the spectrum of invasive lobular breast cancers.
Published: 2022

26. Survival outcomes after neoadjuvant letrozole and palbociclib versus third generation chemotherapy for patients with high-risk oestrogen receptor-positive HER2-negative breast cancer

Author: Delaloge, Suzette, Dureau, Sylvain, D'Hondt, Véronique, Desmoulins, Isabelle, Heudel, Pierre-Etienne, Duhoux, François, Levy, Christelle, Lerebours, Florence, Mouret-Reynier, Marie A, Dalenc, Florence, Frenel, Jean-Sébastien, Jouannaud, Christelle, Venat-Bouvet, Laurence, Nguyen, Suzanne, Callens, Cécile, Gentien, David, Rapinat, Audrey, Manduzio, Helene, Vincent-Salomon, Anne, Lemonnier, Jérôme, Cottu, Paul, French Breast cancer Intergroup Unicancer-UCBG, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)
Subjects: Cancer Research, Survival, Pyridines, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], Breast Neoplasms, Survival Analysis, Neoadjuvant Therapy, Piperazines, CDK4/6 inhibitor, Oncology, Receptors, Estrogen, Luminal breast cancer, Antineoplastic Combined Chemotherapy Protocols, Letrozole, Humans, Chemotherapy, Female, Neoadjuvant
Abstract: Besides their development as additional adjuvant treatments, CDK4/6 inhibitors combined with endocrine therapy could represent less toxic alternatives to chemotherapy in postmenopausal women with high-risk oestrogen receptor-positive, HER2-negative breast cancer currently a candidate for chemotherapy. The multicentre, international, randomised phase 2 NEOPAL trial showed that the letrozole-palbociclib combination led to clinical and pathological responses equivalent to sequential anthracycline-taxanes chemotherapy. Secondary objectives included survival outcomes. Secondary end-points of NEOPAL included progression-free survival (PFS) and invasive-disease free survival (iDFS) in the intent-to-treat population. Exploratory end-points were overall survival (OS) and breast cancer specific survival (BCSS) in the intent-to-treat population, as well as iDFS, OS and BCSS according to the administration of chemotherapy. Hundred and six patients were randomised. Pathological complete response rates were 3.8% and 5.9%. Twenty-three of the 53 patients in the letrozole-palbociclib arm received postoperative adjuvant chemotherapy. At a median follow-up of 40.4 months [0-56.6], 11 progressions have been observed, of which three were in the letrozole-palbociclib and 8 in the control arm. PFS (HR = 1.01; [95%CI 0.36-2.90], p = 0.98) and iDFS (HR = 0.83; [95%CI 0.31-2.23], p = 0.71) did not differ between both arms. The 40 months PFS rate was 86.7% [95%CI 78.0-96.4] and 89.9% [95%CI 81.8-98.7] in letrozole-palbociclib and control arms, respectively. Outcomes of patients who did not receive chemotherapy were not statistically different from those who received it. NEOPAL suggests that a neoadjuvant letrozole-palbociclib strategy may allow sparing chemotherapy in some patients with luminal breast cancer while allowing good long-term outcomes. Larger confirmatory studies are needed.
Published: 2022
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27. Corrigendum to 'Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer'

Author: K. Van Baelen, T. Geukens, M. Maetens, V. Tjan-Heijnen, C.J. Lord, S. Linn, F.-C. Bidard, F. Richard, W.W. Yang, R.E. Steele, S.J. Pettitt, C. Van Ongeval, M. De Schepper, E. Isnaldi, I. Nevelsteen, A. Smeets, K. Punie, L. Voorwerk, H. Wildiers, G. Floris, A. Vincent Salomon, P.W.B. Derksen, P. Neven, E. Senkus, E. Sawyer, M. Kok, and C. Desmedt
Subjects: Oncology, Hematology
Published: 2023
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28. 21TiP Molecular alterations predictive of outcome in early staged cervical cancer: A translational investigation in the international validation study of sentinel node biopsy in early cervical cancer SENTICOL III

Author: M. El Gani, S. Ibadioune, Z. El Beaino, S. Vacher, A. Degnieau, E. Jeannot, J. Masliah-Planchon, A. Vincent-Salomon, M. Caly, G. Baiocchi, G. Guitmann, M. Plante, D. Cibula, V. Zanagnolo, A.G.Z. Eriksson, P. Mathevet, M. Kamal, F. Lecuru, and I. Bieche
Subjects: Cancer Research, Oncology
Published: 2023
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29. The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group

Author: El Bairi, K., Haynes, H. R., Blackley, E., Fineberg, S., Shear, J., Turner, S., de Freitas, J. R., Sur, D., Amendola, L. C., Gharib, M., Kallala, A., Arun, I., Azmoudeh-Ardalan, F., Fujimoto, L., Sua, L. F., Liu, S. -W., Lien, H. -C., Kirtani, P., Balancin, M., El Attar, H., Guleria, P., Yang, W., Shash, E., Chen, I. -C., Bautista, V., Do Prado Moura, J. F., Rapoport, B. L., Castaneda, C., Spengler, E., Acosta-Haab, G., Frahm, I., Sanchez, J., Castillo, M., Bouchmaa, N., Md Zin, R. R., Shui, R., Onyuma, T., Husain, Z., Willard-Gallo, K., Coosemans, A., Perez, E. A., Provenzano, E., Ericsson, P. G., Richardet, E., Mehrotra, R., Sarancone, S., Ehinger, A., Rimm, D. L., Bartlett, J. M. S., Viale, G., Denkert, C., Hida, A. I., Sotiriou, C., Loibl, S., Hewitt, S. M., Badve, S., Symmans, W. F., Kim, R. S., Pruneri, G., Goel, S., Francis, P. A., Inurrigarro, G., Yamaguchi, R., Garcia-Rivello, H., Horlings, H., Afqir, S., Salgado, R., Adams, S., Kok, M., Dieci, M. V., Michiels, S., Demaria, S., Loi, S., Schelfhout, V., Arbzadeh, E., Bondanar, A., Reyes, S. A. G., Ruz, J. R., Kang, J., Xiang, L., Zimovjanova, M., Togores, P., Ozturk, T., Patil, A., Corpa, M., Whitehouse, A., Tan, B., de Paula, A., Rossetti, C., Lang-Schwarz, C., Mahon, S., Giacometti, C., Linderholm, B., Deman, F., Montagna, G., Gong, G., Pavcovich, M., Chaer, Y., Cabrero, I. A., de Brito, M. L., Ilieva, N., Fulop, A., Souza, M., Bilancia, D., Idowu, M., Johri, R., Szpor, J., Bachani, L., Schmitt, F., Giannotti, M., Kurebayashi, Y., Ramirez, B. E. A., Salido, E., Bortesi, L., Bonetto, S., Elomina, K., Lopez, P., Sharma, V., Edirisinghe, A., Mathur, D., Sahay, A., Mouloud, M. A., Giang, C. H., Mukolwe, E., Kiruka, E., Samberg, N., Abe, N., Brown, M., Millar, E., X. B., Li, Yuan, Z., Pasupathy, A., Miele, R., Luff, R., e Porfirio, M. M. A., Ajemba, O., Soni, R., Orvieto, E., Dimaio, M., Thomas, J., Merard, R., Subramaniam, M. M., Apolinario, T., Preda, O., Preda, R., Makanga, A., Maior, M. S., Li, L., Saghatchian, M., Saurine, T., Janssen, E., Cochran, J., Vlada, N., Cappellesso, R., Elfer, K., Hollick, M., Desai, S., Oner, G., Schreurs, A., Liu, S., Perera, R., Mercurio, P., Garcia, F., Hosny, K., Matsumoto, H., van Deurzen, C., Bianchini, G., Coban, I., Jahangir, A., Rahman, A., Stover, D., Luz, P., Martel, A., Waumans, Y., Stenzinger, A., Cortes, J., Dimitrova, P., Nauwelaers, I., Velasco, M., Fan, F., Akturk, G., Firer, M., Roxanis, I., Schneck, M., Wen, H., Cockenpot, V., Konstantinov, A., Calatrava, A., Vidya, M. N., Choi, H. J., Jank, P., Ciinen, A. H., Sabanathan, D., Floris, G., Hoeflmayer, D., Hamada, T., Laudus, N., Grigoriadis, A., Porcellato, I., Acs, B., Miglietta, F., Parrodi, J., Clunie, D., Calhoun, B., F. -I., Lu, Lefevre, A., Tabbarah, S., Tran, W., Garcia-murillas, I., Jelinic, P., Boeckx, C., Souza, S., Cebollero, M. C., Felip, E., Rendon, J. L. S., El Gabry, E., Saltz, J., Bria, E., Garufi, G., Hartman, J., Sebastian, M., Olofsson, H., Kooreman, L., Cucherousset, J., Mathieu, M. -C., Ballesteros-Merino, C., Siziopikou, P., Fong, J., Klein, M., Qulis, I. R. I., Wesseling, J., Bellolio, E., Araya, J. C., Naber, S., Cheang, M., Castellano, I., Ales, A., Laenkholm, A. -V., Kulka, J., Quinn, C., Sapino, A., Amendoeira, I., Marchio, C., Braybrooke, J., Vincent-Salomon, A., Korski, K. P., Sofopoulos, M., Stovgaard, E. I. S., Bianchi, S., Bago-Horvath, Z., Yu, C., Regitnig, P., Hall, S., Kos, Z., Sant, S., Tille, J. -C., Gallas, B., Bethmann, D., Savas, P., Mendes, L., Soler, T., van Seijen, M., Gruosso, T., Quintana, A., Giltnane, J., Van den Eynden, G., Duregon, E., de Cabo, R., Recamo, P. C., Gaboury, L., Zimmerman, J., Pop, C. S., Wernicke, A., Williams, D., Gill, A., Solomon, B., Thapa, B., Farshid, G., Gilham, L., Christie, M., O'Toole, S., Hendry, S., Fox, S. B., Luen, S. J., Lakhani, S. R., Fuchs, T., John, T., Brcic, I., Hainfellner, J., Sigurd, L., Preusser, M., Poortmans, P., Decaluwe, A., Carey, C., Colpaert, C., Larsimont, D., Peeters, D., Broeckx, G., van de Vijver, K., Buisseret, L., Dirix, L., Hertoghs, M., Piccart, M., Ignatiadis, M., Van Bockstal, M., Sirtaine, N., Vermeulen, P., de Wind, R., Declercq, S., Gevaert, T., Haibe-Kans, B., Nelson, B. H., Watson, P. H., Leung, S., Nielsen, T., Shi, L., Balslev, E., Thagaard, J., Almangush, A., Makitie, A., Joensuu, H., Lundin, J., Drubay, D., Roblin, E., Andre, F., Penault-Llorca, F., Lemonnier, J., Adam, J., Lacroix-Triki, M., Ternes, N., Radosevic-Robin, N., Klaushen, F., Weber, K., Harbeck, N., Gluz, O., Wienert, S., Cserni, G., Vingiani, A., Criscitiello, C., Solinas, C., Curigliano, G., Konishi, E., Suzuki, E., Yoshikawa, K., Kawaguchi, K., Takada, M., Toi, M., Ishida, M., Shibata, N., Saji, S., Kogawa, T., Sakatani, T., Okamoto, T., Moriya, T., Kataoka, T., Shimoi, T., Sugie, T., Mukohara, T., Shu, Y., Kikawa, Y., Kozuka, Y., Sayed, S., Rahayu, R., Ramsaroop, R., Senkus-Konefka, E., Chmielik, E., Cardoso, F., Ribeiro, J., Chan, J., Dent, R., Martin, M., Hagen, C., Guerrero, A., Rojo, F., Comerma, L., Nuciforo, P., Serrano, V. V., Camaea, V. P., Steenbruggen, T., Ciompi, F., Nederlof, I., Jan, Hudecek, van der Laak, J., van den Berg, J., Voorwerk, L., van de Vijver, M., de Maaker, M., Linn, S., Mckenzie, H., Somaiah, N., Tutt, A., Swanton, C., Hiley, C., Moore, D. A., Hall, J. A., Le Quesne, J., Jabbar, K. A., al Bakir, M., Hills, R., Irshad, S., Yuan, Y., Li, Z., Liu, M., Klein, J., Fadare, O., Thompson, A., Lazar, A. J., Gown, A., Lo, A., Garrido Castro, A. C., Madabhushi, A., Moreira, A., Richardson, A., Beck, A. H., Bellizzi, A. M., Wolff, A., Harbhajanka, A., Sharma, A., Cimino-Mathews, A., Srinivasan, A., Singh, B., Chennubhotla, C. S., Chauhan, C., Dillon, D. A., Zardavas, D., Johnson, D. B., Thompson, A. E., Brogi, E., Reisenbichler, E., Huang, E., Hirsch, F. R., Mcarthur, H., Ziai, J., Brock, J., Kerner, J., Zha, J., Lennerz, J. K., Carter, J. M., Reis-Filho, J., Sparano, J., Balko, J. M., Pogue-Geile, K., Steele, K. E., Blenman, K. R. M., Allison, K. H., Pusztai, L., Cooper, L., Estrada, V. M., Flowers, M., Robson, M., Rebelatto, M. C., Hanna, M. G., Goetz, M. P., Khojasteh, M., Sanders, M. E., Regan, M. M., Misialek, M., Amgad, M., Tung, N., Singh, R., Huang, R., Pierce, R. H., Leon-Ferre, R., Swain, S., Ely, S., Kim, S. -R., Bedri, S., Paik, S., Schnitt, S., D'Alfons, T., Kurkure, U., Bossuyt, V., Tong, W., Wang, Y., Dos Anjos, C. H., Gaire, F., Van Diest, P. J., El Bairi, Khalid [0000-0002-8414-4145], de Freitas, Juliana Ribeiro [0000-0003-4978-7273], Sur, Daniel [0000-0002-0926-4614], Amendola, Luis Claudio [0000-0002-6404-450X], Azmoudeh-Ardalan, Farid [0000-0003-4701-0532], Kirtani, Pawan [0000-0002-2343-7016], Yang, Wenxian [0000-0002-5349-9680], Castillo, Miluska [0000-0002-0111-3176], Provenzano, Elena [0000-0003-3345-3965], Mehrotra, Ravi [0000-0001-9453-1408], Ehinger, Anna [0000-0001-9225-7396], Rimm, David L [0000-0001-5820-4397], Bartlett, John MS [0000-0002-0347-3888], Denkert, Carsten [0000-0002-2249-0982], Hida, Akira I [0000-0002-4486-8819], Sotiriou, Christos [0000-0002-5745-9977], Hewitt, Stephen M [0000-0001-8283-1788], Badve, Sunil [0000-0001-8861-9980], Symmans, William Fraser [0000-0002-1526-184X], Goel, Shom [0000-0001-8329-9084], Francis, Prudence A [0000-0002-7207-9286], Horlings, Hugo [0000-0003-4782-8828], Salgado, Roberto [0000-0002-1110-3801], Demaria, Sandra [0000-0003-4426-0499], Loi, Sherene [0000-0001-6137-9171], Apollo - University of Cambridge Repository, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), and UNICANCER
Subjects: Oncology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], TRASTUZUMAB, Improved survival, MICROENVIRONMENT, Review Article, SUBTYPES, NEOADJUVANT CHEMOTHERAPY, 0302 clinical medicine, Breast cancer, Ecology,Evolution & Ethology, PROGNOSTIC-SIGNIFICANCE, Medicine and Health Sciences, Pharmacology (medical), TUMOR-INFILTRATING LYMPHOCYTES, Stage (cooking), RC254-282, Chemical Biology & High Throughput, 0303 health sciences, Human Biology & Physiology, Genome Integrity & Repair, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, ASSOCIATION, 3. Good health, 030220 oncology & carcinogenesis, Biomarker (medicine), Life Sciences & Biomedicine, Genetics & Genomics, medicine.medical_specialty, chemical and pharmacologic phenomena, International Immuno-Oncology Biomarker Working Group, Predictive markers, 03 medical and health sciences, Signalling & Oncogenes, SDG 3 - Good Health and Well-being, Internal medicine, 692/53/2423, medicine, Radiology, Nuclear Medicine and imaging, In patient, 030304 developmental biology, Computational & Systems Biology, Science & Technology, IDENTIFICATION, business.industry, review-article, Cancer, 03.01. Általános orvostudomány, Immunotherapy, Tumour Biology, medicine.disease, PREDICTIVE-VALUE, 692/4028/67/1347, Programmed death 1, business, FREE SURVIVAL
Abstract: The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC. ispartof: NPJ BREAST CANCER vol:7 issue:1 ispartof: location:United States status: published
Published: 2021
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30. CD73-Mediated Immunosuppression Is Linked to a Specific Fibroblast Population That Paves the Way for New Therapy in Breast Cancer

Author: Yann Kieffer, Monika Licaj, Rana Mhaidly, Nicolas Gourdin, Carine Paturel, Ariane Morel, Ilaria Magagna, Fatima Mechta-Grigoriou, Anne Vincent-Salomon, and Pascale Andre
Subjects: Cancer Research, medicine.medical_treatment, Population, Tregs, Article, NT5E, Immune system, Breast cancer, breast cancer, Stroma, medicine, education, RC254-282, education.field_of_study, immunosuppression, biology, anti-CD73 antibody, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunosuppression, Immunotherapy, medicine.disease, CAF subsets, Oncology, Cancer research, biology.protein, Antibody, business
Abstract: Simple Summary Recent findings have revealed the contribution of cancer-associated fibroblasts (CAF) in immune escape in breast cancer. Still, how to specifically target immunosuppressive CAF remains an unmet medical question. Here, we provide a promising therapeutic strategy by highlighting the role of CD73 in immunosuppressive CAF. By studying cohorts of breast cancer patients and performing functional assays, our study uncovers how CD73 contributes to immunosuppression by acting in a specific CAF subpopulation (referred to as CAF-S1) in breast cancer. In addition, we validate that using an anti-CD73 antibody significantly reduces CAF-S1-mediated immunosuppression, thereby highlighting a new interesting therapeutic strategy for breast cancer patients. Abstract Background: Cancer-associated fibroblasts (CAF) are heterogeneous with multiple functions in breast cancer. Recently, we identified a specific CAF subpopulation (referred to as CAF-S1), which promotes immunosuppression and immunotherapy resistance. Methods and Results: Here, by studying a large collection of human samples, we highlight the key function of CD73/NT5E in CAF-S1-mediated immunosuppression in breast cancer. We first reveal that CD73 protein level specifically accumulates in CAF-S1 in breast cancer patients. Interestingly, infiltration of regulatory T lymphocytes (Tregs) is significantly correlated with CD73 expression in stroma but not in epithelium, indicating that CD73 contributes to immunosuppression when expressed in CAF-S1 and not in tumor cells. By performing functional assays based on relevant systems using primary CAF-S1 isolated from patients, we demonstrate that CAF-S1 increase the content in both PD-1+ and CTLA-4+ Tregs. Importantly, the use of a blocking anti-CD73 antibody on CAF-S1 reduces CAF-S1-mediated immunosuppression by preventing expression of these immune checkpoints on Tregs. Conclusions: Our data support the potential clinical benefit of using both anti-CD73 and immune-checkpoint inhibitors in breast cancer patients for inhibiting CAF-S1-mediated immunosuppression and enhancing anti-tumor immune response.
Published: 2021
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31. Neoadjuvant Concurrent Radiotherapy and Chemotherapy in Early Breast Cancer Patients: Long-Term Results of a Prospective Phase II Trial

Author: Fatima Laki, Youlia M. Kirova, Alain Fourquet, Jean-Yves Pierga, Anne Vincent-Salomon, Diane Jornet, Pierre Loap, Institut Curie [Paris], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
Subjects: prospective phase II, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Breast surgery, Urology, Phases of clinical research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Vinorelbine, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, medicine, 030212 general & internal medicine, Telangiectasia, RC254-282, Chemotherapy, long term results, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, Radiation therapy, Oncology, 030220 oncology & carcinogenesis, medicine.symptom, business, Mastectomy, neoadjuvant concurrent radiotherapy and chemotherapy, medicine.drug
Abstract: Simple Summary The originality of this prospective study is to use radiation therapy in association with chemotherapy before surgery and permit patients to preserve their breasts or to undergo immediate reconstruction. This neoadjuvant strategy can therefore allow one-stage breast reconstructive surgery, the so-called “reverse technique”. Abstract Background: Neoadjuvant concurrent radiochemotherapy makes it possible to increase the breast conservation rate. This study reports the long term outcome of this treatment. Methods: From 2001 to 2003, 59 women with T2–3 N0–2 M0 invasive breast cancer (BC) not amenable to upfront breast conserving treatment (BCS) were included in this prospective, non-randomized phase II study. Chemotherapy (CT) consisted of four cycles of continuous 5-FU infusion and Vinorelbine. Starting concurrently with the second CT cycle, normofractionated RT was delivered to the breast and LN. Breast surgery was then performed. Results: Median follow-up (FU) was 13 years [3–18]. BCS was performed in 41 (69%) patients and mastectomy in 18 patients, with pathological complete response rate of 27%. Overall and distant-disease free survivals rates at 13 years were 70.9% [95% CI 59.6–84.2] and 71.5% [95% CI 60.5–84.5] respectively. Loco regional and local controls rates were 83.4% [95% CI 73.2–95.0] and 92.1% [95% CI 83.7–100], respectively. Late toxicity (CTCAE-V3) was assessed in 51 patients (86%) with a median follow-up of 13 years. Fifteen presented grade 2 fibrosis (29.4%), 8 (15.7%) had telangiectasia, and 1 had radiodermatitis. Conclusions: This combined treatment provided high long-term local control rates with limited side-effects.
Published: 2021
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32. Abstract IA002: DCIS: Pathological heterogeneity and prognosis definition

Author: Anne Vincent-Salomon
Subjects: Cancer Research, Oncology
Abstract: Ductal carcinoma in situ represents 15 to 20% of all breast carcinomas and is a non-obligate precursor of invasive carcinomas. Clinically DCIS presents most frequently as microcalcifications detected on screening mammography. DCIS is a proliferation of neoplastic cells confined to the ductulo-lobular tree. Its morphology can recapitulate the diversity of that of invasive carcinomas. DCIS lesions are classified according to the nuclear grade (low, intermediate, high), the presence of necrosis and microinvasion. In resection specimens, the extent of the disease and the quality of the margins are key element for patients management as well as the association of DCIS to the microcalcifications. The reproducibility of the DCIS grading system is relatively poor and promising help emerges from deep learning approaches. The four molecular classes of invasive carcinomas exist but with different proportion in DCIS. Triple negative represent 5-8% of DCIS. Conversely, HER2 overexpression is more frequently observed in particular in high grade DCIS (up to 60% of the cases). The analysis of Estrogens and progesterone receptors is not systematic in clinical practice unless an endocrine therapy may be decided after the patient has completed the loco-regional treatment. At initial diagnosis, it remains very challenging to predict the clinical outcome of the lesion. However, after complete surgical excision followed by whole breast irradiation therapy, the prognosis is excellent with a mortality of 3.7%. The rate of relapse is 7% at 5 years and 16% at 10 years of follow-up. Concerns about overdiagnosis and overtreatment exist worldwide. Retrospective studies identified older age, mammographic detection, small size, non-high grade histology and negative margins at excision associated with favorable outcome. Unfortunately, de-escalation clinical prospective trials based on these criteria, failed to identify the patients presenting DCIS of good prognosis. Biological parameters have been retrospectively associated with a poor prognosis (HER2 amplification, proliferation, RB loss, COX2 expression…). The molecular signature Oncotype DCIS®, has been validated retrospectively in a subgroup of patients from the ECOG E5194, and determined DCIS associated with different risk of relapse. Its prospective validation is on-going in a non randomized trial (DUCHESS). Three on-going trials based in part on clinical criteria, one adding estrogen receptors expression, the other comedonecrosis, propose after a diagnostic biopsy, a simple surveillance. Another trial, leaded by UNITRAD/UNICANCER (France), Romance is a prospective randomized study of omission of whole-breast radiotherapy following breast-conserving surgery in patients with very low risk luminal A ductal carcinoma in situ and enrolment is on. Research efforts is moving into the integration the ecosystem of DCIS (myoepithelial cells, stroma, immune cells and carcinomatous cells) to identify more accurately the DCIS associated with a higher aggressiveness that would allow secure de-escalation clinical trials. Citation Format: Anne Vincent-Salomon. DCIS: Pathological heterogeneity and prognosis definition [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA002.
Published: 2022
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33. The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice

Author: Gonzalez-Ericsson, Paula, Stovgaard, Elisabeth, Sua, Luz, Reisenbichler, Emily, Kos, Zuzana, Carter, Jodi, Michiels, Stefan, Le Quesne, John, Nielsen, Torsten, Laenkholm, Anne-Vibeke, Fox, Stephen, Adam, Julien, Bartlett, John MS, Rimm, David, Quinn, Cecily, Peeters, Dieter, Dieci, Maria, Vincent-Salomon, Anne, Cree, Ian, Hida, Akira, Balko, Justin, Haynes, Harry, Frahm, Isabel, Acosta-Haab, Gabriela, Balancin, Marcelo, Bellolio, Enrique, Yang, Wentao, Kirtani, Pawan, Sugie, Tomoharu, Ehinger, Anna, Castaneda, Carlos, Kok, Marleen, McArthur, Heather, Siziopikou, Kalliopi, Badve, Sunil, Fineberg, Susan, Gown, Allen, Viale, Giuseppe, Schnitt, Stuart, Pruneri, Giancarlo, Penault-Llorca, Frédérique, Hewitt, Stephen, Thompson, E Aubrey, Allison, Kimberly, Symmans, William, Bellizzi, Andrew, Brogi, Edi, Moore, David, Larsimont, Denis, Dillon, Deborah, Lazar, Alexander, Lien, Huangchun, Goetz, Matthew, Broeckx, Glenn, El Bairi, Khalid, Harbeck, Nadia, Cimino-Mathews, Ashley, Sotiriou, Christos, Adams, Sylvia, Liu, Shi-Wei, Loibl, Sibylle, Chen, I-Chun, Lakhani, Sunil, Juco, Jonathan, Denkert, Carsten, Blackley, Elizabeth, Demaria, Sandra, Leon-Ferre, Roberto, Gluz, Oleg, Zardavas, Dimitrios, Emancipator, Kenneth, Ely, Scott, Loi, Sherene, Salgado, Roberto, Sanders, Melinda, Gonzalez‐Ericsson, Paula, Lænkholm, Anne‐Vibeke, Vincent‐Salomon, Anne, Acosta‐Haab, Gabriela, Penault‐Llorca, Frederique, Cimino‐Mathews, Ashley, Liu, Shi‐wei, Chen, I‐Chun, Leon‐Ferre, Roberto, Int Immuno-Oncology Biomarker Work, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), University of Leicester, Department of Pathology, Odense University Hospital, Universita degli Studi di Padova, Pharmacogenomics Unit [Paris], Department of Genetics [Paris], Institut Curie [Paris]-Institut Curie [Paris], Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Helsingborg Hospital, Ctr Biomol Struct & Org, University of Maryland [College Park], University of Maryland System-University of Maryland System, The Netherlands Cancer Institute, Division of Pathology and Laboratory Medicine, Università degli Studi di Milano [Milano] (UNIMI)-European Institute of Oncology [Milan] (ESMO), European Institute of Oncology [Milan] (ESMO), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Innovation North - Faculty of Information and Technology, Leeds Metropolitan University, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), The University of Texas M.D. Anderson Cancer Center [Houston], Université Mohamed 1 Oujda MAROC, Frauenklinik, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), German Breast Group, University of Southern Queensland (USQ), Charité, Institute of Pathology, Translational Tumorpathology Unit, West German Study Group, Breast International Group [Brussels, Belgium] (BIG aisbl), Breast Cancer Translational Research Laboratory, Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Università degli Studi di Padova = University of Padua (Unipd), Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), and German Breast Group (GBG)
Subjects: 0301 basic medicine, Oncology, PD-L1, medicine.medical_specialty, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Triple Negative Breast Neoplasms, Pembrolizumab, biomarker risk-management, B7-H1 Antigen, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, Lymphocytes, Tumor-Infiltrating, Atezolizumab, Internal medicine, Biomarkers, Tumor, Medicine, Humans, TILs, Triple-negative breast cancer, Tumor marker, Cancer immunology, Risk Management, business.industry, Médecine pathologie humaine, Sciences bio-médicales et agricoles, immunotherapy, medicine.disease, 3. Good health, Clinical trial, Cancérologie, 030104 developmental biology, 030220 oncology & carcinogenesis, Human medicine, Nivolumab, business
Abstract: Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer. TILs can be easily assessed on hematoxylin and eosin stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Since TILs and PD-L1 are parts of an immunological spectrum in breast cancer, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immune-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with breast cancer. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in breast cancer. This article is protected by copyright. All rights reserved., info:eu-repo/semantics/published
Published: 2020
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34. Author Correction: Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Author: Bailey M. H., Meyerson W. U., Dursi L. J., Wang L. -B., Dong G., Liang W. -W., Weerasinghe A., Li S., Li Y., Kelso S., Akbani R., Anur P., Buchanan A., Chiotti K., Covington K., Creason A., Ding L., Ellrott K., Fan Y., Foltz S., Getz G., Hale W., Haussler D., Hess J. M., Hutter C. M., Kandoth C., Kasaian K., Kasapi M., Larson D., Leshchiner I., Letaw J., Ma S., McLellan M. D., Men Y., Mills G. B., Niu B., Peto M., Radenbaugh A., Reynolds S. M., Saksena G., Sofia H., Stewart C., Struck A. J., Stuart J. M., Wang W., Weinstein J. N., Wheeler D. A., Wong C. K., Xi L., Ye K., Bieg M., Boutros P. C., Buchhalter I., Butler A. P., Chen K., Chong Z., Drechsel O., Jonathan Dursi L., Eils R., Espiritu S. M. G., Fulton R. S., Gao S., Gelpi J. L., Gerstein M. B., Gonzalez S., Gut I. G., Hach F., Heinold M. C., Hinton J., Hu T., Huang V., Huang Y., Hutter B., Jones D. R., Jung J., Jager N., Kim H. -L., Kleinheinz K., Kumar S., Kumar Y., Lalansingh C. M., Letunic I., Livitz D., Ma E. Z., Maruvka Y. E., Mashl R. J., Menzies A., Milovanovic A., Nielsen M. M., Ossowski S., Paramasivam N., Pedersen J. S., Perry M. D., Puiggros M., Raine K. M., Rheinbay E., Royo R., Sahinalp S. C., Sarrafi I., Schlesner M., Simpson J. T., Stebbings L., Stobbe M. D., Teague J. W., Tiao G., Torrents D., Wala J. A., Wang J., Waszak S. M., Weischenfeldt J., Wendl M. C., Werner J., Wu Z., Xue H., Yakneen S., Yamaguchi T. N., Yellapantula V. D., Yung C. K., Zhang J., Aaltonen L. A., Abascal F., Abeshouse A., Aburatani H., Adams D. J., Agrawal N., Ahn K. S., Ahn S. -M., Aikata H., Akdemir K. C., Al-Ahmadie H., Al-Sedairy S. T., Al-Shahrour F., Alawi M., Albert M., Aldape K., Alexandrov L. B., Ally A., Alsop K., Alvarez E. G., Amary F., Amin S. B., Aminou B., Ammerpohl O., Anderson M. J., Ang Y., Antonello D., Aparicio S., Appelbaum E. L., Arai Y., Aretz A., Arihiro K., Ariizumi S. -I., Armenia J., Arnould L., Asa S., Assenov Y., Atwal G., Aukema S., Auman J. T., Aure M. 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L., Chuah E., Cibulskis C., Cibulskis K., Cingarlini S., Clapham P., Claviez A., Cleary S., Cloonan N., Cmero M., Collins C. C., Connor A. A., Cooke S. L., Cooper C. S., Cope L., Corbo V., Cordes M. G., Cordner S. M., Cortes-Ciriano I., Cowin P. A., Craft B., Craft D., Creighton C. J., Cun Y., Curley E., Cutcutache I., Czajka K., Czerniak B., Dagg R. A., Danilova L., Davi M. V., Davidson N. R., Davies H., Davis I. J., Davis-Dusenbery B. N., Dawson K. J., De La Vega F. M., De Paoli-Iseppi R., Defreitas T., Dei Tos A. P., Delaneau O., Demchok J. A., Demeulemeester J., Demidov G. M., Demircioglu D., Dennis N. M., Denroche R. E., Dentro S. C., Desai N., Deshpande V., Deshwar A. G., Desmedt C., Deu-Pons J., Dhalla N., Dhani N. C., Dhingra P., Dhir R., DiBiase A., Diamanti K., Ding S., Dinh H. Q., Dirix L., Doddapaneni H. V., Donmez N., Dow M. T., Drapkin R., Drews R. M., Serge S., Dudderidge T., Dueso-Barroso A., Dunford A. J., Dunn M., Duthie F. 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Subjects: Science, MEDLINE, Medizin, General Physics and Astronomy, Pain, 610 Medicine & health, 1600 General Chemistry, Computational biology, Biology, 10 kHz spinal cord stimulation, Genome, responders, MC3 Working Group, General Biochemistry, Genetics and Molecular Biology, whole exome sequencing, Machine Learning, 1300 General Biochemistry, Genetics and Molecular Biology, PCAWG novel somatic mutation calling methods working group, medicine, cancer, Genome mutation, Exome, Exome sequencing, Whole genome sequencing, whole genome sequencing, Multidisciplinary, Published Erratum, Cancer, PCAWG Consortium, General Chemistry, medicine.disease, 3100 General Physics and Astronomy, oncology, 10032 Clinic for Oncology and Hematology, Prediction
Abstract: Weitere Nicht-UDE-Autoren sind nicht genannt. Originalpublikation: 10.1038/s41467-020-18151-y. CA extern The original version of this Article omitted from the author list the 9th author Yize Li, who is from the ‘The McDonnell Genome Institute at Washington University, St. Louis, MO 63108, USA and Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA’. This has been corrected in both the PDF and HTML versions of the Article. © 2020, The Author(s).
Published: 2020

35. Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Author: Bailey, Matthew H, Meyerson, William U, Dursi, Lewis Jonathan, Wang, Liang-Bo, Dong, Guanlan, Liang, Wen-Wei, Weerasinghe, Amila, Shantao, Li, Kelso, Sean, Saksena, Gordon, Ellrott, Kyle, Wendl, Michael C, Wheeler, David A, Getz, Gad, Simpson, Jared T, Gerstein, Mark B, Ding, Lirehan, Akbani, Pavana, Anur, Matthew, H Bailey, Alex, Buchanan, Kami, Chiotti, Kyle, Covington, Allison, Creason, Ding, Li, Kyle, Ellrott, Fan, Yu, Steven, Foltz, Gad, Getz, Walker, Hale, David, Haussler, Julian, M Hess, Carolyn, M Hutter, Cyriac, Kandoth, Katayoon, Kasaian, Melpomeni, Kasapi, Dave, Larson, Ignaty, Leshchiner, John, Letaw, Singer, Ma, Michael, D McLellan, Yifei, Men, Gordon, B Mills, Beifang, Niu, Myron, Peto, Amie, Radenbaugh, Sheila, M Reynolds, Gordon, Saksena, Heidi, Sofia, Chip, Stewart, Adam, J Struck, Joshua, M Stuart, Wenyi, Wang, John, N Weinstein, David, A Wheeler, Christopher, K Wong, Liu, Xi, Kai, Ye, Matthias, Bieg, Paul, C Boutros, Ivo, Buchhalter, Adam, P Butler, Ken, Chen, Zechen, Chong, Oliver, Drechsel, Lewis Jonathan Dursi, Roland, Eils, Shadrielle M, G Espiritu, Robert, S Fulton, Shengjie, Gao, Josep L, L Gelpi, Mark, B Gerstein, Santiago, Gonzalez, Ivo, G Gut, Faraz, Hach, Michael, C Heinold, Jonathan, Hinton, Taobo, Hu, Vincent, Huang, Huang, Yi, Barbara, Hutter, David, R Jones, Jongsun, Jung, Natalie, Jäger, Hyung-Lae, Kim, Kortine, Kleinheinz, Sushant, Kumar, Yogesh, Kumar, Christopher, M Lalansingh, Ivica, Letunic, Dimitri, Livitz, Eric, Z Ma, Yosef, E Maruvka, R Jay Mashl, Andrew, Menzies, Ana, Milovanovic, Morten Muhlig Nielsen, Stephan, Ossowski, Nagarajan, Paramasivam, Jakob Skou Pedersen, Marc, D Perry, Montserrat, Puiggròs, Keiran, M Raine, Esther, Rheinbay, Romina, Royo, S Cenk Sahinalp, Iman, Sarrafi, Matthias, Schlesner, Jared, T Simpson, Lucy, Stebbings, Miranda, D Stobbe, Jon, W Teague, Grace, Tiao, David, Torrents, Jeremiah, A Wala, Jiayin, Wang, Sebastian, M Waszak, Joachim, Weischenfeldt, Michael, C Wendl, Johannes, Werner, 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T, Nakano, K, Nandi, T, Nangalia, J, Nastic, M, Navarro, A, Navarro, F, Neal, D, Nettekoven, G, Newell, F, Newhouse, S, Newton, Y, Ng, A, Nicholson, J, Nicol, D, Nie, Y, Nielsen, G, Nik-Zainal, S, Noble, M, Nones, K, Northcott, P, Notta, F, O'Connor, B, O'Donnell, P, O'Donovan, M, O'Meara, S, O'Neill, B, O'Neill, J, Ocana, D, Ochoa, A, Oesper, L, Ogden, C, Ohdan, H, Ohi, K, Ohno-Machado, L, Oien, K, Ojesina, A, Ojima, H, Okusaka, T, Omberg, L, Ong, C, Ott, G, Ouellette, B, P'Ng, C, Paczkowska, M, Paiella, S, Pairojkul, C, Pajic, M, Pan-Hammarstrom, Q, Papaemmanuil, E, Papatheodorou, I, Park, J, Park, K, Park, P, Parker, J, Parsons, S, Pass, H, Pasternack, D, Pastore, A, Patch, A, Pauporte, I, Pea, A, Pearson, J, Pedamallu, C, Pederzoli, P, Peifer, M, Pennell, N, Perou, C, Petersen, G, Petrelli, N, Petryszak, R, Pfister, S, Phillips, M, Pich, O, Pickett, H, Pihl, T, Pillay, N, Pinder, S, Pinese, M, Pinho, A, Pitkanen, E, Pivot, X, Pineiro-Yanez, E, Planko, L, Plass, C, Polak, P, Pons, T, Popescu, I, Potapova, O, Prasad, A, Preston, S, Prinz, M, Pritchard, A, Prokopec, S, Provenzano, E, Puente, X, Puig, S, Pulido-Tamayo, S, Pupo, G, Purdie, C, Quinn, M, Rabionet, R, Rader, J, Radlwimmer, B, Radovic, P, Raeder, B, Ramakrishna, M, Ramakrishnan, K, Ramalingam, S, Raphael, B, Rathmell, W, Rausch, T, Reifenberger, G, Reimand, J, Reis-Filho, J, Reuter, V, Reyes-Salazar, I, Reyna, M, Riazalhosseini, Y, Richardson, A, Richter, J, Ringel, M, Ringner, M, Rino, Y, Rippe, K, Roach, J, Roberts, L, Roberts, N, Roberts, S, Robertson, A, Rodriguez, J, Rodriguez-Martin, B, Rodriguez-Gonzalez, F, Roehrl, M, Rohde, M, Rokutan, H, Romieu, G, Rooman, I, Roques, T, Rosebrock, D, Rosenberg, M, Rosenstiel, P, Rosenwald, A, Rowe, E, Rozen, S, Rubanova, Y, Rubin, M, Rubio-Perez, C, Rudneva, V, Rusev, B, Ruzzenente, A, Ratsch, G, Sabarinathan, R, Sabelnykova, V, Sadeghi, S, Saini, N, Saito-Adachi, M, Salcedo, A, Salgado, R, Salichos, L, Sallari, R, Saller, C, Salvia, R, Sam, M, Samra, J, 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Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Cellular Medicine Division, University of St Andrews. Statistics, University of St Andrews. School of Medicine, University of Zurich, Gerstein, Mark B, Ding, Li, Bailey, Matthew H [0000-0003-4526-9727], Wheeler, David A [0000-0002-9056-6299], Gerstein, Mark B [0000-0002-9746-3719], Faculty of Economic and Social Sciences and Solvay Business School, Lauri Antti Aaltonen / Principal Investigator, Genome-Scale Biology (GSB) Research Program, Department of Medical and Clinical Genetics, Organismal and Evolutionary Biology Research Programme, Helsinki Institute for Information Technology, Institute of Biotechnology, Bioinformatics, Department of Computer Science, Faculty of Medicine, and HUS Helsinki and Uusimaa Hospital District
Subjects: VARIANTS, 0302 clinical medicine, 706/648/697/129/2043, Databases, Genetic, Cancer genomics, SOMATIC POINT MUTATIONS, Càncer, lcsh:Science, Exome, Exome sequencing, Cancer, Base Composition, Neoplasms -- genetics, 1184 Genetics, developmental biology, physiology, 3100 General Physics and Astronomy, 3. Good health, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Transformació genètica, Genetic databases, Erfðarannsóknir, Human, GENES, Science, 1600 General Chemistry, General Biochemistry, Genetics and Molecular Biology, RC0254, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, 1300 General Biochemistry, Genetics and Molecular Biology, Exome Sequencing, Genetics, Humans, Author Correction, Retrospective Studies, Whole genome sequencing, Comparative genomics, Science & Technology, RC0254 Neoplasms. Tumors. Oncology (including Cancer), INSERTIONS, DNA, PERFORMANCE, Human genetics, Communication and replication, Cancérologie, 692/4028/67/69, Genòmica, 030104 developmental biology, Mutation, Genome mutation, Human genome, lcsh:Q, COMPREHENSIVE CHARACTERIZATION, Genètica, 0301 basic medicine, Medizin, General Physics and Astronomy, Genome, Whole Exome Sequencing, Genetic transformation, International Cancer Genome Consortium, Neoplasms, 631/114/2399, Genamengi, Medicine and Health Sciences, Medicine(all), Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, 318 Medical biotechnology, Exome -- genetics, article, Exons, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Multidisciplinary Sciences, CAPTURE, 1181 Ecology, evolutionary biology, oncology, DNA, Intergenic, 139, Medical Genetics, Biotechnology, ICGC/TCGA Pan-Cancer Analysis, 3122 Cancers, 610 Medicine & health, 45/23, QH426 Genetics, Biology, MC3 Working Group, Databases, Germline mutation, PCAWG novel somatic mutation calling methods working group, Krabbameinsrannsóknir, Cancer Genome Atlas, Genome, Human -- genetics, ddc:610, QH426, Medicinsk genetik, Krabbamein, Intergenic, Whole Genome Sequencing, Genome, Human, Human Genome, PCAWG Consortium, DAS, General Chemistry, DELETIONS, Good Health and Well Being, 10032 Clinic for Oncology and Hematology, 3111 Biomedicine, 631/1647/2217/748
Abstract: MC3 Working Group: Rehan Akbani21, Pavana Anur22, Matthew H. Bailey1,2,3, Alex Buchanan9, Kami Chiotti9, Kyle Covington12,23, Allison Creason9, Li Ding1,2,3,20, Kyle Ellrott9, Yu Fan21, Steven Foltz1,2, Gad Getz8,14,15,16, Walker Hale12, David Haussler24,25, Julian M. Hess8,26, Carolyn M. Hutter27, Cyriac Kandoth28, Katayoon Kasaian29,30, Melpomeni Kasapi27, Dave Larson1 , Ignaty Leshchiner8, John Letaw31, Singer Ma32, Michael D. McLellan1,3,20, Yifei Men32, Gordon B. Mills33,34, Beifang Niu35, Myron Peto22, Amie Radenbaugh24, Sheila M. Reynolds36, Gordon Saksena8, Heidi Sofia27, Chip Stewart8, Adam J. Struck31, Joshua M. Stuart24,37, Wenyi Wang21, John N. Weinstein38, David A. Wheeler12,13, Christopher K. Wong24,39, Liu Xi12 & Kai Ye40,41 21Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 22Molecular and Medical Genetics, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. 23Castle Biosciences Inc, Friendswood, TX 77546, USA. 24UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 25Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 26Massachusetts General Hospital Center for Cancer Research, Charlestown, MA 02114, USA. 27National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20894, USA. 28Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. 29Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. 30Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 4S6, Canada. 31Computational Biology Program, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USA. 32DNAnexus Inc, Mountain View, CA 94040, USA. 33Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA. 34Precision Oncology, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. 35Computer Network Information Center, Chinese Academy of Sciences, Beijing, China. 36Institute for Systems Biology, Seattle, WA 98109, USA. 37Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 38Department of Bioinformatics and Computational Biology and Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 39Biomolecular Engineering Department, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 40School of Elect, PCAWG novel somatic mutation calling methods working group: Matthew H. Bailey1,2,3, Beifang Niu35, Matthias Bieg42,43, Paul C. Boutros6,44,45,46, Ivo Buchhalter43,47,48, Adam P. Butler49, Ken Chen50, Zechen Chong51, Li Ding1,2,3,20, Oliver Drechsel52,53, Lewis Jonathan Dursi6,7, Roland Eils47,48,54,55, Kyle Ellrott9, Shadrielle M. G. Espiritu6, Yu Fan21, Robert S. Fulton1,3,20, Shengjie Gao56, Josep L. l. Gelpi57,58, Mark B. Gerstein5,18,19, Gad Getz8,14,15,16, Santiago Gonzalez59,60, Ivo G. Gut52,61, Faraz Hach62,63, Michael C. Heinold47,48, Julian M. Hess8,26, Jonathan Hinton49, Taobo Hu64, Vincent Huang6, Yi Huang65,66, Barbara Hutter43,67,68, David R. Jones49, Jongsun Jung69, Natalie Jäger47, Hyung-Lae Kim70, Kortine Kleinheinz47,48, Sushant Kumar5,19, Yogesh Kumar64, Christopher M. Lalansingh6, Ignaty Leshchiner8, Ivica Letunic71, Dimitri Livitz8, Eric Z. Ma64, Yosef E. Maruvka8,26,72, R. Jay Mashl1,2, Michael D. McLellan1,3,20, Andrew Menzies49, Ana Milovanovic57, Morten Muhlig Nielsen73, Stephan Ossowski52,53,74, Nagarajan Paramasivam43,47, Jakob Skou Pedersen73,75, Marc D. Perry76,77, Montserrat Puiggròs57, Keiran M. Raine49, Esther Rheinbay8,14,72, Romina Royo57, S. Cenk Sahinalp62,78,79, Gordon Saksena8, Iman Sarrafi62,78, Matthias Schlesner47,80, Jared T. Simpson6,17, Lucy Stebbings49, Chip Stewart8, Miranda D. Stobbe52,61, Jon W. Teague49, Grace Tiao8, David Torrents57,81, Jeremiah A. Wala8,14,82, Jiayin Wang1,40,66, Wenyi Wang21, Sebastian M. Waszak60, Joachim Weischenfeldt60,83,84, Michael C. Wendl1,10,11, Johannes Werner47,85, Zhenggang Wu64, Hong Xue64, Sergei Yakneen60, Takafumi N. Yamaguchi6, Kai Ye40,41, Venkata D. Yellapantula20,86, Christina K. Yung76 & Junjun Zhang76, PCAWG Consortium: Lauri A. Aaltonen87, Federico Abascal49, Adam Abeshouse88, Hiroyuki Aburatani89, David J. Adams49, Nishant Agrawal90, Keun Soo Ahn91, Sung-Min Ahn92, Hiroshi Aikata93, Rehan Akbani21, Kadir C. Akdemir50, Hikmat Al-Ahmadie88, Sultan T. Al-Sedairy94, Fatima Al-Shahrour95, Malik Alawi96,97, Monique Albert98, Kenneth Aldape99,100, Ludmil B. Alexandrov49,101,102, Adrian Ally30, Kathryn Alsop103, Eva G. Alvarez104,105,106, Fernanda Amary107, Samirkumar B. Amin108,109,110, Brice Aminou76, Ole Ammerpohl111,112, Matthew J. Anderson113, Yeng Ang114, Davide Antonello115, Pavana Anur22, Samuel Aparicio116, Elizabeth L. Appelbaum1,117, Yasuhito Arai118, Axel Aretz119, Koji Arihiro93, Shun-ichi Ariizumi120, Joshua Armenia121, Laurent Arnould122, Sylvia Asa123,124, Yassen Assenov125, Gurnit Atwal6,126,127, Sietse Aukema112,128, J. Todd Auman129, Miriam R. Aure130, Philip Awadalla6,126, Marta Aymerich131, Gary D. Bader126, Adrian Baez-Ortega132, Matthew H. Bailey1,2,3, Peter J. Bailey133, Miruna Balasundaram30, Saianand Balu134, Pratiti Bandopadhayay8,135,136, Rosamonde E. Banks137, Stefano Barbi138, Andrew P. Barbour139,140, Jonathan Barenboim6, Jill Barnholtz-Sloan141,142, Hugh Barr143, Elisabet Barrera59, John Bartlett98,144, Javier Bartolome57, Claudio Bassi115, Oliver F. Bathe145,146, Daniel Baumhoer147, Prashant Bavi148, Stephen B. Baylin149,150, Wojciech Bazant59, Duncan Beardsmore151, Timothy A. Beck152,153, Sam Behjati49, Andreas Behren154, Beifang Niu35, Cindy Bell155, Sergi Beltran52,61, Christopher Benz156, Andrew Berchuck157, Anke K. Bergmann158, Erik N. Bergstrom101,102, Benjamin P. Berman159,160,161, Daniel M. Berney162, Stephan H. Bernhart163,164,165, Rameen Beroukhim8,14,82, Mario Berrios166, Samantha Bersani167, Johanna Bertl73,168, Miguel Betancourt169, Vinayak Bhandari6,44, Shriram G. Bhosle49, Andrew V. Biankin133,170,171,172, Matthias Bieg42,43, Darell Bigner173, Hans Binder163,164, Ewan Birney59, Michael Birrer72, Nidhan K. Biswas174, Bodil Bjerkehagen147,175, Tom Bodenheimer134, Lori Boice176, Giada Bonizzato177, Johann S. De Bono178, Arnoud Boot179,180, Moiz S. Bootwalla166, Ake Borg181, Arndt Borkhardt182, Keith A. Boroevich183,184, Ivan Borozan6, Christoph Borst185, Marcus Bosenberg186, Mattia Bosio52,53,57, Jacqueline Boultwood187, Guillaume Bourque188,189, Paul C. Boutros6,44,45,46, G. Steven Bova190, David T. Bowen49,191, Reanne Bowlby30, David D. L. Bowtell103, Sandrine Boyault192, Rich Boyce59, Jeffrey Boyd193, Alvis Brazma59, Paul Brennan194, Daniel S. Brewer195,196, Arie B. Brinkman197, Robert G. Bristow44,198,199,200,201, Russell R. Broaddus99, Jane E. Brock202, Malcolm Brock203, Annegien Broeks204, Angela N. Brooks8,24,37,82, Denise Brooks30, Benedikt Brors67,205,206, Søren Brunak207,208, Timothy J. C. Bruxner113,209, Alicia L. Bruzos104,105,106, Alex Buchanan9, Ivo Buchhalter43,47,48, Christiane Buchholz210, Susan Bullman8,82, Hazel Burke211, Birgit Burkhardt212, Kathleen H. Burns213,214, John Busanovich8,215, Carlos D. Bustamante216,217, Adam P. Butler49, Atul J. Butte218, Niall J. Byrne76, Anne-Lise Børresen-Dale130,219, Samantha J. Caesar-Johnson220, Andy Cafferkey59, Declan Cahill221, Claudia Calabrese59,60, Carlos Caldas222,223, Fabien Calvo224, Niedzica Camacho178, Peter J. Campbell49,225, Elias Campo226,227, Cinzia Cantù177, Shaolong Cao21, Thomas E. Carey228, Joana Carlevaro-Fita229,230,231, Rebecca Carlsen30, Ivana Cataldo167,177, Mario Cazzola232, Jonathan Cebon154, Robert Cerfolio233, Dianne E. Chadwick234, Dimple Chakravarty235, Don Chalmers236, Calvin Wing Yiu Chan47,237, Kin Chan238, Michelle Chan-Seng-Yue148, Vishal S. Chandan239, David K. Chang133,170, Stephen J. Chanock240, Lorraine A. Chantrill170,241, Aurélien Chateigner76,242, Nilanjan Chatterjee149,243, Kazuaki Chayama93, Hsiao-Wei Chen114,121, Jieming Chen218, Ken Chen50, Yiwen Chen21, Zhaohong Chen244, Andrew D. Cherniack8,82, Jeremy Chien245, Yoke-Eng Chiew246,247, Suet-Feung Chin222,223, Juok Cho8, Sunghoon Cho248, Jung Kyoon Choi249, Wan Choi250, Christine Chomienne251, Zechen Chong51, Su Pin Choo252, Angela Chou170,246, Angelika N. Christ113, Elizabeth L. Christie103, Eric Chuah30, Carrie Cibulskis8, Kristian Cibulskis8, Sara Cingarlini253, Peter Clapham49, Alexander Claviez254, Sean Cleary148,255, Nicole Cloonan256, Marek Cmero257,258,259, Colin C. Collins62, Ashton A. Connor255,260, Susanna L. Cooke133, Colin S. Cooper178,196,261, Leslie Cope149, Vincenzo Corbo138,177, Matthew G. Cordes1,262, Stephen M. Cordner263, Isidro Cortés-Ciriano264,265,266, Kyle Covington12,23, Prue A. Cowin267, Brian Craft24, David Craft8,268, Chad J. Creighton269, Yupeng Cun270, Erin Curley271, Ioana Cutcutache179,180, Karolina Czajka272, Bogdan Czerniak99,273, Rebecca A. Dagg274, Ludmila Danilova149, Maria Vittoria Davi275, Natalie R. Davidson276,277,278,279,280, Helen Davies49,281,282, Ian J. Davis283, Brandi N. Davis-Dusenbery284, Kevin J. Dawson49, Francisco M. De La Vega216,217,285, Ricardo De Paoli-Iseppi211, Timothy Defreitas8, Angelo P. Dei Tos286, Olivier Delaneau287,288,289, John A. Demchok220, Jonas Demeulemeester290,291, German M. Demidov52,53,74, Deniz Demircioğlu292,293, Nening M. Dennis221, Robert E. Denroche148, Stefan C. Dentro49,290,294, Nikita Desai76, Vikram Deshpande72, Amit G. Deshwar295, Christine Desmedt296,297, Jordi Deu-Pons298,299, Noreen Dhalla30, Neesha C. Dhani300, Priyanka Dhingra301,302, Rajiv Dhir303, Anthony DiBiase304, Klev Diamanti305, Li Ding1,2,3,20, Shuai Ding306, Huy Q. Dinh159, Luc Dirix307, HarshaVardhan Doddapaneni12, Nilgun Donmez62,78, Michelle T. Dow244, Ronny Drapkin308, Oliver Drechsel52,53, Ruben M. Drews223, Serge Serge49, Tim Dudderidge150,221, Ana Dueso-Barroso57, Andrew J. Dunford8, Michael Dunn309, Lewis Jonathan Dursi6,7, Fraser R. Duthie133,310, Ken Dutton-Regester311, Jenna Eagles272, Douglas F. Easton312,313, Stuart Edmonds314, Paul A. Edwards223,315, Sandra E. Edwards178, Rosalind A. Eeles178,221, Anna Ehinger316, Juergen Eils54,55, Roland Eils47,48,54,55, Adel El-Naggar99,273, Matthew Eldridge223, Kyle Ellrott9, Serap Erkek60, Georgia Escaramis53,317,318, Shadrielle M. G. Espiritu6, Xavier Estivill53,319, Dariush Etemadmoghadam103, Jorunn E. Eyfjord320, Bishoy M. Faltas280, Daiming Fan321, Yu Fan21, William C. Faquin72, Claudiu Farcas244, Matteo Fassan322, Aquila Fatima323, Francesco Favero324, Nodirjon Fayzullaev76, Ina Felau220, Sian Fereday103, Martin L. Ferguson325, Vincent Ferretti76,326, Lars Feuerbach205, Matthew A. Field327, J. Lynn Fink57,113, Gaetano Finocchiaro328, Cyril Fisher221, Matthew W. Fittall290, Anna Fitzgerald329, Rebecca C. Fitzgerald282, Adrienne M. Flanagan330, Neil E. Fleshner331, Paul Flicek59, John A. Foekens332, Kwun M. Fong333, Nuno A. Fonseca59,334, Christopher S. Foster335,336, Natalie S. Fox6, Michael Fraser6, Scott Frazer8, Milana Frenkel-Morgenstern337, William Friedman338, Joan Frigola298, Catrina C. Fronick1,262, Akihiro Fujimoto184, Masashi Fujita184, Masashi Fukayama339, Lucinda A. Fulton1 , Robert S. Fulton1,3,20, Mayuko Furuta184, P. Andrew Futreal340, Anja Füllgrabe59, Stacey B. Gabriel8, Steven Gallinger148,255,260, Carlo Gambacorti-Passerini341, Jianjiong Gao121, Shengjie Gao56, Levi Garraway82, Øystein Garred342, Erik Garrison49, Dale W. Garsed103, Nils Gehlenborg8,343, Josep L. l. Gelpi57,58, Joshy George110, Daniela S. Gerhard344, Clarissa Gerhauser345, Jeffrey E. Gershenwald346,347, Mark B. Gerstein5,18,19, Moritz Gerstung59,60, Gad Getz8,14,15,16, Mohammed Ghori49, Ronald Ghossein348, Nasra H. Giama349, Richard A. Gibbs12, Anthony J. Gill170,350, Pelvender Gill351, Dilip D. Giri348, Dominik Glodzik49, Vincent J. Gnanapragasam352,353, Maria Elisabeth Goebler354, Mary J. Goldman24, Carmen Gomez355, Santiago Gonzalez59,60, Abel Gonzalez-Perez298,299,356, Dmitry A. Gordenin357, James Gossage358, Kunihito Gotoh359, Ramaswamy Govindan3, Dorthe Grabau360, Janet S. Graham133,361, Robert C. Grant148,260, Anthony R. Green315, Eric Green27, Liliana Greger59, Nicola Grehan282, Sonia Grimaldi177, Sean M. Grimmond362, Robert L. Grossman363, Adam Grundhoff97,364, Gunes Gundem88, Qianyun Guo75, Manaswi Gupta8, Shailja Gupta365, Ivo G. Gut52,61, Marta Gut52,61, Jonathan Göke292,366, Gavin Ha8, Andrea Haake111, David Haan37, Siegfried Haas185, Kerstin Haase290, James E. Haber367, Nina Habermann60, Faraz Hach62,63, Syed Haider6, Natsuko Hama118, Freddie C. Hamdy351, Anne Hamilton267, Mark P. Hamilton368, Leng Han369, George B. Hanna370, Martin Hansmann371, Nicholas J. Haradhvala8,72, Olivier Harismendy102,372, Ivon Harliwong113, Arif O. Harmanci5,373, Eoghan Harrington374, Takanori Hasegawa375, David Haussler24,25, Steve Hawkins223, Shinya Hayami376, Shuto Hayashi375, D. Neil Hayes134,377,378, Stephen J. Hayes379,380, Nicholas K. Hayward211,311, Steven Hazell221, Yao He381, Allison P. Heath382, Simon C. Heath52,61, David Hedley300, Apurva M. Hegde38, David I. Heiman8, Michael C. Heinold47,48, Zachary Heins88, Lawrence E. Heisler152, Eva Hellstrom-Lindberg383, Mohamed Helmy384, Seong Gu Heo385, Austin J. Hepperla134, José María Heredia-Genestar386, Carl Herrmann47,48,387, Peter Hersey211, Julian M. Hess8,26, Holmfridur Hilmarsdottir320, Jonathan Hinton49, Satoshi Hirano388, Nobuyoshi Hiraoka389, Katherine A. Hoadley134,390, Asger Hobolth75,168, Ermin Hodzic78, Jessica I. Hoell182, Steve Hoffmann163,164,165,391, Oliver Hofmann392, Andrea Holbrook166, Aliaksei Z. Holik53, Michael A. Hollingsworth393, Oliver Holmes209,311, Robert A. Holt30, Chen Hong205,237, Eun Pyo Hong385, Jongwhi H. Hong394, Gerrit K. Hooijer395, Henrik Hornshøj73, Fumie Hosoda118, Yong Hou56,396, Volker Hovestadt397, William Howat352, Alan P. Hoyle134, Ralph H. Hruban149, Jianhong Hu12, Taobo Hu64, Xing Hua240, Kuan-lin Huang1,398, Mei Huang176, Mi Ni Huang179,180, Vincent Huang6, Yi Huang65,66, Wolfgang Huber60, Thomas J. Hudson272,399, Michael Hummel400, Jillian A. Hung246,247, David Huntsman401, Ted R. Hupp402, Jason Huse88, Matthew R. Huska403, Barbara Hutter43,67,68, Carolyn M. Hutter27, Daniel Hübschmann48,54,404,405,406, Christine A. Iacobuzio-Donahue348, Charles David Imbusch205, Marcin Imielinski407,408, Seiya Imoto375, William B. Isaacs409, Keren Isaev6,44, Shumpei Ishikawa410, Murat Iskar397, S. M. Ashiqul Islam244, Michael Ittmann411,412,413, Sinisa Ivkovic284, Jose M. G. Izarzugaza414, Jocelyne Jacquemier415, Valerie Jakrot211, Nigel B. Jamieson133,172,416, Gun Ho Jang148, Se Jin Jang417, Joy C. Jayaseelan12, Reyka Jayasinghe1 , Stuart R. Jefferys134, Karine Jegalian418, Jennifer L. Jennings419, Seung-Hyup Jeon250, Lara Jerman60,420, Yuan Ji421,422, Wei Jiao6, Peter A. Johansson311, Amber L. Johns170, Jeremy Johns272, Rory Johnson230,423, Todd A. Johnson183, Clemency Jolly290, Yann Joly424, Jon G. Jonasson320, Corbin D. Jones425, David R. Jones49, David T. W. Jones426,427, Nic Jones428, Steven J. M. Jones30, Jos Jonkers204, Young Seok Ju49,249, Hartmut Juhl429, Jongsun Jung69, Malene Juul73, Randi Istrup Juul73, Sissel Juul374, Natalie Jäger47, Rolf Kabbe47, Andre Kahles276,277,278,279,430, Abdullah Kahraman431,432,433, Vera B. Kaiser434, Hojabr Kakavand211, Sangeetha Kalimuthu148, Christof von Kalle405, Koo Jeong Kang91, Katalin Karaszi351, Beth Karlan435, Rosa Karlić436, Dennis Karsch437, Katayoon Kasaian29,30, Karin S. Kassahn113,438, Hitoshi Katai439, Mamoru Kato440, Hiroto Katoh410, Yoshiiku Kawakami93, Jonathan D. Kay117, Stephen H. Kazakoff209,311, Marat D. Kazanov441,442,443, Maria Keays59, Electron Kebebew444,445, Richard F. Kefford446, Manolis Kellis8,447, James G. Kench170,350,448, Catherine J. Kennedy246,247, Jules N. A. Kerssemakers47, David Khoo273, Vincent Khoo221, Narong Khuntikeo115,449, Ekta Khurana301,302,450,451, Helena Kilpinen117, Hark Kyun Kim452, Hyung-Lae Kim70, Hyung-Yong Kim415, Hyunghwan Kim250, Jaegil Kim8, Jihoon Kim453, Jong K. Kim454, Youngwook Kim455,456, Tari A. King457,458,459, Wolfram Klapper128, Kortine Kleinheinz47,48, Leszek J. Klimczak460, Stian Knappskog49,461, Michael Kneba437, Bartha M. Knoppers424, Youngil Koh462,463, Jan Komorowski305,464, Daisuke Komura410, Mitsuhiro Komura375, Gu Kong415, Marcel Kool426,465, Jan O. Korbel59,60, Viktoriya Korchina12, Andrey Korshunov465, Michael Koscher465, Roelof Koster466, Zsofia Kote-Jarai178, Antonios Koures244, Milena Kovacevic284, Barbara Kremeyer49, Helene Kretzmer164,165, Markus Kreuz467, Savitri Krishnamurthy99,468, Dieter Kube469, Kiran Kumar8, Pardeep Kumar221, Sushant Kumar5,19, Yogesh Kumar64, Ritika Kundra114,121, Kirsten Kübler8,14,72, Ralf Küppers470, Jesper Lagergren383,471, Phillip H. Lai166, Peter W. Laird472, Sunil R. Lakhani473, Christopher M. Lalansingh6, Emilie Lalonde6, Fabien C. Lamaze6, Adam Lambert351, Eric Lander8, Pablo Landgraf474,475, Luca Landoni115, Anita Langerød130, Andrés Lanzós230,231,423, Denis Larsimont476, Erik Larsson477, Mark Lathrop189, Loretta M. S. Lau478, Chris Lawerenz55, Rita T. Lawlor177, Michael S. Lawrence8,72,183, Alexander J. Lazar99,108, Xuan Le479, Darlene Lee30, Donghoon Lee5, Eunjung Alice Lee480, Hee Jin Lee417, Jake June-Koo Lee264,266, Jeong-Yeon Lee481, Juhee Lee482, Ming Ta Michael Lee340, Henry Lee-Six49, Kjong-Van Lehmann276,277,278,279,430, Hans Lehrach483, Dido Lenze400, Conrad R. Leonard209,311, Daniel A. Leongamornlert49,178, Ignaty Leshchiner8, Louis Letourneau484, Ivica Letunic71, Douglas A. Levine88,485, Lora Lewis12, Tim Ley486, Chang Li56,396, Constance H. Li6,44, Haiyan Irene Li30, Jun Li21, Lin Li56, Shantao Li5, Siliang Li56,396, Xiaobo Li56,396, Xiaotong Li5, Xinyue Li56, Yilong Li49, Han Liang21, Sheng-Ben Liang234, Peter Lichter68,397, Pei Lin8, Ziao Lin8,487, W. M. Linehan488, Ole Christian Lingjærde489, Dongbing Liu56,396, Eric Minwei Liu88,301,302, Fei-Fei Liu201,490, Fenglin Liu381,491, Jia Liu492, Xingmin Liu56,396, Julie Livingstone6, Dimitri Livitz8, Naomi Livni221, Lucas Lochovsky5,19,110, Markus Loeffler467, Georgina V. Long211, Armando Lopez-Guillermo493, Shaoke Lou5,19, David N. Louis72, Laurence B. Lovat117, Yiling Lu38, Yong-Jie Lu162,494, Youyong Lu495,496,497, Claudio Luchini167, Ilinca Lungu144,148, Xuemei Luo152, Hayley J. Luxton117, Andy G. Lynch223,315,498, Lisa Lype36, Cristina López111,112, Carlos López-Otín499, Eric Z. Ma64, Yussanne Ma30, Gaetan MacGrogan500, Shona MacRae501, Geoff Macintyre223, Tobias Madsen73, Kazuhiro Maejima184, Andrea Mafficini177, Dennis T. Maglinte166,502, Arindam Maitra174, Partha P. Majumder174, Luca Malcovati232, Salem Malikic62,78, Giuseppe Malleo115, Graham J. Mann211,246,503, Luisa Mantovani-Löffler504, Kathleen Marchal505,506, Giovanni Marchegiani115, Elaine R. Mardis1,193,507, Adam A. Margolin31, Maximillian G. Marin37, Florian Markowetz223,315, Julia Markowski403, Jeffrey Marks508, Tomas Marques-Bonet61,81,386,509, Marco A. Marra30, Luke Marsden351, John W. M. Martens332, Sancha Martin49,510, Jose I. Martin-Subero81,511, Iñigo Martincorena49, Alexander Martinez-Fundichely301,302,451 Yosef E. Maruvka8,26,72, R. Jay Mashl1,2, Charlie E. Massie223, Thomas J. Matthew37, Lucy Matthews178, Erik Mayer221,512, Simon Mayes513, Michael Mayo30, Faridah Mbabaali272, Karen McCune514, Ultan McDermott49, Patrick D. McGillivray19, Michael D. McLellan1,3,20, John D. McPherson148,272,515, John R. McPherson179,180, Treasa A. McPherson260, Samuel R. Meier8, Alice Meng516, Shaowu Meng134, Andrew Menzies49, Neil D. Merrett115,517, Sue Merson178, Matthew Meyerson8,14,82, William U. Meyerson4,5, Piotr A. Mieczkowski518, George L. Mihaiescu76, Sanja Mijalkovic284, Ana Mijalkovic Mijalkovic-Lazic284, Tom Mikkelsen519, Michele Milella253, Linda Mileshkin103, Christopher A. Miller1 , David K. Miller113,170, Jessica K. Miller272, Gordon B. Mills33,34, Ana Milovanovic57, Sarah Minner520, Marco Miotto115, Gisela Mir Arnau267, Lisa Mirabello240, Chris Mitchell103, Thomas J. Mitchell49,315,352, Satoru Miyano375, Naoki Miyoshi375, Shinichi Mizuno521, Fruzsina Molnár-Gábor522, Malcolm J. Moore300, Richard A. Moore30, Sandro Morganella49, Quaid D. Morris127,490, Carl Morrison523,524, Lisle E. Mose134, Catherine D. Moser349, Ferran Muiños298,299, Loris Mularoni298,299, Andrew J. Mungall30, Karen Mungall30, Elizabeth A. Musgrove133, Ville Mustonen525,526,527, David Mutch528, Francesc Muyas52,53,74, Donna M. Muzny12, Alfonso Muñoz59, Jerome Myers529, Ola Myklebost461, Peter Möller530, Genta Nagae89, Adnan M. Nagrial170, Hardeep K. Nahal-Bose76, Hitoshi Nakagama531, Hidewaki Nakagawa184, Hiromi Nakamura118, Toru Nakamura388, Kaoru Nakano184, Tannistha Nandi532, Jyoti Nangalia49, Mia Nastic284, Arcadi Navarro61,81,386, Fabio C. P. Navarro19, David E. Neal223,352, Gerd Nettekoven533, Felicity Newell209,311, Steven J. Newhouse59, Yulia Newton37, Alvin Wei Tian Ng534, Anthony Ng535, Jonathan Nicholson49, David Nicol221, Yongzhan Nie321,536, G. Petur Nielsen72, Morten Muhlig Nielsen73, Serena Nik-Zainal49,281,282,537, Michael S. Noble8, Katia Nones209,311, Paul A. Northcott538, Faiyaz Notta148,539, Brian D. O’Connor76,540, Peter O’Donnell541, Maria O’Donovan282, Sarah O’Meara49, Brian Patrick O’Neill542, J. Robert O’Neill543, David Ocana59, Angelica Ochoa88, Layla Oesper544, Christopher Ogden221, Hideki Ohdan93, Kazuhiro Ohi375, Lucila Ohno-Machado244, Karin A. Oien523,545, Akinyemi I. Ojesina546,547,548, Hidenori Ojima549, Takuji Okusaka550, Larsson Omberg551, Choon Kiat Ong552, Stephan Ossowski52,53,74, German Ott553, B. F. Francis Ouellette76,554, Christine P’ng6, Marta Paczkowska6, Salvatore Paiella115, Chawalit Pairojkul523, Marina Pajic170, Qiang Pan-Hammarström56,555, Elli Papaemmanuil49, Irene Papatheodorou59, Nagarajan Paramasivam43,47, Ji Wan Park385, Joong-Won Park556, Keunchil Park557,558, Kiejung Park559, Peter J. Park264,266, Joel S. Parker518, Simon L. Parsons124, Harvey Pass560, Danielle Pasternack272, Alessandro Pastore276, Ann-Marie Patch209,311, Iris Pauporté251, Antonio Pea115, John V. Pearson209,311, Chandra Sekhar Pedamallu8,14,82, Jakob Skou Pedersen73,75, Paolo Pederzoli115, Martin Peifer270, Nathan A. Pennell561, Charles M. Perou129,518, Marc D. Perry76,77, Gloria M. Petersen562, Myron Peto22, Nicholas Petrelli563, Robert Petryszak59, Stefan M. Pfister426,465,564, Mark Phillips424, Oriol Pich298,299, Hilda A. Pickett478, Todd D. Pihl565, Nischalan Pillay566, Sarah Pinder567, Mark Pinese170, Andreia V. Pinho568, Esa Pitkänen60, Xavier Pivot569, Elena Piñeiro-Yáñez95, Laura Planko533, Christoph Plass345, Paz Polak8,14,15, Tirso Pons570, Irinel Popescu571, Olga Potapova572, Aparna Prasad52, Shaun R. Preston573, Manuel Prinz47, Antonia L. Pritchard311, Stephenie D. Prokopec6, Elena Provenzano574, Xose S. Puente499, Sonia Puig176, Montserrat Puiggròs57, Sergio Pulido-Tamayo505,506, Gulietta M. Pupo246, Colin A. Purdie575, Michael C. Quinn209,311, Raquel Rabionet52,53,576, Janet S. Rader577, Bernhard Radlwimmer397, Petar Radovic284, Benjamin Raeder60, Keiran M. Raine49, Manasa Ramakrishna49, Kamna Ramakrishnan49, Suresh Ramalingam578, Benjamin J. Raphael579, W. Kimryn Rathmell580, Tobias Rausch60, Guido Reifenberger475, Jüri Reimand6,44, Jorge Reis-Filho348, Victor Reuter348, Iker Reyes-Salazar298, Matthew A. Reyna579, Sheila M. Reynolds36, Esther Rheinbay8,14,72, Yasser Riazalhosseini189, Andrea L. Richardson323, Julia Richter111,128, Matthew Ringel581, Markus Ringnér181, Yasushi Rino582, Karsten Rippe405, Jeffrey Roach583, Lewis R. Roberts349, Nicola D. Roberts49, Steven A. Roberts584, A. Gordon Robertson30, Alan J. Robertson113, Javier Bartolomé Rodriguez57, Bernardo Rodriguez-Martin104,105,106, F. Germán Rodríguez-González83,332, Michael H. A. Roehrl44,123,148,234,585,586, Marius Rohde587, Hirofumi Rokutan440, Gilles Romieu588, Ilse Rooman170, Tom Roques262, Daniel Rosebrock8, Mara Rosenberg8,72, Philip C. Rosenstiel589, Andreas Rosenwald590, Edward W. Rowe221,591, Romina Royo57, Steven G. Rozen179,180,592, Yulia Rubanova17,127, Mark A. Rubin423,593,594,595,596, Carlota Rubio-Perez298,299,597, Vasilisa A. Rudneva60, Borislav C. Rusev177, Andrea Ruzzenente598, Gunnar Rätsch276,277,278,279,280,430, Radhakrishnan Sabarinathan298,299,599, Veronica Y. Sabelnykova6, Sara Sadeghi30, S. Cenk Sahinalp62,78,79, Natalie Saini357, Mihoko Saito-Adachi440, Gordon Saksena8, Adriana Salcedo6, Roberto Salgado600, Leonidas Salichos5,19, Richard Sallari8, Charles Saller601, Roberto Salvia115, Michelle Sam272, Jaswinder S. Samra115,602, Francisco Sanchez-Vega114,121, Chris Sander276,603,604, Grant Sanders134, Rajiv Sarin605, Iman Sarrafi62,78, Aya Sasaki-Oku184, Torill Sauer489, Guido Sauter520, Robyn P. M. Saw211, Maria Scardoni167, Christopher J. Scarlett170,606, Aldo Scarpa177, Ghislaine Scelo194, Dirk Schadendorf68,607, Jacqueline E. Schein30, Markus B. Schilhabel589, Matthias Schlesner47,80, Thorsten Schlomm84,608, Heather K. Schmidt1 , Sarah-Jane Schramm246, Stefan Schreiber609, Nikolaus Schultz121, Steven E. Schumacher8,323, Roland F. Schwarz59,403,405,610, Richard A. Scolyer211,448,602, David Scott428, Ralph Scully611, Raja Seethala612, Ayellet V. Segre8,613, Iris Selander260, Colin A. Semple434, Yasin Senbabaoglu276, Subhajit Sengupta614, Elisabetta Sereni115, Stefano Serra585, Dennis C. Sgroi72, Mark Shackleton103, Nimish C. Shah352, Sagedeh Shahabi234, Catherine A. Shang329, Ping Shang211, Ofer Shapira8,323, Troy Shelton271, Ciyue Shen603,604, Hui Shen615, Rebecca Shepherd49, Ruian Shi490, Yan Shi134, Yu-Jia Shiah6, Tatsuhiro Shibata118,616, Juliann Shih8,82, Eigo Shimizu375, Kiyo Shimizu617, Seung Jun Shin618, Yuichi Shiraishi375, Tal Shmaya285, Ilya Shmulevich36, Solomon I. Shorser6, Charles Short59, Raunak Shrestha62, Suyash S. Shringarpure217, Craig Shriver619, Shimin Shuai6,126, Nikos Sidiropoulos83, Reiner Siebert112,620, Anieta M. Sieuwerts332, Lina Sieverling205,237, Sabina Signoretti202,621, Katarzyna O. Sikora177, Michele Simbolo138, Ronald Simon520, Janae V. Simons134, Jared T. Simpson6,17, Peter T. Simpson473, Samuel Singer115,458, Nasa Sinnott-Armstrong8,217, Payal Sipahimalani30, Tara J. Skelly390, Marcel Smid332, Jaclyn Smith622, Karen Smith-McCune514, Nicholas D. Socci276, Heidi J. Sofia27, Matthew G. Soloway134, Lei Song240, Anil K. Sood623,624,625, Sharmila Sothi626, Christos Sotiriou244, Cameron M. Soulette37, Paul N. Span627, Paul T. Spellman22, Nicola Sperandio177, Andrew J. Spillane211, Oliver Spiro8, Jonathan Spring628, Johan Staaf181, Peter F. Stadler163,164,165, Peter Staib629, Stefan G. Stark277,279,618,630, Lucy Stebbings49, Ólafur Andri Stefánsson631, Oliver Stegle59,60,632, Lincoln D. Stein6,126, Alasdair Stenhouse633, Chip Stewart8, Stephan Stilgenbauer634, Miranda D. Stobbe52,61, Michael R. Stratton49, Jonathan R. Stretch211, Adam J. Struck31, Joshua M. Stuart24,37, Henk G. Stunnenberg396,635, Hong Su56,396, Xiaoping Su99, Ren X. Sun6, Stephanie Sungalee60, Hana Susak52,53, Akihiro Suzuki89,636, Fred Sweep637, Monika Szczepanowski128, Holger Sültmann67,638, Takashi Yugawa617, Angela Tam30, David Tamborero298,299, Benita Kiat Tee Tan639, Donghui Tan518, Patrick Tan180,532,592,640, Hiroko Tanaka375, Hirokazu Taniguchi616, Tomas J. Tanskanen641, Maxime Tarabichi49,290, Roy Tarnuzzer220, Patrick Tarpey642, Morgan L. Taschuk152, Kenji Tatsuno89, Simon Tavaré223,643, Darrin F. Taylor113, Amaro Taylor-Weiner8, Jon W. Teague49, Bin Tean Teh180,592,640,644,645, Varsha Tembe246, Javier Temes104,105, Kevin Thai76, Sarah P. Thayer393, Nina Thiessen30, Gilles Thomas646, Sarah Thomas221, Alan Thompson221, Alastair M. Thompson633, John F. Thompson211, R. Houston Thompson647, Heather Thorne103, Leigh B. Thorne176, Adrian Thorogood424, Grace Tiao8, Nebojsa Tijanic284, Lee E. Timms272, Roberto Tirabosco648, Marta Tojo106, Stefania Tommasi649, Christopher W. Toon170, Umut H. Toprak48,650, David Torrents57,81, Giampaolo Tortora651,652, Jörg Tost653, Yasushi Totoki118, David Townend654, Nadia Traficante103, Isabelle Treilleux655,656, Jean-Rémi Trotta61, Lorenz H. P. Trümper469, Ming Tsao124,539, Tatsuhiko Tsunoda183,657,658,659, Jose M. C. Tubio104,105,106, Olga Tucker660, Richard Turkington661, Daniel J. Turner513, Andrew Tutt323, Masaki Ueno376, Naoto T. Ueno662, Christopher Umbricht151,213,663, Husen M. Umer305,664, Timothy J. Underwood665, Lara Urban59,60, Tomoko Urushidate616, Tetsuo Ushiku339, Liis Uusküla-Reimand666,667, Alfonso Valencia57,81, David J. Van Den Berg166, Steven Van Laere307, Peter Van Loo290,291, Erwin G. Van Meir668, Gert G. Van den Eynden307, Theodorus Van der Kwast123, Naveen Vasudev137, Miguel Vazquez57,669, Ravikiran Vedururu267, Umadevi Veluvolu518, Shankar Vembu490,670, Lieven P. C. Verbeke506,671, Peter Vermeulen307, Clare Verrill351,672, Alain Viari177, David Vicente57, Caterina Vicentini177, K. Vijay Raghavan365, Juris Viksna673, Ricardo E. Vilain674, Izar Villasante57, Anne Vincent-Salomon635, Tapio Visakorpi190, Douglas Voet8, Paresh Vyas311,351, Ignacio Vázquez-García49,86,675,676, Nick M. Waddell209, Nicola Waddell209,311, Claes Wadelius677, Lina Wadi6, Rabea Wagener111,112, Jeremiah A. Wala8,14,82, Jian Wang56, Jiayin Wang1,40,66, Linghua Wang12, Qi Wang465, Wenyi Wang21, Yumeng Wang21, Zhining Wang220, Paul M. Waring523, Hans-Jörg Warnatz483, Jonathan Warrell5,19, Anne Y. Warren352,678, Sebastian M. Waszak60, David C. Wedge49,294,679, Dieter Weichenhan345, Paul Weinberger680, John N. Weinstein38, Joachim Weischenfeldt60,83,84, Daniel J. Weisenberger166, Ian Welch681, Michael C. Wendl1,10,11, Johannes Werner47,85, Justin P. Whalley61,682, David A. Wheeler12,13, Hayley C. Whitaker117, Dennis Wigle683, Matthew D. Wilkerson518, Ashley Williams244, James S. Wilmott211, Gavin W. Wilson6,148, Julie M. Wilson148, Richard K. Wilson1,684, Boris Winterhoff685, Jeffrey A. Wintersinger17,127,384, Maciej Wiznerowicz686,687, Stephan Wolf688, Bernice H. Wong689, Tina Wong1,30, Winghing Wong690, Youngchoon Woo250, Scott Wood209,311, Bradly G. Wouters44, Adam J. Wright6, Derek W. Wright133,691, Mark H. Wright217, Chin-Lee Wu72, Dai-Ying Wu285, Guanming Wu692, Jianmin Wu170, Kui Wu56,396, Yang Wu179,180, Zhenggang Wu64, Liu Xi12, Tian Xia693, Qian Xiang76, Xiao Xiao66, Rui Xing497, Heng Xiong56,396, Qinying Xu209,311, Yanxun Xu694, Hong Xue64, Shinichi Yachida118,695, Sergei Yakneen60, Rui Yamaguchi375, Takafumi N. Yamaguchi6, Masakazu Yamamoto120, Shogo Yamamoto89, Hiroki Yamaue376, Fan Yang490, Huanming Yang56, Jean Y. Yang696, Liming Yang220, Lixing Yang697, Shanlin Yang306, Tsun-Po Yang270, Yang Yang369, Xiaotong Yao408,698, Marie-Laure Yaspo483, Lucy Yates49, Christina Yau156, Chen Ye56,396, Kai Ye40,41, Venkata D. Yellapantula20,86, Christopher J. Yoon249, Sung-Soo Yoon463, Fouad Yousif6, Jun Yu699, Kaixian Yu700, Willie Yu701, Yingyan Yu702, Ke Yuan223,510,703, Yuan Yuan21, Denis Yuen6, Takashi Yugawa617, Christina K. Yung76, Olga Zaikova704, Jorge Zamora49,104,105,106, Marc Zapatka397, Jean C. Zenklusen220, Thorsten Zenz67, Nikolajs Zeps705,706, Cheng-Zhong Zhang8,707, Fan Zhang381, Hailei Zhang8, Hongwei Zhang494, Hongxin Zhang121, Jiashan Zhang220, Jing Zhang5, Junjun Zhang76, Xiuqing Zhang56, Xuanping Zhang66,369, Yan Zhang5,708,709, Zemin Zhang381,710, Zhongming Zhao711, Liangtao Zheng381, Xiuqing Zheng381, Wanding Zhou615, Yong Zhou56, Bin Zhu240, Hongtu Zhu700,712, Jingchun Zhu24, Shida Zhu56,396, Lihua Zou713, Xueqing Zou49, Anna deFazio246,247,714, Nicholas van As221, Carolien H. M. van Deurzen715, Marc J. van de Vijver523, L. van’t Veer716 & Christian von Mering433,717, The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.
Published: 2020
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36. Sex differences in oncogenic mutational processes

Author: Li C. H., Prokopec S. D., Sun R. X., Yousif F., Schmitz N., Al-Shahrour F., Atwal G., Bailey P. J., Biankin A. V., Boutros P. C., Campbell P. J., Chang D. K., Cooke S. L., Deshpande V., Faltas B. M., Faquin W. C., Garraway L., Getz G., Grimmond S. M., Haider S., Hoadley K. A., Jiao W., Kaiser V. B., Karlic R., Kato M., Kubler K., Lazar A. J., Louis D. N., Margolin A., Martin S., Nahal-Bose H. K., Nielsen G. P., Nik-Zainal S., Omberg L., P'ng C., Perry M. D., Polak P., Rheinbay E., Rubin M. A., Semple C. A., Sgroi D. C., Shibata T., Siebert R., Smith J., Stein L. D., Stobbe M. D., Thai K., Wright D. W., Wu C. -L., Yuan K., Zhang J., Aaltonen L. A., Abascal F., Abeshouse A., Aburatani H., Adams D. J., Agrawal N., Ahn K. S., Ahn S. -M., Aikata H., Akbani R., Akdemir K. C., Al-Ahmadie H., Al-Sedairy S. T., Alawi M., Albert M., Aldape K., Alexandrov L. B., Ally A., Alsop K., Alvarez E. G., Amary F., Amin S. B., Aminou B., Ammerpohl O., Anderson M. J., Ang Y., Antonello D., Anur P., Aparicio S., Appelbaum E. L., Arai Y., Aretz A., Arihiro K., Ariizumi S. -I., Armenia J., Arnould L., Asa S., Assenov Y., Aukema S., Auman J. T., Aure M. R., Awadalla P., Aymerich M., Bader G. D., Baez-Ortega A., Bailey M. H., Balasundaram M., Balu S., Bandopadhayay P., Banks R. E., Barbi S., Barbour A. P., Barenboim J., Barnholtz-Sloan J., Barr H., Barrera E., Bartlett J., Bartolome J., Bassi C., Bathe O. F., Baumhoer D., Bavi P., Baylin S. B., Bazant W., Beardsmore D., Beck T. A., Behjati S., Behren A., Niu B., Bell C., Beltran S., Benz C., Berchuck A., Bergmann A. K., Bergstrom E. N., Berman B. P., Berney D. M., Bernhart S. H., Beroukhim R., Berrios M., Bersani S., Bertl J., Betancourt M., Bhandari V., Bhosle S. G., Bieg M., Bigner D., Binder H., Birney E., Birrer M., Biswas N. K., Bjerkehagen B., Bodenheimer T., Boice L., Bonizzato G., De Bono J. S., Boot A., Bootwalla M. S., Borg A., Borkhardt A., Boroevich K. A., Borozan I., Borst C., Bosenberg M., Bosio M., Boultwood J., Bourque G., Bova G. S., Bowen D. T., Bowlby R., Bowtell D. D. L., Boyault S., Boyce R., Boyd J., Brazma A., Brennan P., Brewer D. S., Brinkman A. B., Bristow R. G., Broaddus R. R., Brock J. E., Brock M., Broeks A., Brooks A. N., Brooks D., Brors B., Brunak S., Bruxner T. J. C., Bruzos A. L., Buchanan A., Buchhalter I., Buchholz C., Bullman S., Burke H., Burkhardt B., Burns K. H., Busanovich J., Bustamante C. D., Butler A. P., Butte A. J., Byrne N. J., Borresen-Dale A. -L., Caesar-Johnson S. J., Cafferkey A., Cahill D., Calabrese C., Caldas C., Calvo F., Camacho N., Campo E., Cantu C., Cao S., Carey T. E., Carlevaro-Fita J., Carlsen R., Cataldo I., Cazzola M., Cebon J., Cerfolio R., Chadwick D. E., Chakravarty D., Chalmers D., Chan C. W. Y., Chan K., Chan-Seng-Yue M., Chandan V. S., Chanock S. J., Chantrill L. A., Chateigner A., Chatterjee N., Chayama K., Chen H. -W., Chen J., Chen K., Chen Y., Chen Z., Cherniack A. D., Chien J., Chiew Y. -E., Chin S. -F., Cho J., Cho S., Choi J. K., Choi W., Chomienne C., Chong Z., Choo S. P., Chou A., Christ A. N., Christie E. L., Chuah E., Cibulskis C., Cibulskis K., Cingarlini S., Clapham P., Claviez A., Cleary S., Cloonan N., Cmero M., Collins C. C., Connor A. A., Cooper C. S., Cope L., Corbo V., Cordes M. G., Cordner S. M., Cortes-Ciriano I., Covington K., Cowin P. A., Craft B., Craft D., Creighton C. J., Cun Y., Curley E., Cutcutache I., Czajka K., Czerniak B., Dagg R. A., Danilova L., Davi M. V., Davidson N. R., Davies H., Davis I. J., Davis-Dusenbery B. N., Dawson K. J., De La Vega F. M., De Paoli-Iseppi R., Defreitas T., Dei Tos A. P., Delaneau O., Demchok J. A., Demeulemeester J., Demidov G. M., Demircioglu D., Dennis N. M., Denroche R. E., Dentro S. C., Desai N., Deshwar A. G., Desmedt C., Deu-Pons J., Dhalla N., Dhani N. C., Dhingra P., Dhir R., DiBiase A., Diamanti K., Ding L., Ding S., Dinh H. Q., Dirix L., Doddapaneni H. V., Donmez N., Dow M. T., Drapkin R., Drechsel O., Drews R. M., Serge S., Dudderidge T., Dueso-Barroso A., Dunford A. J., Dunn M., Dursi L. J., Duthie F. R., Dutton-Regester K., Eagles J., Easton D. F., Edmonds S., Edwards P. A., Edwards S. E., Eeles R. A., Ehinger A., Eils J., Eils R., El-Naggar A., Eldridge M., Ellrott K., Erkek S., Escaramis G., Espiritu S. M. G., Estivill X., Etemadmoghadam D., Eyfjord J. E., Fan D., Fan Y., Farcas C., Fassan M., Fatima A., Favero F., Fayzullaev N., Felau I., Fereday S., Ferguson M. L., Ferretti V., Feuerbach L., Field M. A., Fink J. L., Finocchiaro G., Fisher C., Fittall M. W., Fitzgerald A., Fitzgerald R. C., Flanagan A. M., Fleshner N. E., Flicek P., Foekens J. A., Fong K. M., Fonseca N. A., Foster C. S., Fox N. S., Fraser M., Frazer S., Frenkel-Morgenstern M., Friedman W., Frigola J., Fronick C. C., Fujimoto A., Fujita M., Fukayama M., Fulton L. A., Fulton R. S., Furuta M., Futreal P. A., Fullgrabe A., Gabriel S. B., Gallinger S., Gambacorti Passerini C., Gao J., Gao S., Garred O., Garrison E., Garsed D. W., Gehlenborg N., Gelpi J. L. L., George J., Gerhard D. S., Gerhauser C., Gershenwald J. E., Gerstein M., Gerstung M., Ghori M., Ghossein R., Giama N. H., Gibbs R. A., Gill A. J., Gill P., Giri D. D., Glodzik D., Gnanapragasam V. J., Goebler M. E., Goldman M. J., Gomez C., Gonzalez S., Gonzalez-Perez A., Gordenin D. A., Gossage J., Gotoh K., Govindan R., Grabau D., Graham J. S., Grant R. C., Green A. R., Green E., Greger L., Grehan N., Grimaldi S., Grossman R. L., Grundhoff A., Gundem G., Guo Q., Gupta M., Gupta S., Gut I. G., Gut M., Goke J., Ha G., Haake A., Haan D., Haas S., Haase K., Haber J. E., Habermann N., Hach F., Hama N., Hamdy F. C., Hamilton A., Hamilton M. P., Han L., Hanna G. B., Hansmann M., Haradhvala N. J., Harismendy O., Harliwong I., Harmanci A. O., Harrington E., Hasegawa T., Haussler D., Hawkins S., Hayami S., Hayashi S., Hayes D. N., Hayes S. J., Hayward N. 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H., Jang S. J., Jayaseelan J. C., Jayasinghe R., Jefferys S. R., Jegalian K., Jennings J. L., Jeon S. -H., Jerman L., Ji Y., Johansson P. A., Johns A. L., Johns J., Johnson R., Johnson T. A., Jolly C., Joly Y., Jonasson J. G., Jones C. D., Jones D. R., Jones D. T. W., Jones N., Jones S. J. M., Jonkers J., Ju Y. S., Juhl H., Jung J., Juul M., Juul R. I., Juul S., Jager N., Kabbe R., Kahles A., Kahraman A., Kakavand H., Kalimuthu S., von Kalle C., Kang K. J., Karaszi K., Karlan B., Karsch D., Kasaian K., Kassahn K. S., Katai H., Katoh H., Kawakami Y., Kay J. D., Kazakoff S. H., Kazanov M. D., Keays M., Kebebew E., Kefford R. F., Kellis M., Kench J. G., Kennedy C. J., Kerssemakers J. N. A., Khoo D., Khoo V., Khuntikeo N., Khurana E., Kilpinen H., Kim H. K., Kim H. -L., Kim H. -Y., Kim H., Kim J., Kim J. K., Kim Y., King T. A., Klapper W., Kleinheinz K., Klimczak L. J., Knappskog S., Kneba M., Knoppers B. M., Koh Y., Komorowski J., Komura D., Komura M., Kong G., Kool M., Korbel J. O., Korchina V., Korshunov A., Koscher M., Koster R., Kote-Jarai Z., Koures A., Kovacevic M., Kremeyer B., Kretzmer H., Kreuz M., Krishnamurthy S., Kube D., Kumar K., Kumar P., Kumar S., Kumar Y., Kundra R., Kuppers R., Lagergren J., Lai P. H., Laird P. W., Lakhani S. R., Lalansingh C. M., Lalonde E., Lamaze F. C., Lambert A., Lander E., Landgraf P., Landoni L., Langerod A., Lanzos A., Larsimont D., Larsson E., Lathrop M., Lau L. M. S., Lawerenz C., Lawlor R. T., Lawrence M. S., Le X., Lee D., Lee E. A., Lee H. J., Lee J. J. -K., Lee J. -Y., Lee J., Lee M. T. M., Lee-Six H., Lehmann K. -V., Lehrach H., Lenze D., Leonard C. R., Leongamornlert D. A., Leshchiner I., Letourneau L., Letunic I., Levine D. A., Lewis L., Ley T., Li C., Li H. I., Li J., Li L., Li S., Li X., Li Y., Liang H., Liang S. -B., Lichter P., Lin P., Lin Z., Linehan W. M., Lingjaerde O. C., Liu D., Liu E. M., Liu F. -F., Liu F., Liu J., Liu X., Livingstone J., Livitz D., Livni N., Lochovsky L., Loeffler M., Long G. V., Lopez-Guillermo A., Lou S., Lovat L. B., Lu Y., Lu Y. -J., Luchini C., Lungu I., Luo X., Luxton H. J., Lynch A. G., Lype L., Lopez C., Lopez-Otin C., Ma E. Z., Ma Y., MacGrogan G., MacRae S., Macintyre G., Madsen T., Maejima K., Mafficini A., Maglinte D. T., Maitra A., Majumder P. P., Malcovati L., Malikic S., Malleo G., Mann G. J., Mantovani-Loffler L., Marchal K., Marchegiani G., Mardis E. R., Margolin A. A., Marin M. G., Markowetz F., Markowski J., Marks J., Marques-Bonet T., Marra M. A., Marsden L., Martens J. W. M., Martin-Subero J. I., Martincorena I., Martinez-Fundichely A., Maruvka Y. E., Mashl R. J., Massie C. E., Matthew T. J., Matthews L., Mayer E., Mayes S., Mayo M., Mbabaali F., McCune K., McDermott U., McGillivray P. D., McLellan M. D., McPherson J. D., McPherson J. R., McPherson T. A., Meier S. R., Meng A., Meng S., Menzies A., Merrett N. D., Merson S., Meyerson M., Meyerson W., Mieczkowski P. A., Mihaiescu G. L., Mijalkovic S., Mijalkovic-Lazic A. M., Mikkelsen T., Milella M., Mileshkin L., Miller C. A., Miller D. K., Miller J. K., Mills G. B., Milovanovic A., Minner S., Miotto M., Arnau G. M., Mirabello L., Mitchell C., Mitchell T. J., Miyano S., Miyoshi N., Mizuno S., Molnar-Gabor F., Moore M. J., Moore R. A., Morganella S., Morris Q. D., Morrison C., Mose L. E., Moser C. D., Muinos F., Mularoni L., Mungall A. J., Mungall K., Musgrove E. A., Mustonen V., Mutch D., Muyas F., Muzny D. M., Munoz A., Myers J., Myklebost O., Moller P., Nagae G., Nagrial A. M., Nakagama H., Nakagawa H., Nakamura H., Nakamura T., Nakano K., Nandi T., Nangalia J., Nastic M., Navarro A., Navarro F. C. P., Neal D. E., Nettekoven G., Newell F., Newhouse S. J., Newton Y., Ng A. W. T., Ng A., Nicholson J., Nicol D., Nie Y., Nielsen M. M., Noble M. S., Nones K., Northcott P. A., Notta F., O'Connor B. D., O'Donnell P., O'Donovan M., O'Meara S., O'Neill B. P., O'Neill J. R., Ocana D., Ochoa A., Oesper L., Ogden C., Ohdan H., Ohi K., Ohno-Machado L., Oien K. A., Ojesina A. I., Ojima H., Okusaka T., Ong C. K., Ossowski S., Ott G., Ouellette B. F. F., Paczkowska M., Paiella S., Pairojkul C., Pajic M., Pan-Hammarstrom Q., Papaemmanuil E., Papatheodorou I., Paramasivam N., Park J. W., Park J. -W., Park K., Park P. J., Parker J. S., Parsons S. L., Pass H., Pasternack D., Pastore A., Patch A. -M., Pauporte I., Pea A., Pearson J. V., Pedamallu C. S., Pedersen J. S., Pederzoli P., Peifer M., Pennell N. A., Perou C. M., Petersen G. M., Peto M., Petrelli N., Petryszak R., Pfister S. M., Phillips M., Pich O., Pickett H. A., Pihl T. D., Pillay N., Pinder S., Pinese M., Pinho A. V., Pitkanen E., Pivot X., Pineiro-Yanez E., Planko L., Plass C., Pons T., Popescu I., Potapova O., Prasad A., Preston S. R., Prinz M., Pritchard A. L., Provenzano E., Puente X. S., Puig S., Puiggros M., Pulido-Tamayo S., Pupo G. M., Purdie C. A., Quinn M. C., Rabionet R., Rader J. S., Radlwimmer B., Radovic P., Raeder B., Raine K. M., Ramakrishna M., Ramakrishnan K., Ramalingam S., Raphael B. J., Rathmell W. K., Rausch T., Reifenberger G., Reimand J., Reis-Filho J., Reuter V., Reyes-Salazar I., Reyna M. A., Reynolds S. M., Riazalhosseini Y., Richardson A. L., Richter J., Ringel M., Ringner M., Rino Y., Rippe K., Roach J., Roberts L. R., Roberts N. D., Roberts S. A., Robertson A. G., Robertson A. J., Rodriguez J. B., Rodriguez-Martin B., Rodriguez-Gonzalez F. G., Roehrl M. H. A., Rohde M., Rokutan H., Romieu G., Rooman I., Roques T., Rosebrock D., Rosenberg M., Rosenstiel P. C., Rosenwald A., Rowe E. W., Royo R., Rozen S. G., Rubanova Y., Rubio-Perez C., Rudneva V. A., Rusev B. C., Ruzzenente A., Ratsch G., Sabarinathan R., Sabelnykova V. Y., Sadeghi S., Sahinalp S. C., Saini N., Saito-Adachi M., Saksena G., Salcedo A., Salgado R., Salichos L., Sallari R., Saller C., Salvia R., Sam M., Samra J. S., Sanchez-Vega F., Sander C., Sanders G., Sarin R., Sarrafi I., Sasaki-Oku A., Sauer T., Sauter G., Saw R. P. M., Scardoni M., Scarlett C. J., Scarpa A., Scelo G., Schadendorf D., Schein J. E., Schilhabel M. B., Schlesner M., Schlomm T., Schmidt H. K., Schramm S. -J., Schreiber S., Schultz N., Schumacher S. E., Schwarz R. F., Scolyer R. A., Scott D., Scully R., Seethala R., Segre A. V., Selander I., Senbabaoglu Y., Sengupta S., Sereni E., Serra S., Shackleton M., Shah N. C., Shahabi S., Shang C. A., Shang P., Shapira O., Shelton T., Shen C., Shen H., Shepherd R., Shi R., Shi Y., Shiah Y. -J., Shih J., Shimizu E., Shimizu K., Shin S. J., Shiraishi Y., Shmaya T., Shmulevich I., Shorser S. I., Short C., Shrestha R., Shringarpure S. S., Shriver C., Shuai S., Sidiropoulos N., Sieuwerts A. M., Sieverling L., Signoretti S., Sikora K. O., Simbolo M., Simon R., Simons J. V., Simpson J. T., Simpson P. T., Singer S., Sinnott-Armstrong N., Sipahimalani P., Skelly T. J., Smid M., Smith-McCune K., Socci N. D., Sofia H. J., Soloway M. G., Song L., Sood A. K., Sothi S., Sotiriou C., Soulette C. M., Span P. N., Spellman P. T., Sperandio N., Spillane A. J., Spiro O., Spring J., Staaf J., Stadler P. F., Staib P., Stark S. G., Stebbings L., Stefansson O. A., Stegle O., Stenhouse A., Stewart C., Stilgenbauer S., Stratton M. R., Stretch J. R., Struck A. J., Stuart J. M., Stunnenberg H. G., Su H., Su X., Sungalee S., Susak H., Suzuki A., Sweep F., Szczepanowski M., Sultmann H., Yugawa T., Tam A., Tamborero D., Tan B. K. T., Tan D., Tan P., Tanaka H., Taniguchi H., Tanskanen T. J., Tarabichi M., Tarnuzzer R., Tarpey P., Taschuk M. L., Tatsuno K., Tavare S., Taylor D. F., Taylor-Weiner A., Teague J. W., Teh B. T., Tembe V., Temes J., Thayer S. P., Thiessen N., Thomas G., Thomas S., Thompson A., Thompson A. M., Thompson J. F., Thompson R. H., Thorne H., Thorne L. B., Thorogood A., Tiao G., Tijanic N., Timms L. E., Tirabosco R., Tojo M., Tommasi S., Toon C. W., Toprak U. H., Torrents D., Tortora G., Tost J., Totoki Y., Townend D., Traficante N., Treilleux I., Trotta J. -R., Trumper L. H. P., Tsao M., Tsunoda T., Tubio J. M. C., Tucker O., Turkington R., Turner D. J., Tutt A., Ueno M., Ueno N. T., Umbricht C., Umer H. M., Underwood T. J., Urban L., Urushidate T., Ushiku T., Uuskula-Reimand L., Valencia A., Van Den Berg D. J., Van Laere S., Van Loo P., Van Meir E. G., Van den Eynden G. G., Van der Kwast T., Vasudev N., Vazquez M., Vedururu R., Veluvolu U., Vembu S., Verbeke L. P. C., Vermeulen P., Verrill C., Viari A., Vicente D., Vicentini C., Raghavan K. V., Viksna J., Vilain R. E., Villasante I., Vincent-Salomon A., Visakorpi T., Voet D., Vyas P., Vazquez-Garcia I., Waddell N. M., Waddell N., Wadelius C., Wadi L., Wagener R., Wala J. A., Wang J., Wang L., Wang Q., Wang W., Wang Y., Wang Z., Waring P. M., Warnatz H. -J., Warrell J., Warren A. Y., Waszak S. M., Wedge D. C., Weichenhan D., Weinberger P., Weinstein J. N., Weischenfeldt J., Weisenberger D. J., Welch I., Wendl M. C., Werner J., Whalley J. P., Wheeler D. A., Whitaker H. C., Wigle D., Wilkerson M. D., Williams A., Wilmott J. S., Wilson G. W., Wilson J. M., Wilson R. K., Winterhoff B., Wintersinger J. A., Wiznerowicz M., Wolf S., Wong B. H., Wong T., Wong W., Woo Y., Wood S., Wouters B. G., Wright A. J., Wright M. H., Wu D. -Y., Wu G., Wu J., Wu K., Wu Y., Wu Z., Xi L., Xia T., Xiang Q., Xiao X., Xing R., Xiong H., Xu Q., Xu Y., Xue H., Yachida S., Yakneen S., Yamaguchi R., Yamaguchi T. N., Yamamoto M., Yamamoto S., Yamaue H., Yang F., Yang H., Yang J. Y., Yang L., Yang S., Yang T. -P., Yang Y., Yao X., Yaspo M. -L., Yates L., Yau C., Ye C., Ye K., Yellapantula V. D., Yoon C. J., Yoon S. -S., Yu J., Yu K., Yu W., Yu Y., Yuan Y., Yuen D., Yung C. K., Zaikova O., Zamora J., Zapatka M., Zenklusen J. C., Zenz T., Zeps N., Zhang C. -Z., Zhang F., Zhang H., Zhang X., Zhang Y., Zhang Z., Zhao Z., Zheng L., Zheng X., Zhou W., Zhou Y., Zhu B., Zhu H., Zhu J., Zhu S., Zou L., Zou X., deFazio A., van As N., van Deurzen C. H. M., van de Vijver M. J., Veer L., von Mering C., Lauri Antti Aaltonen / Principal Investigator, Genome-Scale Biology (GSB) Research Program, Department of Medical and Clinical Genetics, Organismal and Evolutionary Biology Research Programme, Helsinki Institute for Information Technology, Institute of Biotechnology, Bioinformatics, Department of Computer Science, Faculty of Medicine, HUS Helsinki and Uusimaa Hospital District, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Cellular Medicine Division, University of St Andrews. Statistics, University of St Andrews. School of Medicine, Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Li, C, Prokopec, S, Sun, R, Yousif, F, Schmitz, N, Al-Shahrour, F, Atwal, G, Bailey, P, Biankin, A, Boutros, P, Campbell, P, Chang, D, Cooke, S, Deshpande, V, Faltas, B, Faquin, W, Garraway, L, Getz, G, Grimmond, S, Haider, S, Hoadley, K, Jiao, W, Kaiser, V, Karlic, R, Kato, M, Kubler, K, Lazar, A, Louis, D, Margolin, A, Martin, S, Nahal-Bose, H, Nielsen, G, Nik-Zainal, S, Omberg, L, P'Ng, C, Perry, M, Polak, P, Rheinbay, E, Rubin, M, Semple, C, Sgroi, D, Shibata, T, Siebert, R, Smith, J, Stein, L, Stobbe, M, Thai, K, Wright, D, Wu, C, Yuan, K, Zhang, J, Aaltonen, L, Abascal, F, Abeshouse, A, Aburatani, H, Adams, D, Agrawal, N, Ahn, K, Ahn, S, Aikata, H, Akbani, R, Akdemir, K, Al-Ahmadie, H, Al-Sedairy, S, Alawi, M, Albert, M, Aldape, K, Alexandrov, L, Ally, A, Alsop, K, Alvarez, E, Amary, F, Amin, S, Aminou, B, Ammerpohl, O, Anderson, M, Ang, Y, Antonello, D, Anur, P, Aparicio, S, Appelbaum, E, Arai, Y, Aretz, A, Arihiro, K, Ariizumi, S, Armenia, J, Arnould, L, Asa, S, Assenov, Y, Aukema, S, Auman, J, Aure, M, Awadalla, P, Aymerich, M, Bader, G, Baez-Ortega, A, Bailey, M, Balasundaram, M, Balu, S, Bandopadhayay, P, Banks, R, Barbi, S, Barbour, A, Barenboim, J, Barnholtz-Sloan, J, Barr, H, Barrera, E, Bartlett, J, Bartolome, J, Bassi, C, Bathe, O, Baumhoer, D, Bavi, P, Baylin, S, Bazant, W, Beardsmore, D, Beck, T, Behjati, S, Behren, A, Niu, B, Bell, C, Beltran, S, Benz, C, Berchuck, A, Bergmann, A, Bergstrom, E, Berman, B, Berney, D, Bernhart, S, Beroukhim, R, Berrios, M, Bersani, S, Bertl, J, Betancourt, M, Bhandari, V, Bhosle, S, Bieg, M, Bigner, D, Binder, H, Birney, E, Birrer, M, Biswas, N, Bjerkehagen, B, Bodenheimer, T, Boice, L, Bonizzato, G, De Bono, J, Boot, A, Bootwalla, M, Borg, A, Borkhardt, A, Boroevich, K, Borozan, I, Borst, C, Bosenberg, M, Bosio, M, Boultwood, J, Bourque, G, Bova, G, Bowen, D, Bowlby, R, Bowtell, D, Boyault, S, Boyce, R, Boyd, J, Brazma, A, Brennan, P, Brewer, D, Brinkman, A, Bristow, R, Broaddus, R, Brock, J, Brock, M, Broeks, A, Brooks, A, Brooks, D, Brors, B, Brunak, S, Bruxner, T, Bruzos, A, Buchanan, A, Buchhalter, I, Buchholz, C, Bullman, S, Burke, H, Burkhardt, B, Burns, K, Busanovich, J, Bustamante, C, Butler, A, Butte, A, Byrne, N, Borresen-Dale, A, Caesar-Johnson, S, Cafferkey, A, Cahill, D, Calabrese, C, Caldas, C, Calvo, F, Camacho, N, Campo, E, Cantu, C, Cao, S, Carey, T, Carlevaro-Fita, J, Carlsen, R, Cataldo, I, Cazzola, M, Cebon, J, Cerfolio, R, Chadwick, D, Chakravarty, D, Chalmers, D, Chan, C, Chan, K, Chan-Seng-Yue, M, Chandan, V, Chanock, S, Chantrill, L, Chateigner, A, Chatterjee, N, Chayama, K, Chen, H, Chen, J, Chen, K, Chen, Y, Chen, Z, Cherniack, A, Chien, J, Chiew, Y, Chin, S, Cho, J, Cho, S, Choi, J, Choi, W, Chomienne, C, Chong, Z, Choo, S, Chou, A, Christ, A, Christie, E, Chuah, E, Cibulskis, C, Cibulskis, K, Cingarlini, S, Clapham, P, Claviez, A, Cleary, S, 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Estivill, X, Etemadmoghadam, D, Eyfjord, J, Fan, D, Fan, Y, Farcas, C, Fassan, M, Fatima, A, Favero, F, Fayzullaev, N, Felau, I, Fereday, S, Ferguson, M, Ferretti, V, Feuerbach, L, Field, M, Fink, J, Finocchiaro, G, Fisher, C, Fittall, M, Fitzgerald, A, Fitzgerald, R, Flanagan, A, Fleshner, N, Flicek, P, Foekens, J, Fong, K, Fonseca, N, Foster, C, Fox, N, Fraser, M, Frazer, S, Frenkel-Morgenstern, M, Friedman, W, Frigola, J, Fronick, C, Fujimoto, A, Fujita, M, Fukayama, M, Fulton, L, Fulton, R, Furuta, M, Futreal, P, Fullgrabe, A, Gabriel, S, Gallinger, S, Gambacorti Passerini, C, Gao, J, Gao, S, Garred, O, Garrison, E, Garsed, D, Gehlenborg, N, Gelpi, J, George, J, Gerhard, D, Gerhauser, C, Gershenwald, J, Gerstein, M, Gerstung, M, Ghori, M, Ghossein, R, Giama, N, Gibbs, R, Gill, A, Gill, P, Giri, D, Glodzik, D, Gnanapragasam, V, Goebler, M, Goldman, M, Gomez, C, Gonzalez, S, Gonzalez-Perez, A, Gordenin, D, Gossage, J, Gotoh, K, Govindan, R, Grabau, D, Graham, J, Grant, R, Green, A, Green, E, Greger, L, Grehan, N, Grimaldi, S, Grossman, R, Grundhoff, A, Gundem, G, Guo, Q, Gupta, M, Gupta, S, Gut, I, Gut, M, Goke, J, Ha, G, Haake, A, Haan, D, Haas, S, Haase, K, Haber, J, Habermann, N, Hach, F, Hama, N, Hamdy, F, Hamilton, A, Hamilton, M, Han, L, Hanna, G, Hansmann, M, Haradhvala, N, Harismendy, O, Harliwong, I, Harmanci, A, Harrington, E, Hasegawa, T, Haussler, D, Hawkins, S, Hayami, S, Hayashi, S, Hayes, D, Hayes, S, Hayward, N, Hazell, S, He, Y, Heath, A, Heath, S, Hedley, D, Hegde, A, Heiman, D, Heinold, M, Heins, Z, Heisler, L, Hellstrom-Lindberg, E, Helmy, M, Heo, S, Hepperla, A, Heredia-Genestar, J, Herrmann, C, Hersey, P, Hess, J, Hilmarsdottir, H, Hinton, J, Hirano, S, Hiraoka, N, Hobolth, A, Hodzic, E, Hoell, J, Hoffmann, S, Hofmann, O, Holbrook, A, Holik, A, Hollingsworth, M, Holmes, O, Holt, R, Hong, C, Hong, E, Hong, J, Hooijer, G, Hornshoj, H, Hosoda, F, Hou, Y, Hovestadt, V, Howat, W, Hoyle, A, Hruban, R, Hu, J, Hu, T, Hua, X, Huang, K, Huang, M, Huang, V, Huang, Y, Huber, W, Hudson, T, Hummel, M, Hung, J, Huntsman, D, Hupp, T, Huse, J, Huska, M, Hutter, B, Hutter, C, Hubschmann, D, Iacobuzio-Donahue, C, Imbusch, C, Imielinski, M, Imoto, S, Isaacs, W, Isaev, K, Ishikawa, S, Iskar, M, Islam, S, Ittmann, M, Ivkovic, S, Izarzugaza, J, Jacquemier, J, Jakrot, V, Jamieson, N, Jang, G, Jang, S, Jayaseelan, J, Jayasinghe, R, Jefferys, S, Jegalian, K, Jennings, J, Jeon, S, Jerman, L, Ji, Y, Johansson, P, Johns, A, Johns, J, Johnson, R, Johnson, T, Jolly, C, Joly, Y, Jonasson, J, Jones, C, Jones, D, Jones, N, Jones, S, Jonkers, J, Ju, Y, Juhl, H, Jung, J, Juul, M, Juul, R, Juul, S, Jager, N, Kabbe, R, Kahles, A, Kahraman, A, Kakavand, H, Kalimuthu, S, von Kalle, C, Kang, K, Karaszi, K, Karlan, B, Karsch, D, Kasaian, K, Kassahn, K, Katai, H, Katoh, H, Kawakami, Y, Kay, J, Kazakoff, S, Kazanov, M, Keays, M, Kebebew, E, Kefford, R, Kellis, M, Kench, J, Kennedy, C, Kerssemakers, J, Khoo, D, Khoo, V, Khuntikeo, N, Khurana, E, Kilpinen, H, Kim, H, Kim, J, Kim, Y, King, T, Klapper, W, Kleinheinz, K, Klimczak, L, Knappskog, S, Kneba, M, Knoppers, B, Koh, Y, Komorowski, J, Komura, D, Komura, M, Kong, G, Kool, M, Korbel, J, Korchina, V, Korshunov, A, Koscher, M, Koster, R, Kote-Jarai, Z, Koures, A, Kovacevic, M, Kremeyer, B, Kretzmer, H, Kreuz, M, Krishnamurthy, S, Kube, D, Kumar, K, Kumar, P, Kumar, S, Kumar, Y, Kundra, R, Kuppers, R, Lagergren, J, Lai, P, Laird, P, Lakhani, S, Lalansingh, C, Lalonde, E, Lamaze, F, Lambert, A, Lander, E, Landgraf, P, Landoni, L, Langerod, A, Lanzos, A, Larsimont, D, Larsson, E, Lathrop, M, Lau, L, Lawerenz, C, Lawlor, R, Lawrence, M, Le, X, Lee, D, Lee, E, Lee, H, Lee, J, Lee, M, Lee-Six, H, Lehmann, K, Lehrach, H, Lenze, D, Leonard, C, Leongamornlert, D, Leshchiner, I, Letourneau, L, Letunic, I, Levine, D, Lewis, L, Ley, T, Li, H, Li, J, Li, L, Li, S, Li, X, Li, Y, Liang, H, Liang, S, Lichter, P, Lin, P, Lin, Z, Linehan, W, Lingjaerde, O, Liu, D, Liu, E, Liu, F, Liu, J, Liu, X, Livingstone, J, Livitz, D, Livni, N, Lochovsky, L, Loeffler, M, Long, G, Lopez-Guillermo, A, Lou, S, Lovat, L, Lu, Y, Luchini, C, Lungu, I, Luo, X, Luxton, H, Lynch, A, Lype, L, Lopez, C, Lopez-Otin, C, Ma, E, Ma, Y, Macgrogan, G, Macrae, S, Macintyre, G, Madsen, T, Maejima, K, Mafficini, A, Maglinte, D, Maitra, A, Majumder, P, Malcovati, L, Malikic, S, Malleo, G, Mann, G, Mantovani-Loffler, L, Marchal, K, Marchegiani, G, Mardis, E, Marin, M, Markowetz, F, Markowski, J, Marks, J, Marques-Bonet, T, Marra, M, Marsden, L, Martens, J, Martin-Subero, J, Martincorena, I, Martinez-Fundichely, A, Maruvka, Y, Mashl, R, Massie, C, Matthew, T, Matthews, L, Mayer, E, Mayes, S, Mayo, M, Mbabaali, F, Mccune, K, Mcdermott, U, Mcgillivray, P, Mclellan, M, Mcpherson, J, Mcpherson, T, Meier, S, Meng, A, Meng, S, Menzies, A, Merrett, N, Merson, S, Meyerson, M, Meyerson, W, Mieczkowski, P, Mihaiescu, G, Mijalkovic, S, Mijalkovic-Lazic, A, Mikkelsen, T, Milella, M, Mileshkin, L, Miller, C, Miller, D, Miller, J, Mills, G, Milovanovic, A, Minner, S, Miotto, M, Arnau, G, Mirabello, L, Mitchell, C, Mitchell, T, Miyano, S, Miyoshi, N, Mizuno, S, Molnar-Gabor, F, Moore, M, Moore, R, Morganella, S, Morris, Q, Morrison, C, Mose, L, Moser, C, Muinos, F, Mularoni, L, Mungall, A, Mungall, K, Musgrove, E, Mustonen, V, Mutch, D, Muyas, F, Muzny, D, Munoz, A, Myers, J, Myklebost, O, Moller, P, Nagae, G, Nagrial, A, Nakagama, H, Nakagawa, H, Nakamura, H, Nakamura, T, Nakano, K, Nandi, T, Nangalia, J, Nastic, M, Navarro, A, Navarro, F, Neal, D, Nettekoven, G, Newell, F, Newhouse, S, Newton, Y, Ng, A, Nicholson, J, Nicol, D, Nie, Y, Nielsen, M, Noble, M, Nones, K, Northcott, P, Notta, F, O'Connor, B, O'Donnell, P, O'Donovan, M, O'Meara, S, O'Neill, B, O'Neill, J, Ocana, D, Ochoa, A, Oesper, L, Ogden, C, Ohdan, H, Ohi, K, Ohno-Machado, L, Oien, K, Ojesina, A, Ojima, H, Okusaka, T, Ong, C, Ossowski, S, Ott, G, Ouellette, B, Paczkowska, M, Paiella, S, Pairojkul, C, Pajic, M, Pan-Hammarstrom, Q, Papaemmanuil, E, Papatheodorou, I, Paramasivam, N, Park, J, Park, K, Park, P, Parker, J, Parsons, S, Pass, H, Pasternack, D, Pastore, A, Patch, A, Pauporte, I, Pea, A, Pearson, J, Pedamallu, C, Pedersen, J, Pederzoli, P, Peifer, M, Pennell, N, Perou, C, Petersen, G, Peto, M, Petrelli, N, Petryszak, R, Pfister, S, Phillips, M, Pich, O, Pickett, H, Pihl, T, Pillay, N, Pinder, S, Pinese, M, Pinho, A, Pitkanen, E, Pivot, X, Pineiro-Yanez, E, Planko, L, Plass, C, Pons, T, Popescu, I, Potapova, O, Prasad, A, Preston, S, Prinz, M, Pritchard, A, Provenzano, E, Puente, X, Puig, S, Puiggros, M, Pulido-Tamayo, S, Pupo, G, Purdie, C, Quinn, M, Rabionet, R, Rader, J, Radlwimmer, B, Radovic, P, Raeder, B, Raine, K, Ramakrishna, M, Ramakrishnan, K, Ramalingam, S, Raphael, B, Rathmell, W, Rausch, T, Reifenberger, G, Reimand, J, Reis-Filho, J, Reuter, V, Reyes-Salazar, I, Reyna, M, Reynolds, S, Riazalhosseini, Y, Richardson, A, Richter, J, Ringel, M, Ringner, M, Rino, Y, Rippe, K, Roach, J, Roberts, L, Roberts, N, Roberts, S, Robertson, A, Rodriguez, J, Rodriguez-Martin, B, Rodriguez-Gonzalez, F, Roehrl, M, Rohde, M, Rokutan, H, Romieu, G, Rooman, I, Roques, T, Rosebrock, D, Rosenberg, M, Rosenstiel, P, Rosenwald, A, Rowe, E, Royo, R, Rozen, S, Rubanova, Y, Rubio-Perez, C, Rudneva, V, Rusev, B, Ruzzenente, A, Ratsch, G, Sabarinathan, R, Sabelnykova, V, Sadeghi, S, Sahinalp, S, Saini, N, Saito-Adachi, M, Saksena, G, Salcedo, A, Salgado, R, Salichos, L, Sallari, R, Saller, C, Salvia, R, Sam, M, Samra, J, Sanchez-Vega, F, Sander, C, Sanders, G, Sarin, R, Sarrafi, I, Sasaki-Oku, A, Sauer, T, Sauter, G, Saw, R, Scardoni, M, Scarlett, C, Scarpa, A, Scelo, G, Schadendorf, D, Schein, J, Schilhabel, M, Schlesner, M, Schlomm, T, Schmidt, H, Schramm, S, Schreiber, S, Schultz, N, Schumacher, S, Schwarz, R, Scolyer, R, Scott, D, Scully, R, Seethala, R, Segre, A, Selander, I, Senbabaoglu, Y, Sengupta, S, Sereni, E, Serra, S, Shackleton, M, Shah, N, Shahabi, S, Shang, C, Shang, P, Shapira, O, Shelton, T, Shen, C, Shen, H, Shepherd, R, Shi, R, Shi, Y, Shiah, Y, Shih, J, Shimizu, E, Shimizu, K, Shin, S, Shiraishi, Y, Shmaya, T, Shmulevich, I, Shorser, S, Short, C, Shrestha, R, Shringarpure, S, Shriver, C, Shuai, S, Sidiropoulos, N, Sieuwerts, A, Sieverling, L, Signoretti, S, Sikora, K, Simbolo, M, Simon, R, Simons, J, Simpson, J, Simpson, P, Singer, S, Sinnott-Armstrong, N, Sipahimalani, P, Skelly, T, Smid, M, Smith-McCune, K, Socci, N, Sofia, H, Soloway, M, Song, L, Sood, A, Sothi, S, Sotiriou, C, Soulette, C, Span, P, Spellman, P, Sperandio, N, Spillane, A, Spiro, O, Spring, J, Staaf, J, Stadler, P, Staib, P, Stark, S, Stebbings, L, Stefansson, O, Stegle, O, Stenhouse, A, Stewart, C, Stilgenbauer, S, Stratton, M, Stretch, J, Struck, A, Stuart, J, Stunnenberg, H, Su, H, Su, X, Sungalee, S, Susak, H, Suzuki, A, Sweep, F, Szczepanowski, M, Sultmann, H, Yugawa, T, Tam, A, Tamborero, D, Tan, B, Tan, D, Tan, P, Tanaka, H, Taniguchi, H, Tanskanen, T, Tarabichi, M, Tarnuzzer, R, Tarpey, P, Taschuk, M, Tatsuno, K, Tavare, S, Taylor, D, Taylor-Weiner, A, Teague, J, Teh, B, Tembe, V, Temes, J, Thayer, S, Thiessen, N, Thomas, G, Thomas, S, Thompson, A, Thompson, J, Thompson, R, Thorne, H, Thorne, L, Thorogood, A, Tiao, G, Tijanic, N, Timms, L, Tirabosco, R, Tojo, M, Tommasi, S, Toon, C, Toprak, U, Torrents, D, Tortora, G, Tost, J, Totoki, Y, Townend, D, Traficante, N, Treilleux, I, Trotta, J, Trumper, L, Tsao, M, Tsunoda, T, Tubio, J, Tucker, O, Turkington, R, Turner, D, Tutt, A, Ueno, M, Ueno, N, Umbricht, C, Umer, H, Underwood, T, Urban, L, Urushidate, T, Ushiku, T, Uuskula-Reimand, L, Valencia, A, Van Den Berg, D, Van Laere, S, Van Loo, P, Van Meir, E, Van den Eynden, G, Van der Kwast, T, Vasudev, N, Vazquez, M, Vedururu, R, Veluvolu, U, Vembu, S, Verbeke, L, Vermeulen, P, Verrill, C, Viari, A, Vicente, D, Vicentini, C, Raghavan, K, Viksna, J, Vilain, R, Villasante, I, Vincent-Salomon, A, Visakorpi, T, Voet, D, Vyas, P, Vazquez-Garcia, I, Waddell, N, Wadelius, C, Wadi, L, Wagener, R, Wala, J, Wang, J, Wang, L, Wang, Q, Wang, W, Wang, Y, Wang, Z, Waring, P, Warnatz, H, Warrell, J, Warren, A, Waszak, S, Wedge, D, Weichenhan, D, Weinberger, P, Weinstein, J, Weischenfeldt, J, Weisenberger, D, Welch, I, Wendl, M, Werner, J, Whalley, J, Wheeler, D, Whitaker, H, Wigle, D, Wilkerson, M, Williams, A, Wilmott, J, Wilson, G, Wilson, J, Wilson, R, Winterhoff, B, Wintersinger, J, Wiznerowicz, M, Wolf, S, Wong, B, Wong, T, Wong, W, Woo, Y, Wood, S, Wouters, B, Wright, A, Wright, M, Wu, D, Wu, G, Wu, J, Wu, K, Wu, Y, Wu, Z, Xi, L, Xia, T, Xiang, Q, Xiao, X, Xing, R, Xiong, H, Xu, Q, Xu, Y, Xue, H, Yachida, S, Yakneen, S, Yamaguchi, R, Yamaguchi, T, Yamamoto, M, Yamamoto, S, Yamaue, H, Yang, F, Yang, H, Yang, J, Yang, L, Yang, S, Yang, T, Yang, Y, Yao, X, Yaspo, M, Yates, L, Yau, C, Ye, C, Ye, K, Yellapantula, V, Yoon, C, Yoon, S, Yu, J, Yu, K, Yu, W, Yu, Y, Yuan, Y, Yuen, D, Yung, C, Zaikova, O, Zamora, J, Zapatka, M, Zenklusen, J, Zenz, T, Zeps, N, Zhang, C, Zhang, F, Zhang, H, Zhang, X, Zhang, Y, Zhang, Z, Zhao, Z, Zheng, L, Zheng, X, Zhou, W, Zhou, Y, Zhu, B, Zhu, H, Zhu, J, Zhu, S, Zou, L, Zou, X, Defazio, A, van As, N, van Deurzen, C, van de Vijver, M, Veer, L, von Mering, C, Natural Sciences and Engineering Research Council of Canada, Canadian Institutes of Health Research, Genome Canada, Canada Foundation for Innovation, National Institutes of Health (US), National Cancer Institute (US), Pathology, CCA - Cancer biology and immunology, Graduate School, Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Li, Constance H. [0000-0002-5487-7225], Prokopec, Stephenie D. [0000-0001-7936-8577], Boutros, Paul C. [0000-0003-0553-7520], Apollo - University of Cambridge Repository, Tampere University, BioMediTech, TAYS Cancer Centre, Basic (bio-) Medical Sciences, Li, Constance H [0000-0002-5487-7225], Prokopec, Stephenie D [0000-0001-7936-8577], Boutros, Paul C [0000-0003-0553-7520], and Medical Oncology
Subjects: sex differences, Male, Colorectal cancer, Kynferði, 02 engineering and technology, 0302 clinical medicine, DISPARITIES, Epidemiology of cancer, Cancer genomics, lcsh:Science, Càncer, Cancer genetics, Genome informatics, Cancer genomics, Oncogenes, Cancer genetics, Exome, Cancer, 0303 health sciences, Mutation, Neoplasms -- genetics, 1184 Genetics, developmental biology, physiology, Neoplasms/genetics, 3. Good health, 030220 oncology & carcinogenesis, Medical genetics, 0210 nano-technology, Human, Sex characteristics, medicine.medical_specialty, Science, Genomic Instability, General Biochemistry, Genetics and Molecular Biology, RC0254, Càncer -- Epidemiologia, Open Reading Frames, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Chromosomal Instability, Sex differences, Genetics, Humans, beta Catenin -- genetics, Sex organ, SIGNATURES, 45, RC0254 Neoplasms. Tumors. Oncology (including Cancer), Oncogenes, medicine.disease, 692/4028/67/69, Cancérologie, Genòmica, Logistic Models, 030104 developmental biology, lcsh:Q, PCAWG Tumour Subtypes and Clinical Translation, Human genome, 119, 0301 basic medicine, Medizin, General Physics and Astronomy, medicine.disease_cause, Bioinformatics, Genome informatics, Genome, Neoplasms, 38/23, Medicine and Health Sciences, Body Size, beta Catenin, Sex Characteristics, 318 Medical biotechnology, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, article, 3rd-DAS, 021001 nanoscience & nanotechnology, humanities, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Causality, oncology, 1181 Ecology, evolutionary biology, SURVIVAL, 631/114/2785, Female, Càncer -- Tractament, Oncogenes -- genetics, beta Catenin/genetics, 3122 Cancers, 610 Medicine & health, QH426 Genetics, Biology, Cancer epidemiology, Rare Diseases, 631/67/68, Krabbameinsrannsóknir, medicine, ddc:610, Gene, QH426, 030304 developmental biology, Krabbamein, Oncogenes/genetics, Genome, Human, Sex organs, Human Genome, PCAWG Consortium, General Chemistry, GENE, Good Health and Well Being, Estudis de gènere, oncogenic mutational processes, 692/4028/67/395, Diferències entre sexes, Gender studies, 3111 Biomedicine
Abstract: Publisher's version (útgefin grein), Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research., We thank all the members of the Boutros lab for insightful discussions. This study was conducted with the support of the Ontario Institute for Cancer Research to P.C.B. through funding provided by the Government of Ontario. This work was supported by the Discovery Frontiers: Advancing Big Data Science in Genomics Research program, which is jointly funded by the Natural Sciences and Engineering Research Council (NSERC) of Canada, the Canadian Institutes of Health Research (CIHR), Genome Canada and the Canada Foundation for Innovation (CFI). P.C.B. was supported by a Terry Fox Research Institute New Investigator Award and a CIHR New Investigator Award. This work was supported by an NSERC Discovery grant and by Canadian Institutes of Health Research, grant #SVB-145586, to P.C.B. This work was supported by the NIH/NCI under award number P30CA016042 and an operating grant from the National Cancer Institute Early Detection Research Network (1U01CA214194-01). We acknowledge the contributions of the many clinical networks across ICGC and TCGA who provided samples and data to the PCAWG Consortium, and the contributions of the Technical Working Group and the Germline Working Group of the PCAWG Consortium for collation, realignment and harmonised variant calling of the cancer genomes used in this study. We thank the patients and their families for their participation in the individual ICGC and TCGA projects.
Published: 2020
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37. Primary vitreoretinal lymphoma: short review of the literature, results of a European survey and French guidelines of the LOC network for diagnosis, treatment and follow-up

Author: Anne Vincent-Salomon, Denis Malaise, Nathalie Cassoux, Khê Hoang-Xuan, Sylvain Choquet, Carole Soussain, Karim Maloum, Loïc Feuvret, Frederic Davi, Caroline Houillier, Valérie Touitou, Magali Le Garff-Tavernier, Laboratoire d'Imagerie Translationnelle en Oncologie (LITO ), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Curie - Saint Cloud (ICSC), Immunité et cancer (U932), and Malaise, Denis
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Cancer Research, medicine.medical_specialty, Lymphoma, Retinal Neoplasms, MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, primary vitreoretinal lymphoma, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, guidelines, Intensive care medicine, Lenalidomide, diagnosis and management challenges, Temozolomide, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, treatment, business.industry, European mapping, Optimal treatment, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, Vitreous Body, Oncology, Diagnosis treatment, Rituximab, Neoplasm Recurrence, Local, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug, Vitreoretinal lymphoma, Follow-Up Studies
Abstract: International audience; Purpose of review. The aim of this study was to highlight the diagnostic and management challenges of primary vitreoretinal lymphoma (PVRL) through a review of the literature and a European survey on real-life practices for PVRL.Recent findings. The care of PVRL patients is heterogeneous between specialists and countries. Upfront systemic treatment based on highdose methotrexate chemotherapy, with or without local treatment, might reduce or delay the risk of brain relapse. Ibrutinib, lenalidomide with or without rituximab, and temozolomide are effective for patients with relapsed/refractory PVRL and should be tested as first-line treatments.Summary. The prognosis of PVRL remains dismal. No firm conclusion regarding optimal treatment can yet be drawn. The risk of brain relapse remains high. Diagnostic procedures and assessment of therapeutic responses need to be homogenized. Collaboration between specialists involved in PVRL and multicentric prospective therapeutic studies are strongly needed. The recommendations of the French group for primary oculocerebral lymphoma (LOC network) are provided, as a basis for further European collaborative work.
Published: 2021
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38. HRAS is a therapeutic target in malignant chemo-resistant adenomyoepithelioma of the breast

Author: Cécile Reyes, David Gentien, Francesco Ricci, André Nicolas, Sophie Vacher, Elisabetta Marangoni, Florence Coussy, Fabien Reyal, Sophie Château-Joubert, Rania El-Botty, Caterina Marchiò, Anne Vincent-Salomon, Ahmed Dahmani, Elodie Montaudon, Ivan Bièche, and Marick Laé
Subjects: Cancer Research, medicine.medical_specialty, Pyridones, medicine.medical_treatment, Antineoplastic Agents, Breast Neoplasms, Pyrimidinones, Proto-Oncogene Proteins p21(ras), Breast cancer, Internal medicine, Oximes, medicine, Humans, Point Mutation, Diseases of the blood and blood-forming organs, HRAS, Breast, Molecular Biology, Letter to the Editor, Protein Kinase Inhibitors, RC254-282, PDX, Aged, Trametinib, Aged, 80 and over, Chemotherapy, MEK inhibitor, Hematology, Adenomyoepithelioma, business.industry, Imidazoles, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Dabrafenib, Middle Aged, medicine.disease, Oncology, Drug Resistance, Neoplasm, Cancer research, Female, RC633-647.5, business, medicine.drug
Abstract: Malignant adenomyoepithelioma (AME) of the breast is an exceptionally rare form of breast cancer, with a significant metastatic potential. Chemotherapy has been used in the management of advanced AME patients, however the majority of treatments are not effective. Recent studies report recurrent mutations in the HRAS Q61 hotspot in small series of AMEs, but there are no preclinical or clinical data showing H-Ras protein as a potential therapeutic target in malignant AMEs. We performed targeted sequencing of tumours’ samples from new series of 13 AMEs, including 9 benign and 4 malignant forms. Samples from the breast tumour and the matched axillary metastasis of one malignant HRAS mutated AME were engrafted and two patient-derived xenografts (PDX) were established that reproduced the typical AME morphology. The metastasis-derived PDX was treated in vivo by different chemotherapies and a combination of MEK and BRAF inhibitors (trametinib and dabrafenib). All malignant AMEs presented a recurrent mutation in the HRAS G13R or G12S hotspot. Mutation of PIK3CA were found in both benign and malignant AMEs, while AKT1 mutations were restricted to benign AMEs. Treatment of the PDX by the MEK inhibitor trametinib, resulted in a marked anti-tumor activity, in contrast to the BRAF inhibitor and the different chemotherapies that were ineffective. Overall, these findings further expand on the genetic features of AMEs and suggest that patients carrying advanced HRAS-mutated AMEs could potentially be treated with MEK inhibitors.
Published: 2021

39. Tumor BRCA testing can reveal a high tumor mutational burden related to POLE pathogenic variants

Author: Lisa Golmard, O. Trabelsi Grati, Elodie Girard, Guillaume Bataillon, Ivan Bièche, Julien Masliah-Planchon, Dominique Stoppa-Lyonnet, Samia Melaabi, Chrystelle Colas, J. Le Gall, Marie-Charlotte Villy, and Anne Vincent-Salomon
Subjects: Large tumor, business.industry, medicine.medical_treatment, Obstetrics and Gynecology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunotherapy, Brca testing, Gynecology and obstetrics, Oncogenetics, Oncology, POLE, medicine, Cancer research, RG1-991, Routine clinical practice, Tumor BRCA testing, business, RC254-282
Abstract: Objective Tumors harboring a POLE pathogenic variant, associated with high tumor mutational burden, are good candidates for immunotherapy. However, POLE pathogenic variants are not currently screened in routine clinical practice. Can these tumors be identified by means of an already available test? Methods We describe seven tumors harboring a POLE pathogenic variant, among eight patients with tumors harboring multiple BRCA1/2 variants (from 4 to 20). All patients were managed at Institut Curie, Paris. Five patients were selected because of unexpected tumor BRCA testing results with multiple variants and another three patients were selected because of a POLE pathogenic variant detected by large tumor testing. We looked for other tumor variants by Next-Generation Sequencing in tumors harboring multiple BRCA1/2 variants, and for multiple BRCA1/2 variants in tumors harboring a POLE pathogenic variant. Results Four of the five tumors selected because of multiple BRCA1/2 variants exhibited a POLE pathogenic variant, and all three tumors selected for POLE pathogenic variants exhibited multiple BRCA1/2 variants. Conclusions Tumor BRCA testing could be a way to detect tumors harboring a highly mutagenic POLE pathogenic variant.
Published: 2021

40. Lobular Breast Cancer: Histomorphology and Different Concepts of a Special Spectrum of Tumors

Author: Lounes Djerroudi, Matthias Christgen, Patrick W. B. Derksen, Anne Vincent-Salomon, Hans Kreipe, Gábor Cserni, Caterina Marchiò, and Giuseppe Floris
Subjects: 0301 basic medicine, Cancer Research, Pathology, medicine.medical_specialty, CARCINOMA-IN-SITU, Review, Patient care, MAMMARY-GLAND DEVELOPMENT, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, E-CADHERIN EXPRESSION, HER2, INDEPENDENT PROGNOSTIC-FACTOR, medicine, COMPREHENSIVE MOLECULAR PORTRAITS, skin and connective tissue diseases, pleomorphic, RC254-282, SURGICAL ADJUVANT BREAST, LCIS, Tumor microenvironment, RING CELL-CARCINOMA, Science & Technology, Histological type, Tumor-infiltrating lymphocytes, Tumor biology, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, beta-catenin, EXTRACELLULAR MUCIN, p120-catenin, medicine.disease, LIN, body regions, 030104 developmental biology, Oncology, INVASIVE DUCTAL CARCINOMAS, solid, tubulolobular, Beta-catenin, P120-catenin, Pleomorphic, Solid, Tubulolobular, 030220 oncology & carcinogenesis, Treatment strategy, NEEDLE CORE BIOPSY, Differential diagnosis, business, Life Sciences & Biomedicine
Abstract: Simple Summary Invasive lobular breast cancer (ILC) is a special type of breast cancer (BC) that was first described in 1941. The diagnosis of ILC is made by microscopy of tumor specimens, which reveals a distinct morphology. This review recapitulates the developments in the microscopic assessment of ILC from 1941 until today. We discuss different concepts of ILC, provide an overview on ILC variants, and highlight advances which have contributed to a better understanding of ILC as a special histologic spectrum of tumors. Abstract Invasive lobular breast cancer (ILC) is the most common special histological type of breast cancer (BC). This review recapitulates developments in the histomorphologic assessment of ILC from its beginnings with the seminal work of Foote and Stewart, which was published in 1941, until today. We discuss different concepts of ILC and their implications. These concepts include (i) BC arising from mammary lobules, (ii) BC growing in dissociated cells and single files, and (iii) BC defined as a morpho-molecular spectrum of tumors with distinct histological and molecular characteristics related to impaired cell adhesion. This review also provides a comprehensive overview of ILC variants, their histomorphology, and differential diagnosis. Furthermore, this review highlights recent advances which have contributed to a better understanding of the histomorphology of ILC, such as the role of the basal lamina component laminin, the molecular specificities of triple-negative ILC, and E-cadherin to P-cadherin expression switching as the molecular determinant of tubular elements in CDH1-deficient ILC. Last but not least, we provide a detailed account of the tumor microenvironment in ILC, including tumor infiltrating lymphocyte (TIL) levels, which are comparatively low in ILC compared to other BCs, but correlate with clinical outcome. The distinct histomorphology of ILC clearly reflects a special tumor biology. In the clinic, special treatment strategies have been established for triple-negative, HER2-positive, and ER-positive BC. Treatment specialization for patients diagnosed with ILC is just in its beginnings. Accordingly, ILC deserves greater attention as a special tumor entity in BC diagnostics, patient care, and cancer research.
Published: 2021

41. Abstract P1-02-09: Results of a worldwide survey on the currently used histopathological diagnostic criteria for invasive lobular breast cancer (ILC)

Author: Maxim De Schepper, Anne Vincent-Salomon, Matthias Christgen, Karen Van Baelen, Hitoshi Tsuda, Sasagu Kurozumi, Maria Jose Brito, Gabor Cserni, Stuart Schnitt, Denis Larsimont, Janina Kulka, Pedro Luis Fernandez, Paula Rodriguez, Ana Aula, Cristina Mendelez, Mieke Van Bockstal, Aniko Kovacs, Zsuzsanna Varga, Jelle Wesseling, Rohit Bhargava, Pia Boström, Camille Franchet, Blessing Zambuko, Gustavo Matute, Anca Berghian, Paul van Diest, Steffi Oesterreich, Patrick WB Derksen, Giuseppe Floris, and Christine Desmedt
Subjects: Cancer Research, Oncology
Abstract: Background. ILC represents the second most common histological type of breast cancer (BC), accounting for approximately 15% of all invasive BCs. Loss of cell-cell adhesion due to genomic alterations of CDH1,. the gene coding for E-cadherin, is the hallmark of ILC. So far, in the WHO guidelines, it is essential to recognize the dispersed or linear discohesive cells but it is not mandatory to demonstrate E-cadherin loss by immunohistochemistry (IHC) for diagnosing ILC. Recent central pathology revisions of clinical trials have demonstrated overdiagnosis of ILC in local pathological diagnosis, as only ~60% of the locally diagnosed ILCs were confirmed by central pathology. To understand the possible underlying reasons, we undertook a worldwide survey on the currently used histopathological diagnostic criteria for ILC. Materials and Methods. A survey was drafted using the online tool SurveyMonkey by a panel of pathologists and researchers from the European Lobular Breast Cancer Consortium (ELBCC). This survey was circulated to pathologists from December 14, 2020 until July, 1 2021. The main goals were to register the use of E-cadherin as a diagnostic marker for ILC and the systematic reporting of the ILC subtypes. Results. A total of 149 entries were recorded from 34 different countries from 6 continents. Pathologists declared working in a large tertiary (30%, 44/149) or university hospital (56%, 84/149), with an average yearly volume of BC samples >300 in 111/149 (74%) and >500 in 80/149 (54%) respondents. 117/149 (79%) are specialized in breast pathology. About half of the pathologists systematically perform IHC for ILC diagnosis (52%, 77/149), whilst others only perform staining in case of doubt (43%, 64/149) or for differentiating DCIS from LCIS (3%, 4/149). There was no association between the systematic use of IHC, the volume of BC samples, the type of institution (academic, large tertiary, private), and the number of pathologists in the institution. Concerning the use of IHC, 141/145(97%) participants use E-cadherin, 35/145 (24%) use β-catenin and 49/145 (34%) use p120-catenin. The majority (50%, 73/145) uses only E-cadherin, 13% (19/145) use E-cadherin in combination with β-catenin or 23% (33/145) use E-cadherin with p120-catenin, while 11% (16/145) use all 3 antibodies. For E-cadherin, 11 different clones were reported, of which the NCH-38 is the most frequently used (45%, 39/86), followed by Clone 36 (17%, 15/86) and EP700Y (16%, 14/86). Heterogeneity is reported regarding the used concentration per clone. The most frequently used modality of antigen retrieval is the heat induced one. Similar findings were observed for β-catenin and p120-catenin with each 4 different clones reported, again with variable concentrations. Only 4/104 (4%) respondents reported to perform DNA sequencing for CDH1 for diagnosing ILC. Most special lobular types are systematically reported by the vast majority of the pathologists: classic (149/149, 100%), pleomorphic (140/149, 94%), solid (108/149, 72%), histiocytoid/apocrine (90/149, 60%), alveolar (90/149, 60%), trabecular (54/149, 36%), mixed non-classic (54/149, 36%) and mucinous (51/149, 34%). Conclusions. We report the results of the first worldwide survey concerning diagnosis of ILC in pathological practice. The results demonstrate that ~half of the institutions systematically perform E-cadherin IHC to support the diagnosis of ILC. There is a great variability in E-cadherin antibody clones used as well as their concentrations, which might result in differences in staining results and their interpretation. As ILC-specific therapeutic avenues are currently being explored, some of which already in the context of clinical trials, it is of utmost importance to further improve the standardization of ILC diagnosis at the pathology level. Citation Format: Maxim De Schepper, Anne Vincent-Salomon, Matthias Christgen, Karen Van Baelen, Hitoshi Tsuda, Sasagu Kurozumi, Maria Jose Brito, Gabor Cserni, Stuart Schnitt, Denis Larsimont, Janina Kulka, Pedro Luis Fernandez, Paula Rodriguez, Ana Aula, Cristina Mendelez, Mieke Van Bockstal, Aniko Kovacs, Zsuzsanna Varga, Jelle Wesseling, Rohit Bhargava, Pia Boström, Camille Franchet, Blessing Zambuko, Gustavo Matute, Anca Berghian, Paul van Diest, Steffi Oesterreich, Patrick WB Derksen, Giuseppe Floris, Christine Desmedt. Results of a worldwide survey on the currently used histopathological diagnostic criteria for invasive lobular breast cancer (ILC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-02-09.
Published: 2022
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42. Decentralization of Next-Generation RNA Sequencing-Based MammaPrint® and BluePrint® Kit at University Hospitals Leuven and Curie Institute Paris

Author: Hans Wildiers, Cécile Reyes, Sileny Han, Lorenza Mittempergher, Timothé Cynober, F Reyal, Leonie J. M. J. Delahaye, Kevin Punie, Liesbet Vliegen, Ines Nevelsteen, Enora Laas Faron, Laurence Slembrouck, Petra Sintubin, Sara Vander Borght, G Hoste, Patrick Neven, Giuseppe Floris, Audrey Rapinat, Ann Smeets, Sylvain Baulande, Lynn Jongen, Mylène Bohec, Virginie Raynal, David Gentien, Céline Helsmoortel, Mireille Snel, Els Van Nieuwenhuysen, Lauren Darrigues, Isabelle Vanden Bempt, Anke T. Witteveen, Sari Neijenhuis, Cecile Laurent, Annuska M. Glas, and Anne Vincent Salomon
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Original article, Microarray, Concordance, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, MammaPrint, Internal medicine, medicine, medicine.diagnostic_test, business.industry, medicine.disease, University hospital, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Subtyping, 030104 developmental biology, 030220 oncology & carcinogenesis, Gene chip analysis, Risk classification, business
Abstract: A previously developed and centrally validated MammaPrint® (MP) and BluePrint® (BP) targeted RNA next-generation sequencing (NGS) kit was implemented and validated in two large academic European hospitals. Additionally, breast cancer molecular subtypes by MP and BP RNA sequencing were compared with immunohistochemistry (IHC). Patients with early breast cancer diagnosed at University Hospitals Leuven and Curie Institute Paris were prospectively included between September 2017 and January 2018. Formalin-fixed paraffin-embedded tissue sections were analyzed with MP and BP NGS technology at the beta sites and with both NGS and microarray technology at Agendia. Raw NGS data generated on Illumina MiSeq instruments at the beta sites were interpreted and compared with NGS and microarray data at Agendia. MP and BP NGS molecular subtypes were compared to surrogate IHC breast cancer subtypes. Equivalence of MP and BP indices was determined by Pearson's correlation coefficient. Acceptable limits were defined a priori, based on microarray data generated at Agendia between 2012 and 2016. The concordance, the Negative Percent Agreement and the Positive Percent Agreement were calculated based on the contingency tables and had to be equal to or higher than 90%. Out of 124 included samples, 48% were MP Low and 52% High Risk with microarray. Molecular subtypes were BP luminal, HER2 or basal in 82%, 8% and 10% respectively. Concordance between MP microarray at Agendia and MP NGS at the beta sites was 91.1%. Concordance of MP High and Low Risk classification between NGS at the beta sites and NGS at Agendia was 93.9%. Concordance of MP and BP molecular subtyping using NGS at the beta sites and microarray at Agendia was 89.5%. Concordance between MP and BP NGS subtyping, and IHC was 71.8% and 76.6%, for two IHC surrogate models. The MP/BP NGS kit was successfully validated in a decentralized setting. ispartof: Translational Oncology vol:12 issue:12 pages:1557-1565 ispartof: location:United States status: Published online
Published: 2019

43. Clinical Validity of HPV Circulating Tumor DNA in Advanced Anal Carcinoma: An Ancillary Study to the Epitopes-HPV02 Trial

Author: Ivan Bièche, Romain Cohen, Stefano Kim, Aurélia Meurisse, Alice Bernard-Tessier, Charlotte Proudhon, Marine Jary, Marc Michel, Nabil Baba-Hamed, Jean-Yves Pierga, Emmanuelle Samalin, Christophe Borg, Eric Francois, Alice Debernardi, Anne Vincent-Salomon, Emmanuelle Jeannot, Farid El Hajbi, François-Clément Bidard, Véronique Vendrely, Bruno Buecher, and David Guenat
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Anal Carcinoma, medicine.medical_treatment, Article, Epitope, Circulating Tumor DNA, Epitopes, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Medicine, Prospective Studies, Prospective cohort study, Papillomaviridae, Cisplatin, Chemotherapy, business.industry, Papillomavirus Infections, Area under the curve, Anal canal, 030104 developmental biology, medicine.anatomical_structure, Docetaxel, 030220 oncology & carcinogenesis, business, medicine.drug
Abstract: Purpose: Human papillomavirus (HPV) is found in 90% of squamous cell carcinomas of the anal canal (SCCA). We investigated the clinical validity of HPV circulating tumor DNA (ctDNA) detection in patients enrolled in the Epitopes-HPV02 trial that demonstrated the efficacy of docetaxel, cisplatin, and 5-FU as first-line chemotherapy in advanced SCCA. Experimental Design: According to the protocol, serum samples were collected before chemotherapy and on completion of chemotherapy. HPV16 ctDNA was quantified by droplet digital PCR (ddPCR) and correlated with prospectively registered patient characteristics and outcomes. A landmark was set at the time of chemotherapy completion for postchemotherapy progression-free survival (PFS) analyses. Results: Among 57 patients with HPV16-related advanced SCCA, HPV ctDNA was detected in 91.1% (95% confidence interval, 81.1–96.2) of baseline samples. Baseline HPV ctDNA levels were not associated with any patient characteristics; baseline ctDNA level below the cutoff obtained by AUC (area under the curve) was associated with a longer PFS (HR = 2.1; P = 0.04). Among the 36 patients who completed 5 months of chemotherapy, residual HPV ctDNA was detected after chemotherapy in 38.9% of patients. Residual HPV ctDNA detected at chemotherapy completion was associated with shorter postchemotherapy PFS (median PFS 3.4 months vs. not reached; HR = 5.5; P < 0.001) and a reduction of 1-year overall survival rate (OR = 7.0; P = 0.02). Conclusions: This prospective study in advanced SCCA demonstrated a significant prognostic impact of HPV ctDNA level before first-line chemotherapy and HPV ctDNA negativity after chemotherapy completion. With a limited cost and short turnaround, this assay is a promising tool to optimize the therapeutic management of SCCA. See related commentary by Morris, p. 2030
Published: 2019
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44. Abstract P1-09-07: Breast cancer characteristics and outcomes in patients with TP53 germline mutation

Author: F-C Bidard, Dominique Stoppa-Lyonnet, Luc Cabel, M Tran, Chrystelle Colas, A De Pauw, L Bozec, Florence Lerebours, Marion Lavigne, Delphine Loirat, A Vincent-Salomon, Valérie Laurence, and Marion Gauthier-Villars
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Breast cancer, Germline mutation, business.industry, Internal medicine, Medicine, In patient, business, medicine.disease
Abstract: Introduction Li-Fraumeni syndrome (LFS) resulting from monoallelic germline TP53 gene mutation is a rare hereditary cancer predisposition. Breast cancer (BC) is the most common cancer among women with TP53 germline mutation with a risk ranging from 49% to 85% by the age of 60 years old. Most of these cancers are early onset. Few patients' cases have been reported so far in the literature. Our aim was to describe the medical history of a cohort of LFS women diagnosed with BC recruited from a single institution. The characteristics combined were genetic alteration diagnosis, tumor characteristics, treatment, outcome, and LFS associated cancers. Methods We retrospectively identified breast cancer patients with TP53 germline mutation from the Institut Curie (Paris, France) database and described their cancer characteristics and medical history. Results From 1989 to 2015, 25 patients affected with BC (31 tumors) and TP53 germline mutation carrier were identified, with a median follow up of 6.5 years. Median age at BC diagnosis was 30.5 years. All patients were women. 33% had a previously identified TP53 mutation in their family. 70% of them had BC as their first cancer event. 60% of the patients presented with another LFS associated cancer or non-related cancers: osteosarcoma (22%), glioblastoma (18%), pulmonary carcinoma (13%), gastric linitis plastica (9%), malignant hemopathy (9%), soft tissue sarcoma (9%), adrenocortical carcinoma (4%), ovarian cystadenocarcinoma (4%), renal tumor (4%), choroid plexus carcinoma (4%). 92% of the breast tumors were ductal carcinoma (28% DCIS and 64% IDC), 7% were sarcoma (1 phyllodesarcoma, 1 pleiomorphic liposarcoma); there were no lobular carcinoma. Among the IDC, 50% were HER2 positive, 72% were hormone-receptor positive. Most patients had a mastectomy (64%), and most of them received radiation (55%). However, when TP53 mutation had been identified prior to the treatment, none of the patients received radiotherapy (5 patients). Most patients received chemotherapy (70%) (37% in neoadjuvant setting, 33% in adjuvant setting, 25% for metastatic setting). 40% of the patients received hormone therapy (37% as adjuvant treatment, 7% for metastatic disease) Most of the patients did not relapse from BC (75%). Overall, only 17% of the patients had metastatic BC. To date, 12 patients of our series have died (48%), 6 patients (24%) from other LFS-associated cancers and 4 patients from BC (16%). Conclusion To the best of our knowledge, this descriptive series is the largest study of tumor characteristics and medical history of LFS-women with BC, the most frequent cancer among women with TP53 germline mutation. It confirms the higher HER2 overexpression rate observed in LFS-patients BC, as suggested in the literature and showed a high rate of DCIS at initial presentation. Most of the patients developed other LFS-associated cancers. In depth molecular analysis of these BC will be performed in order to gain insight into their biological specificities and to adapt the therapeutic management of this poor prognosis syndrome. Citation Format: Tran M, Loirat D, Colas C, Bozec L, Laurence V, Lerebours F, Cabel L, Bidard F-C, Stoppa-Lyonnet D, Vincent-Salomon A, Gauthier-Villars M, Lavigne M, De Pauw A. Breast cancer characteristics and outcomes in patients with TP53 germline mutation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-07.
Published: 2019
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45. Abstract P4-08-23: EndoPredict prognostic signature in pN1mi, estrogen receptor-positive breast cancer: analysis of the French national registry for molecular signatures

Author: A Vincent-Salomon, Gaëtan MacGrogan, P-J Lamy, Véronique Quillien, Laurent Arnould, Magali Lacroix-Triki, Etienne Rouleau, Agnes Garnier, Juliette Haudebourg, Catherine Miquel, Frédérique Penault-Llorca, J Lehmann-Che, P Tas, Céline Callens, P. de Cremoux, and Anne Cayre
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Framingham Risk Score, Tumor size, Prognostic signature, business.industry, Estrogen receptor, Cancer, medicine.disease, Breast cancer, Invasive carcinoma of no special type, Internal medicine, Medicine, National registry, business
Abstract: Background The EndoPredict (EP) test has been developed and validated for assessing recurrence risk in patients with estrogen receptor (ER)-positive HER2-negative breast cancer (BC). This test is based on the expression of 12 genes (molecular score), combined with clinicopathological criteria (i.e. tumor size and nodal status) (EPclin risk score). For node-positive patients, the weight given to the node status in the EPclin score is similar when considering pN1mi (]0.2-2mm]) or pN1 (>2mm, 1-3 positive lymph nodes). Our aim was to characterize the EPclin classification of the pN1mi subgroup in the French national registry for molecular signatures in ER+ BC. Methods Since April 2016, nine French laboratories using EP test in clinical practice prospectively implement a national registry for molecular prognostic signatures in ER+ BC. We analyzed the pN1mi subgroup with regards to their clinico-pathological characteristics, molecular EP score and EPclin risk score. Using the definition formula of the EPclin score [EPclin=0.35t + 0.64n + 0.28EP, with n=1 for pN0, 2 for pN1mi/pN1, 3 for pN2, 4 for pN3], we could calculate a hypothetical EPclin score if the pN1mi had been considered as pN0 [n factor=1]. Results By the end of 2017, the database included 1246 EP tests performed in routine practice, including 67 (5.4%) pN1mi. The pN1mi BC were ER+ HER2- (67/67, 100%), invasive carcinoma of no special type in 52/67 (78%), with a median tumor size of 18 mm (range 7-45; pT1c in 40/67). Among these, 22 were classified as EPclin low and 45 as EPclin high, with a median EP score of 6 (range 2-14), a median EPclin score of 3.70 (range 3-6), and a median relapse risk at 10-year of 15%(range 5-73). Most interestingly, 23/67 (34%; i.e. 1.8% of all EP tests performed) pN1mi BC displayed an EPclin score comprised between 3.4 and 4, just above the cut-off value of 3.3: these cases (and only these cases) would have been classified in a different risk category (i.e. EPclin low risk) if the node status would have been considered as negative. Conclusion With regards to EndoPredict test in pN1mi BC - and the persistent debate as to whether they should bear the same weight as node-positive (pN1) or negative (pN0) tumors - categorization in the EPclin class is not likely to be impacted by the node factor weight in the vast majority (>65%) of the pN1mi cases and >98% of all patients tested with EP. Only cases with an EPclin between 3.4 and 4 might be impacted. Citation Format: LaCroix-Triki M, Arnould L, MacGrogan G, Penault-Llorca F, Haudebourg J, Tas P, Garnier A, Vincent-Salomon A, Miquel C, Lehmann-Che J, Callens C, Quillien V, Cayre A, Lamy P-J, Rouleau E, De Cremoux P. EndoPredict prognostic signature in pN1mi, estrogen receptor-positive breast cancer: analysis of the French national registry for molecular signatures [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-23.
Published: 2019
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46. Abstract P5-12-05: Phenotypic discordance between primary and metastatic breast cancer (MBC) in a large scale real-life multicentre French cohort

Author: Emmanuelle Charafe-Jauffret, E. Brain, S Delaloge, Natacha Joyon, Isabelle Treilleux, Gaëtan MacGrogan, Thomas Filleron, Laurent Arnould, P Tas, Amélie Lusque, C. Courtinard, S. Lefèvre, A Vincent-Salomon, A Maran-Gonzalez, Magali Lacroix-Triki, Juliette Haudebourg, Frédérique Penault-Llorca, Camille Franchet, and Véronique Verriele
Subjects: Oncology, Cancer Research, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Cancer, medicine.disease, Metastatic breast cancer, Primary tumor, Metastasis, Breast cancer, Internal medicine, Biopsy, Cohort, medicine, Clinical endpoint, skin and connective tissue diseases, business
Abstract: Background: Therapeutic options at diagnosis for metastatic breast cancers (MBC) differ largely according to cancer phenotype (namely, hormone receptor (HR) and HER2 status). Reported discordance rates between primary tumor and metastasis vary widely in literature, with a median of 18% for estrogen receptor, 31% for progesterone receptor and 10% for HER2. The present study aimed to compare phenotypic profiles between primary and MBC in the real-life setting. Patients (pts) and methods: Epidemio-Strategy and Medical Economics (ESME)MBC data platform (NCT03275311) is a French national, multicenter, observational cohort using clinical trials' methodology for data capture, monitoring and quality controls. At the time of analysis, it comprised data of 16703 consecutive newly diagnosed MBC pts (1/01/08-31/12/14) treated in 18 French comprehensive cancer centres. The primary endpoint was the discordance rate of HR and HER2 status between primary tumor and MBC (biopsy of metastatic site done within 6 months of MBC diagnosis). Only patients with both histological reports available were considered. Potential factors associated with phenotype discordance were assessed in a multivariate logistic regression. Results: 2933 out of 16703 (17.6%) had a biopsy in the first 6 months of metastatic disease. HR and/or HER2 status was available in 1677 pts. The discordance rate between primary and matched MBC was 14.2% (222/1566) for HR: loss of expression in 72.5%, gain in 27.5%. For HER2, the discordance rate was 7.8% (84/1076): 45.2% of losses and 54.8% of gains of expression. The primary HR+/HER2+ subgroup had the highest rate of changes: 53% (49/92) with either a loss of HR (43%), loss of HER2 (43%) or a loss of both (14%). 18% (33/181) of primary triple-negative breast cancer (TNBC) had a phenotypic change with a majority of HR gain (79%). In multivariate analysis, administration of adjuvant chemotherapy +/- targeted therapy was the sole independent predictor of HR status modification (OR: 1.73, 95%CI 1.27-2.36, p=0.001). The presence of a mixed histology was the only predictor of HER2 discordance (OR =2.57, 95%CI 1.19-5.55, p=0.016). Patient characteristics Total population (n=16703)Pts with primary and MBC phenotype available (n=1677)Age at metastatic diagnosis Median (range)61 (19-99)60 (24-93)De novo MBC4507 (27.1%)221 (13.2%)Number of metastatic sites Median (range)1 (1-9)2 (1-7)MBC sites Brain1200 (7.2%)138 (8.2%)Visceral7755 (46.4%)928 (55.3%)Non-visceral7748 (46.4%)611 (36.4%)Phenotypic profileN = 2933N=1677TNBC356 (18.5%)272 (19.3%)HR+/HER2-1251 (65.0%)917 (65.2%)HR-/HER2+150 (7.8%)105 (7.5%)HR+/HER2+168 (8.7%)112 (8%)Missing1008271Metastatic site samplingN=2933N=1677Bone692 (24.2%)419 (25.5%)Liver514 (18.0%)355 (21.6%)Skin379 (13.3%)203 (12.4%)Node306 (10.7%)169 (10.3%)Lung258 (9.0%)168 (10.2%)Pleura283 (9.9%)121 (7.4%)CNS/CSF*132 (4.6%)42 (2.6%)Other or multiple296 (10.3%)165 (10.0%)Missing7335* CNS= central nervous system, CSF=cerebro-spinal fluid Conclusion: Biopsy and phenotype re-evaluation of MBC early in the disease course has a confirmed potential significant therapeutic impact in this large scale real life setting and should be proposed as often as possible. Citation Format: Lefevre S, Lusque A, Joyon N, Arnould L, Penault-Llorca F, MacGrogan G, Treilleux I, Vincent-Salomon A, Haudebourg J, Maran-Gonzalez A, Charafe-Jauffret E, Courtinard C, Franchet C, Verriele V, Brain E, Tas P, Delaloge S, Filleron T, LaCroix-Triki M. Phenotypic discordance between primary and metastatic breast cancer (MBC) in a large scale real-life multicentre French cohort [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-12-05.
Published: 2019
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47. Abstract P3-07-02: Metaplastic breast carcinomas and uterine carcinosarcomas are histologically and genetically related

Author: Nicola Fusco, A Vincent-Salomon, Anastasios D. Papanastasiou, David R. Brown, Larry Norton, Felipe C Geyer, Caterina Marchiò, Jorge S. Reis-Filho, Edi Brogi, A Da Cruz Paula, Fresia Pareja, Britta Weigelt, HY Wen, and E. Smith
Subjects: Cancer Research, Pathology, medicine.medical_specialty, Somatic cell, Cancer, Histology, Biology, medicine.disease, Breast cancer, Oncology, medicine, biology.protein, Adenocarcinoma, PTEN, Gene, Exome sequencing
Abstract: Introduction: Metaplastic breast carcinomas (MBCs) and uterine carcinosarcomas (UCSs) are histologically similar, being often characterized by an admixture of adenocarcinoma areas with areas displaying sarcomatoid differentiation. We sought to investigate whether their histologic similarities would be paralleled by similar patterns of genetic alterations, and to determine whether the different histologic components of MBCs and UCSs would be clonally related. Methods: Whole exome sequencing (WES) data from 35 MBCs previously analyzed by our group and 57 UCSs from The Cancer Genome Atlas (TCGA) study were reanalyzed. Somatic single nucleotide variants were detected with MuTect and indels with Strelka, Varscan2, Scalpel and Lancet. Copy number alterations were inferred using FACETS and functional annotation of the non-synonymous somatic mutations, amplifications or homozygous deletions was performed. We further microdissected the histologically distinct components of 11 MBCs and six UCSs and subjected each component to WES. Clonal decomposition was performed using PyClone. Results: The most frequent somatic mutations identified in MBCs were TP53 (69%), PIK3CA (29%), FAT3 (26%) and PTEN (14%), whereas the most frequently mutated genes in UCSs were TP53 (84%), FBXW7 (35%), PIK3CA (29%), PTEN (15%) and PPP2R1A (15%). MBCs displayed a significantly higher frequency of mutations targeting FAT3 (26% vs 4%, P Conclusions: Our findings support the contention that UCSs constitute the uterine counterpart of MBCs due to their similar histology and patterns of genetic alterations affecting the same signaling pathways (i.e. TP53, PI3K, Wnt and Notch). In each MBC and UCS analyzed here, the histologically distinct components were found to be clonally related. Citation Format: Da Cruz Paula A, Brown D, Geyer FC, Smith E, Pareja F, Papanastasiou AD, Fusco N, Marchio C, Brogi E, Wen HY, Vincent-Salomon A, Norton L, Weigelt B, Reis-Filho JS. Metaplastic breast carcinomas and uterine carcinosarcomas are histologically and genetically related [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-07-02.
Published: 2019
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48. Abstract P3-06-07: Recurrent but not pathognomonic fusion genes in mucinous carcinomas of the breast

Author: Salvatore Piscuoglio, A Da Cruz Paula, Jorge S. Reis-Filho, Rodrigo Gularte-Mérida, David R. Brown, Britta Weigelt, Caterina Marchiò, Fresia Pareja, A Vincent-Salomon, Edi Brogi, and Felipe C Geyer
Subjects: Cancer Research, Cancer, Estrogen receptor, Biology, medicine.disease, medicine.disease_cause, Receptor tyrosine kinase, Fusion gene, Exon, Oncology, Cancer research, medicine, biology.protein, Mucinous carcinoma, Carcinogenesis, Gene
Abstract: Introduction: Mucinous carcinoma of the breast (MCB) is a rare histologic subtype of estrogen receptor (ER)-positive invasive carcinoma, and is characterized by tumor cells floating in pools of mucin. Despite their characteristic histology, MCBs are heterogeneous at the genetic level and no driver genetic alterations have been identified. Notably, MCBs lack the common genetic alterations found in ER-positive invasive ductal carcinomas (i.e. 16q losses, 1q gains and PIK3CA mutations). Fusion genes have been reported in breast cancer, including highly recurrent or pathognomonic fusions genes, such as the ETV6-NTRK3 and MYB/MYBL1 rearrangements in secretory carcinoma and adenoid cystic carcinoma, respectively. In this study we sought to define whether MCBs would be underpinned by a pathognomonic fusion gene. Materials and methods: Seven pure mucinous A (hypocellular), seven pure mucinous B (hypercellular), and the mucinous component of a mixed MCB were microdissected, and subjected to RNA extraction followed by RNA-sequencing for fusion gene discovery. Read pairs supporting chimeric transcripts were identified using INTEGRATE, FusionCatcher and STARfusion. The Bayesian driver probability of the candidate fusion genes was annotated using OncoFuse. In-frame fusion gene candidates with a high driver probability were validated using orthogonal methods (RT-PCR and Sanger sequencing). Results: Our analysis identified fusion genes in 47% (7/15) of the MCBs analyzed (29% (2/7) of type A MCBs, 57% (4/7) type B MCBs and in the mucinous component of one mixed MCB). The OAZ1-CSNK1G2 and RFC4-LPP fusion genes were identified in 20% (3/15) and 13% (2/15) of the cases, respectively. The OAZ1-CSNK1G2 chimeric transcript results in the truncation of the kinase domain of CSNK1G2, which represses ER transactivation. The RFC4-LPP chimeric transcript leads to the fusion of exons 1-3 of RFC4 and exons 5-11 of LPP, where the LIM domains of LPP are conserved. LPP is a known partner of fusion genes identified in mesenchymal tumors and reported to mediate TGF-β induced breast oncogenesis via its LIM domain. Additional validated, potentially pathogenic fusion genes identified in MCBs involved kinases, phosphatases or regulators of tyrosine kinase receptor signaling, such as IRAK3-PPM1H (n=1), GIGYF2–GFRA3 (n=1) and PHF20-FAM217B (n=1). Conclusions: MCBs harbor fusion genes in almost half of the cases with two fusions being recurrent, involving primarily genes encoding kinases, phosphatases or receptor tyrosine kinase signaling regulators. Nevertheless, due to the lack of recurrence of a specific fusion gene, this special histologic type of breast cancer is unlikely to be underpinned by a highly recurrent/ pathognomonic pathogenic fusion gene. Citation Format: Pareja F, Gularte-Merida R, Da Cruz Paula A, Brown D, Geyer FC, Piscuoglio S, Marchio C, Vincent-Salomon A, Brogi E, Weigelt B, Reis-Filho JS. Recurrent but not pathognomonic fusion genes in mucinous carcinomas of the breast [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-07.
Published: 2019
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49. Abstract P6-17-25: PAM50 and CGH-array genomic characterization of HER2-equivocal breast cancers defined by the ASCO/CAP2013 recommendations and response to treatment

Author: Gaëlle Pierron, David Gentien, A Vincent-Salomon, Marick Laé, J-Y Pierga, P Morel, Edith Borcoman, C. Ngo, F Simaga, Laetitia Fuhrmann, Heather Ann Brauer, Odette Mariani, Emmanuelle Jeannot, and Audrey Rapinat
Subjects: Oncology, Cancer Research, medicine.medical_specialty, medicine.diagnostic_test, business.industry, medicine.medical_treatment, Cancer, medicine.disease, Targeted therapy, Breast cancer, Median follow-up, Trastuzumab, Internal medicine, medicine, Stage (cooking), skin and connective tissue diseases, business, Comparative genomic hybridization, medicine.drug, Fluorescence in situ hybridization
Abstract: Background HER2 breast cancer status determines patients' eligibility for targeted therapy. HER2 level of amplification is associated with a better response to anti-HER2 therapy (Arnould CCR 2007, Singer CCR 2017). Benefit of anti-HER2 therapy for equivocal cases remains debated. Objectives We aimed to better characterize HER2-equivocal breast cancers by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) according to 2013 ASCO/CAP guidelines using PAM50 gene expression-based molecular subtyping. We then investigated genome-wide copy number alterations of HER2-equivocal cases, assessing agreement between genomic alterations of the chromosome (chr) 17 and molecular subtypes. Methods PAM50 (nCounter assay; Nanostring) was performed on RNA from formalin-fixed paraffin-embedded samples of 40 HER2-equivocal cases. These cases were subsequently analyzed by Agilent 60-mer oligonucleotide microarrays for array-based comparative genomic hybridization (aCGH). Results The 40 HER2-equivocal cases were classified as Luminal B in 16 cases (40%), HER2-Enriched in 14 cases (35%), Luminal A in 9 cases (22.5%) and Basal-like in 1 case (2.5%) using PAM50. By IHC, 34 cases (85%) were ER+, 24 (60%) were also PgR+, 26 (65%) were grade III and 33 (82.5%) showed a high Ki67 > 20%. Using aCGH, 10 cases (25%) presented chr 17q large copy number gain, 10 (25%) showed segmental copy number gains including HER2, 9 (22.5%) showed HER2 amplification, one (2.5%) showed a large copy number loss and 10 cases (25%) didn't show any copy number alteration of the chr 17. Out of the 14 PAM50 HER2-Enriched cases, only 5 (35.7%) showed HER2 genomic amplification (Table 1). Four HER2 amplified cases at the genomic level were classified as Luminal B (3 cases, Ki67 > 20%, ER+, PgR- by IHC) or Luminal A (1 case, Ki6710% by IHC) using PAM50, although these luminal B tumors presented strong correlation with the HER2-Enriched centroid. In total, 13 cases (32.5%) were discordant between molecular classification and genomic alteration status of the chr 17. Among patients with early stage HER2-equivocal breast cancers (n=37), 2 received neo-adjuvant chemotherapy (5.4%), 25 received adjuvant chemotherapy (67.6%) and 2 received adjuvant trastuzumab (5.4%). With a median follow up of 5.8 years (3.8-6.9), one controlateral recurrence (2.7%), four metastatic recurrences (10.8%) and three deaths were observed (8.1%). Conclusion Using PAM50, the majority of HER2-equivocal cases were classified as Luminal tumors. At the genomic level, HER2-equivocal cases harbored mostly chr 17 segmental or large copy number gains. These results emphasized the need of HER2 status genomic determination. In line with the new ASCO 2018 recommendations intending to decrease the number of cases considered as HER2 equivocal, we showed that these tumors were mainly HER2 not amplified, ER positive and grade 3. There is no evidence of benefit of anti-HER2 therapy in these cases. Table 1Genomic alterations of chromosome 17Basal-likeHER2-EnrichedLuminal ALuminal BTotalHER2 amplified05139Large copy number gain013610Segmental copy number gain153110No alteration032510Large copy number loss00011Total11491640 Citation Format: Borcoman E, Ngo C, Rapinat A, Simaga F, Mariani O, Fuhrmann L, Jeannot E, Laé M, Pierga J-Y, Gentien D, Pierron G, Morel P, Brauer HA, Vincent-Salomon A. PAM50 and CGH-array genomic characterization of HER2-equivocal breast cancers defined by the ASCO/CAP2013 recommendations and response to treatment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-25.
Published: 2019
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50. Abstract P4-08-25: Decentralized beta testing of MammaPrint and BluePrint NGS kit at University Hospitals Leuven and Curie Institute Paris

Author: Leonie J. M. J. Delahaye, Liesbet Vliegen, P Sintubin, Laurence Slembrouck, E Van Nieuwenhuysen, I. Vanden Bempt, C Helsmoortel, L Darrigues, S Vander Borght, EL Faron, Cécile Reyes, Sileny Han, H. Wildiers, Lynn Jongen, G Hoste, Annuska M. Glas, Patrick Neven, S Neijenhuis, V Raynal, L. Mittempergher, Anne Vincent Salomon, A Smeets, K Punie, Guiseppe Floris, Anke T. Witteveen, Mylène Bohec, Timothé Cynober, F Reyal, Ines Nevelsteen, Audrey Rapinat, and Cécile Laurent
Subjects: Oncology, Cancer Research, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Concordance, Cancer, medicine.disease, Beta testing, University hospital, Subtyping, Breast cancer, MammaPrint, Internal medicine, Invasive lobular carcinoma, medicine, business
Abstract: Background Many countries restrict patient material exchange to central diagnostic laboratories abroad, limiting access to assays like MammaPrint® (MP) and BluePrint® (BP). Both assays are microarray-based, with MP being prognostic for distant recurrence and BP for molecular subtyping of breast cancer (Luminal-, HER2-, and Basal-type). To increase accessibility, decentralization is required with Next Generation Sequencing (NGS) being the preferred testing platform given that most diagnostic laboratories have the technology in place. The aim of this beta testing study is to validate a previously developed and centrally validated MP and BP NGS kit for RNA samples in two large tertiary academic hospitals in Europe. Patients and Methods Patients with early breast cancer diagnosed at the Multidisciplinary Breast Center at University Hospitals Leuven and Curie Institute Paris were prospectively included between September 2017 and January 2018. Patients with bilateral breast cancer or presenting with more than 3 positive lymph nodes were excluded. Only patients with invasive ductal and invasive lobular carcinoma were included. Twenty tissue sections were cut from formalin-fixed, paraffin-embedded (FFPE) blocks; 10 tissue sections were analyzed at the local site using the MP and BP NGS kit, and 10 tissue sections were analyzed at Agendia using the same kit and procedure, as well as with the golden standard method (gene expression microarrays). Targeted RNA sequencing of the 70 MP and 80 BP signature genes was performed on Illumina MiSeq instruments. The raw NGS data generated at the local test sites was sent through a secure file transfer protocol server to Agendia for interpretation and comparison with microarray and NGS performed in the Agendia laboratories. We aimed for a minimum concordance rate between MP and BP outcome of 90% between each local site and Agendia's centralized site. Results In this study, 116 early breast cancer patients were included (73 from University Hospitals Leuven and 43 from Curie Institute). Out of these patients, 52% were MP Low Risk and 48% MP High Risk according to microarray. The patients had a BP luminal, HER2 or basal subtype in respectively 83%, 9% and 8%. Concordance between MP microarray obtained from Agendia and MP NGS obtained from the local sites was 91.4%. Concordance between MP High and Low Risk classification between NGS Leuven versus NGS Agendia was 92.1% and between NGS Curie versus NGS Agendia 95.3%. For BP subtype outcomes, the results from microarray versus NGS for all patients combined from both local sites gave a 98.3% concordance and NGS Agendia versus NGS from each local site gave a 100% concordance. Conclusion The MP and BP NGS kit was successfully validated in a decentralized setting, showing high concordance between results obtained at three different sites. There was a clear benefit of having well-trained NGS experienced diagnostic technical teams. The MP and BP NGS kit the first FFPE targeted RNA sequencing based multigene signature for breast cancer care, will provide a high and equal standard of MP and BP gene expression testing for breast cancer in a decentralized setting. Citation Format: Slembrouck L, Laurent C, Delahaye LJ, Mittempergher L, Vanden Bempt I, Vander Borght S, Darrigues L, Vliegen L, Sintubin P, Raynal V, Bohec M, Reyes C, Rapinat A, Helsmoortel C, Jongen L, Hoste G, Neven P, Wildiers H, Smeets A, Nevelsteen I, Punie K, Van Nieuwenhuysen E, Han S, Salomon AV, Faron EL, Cynober T, Witteveen AT, Neijenhuis S, Glas AM, Reyal F, Floris G. Decentralized beta testing of MammaPrint and BluePrint NGS kit at University Hospitals Leuven and Curie Institute Paris [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-25.
Published: 2019
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