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Background: Translation of predictive and prognostic image-based learning models to clinical applications is challenging due in part to their lack of interpretability. Some deep-learning-based methods provide information about the regions driving the model output. Yet, due to the high-level abstraction of deep features, these methods do not completely solve the interpretation challenge. In addition, low sample size cohorts can lead to instabilities and suboptimal convergence for models involving a large number of parameters such as convolutional neural networks., Purpose: Here, we propose a method for designing radiomic models that combines the interpretability of handcrafted radiomics with a sub-regional analysis., Materials and Methods: Our approach relies on voxel-wise engineered radiomic features with average global aggregation and logistic regression. The method is illustrated using a small dataset of 51 soft tissue sarcoma (STS) patients where the task is to predict the risk of lung metastasis occurrence during the follow-up period., Results: Using positron emission tomography/computed tomography and two magnetic resonance imaging sequences separately to build two radiomic models, we show that our approach produces quantitative maps that highlight the signal that contributes to the decision within the tumor region of interest. In our STS example, the analysis of these maps identified two biological patterns that are consistent with STS grading systems and knowledge: necrosis development and glucose metabolism of the tumor., Conclusions: We demonstrate how that method makes it possible to spatially and quantitatively interpret radiomic models amenable to sub-regions identification and biological interpretation for patient stratification., (© 2022 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Synthetic lethal interactions, where the simultaneous but not individual inactivation of two genes is lethal to the cell, have been successfully exploited to treat cancer. GATA3 is frequently mutated in estrogen receptor (ER)-positive breast cancers and its deficiency defines a subset of patients with poor response to hormonal therapy and poor prognosis. However, GATA3 is not yet targetable. Here we show that GATA3 and MDM2 are synthetically lethal in ER-positive breast cancer. Depletion and pharmacological inhibition of MDM2 significantly impaired tumor growth in GATA3-deficient models in vitro, in vivo and in patient-derived organoids/xenograft (PDOs/PDX) harboring GATA3 somatic mutations. The synthetic lethality requires p53 and acts via the PI3K/Akt/mTOR pathway. Our results present MDM2 as a therapeutic target in the substantial cohort of ER-positive, GATA3-mutant breast cancer patients. With MDM2 inhibitors widely available, our findings can be rapidly translated into clinical trials to evaluate in-patient efficacy., (© 2022. The Author(s).)

Importance: Breast cancer (BC) diagnosis and treatment expose patients to a 5-fold higher risk of depression compared with the general population, with an estimated prevalence of 10% to 25%. A depressive episode in patients with BC has implications for the tolerance of and adherence to treatment, impairing quality of life and reducing life expectancy., Objective: To identify and characterize distinct longitudinal patterns of depressive symptoms in patients with BC from diagnosis to 3 years after treatment., Design, Settings, and Participants: The CANTO-DEePRESS (Deeper in the Understanding and Prevention of Depression in Breast Cancer Patients) cohort study included women in the French multicenter CANTO (CANcer TOxicities) cohort study (conducted between March 20, 2012 and December 11, 2018), who were 18 years or older with invasive stage I to III BC and no previous BC treatment. The study aimed to characterize toxicities over a 5-year period following stage I to III primary BC treatment. Assessments of depressive symptoms were performed on a subset of patients with available data at diagnosis and at least 2 other time points. All data were extracted from the CANTO database on October 1, 2020., Main Outcomes and Measures: The primary outcome was the level of depressive symptoms at each assessment time point measured with the Hospital Anxiety and Depression Scale and depression subscale at BC diagnosis and at 3 to 6, 12, and 36 months after the end of treatment. The group-based trajectory modeling was used to identify trajectory groups, and multinomial logistic regression models were used to characterize the following factors associated with trajectory group affiliation: demographic, socioeconomic, clinical, lifestyle, and quality-of-life data., Results: A total of 4803 women (mean [SD] age, 56.2 [11.2] years; 2441 patients [50.8%] with stage I BC) were included in the study. Six trajectory groups that described the heterogeneity in the expression of depressive symptoms were identified: noncases with no expression of symptoms (n = 2634 [54.8%]), intermediate worsening (1076 [22.4%]), intermediate improvement (480 [10.0%]), remission (261 [5.4%]), delayed occurrence (200 [4.2%]), and stable depression (152 [3.2%]). HADS-D scores at diagnosis were consistently associated with the 5 depressive trajectory group affiliations, with an estimated higher probability per point increase of experiencing subthreshold or clinically significant depressive symptoms between diagnosis and the 3 years after the end of BC treatment. The higher probabilities ranged from 1.49 (95% CI, 1.43-1.54) for the intermediate worsening group to 10.53 (95% CI, 8.84-12.55) for the stable depression group. Trajectory groups with depressive symptoms differed from the noncases group without symptoms by demographic and clinical factors, such as having dependent children, lower household income, cancer stage, family history of BC, previous psychiatric hospitalizations, obesity, smoking status, higher levels of fatigue, and depression at diagnosis., Conclusions and Relevance: In this cohort study, nearly a third of patients with BC experienced temporary or lasting significant depressive symptoms during and after treatment. Improving early identification of women at risk of developing long-term or delayed depression is therefore critical to increase quality of life and overall survival. Subjected to validation, this study is an important first step toward personalized care of patients with BC at risk of depression.

Objective: The objective of our study was to analyze quality of life (QOL) in an e-cohort of patients treated for breast cancer (BC) by endocrine therapy (ET), by means of validated quality of life questionnaires., Study Design and Setting: A retrospective, observational, e-cohort study was conducted (Seintinelles platform). Female patients treated for nonmetastatic and nonrecurrent BC, treated in France after 2005, filled in online questionnaires concerning: QOL (QLQ-C30 and QLQ-BR23), tolerability of treatment and demographic characteristics. A multivariate analysis including variables significant on univariate analysis (P < .05) to select QOL predictors was performed., Results: We included 1,198 patients, 1140 of whom declared that they were taking ET (37.7% tamoxifen, 17.1% aromatase inhibitor (AI), 5.6% LHRH-agonist and 39.6% sequential tamoxifen and AI). Different tolerability profiles were observed when comparing the tamoxifen and AI groups. Treatment adherence was similar in the 2 groups. QOL varied slightly according to the type of ET. On multivariate analysis, ET had no impact on QOL. However, individual patient characteristics (socioeconomic, education and age) were significantly associated with QOL CONCLUSION: Using a real-life study questionnaire on a large e-cohort, individual patient characteristics were strongly associated with deterioration of QOL. The use of e-cohorts must be encouraged to modulate the conclusions of randomized trials., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To evaluate the impact of catch-up human papillomavirus (HPV) vaccination on conization rates in France in a large population-based study., Methods: We conducted a retrospective real-life cohort study on data collected prospectively by French National Health Insurance. Echantillon généralistes des bénéficiaires (EGB) is a database composed of demographic and health care utilization data for a 1/97th sample of the French population. We extracted data about all women born between 1983 and 1991, corresponding to the catch-up population (vaccination after 14 years old) at the time of implementation of HPV vaccination. The primary outcome was the occurrence of conization (all types of procedures) compared between vaccinated and non-vaccinated women., Results: The cohort consisted of 42,452 women. Vaccination coverage (at least one dose) was low (9.8%, n = 4,129), but increased with time from vaccine implementation, from 0% in the 1983 cohort to 31% in the 1991 cohort. The conization rate was 1% for the overall population. The risk of conization for women between the ages of 19 and 30 years was reduced in the vaccinated group with a Hazard Ratio (HR) of 0.59 (95% CI[0.39-0.90]; p = 0.043)., Conclusions: With a 10-year follow-up, catch-up HPV vaccination is associated with risk reduction of conization between the ages of 19 and 30., Competing Interests: The authors have declared that no competing interests exist.

Background: As a result of progress in diagnosis and treatment, there is a growing prevalence of metastatic breast cancer (MBC) with isolated CNS metastases. This study describes the largest-to-date real-life cohort of this clinical setting and compares it to other clinical presentations., Methods: We retrospectively analysed the French Epidemiological Strategy and Medical Economics (ESME) MBC database including patients who initiated treatment for MBC between 2008 and 2016. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Descriptive statistics and multivariate Cox model were used., Results: Of 22,266 patients, 647 (2.9%) and 929 (4.2%) patients had isolated first-site CNS metastases or combined with extra-CNS metastases, with longer OS for the group with isolated CNS metastases (16.9 versus 13.9 months, adjusted HR = 1.69 (95% CI: 1.50-1.91), p  < 0.001). Among the 541 (2.4%) patients with isolated CNS metastases and no intrathecal therapy (excluding leptomeningeal metastases), HER2+ cases were preponderant over TN or HR+ /HER2- cases (41.6% versus 26.1% versus 28.5%, respectively, p  < 0.01). The treatment strategy consisted of a combination of local treatment and systemic therapy (49.2%), local treatment only (35.5%) or systemic therapy only (11.4%), or symptomatic therapy only (3.9%). Median PFS was 6.1 months (95% CI: 5.7-6.8). Median OS was 20.7 months (95% CI: 17.3-24.3), reaching 37.9 months (95% CI: 25.9-47.6) in the HR+ /HER2+ subgroup. Older age, TN subtype, MBC-free interval of 6-12 months, lower performance status, and WBRT were associated with poorer survival. Patients who received systemic therapy within 3 months from MBC diagnosis had longer OS (24.1 versus 16.1 months, p  = 0.031), but this was not significant on multivariate analysis [HR = 1.0 (95% CI: 0.7-1.3), p  = 0.806]., Conclusions: Patients with isolated CNS metastases at MBC diagnosis represent a distinct population for which the role of systemic therapy needs to be further investigated in prospective studies., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JSF reports consulting fees from Novartis, Pfizer, AstraZeneca, Lilly, Roche, Biocad, Daiichi, Tesaro, GSK, Pierre Fabre. TB reports honoraria from Novartis, Roche, Pfizer, AstraZeneca and Seattle Genetics. The other authors report no conflicts of interest., (© The Author(s), 2022.)

BACKGROUNDProstate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intrafocal heterogeneity. We sought to characterize the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors.METHODSFrom the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ETS-related gene (ERG), serine peptidase inhibitor Kazal type 1 (SPINK1), phosphatase and tensin homolog (PTEN), and speckle type BTB/POZ protein (SPOP) molecular status. We utilized dual ERG/SPINK1 immunohistochemistry and fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, as well as high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status.RESULTSBased on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens.CONCLUSIONInterfocal molecular heterogeneity was identified in about 60% of multifocal RP specimens, and collision tumors were present in about 10%. We present this phenomenon as a model for the intrafocal heterogeneity observed in previous studies and propose that future genomic studies screen for collision tumors to better characterize molecular heterogeneity.FUNDINGEarly Detection Research Network US National Cancer Institute (NCI) 5U01 CA111275-09, Center for Translational Pathology at Weill Cornell Medicine (WCM) Department of Pathology and Laboratory Medicine, US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01), R37CA215040, Damon Runyon Cancer Research Foundation, US MetLife Foundation Family Clinical Investigator Award, Norwegian Cancer Society (grant 208197), and South-Eastern Norway Regional Health Authority (grant 2019016 and 2020063).

Background: Cetuximab plus platinum-based therapy (PBT) followed by cetuximab maintenance until progression (EXTREME) is a guideline-recommended first-line treatment option in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). DIRECT (Dose Intensity RElative to CeTuximab) was the first phase 4 observational study evaluating EXTREME administration in the real-world setting., Aims: The primary aim of this study was to assess the relative dose intensity of cetuximab in patients with R/M SCCHN treated with first-line cetuximab according to the EXTREME regimen., Methods and Results: Patients were ≥18 years old and eligible to receive cetuximab/PBT. Primary endpoint was cetuximab relative dose intensity (RDI). Of prospectively enrolled patients (n = 157), 119 received ≥1 cycle of EXTREME. Practices differing from the EXTREME trial were 5-fluorouracil omission (14%), maintenance cetuximab given every other week (54%), prior cetuximab, disease-free interval <6 months. 64% of patients reached cetuximab RDI ≥80%; mean cetuximab RDI was 88%. 46% of patients received maintenance cetuximab (mean RDI, 91%). Median progression-free survival and overall survival were 4.5 and 9.4 months. No new/unexpected safety findings were observed., Conclusions: The DIRECT study showed that first-line cetuximab plus PBT was a feasible, beneficial first-line treatment regimen in patients with R/M SCCHN in the real-world setting., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: Gynecological carcinosarcomas are rare and aggressive diseases, with a poor prognosis. The rarity of these tumors explains the lack of robust and specific data available in the literature. The objective of this study was to investigate the impact of initial adjuvant treatment and recurrent therapeutic strategies., Patients and Methods: A multicentric cohort study within the French national prospective Rare Malignant Gynecological Tumors (TMRG) network was conducted. Data from all included carcinosarcomas diagnosed between 2011 and 2018 were retrospectively collected., Results: 425 cases of uterine and ovarian carcinosarcomas ( n = 313 and n = 112, respectively) were collected and analyzed from 12 participating centers. At diagnosis, 140 patients (48%) had a FIGO stage III-IV uterine carcinosarcoma (UCS) and 88 patients (83%) had an advanced ovarian carcinosarcoma (OCS) (FIGO stage ≥ III). Two hundred sixty-seven patients (63%) received adjuvant chemotherapy, most preferably carboplatin-paclitaxel regimen ( n = 227, 86%). After a median follow-up of 47.4 months, the median progression-free survival (mPFS) was 15.1 months (95% CI 12.3-20.6) and 14.8 months (95% CI 13.1-17.1) for OCS and UCS, respectively. The median overall survival for OCS and UCS was 37.1 months (95% CI 22.2-49.2) and 30.6 months (95% CI 24.1-40.9), respectively. With adjuvant chemotherapy followed by radiotherapy, mPFS was 41.0 months (95% CI 17.0-NR) and 18.9 months (95% CI 14.0-45.6) for UCS stages I-II and stages III-IV, respectively. In the early stage UCS subgroup (i.e., stage IA, n = 86, 30%), mPFS for patients treated with adjuvant chemotherapy ( n = 24) was not reached (95% CI 22.2-NR), while mPFS for untreated patients ( n = 62) was 19.9 months (95% IC 13.9-72.9) (HR 0.44 (0.20-0.95) p = 0.03). At the first relapse, median PFS for all patients was 4.2 months (95% CI 3.5-5.3). In the first relapse, mPFS was 6.7 months (95% CI 5.1-8.5) and 2.2 months (95% CI 1.9-2.9) with a combination of chemotherapy or monotherapy, respectively ( p < 0.001)., Conclusions: Interestingly, this vast prospective cohort of gynecological carcinosarcoma patients from the French national Rare Malignant Gynecological Tumors network (i) highlights the positive impact of adjuvant CT on survival in all localized stages (including FIGO IA uterine carcinosarcomas), (ii) confirms the importance of platinum-based combination as an option for relapse setting, and (iii) reports median PFS for various therapeutic strategies in the relapse setting.

Background: Most cancer-related deaths result from disseminated diseases that develop resistance to anticancer treatments. Inappropriate communication in this challenging situation may result in unmet patient information and support needs. Patient communication aids such as question prompt lists (QPLs) may help., Objective: This study aims to develop and pilot-test a specific QPL in the following two contrasting clinical contexts in France after cancer resistance has developed: triple-negative and luminal B metastatic breast cancer (MBC) and metastatic uveal melanoma (MUM)., Methods: A sequential study design with a mixed methods collaborative approach will be applied. The first step aims to build a specific QPL. Step 1a will explore oncologist-patient communication issues from oncology professionals' interviews (n=20 approximately). Step 1b will appraise information and support needs experienced by patients with MBC or MUM both quantitatively (n=80) and qualitatively (n=40 approximately). These data will be used to develop and pilot-test a QPL specific to patients with cancer experiencing initial or acquired resistance to treatment. We expect to obtain a core QPL that comprises questions and concerns commonly expressed by patients with resistant cancer and is complemented by specific issues for either MBC or MUM cancer sites. In step 1c, 2 focus groups of patients with any type of metastatic cancer (n=4) and health care professionals (n=4) will be conducted to revise the content of a preliminary QPL and elaborate an acceptable and feasible clinical implementation. In step 1d, the content of the QPL version 1 and implementation guidance will be validated using a Delphi process. Step 2 will pilot-test the QPL version 1 in real practice with patients with MBC or MUM (n=80). Clinical utility will be assessed by comparing responses to questionnaires administered in step 1b (QPL-naive historical control group) and step 2 (QPL intervention group)., Results: This study received grants in March and December 2019 and was approved by the French national ethics committee in July 2019. As of October 2021, interviews with oncology professionals have been conducted and analyzed (N=26 to reach saturation), and 39 and 27 patients with MBC and MUM, respectively, have been recruited., Conclusions: A clinically and culturally tailored QPL is expected to facilitate patients' participation in consultations, improve oncologists' responses to patients' information and support needs, and thus foster patients' psychological adjustment to the diagnosis and follow-up of cancer resistance to treatment., Trial Registration: ClinicalTrials.gov NCT04118062; http://clinicaltrials.gov/ct2/show/NCT04118062., International Registered Report Identifier (irrid): DERR1-10.2196/26414., (©Anne Brédart, Aude Rault, Johanna Terrasson, Etienne Seigneur, Leanne De Koning, Elisabeth Hess, Alexia Savignoni, Paul Cottu, Jean-Yves Pierga, Sophie Piperno-Neumann, Manuel Rodrigues, Carole Bouleuc, Sylvie Dolbeault. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 12.01.2022.)

Background: Plasmacytoid urothelial carcinoma (UC) is a rare pathological variant of UC with low chemotherapeutic sensitivity and dismal outcomes. The molecular and immune profiles of such tumors remain poorly investigated., Methods: Herein, we investigated the phenotypical features of a cohort of plasmacytoid UC (n=32) by comparison to a control group of conventional high-grade UC with matched clinicopathological characteristics (n=30). Histopathological analysis included the following antibodies: p63, GATA3, CK5/6, CK20 and HER2. In addition, the density of intra-tumor CD8 + lymphocytes, and PD-L1 expression in tumor (TC) and immune cells (IC) were evaluated., Results: Plasmacytoid UC expressed GATA3 (97% vs 86% P=0.18), CK20 (59% vs 36% P=0.08) markers and showed a significantly higher rate of HER2 overexpression (2+ and 3+ score: 25% vs 0%, P<0.01) compared to controls. A significantly lower expression of CK5/6 (22% vs 56%, P<0.05) and p63 (41% vs 80%, P<0.05) was observed in plasmacytoid UC compared to controls. The density of tumor-infiltrating CD8+ cells was similar between plasmacytoid and conventional UC (P=0.9). PD-L1 expression on IC was similar compared to conventional UC (P=0.3)., Conclusions: Together, our study demonstrated that plasmacytoid UC belong to the luminal subtype and display a rather inflamed microenvironment similar to conventional UC. These data support the inclusion of plasmacytoid variant of UC in clinical trials evaluating immune checkpoint inhibitors monotherapy or combination immunotherapeutic strategies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: A major question when treating HR+/HER2- metastatic breast cancer (MBC) is whether early introduction of chemotherapy (CT) increases endocrine resistance. We aimed to describe progression-free survival (PFS) under first endocrine therapy (ET) depending on whether given before or after CT in a large nationwide cohort, in the pre-CDK era., Methods: The real-life retrospective ESME database includes all patients with MBC whose first-line treatment was initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. Our primary objective was to compare PFS from start of first ET in patients with HR+/HER2- MBC who received ET or CT first., Results: We identified 6293 patients who received at least one ET line during their first two therapeutic lines for MBC. As first-line therapy, 3832 (60.9%) received ET alone (ET1 1st group), whilst 2461 (39.1%) received CT, including 2024 patients (32.2%) with maintenance ET after CT (ET1 after CT group). Median PFS under first ET was 12.4 months (95% CI 11.9-13.1) in ET 1st group vs. 12.6 months in ET1 after CT group (95% CI 12.1-13.4), HR 0.96 (95% CI 0.90-1.01, P = 0.1277)., Conclusions: PFS under first ET appears identical whether prescribed before or after chemotherapy. These data suggest chemotherapy does not promote endocrine resistance., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Basal/squamous (Ba/Sq) subtype represents an intrinsic and robust group in the consensus molecular classification of muscle-invasive bladder cancer (MIBC), with poor outcome and controversial chemosensitivity. We aimed to investigate the spectrum of intratumor heterogeneity (ITH) in the Ba/Sq subtype. First, we validated a 29-gene NanoString CodeSet to predict the Ba/Sq subtype for FFPE samples. We identified heterogeneous Ba/Sq tumors in a series of 331 MIBC FFPE samples using dual GATA3/KRT5/6 immunohistochemistry (IHC). Heterogeneous regions with distinct immunostaining patterns were studied separately for gene expression using the 29-gene CodeSet, for mutations by targeted next-generation sequencing, and for copy number alteration (CNA) by microarray hybridization. Among 83 Ba/Sq tumors identified by GATA3/KRT5/6 dual staining, 19 tumors showed heterogeneity at the IHC level. In one third of the 19 cases, regions from the same tumor were classified in different distinct molecular subtypes. The mutational and CNA profiles confirmed the same clonal origin for IHC heterogeneous regions with possible subclonal evolution. Overall, two patterns of intratumoral heterogeneity (ITH) were observed in Ba/Sq tumors: low ITH (regions with distinct immunostaining, but common molecular subtype and shared CNA) or high ITH (regions with distinct immunostaining, molecular subtype, and CNA). These results showed multilayer heterogeneity in Ba/Sq MIBC. In view of personalized medicine, this heterogeneity adds complexity and should be taken into account for sampling procedures used for diagnosis and treatment choice. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background: Treatment and outcomes of patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have dramatically improved over the past 20 years. This work evaluated treatment patterns and outcomes according to age., Methods: Women who initiated a treatment for HER2+ MBC between 2008 and 2016 in one of the 18 French comprehensive centers part of the ESME program were included. Objectives were the description of first-line treatment patterns, overall survival (OS), first-line progression-free survival (PFS), and prognostic factors among patients aged 70 years or more (70+), or less than 70 (<70)., Results: Of 4045 women diagnosed with an HER2+ MBC, 814 (20%) were 70+. Standard first-line treatment (chemotherapy combined with an anti-HER2 therapy) was prescribed in 65% of 70+ versus 89% of <70 patients (p < 0.01). Median OS was 49.2 (95% CI, 47.1-52.4), 35.3 (95% CI, 31.5-37.0) and 54.2 months (95% CI, 50.8-55.7) in the whole population, in patients 70+ and <70, respectively. Corresponding median PFS1 were 12.8 (95% CI, 12.3-13.3), 11.1 (95% CI, 10.0-12.3) and 13.2 months (95% CI, 12.7-13.9), respectively. In 70+ women, initiation of non-standard first-line treatment had an independent detrimental time-varying effect on both OS and PFS (HR on OS at 1 year: chemotherapy without anti-HER2 2.79 [95% CI: 2.05-3.79]; endocrine therapy and/or anti-HER2 1.96 [95% CI: 1.43-2.69])., Conclusions: In this large retrospective real-life database, older women with HER2+ MBC received standard first-line treatment less frequently than younger ones. This was independently associated with a worse outcome, but confounding factors and usual selection biases cannot be ruled out., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background The phosphatidylinositol-3 kinase pathway is often altered in head and neck squamous cell carcinoma (HNSCC), and is involved in the resistance to EGFR inhibitors. Objective We investigated the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetics, and preliminary efficacy of the combination of copanlisib, an intravenous, pan-class I PI3K inhibitor, with the anti-EGFR monoclonal antibody cetuximab in recurrent and/or metastatic HNSCC patients in a phase I dose-escalation trial. Patients and methods Copanlisib was given intravenously on days 1, 8, and 15 of 28-day cycles at the dose of 45 mg and 30 mg, in combination with standard doses of weekly cetuximab (400 mg/m 2 loading dose followed by 250 mg/m 2 on days 8, 15, and 22, and weekly thereafter). Results Three patients received copanlisib 45 mg, of whom two experienced grade 3 hyperglycemia during Cycle 1 that met the DLT criteria. Eight patients were then treated with copanlisib at the dose of 30 mg. Because of the occurrence of hyperglycemia, a premedication with metformine was introduced on the day of the injections. No DLTs were reported at this dose level. The trial was stopped early because of the unfavourable toxicity profile of the combination. Among eight evaluable patients for response, four patients (50%) had disease stabilization according to RECIST1.1 as best response. Conclusion Copanlisib combined with cetuximab demonstrated unfavorable toxicity and limited efficacy in heavily pretreated recurrent and/or metastatic HNSCC patients.Trial registration NCT02822482, Date of registration: June 2016., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Immune checkpoint inhibitors have been demonstrated to improve overall survival. Atypical patterns of response have been reported, including dissociated response (DR). We evaluated the prevalence of DR., Patients and Methods: Patients had to have a baseline computed tomography (CT) scan and at least one follow-up CT scan and two target lesions (TLs). Three types of DR were evaluated using RECIST1.1: DR1, defined as at least one progressive and one responding TL; DR2, defined as at least one progressive and one stable TL; and DR3, defined as at least one stable and one responding TL., Results: A total of 1244 measurements of 272 TLs were performed in 100 patients. Forty-nine out of the 272 TLs (18%) had received old or recent radiotherapy, and 42 (15%) had been biopsied. An objective response was observed in 22 patients (22%) and on 52 TLs (19%). DR1 were observed in 8% of patients. At the tumor measurement level, the response rate was lower in the case of prior radiotherapy (29% vs 34%, p = 0.01) and higher in the case of prior biopsy (40% vs 32%, p = 0.02)., Conclusions: A DR was observed in 8% of patients. Response rate was lower in the case of prior radiotherapy and higher in the case of prior biopsy., (© 2021. The Author(s).)

Background: Pembrolizumab has efficacy in programmed death ligand 1 (PD-L1)-positive metastatic or unresectable cervical cancer that has progressed during chemotherapy. We assessed the relative benefit of adding pembrolizumab to chemotherapy with or without bevacizumab., Methods: In a double-blind, phase 3 trial, we randomly assigned patients with persistent, recurrent, or metastatic cervical cancer in a 1:1 ratio to receive pembrolizumab (200 mg) or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy and, per investigator discretion, bevacizumab. The dual primary end points were progression-free survival and overall survival, each tested sequentially in patients with a PD-L1 combined positive score of 1 or more, in the intention-to-treat population, and in patients with a PD-L1 combined positive score of 10 or more. The combined positive score is defined as the number of PD-L1-staining cells divided by the total number of viable tumor cells, multiplied by 100. All results are from the protocol-specified first interim analysis., Results: In 548 patients with a PD-L1 combined positive score of 1 or more, median progression-free survival was 10.4 months in the pembrolizumab group and 8.2 months in the placebo group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.50 to 0.77; P<0.001). In 617 patients in the intention-to-treat population, progression-free survival was 10.4 months and 8.2 months, respectively (hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P<0.001). In 317 patients with a PD-L1 combined positive score of 10 or more, progression-free survival was 10.4 months and 8.1 months, respectively (hazard ratio, 0.58; 95% CI, 0.44 to 0.77; P<0.001). Overall survival at 24 months was 53.0% in the pembrolizumab group and 41.7% in the placebo group (hazard ratio for death, 0.64; 95% CI, 0.50 to 0.81; P<0.001), 50.4% and 40.4% (hazard ratio, 0.67; 95% CI, 0.54 to 0.84; P<0.001), and 54.4% and 44.6% (hazard ratio, 0.61; 95% CI, 0.44 to 0.84; P = 0.001), respectively. The most common grade 3 to 5 adverse events were anemia (30.3% in the pembrolizumab group and 26.9% in the placebo group) and neutropenia (12.4% and 9.7%, respectively)., Conclusions: Progression-free and overall survival were significantly longer with pembrolizumab than with placebo among patients with persistent, recurrent, or metastatic cervical cancer who were also receiving chemotherapy with or without bevacizumab. (Funded by Merck Sharp and Dohme; KEYNOTE-826 ClinicalTrials.gov number, NCT03635567.)., (Copyright © 2021 Massachusetts Medical Society.)

Competing Interests: ECGB has received honoraria or consultation fees from BMS, Eli Lilly, G1 Therapeutics, Pfizer, Sandoz, and Seagen; and travel support for international meetings from AstraZeneca, Novartis, Pfizer, Pierre Fabre, Roche, and Sandoz.

Purpose: Almost all cervical cancers are caused by human papillomavirus (HPV) and patients with advanced stage are at high risk for relapse. Circulating HPV DNA (HPV ctDNA) may serve as a residual tumor marker at the end of chemoradiation or to predict relapse during the follow-up period., Experimental Design: We analyzed serum samples from 94 HPV16- or HPV18-related CCs from the BioRAIDs prospective cohort. Samples were collected before and after treatment and during an 18-month follow-up period. Using digital droplet PCR (ddPCR), we assessed the relevance of circulating HPV E7 gene as a marker for residual disease compared to HPV integration site and PIK3CA mutations. Finally, the prognostic impact of circulating HPV E7 gene was assessed with its prediction value of relapse., Results: HPV E7 gene was the most sensitive tumor marker, superior to both HPV integration sites and PIK3CA mutations in serum. Circulating HPV DNA (HPV ctDNA) was detected in 63% (59/94) of patients, before treatment. HPV ctDNA detection in serum sample was associated with high FIGO stage ( P = 0.02) and para-aortic lymph node involvement ( P = 0.01). The level of HPV ctDNA was positively correlated with HPV copy number in the tumor ( R = 0.39, P < 0.001). Complete clearance of HPV ctDNA by the end of treatment was significantly associated with a longer PFS ( P < 0.0001). Patients with persistent HPV ctDNA in serum relapsed with a median time of 10 months (range, 2-15) from HPV ctDNA detection., Conclusions: HPV ctDNA detection is a useful marker to predict relapse in cervical cancer. See related commentary by Wentzensen and Clarke, p. 5733 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Primary vitreoretinal lymphoma (PVRL) is a rare form of primary central nervous system (CNS) lymphoma (PCNSL) arising in the intraocular compartment without brain involvement. Despite its apparent indolent clinical course, PVRL can cause permanent vision loss and CNS relapse, the major cause of death in patients with PVRL. The pathophysiology of PVRL is unknown. As in PCNSL, the transformation of the tumor cells likely originates outside the CNS, before the cells migrate to the eye and proliferate within an immune-permissive microenvironment. PVRL exhibits a biased immunoglobulin repertoire, suggesting underlying antigen selection. The diagnosis remains challenging, requiring close coordination between ophthalmologists and cytologists. Because of their rarity and fragility in the vitreous, lymphoma cells cannot always be identified. Interleukin levels, molecular biology, and imaging are used in combination with clinical ophthalmological examination to support the diagnosis of PVRL. Multi-institutional prospective studies are urgently needed to validate the equivocal conclusions regarding treatments drawn from heterogeneous retrospective or small cohort studies. Intravitreal injection of methotrexate or rituximab or local radiotherapy is effective at clearing tumor cells within the eyes but does not prevent CNS relapse. Systemic treatment based on high-dose methotrexate chemotherapy, with or without local treatment, might reduce this risk. At relapse, intensive consolidation chemotherapy followed by stem cell transplantation can be considered. Single-agent ibrutinib, lenalidomide, and temozolomide treatments are effective in patients with relapsed PVRL and should be tested as first-line treatments. Therapeutic response assessment based on clinical examination is improved by measuring cytokine levels but still needs to be refined., (© 2021 by The American Society of Hematology.)

Breast cancer and gynecologic cancers affect >3 million women worldwide each year. With advances in precision medicine, a growing number of targeted therapies have been approved recently, and new therapeutic classes have emerged, including cell cycle inhibitors for hormone receptor positive breast cancer, antibody drug conjugate for human epidermal growth factor receptor 2 positive and triple negative breast cancer, and poly-ADP-ribose polymerase inhibitors for ovarian cancer. This article focuses first on the challenges for health care systems to address the specificities of each emerging targeted therapy and new issues raised by oral antitumor treatments, including individualization of prescriptions, drug-drug interaction assessment, pharmaceutical counseling, patient education, and outpatient management. Then, we provide an overview of the main adverse effects of targeted therapies approved for breast and gynecologic cancers, such as hematologic toxicity of cyclin-dependent kinase 4/6 inhibitors and poly-ADP-ribose polymerase inhibitors, metabolic disorders of phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin inhibitors, and cardiovascular toxicity of agents targeting human epidermal growth factor receptor 2., Competing Interests: Dr. Bellesoeur reports travel grants/conference fees from MSD, Novartis, and Lilly and serving on the scientific board for BMS/Pfizer and LeoPharma., (© 2021 Published by Elsevier Inc. on behalf of Women's Dermatologic Society.)

Up to 80% of BRCA1 and BRCA2 genetic variants remain of uncertain clinical significance (VUSs). Only variants classified as pathogenic or likely pathogenic can guide breast and ovarian cancer prevention measures and treatment by PARP inhibitors. We report the first results of the ongoing French national COVAR (cosegregation variant) study, the aim of which is to classify BRCA1/2 VUSs. The classification method was a multifactorial model combining different associations between VUSs and cancer, including cosegregation data. At this time, among the 653 variants selected, 101 (15%) distinct variants shared by 1,624 families were classified as pathogenic/likely pathogenic or benign/likely benign by the COVAR study. Sixty-six of the 101 (65%) variants classified by COVAR would have remained VUSs without cosegregation data. Of note, among the 34 variants classified as pathogenic by COVAR, 16 remained VUSs or likely pathogenic when following the ACMG/AMP variant classification guidelines. Although the initiation and organization of cosegregation analyses require a considerable effort, the growing number of available genetic tests results in an increasing number of families sharing a particular variant, and thereby increases the power of such analyses. Here we demonstrate that variant cosegregation analyses are a powerful tool for the classification of variants in the BRCA1/2 breast-ovarian cancer predisposition genes., Competing Interests: Declaration of interests D.S.-L. and the Institut Curie have received honoraria for her participation in education meetings organized by AstraZeneca or Tesaro. The remaining authors declare no conflict of interest., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Scheduling anticancer drug administration over 24 h may critically impact treatment success in a patient-specific manner. Here, we address personalization of treatment timing using a novel mathematical model of irinotecan cellular pharmacokinetics and -dynamics linked to a representation of the core clock and predict treatment toxicity in a colorectal cancer (CRC) cellular model. The mathematical model is fitted to three different scenarios: mouse liver, where the drug metabolism mainly occurs, and two human colorectal cancer cell lines representing an in vitro experimental system for human colorectal cancer progression. Our model successfully recapitulates quantitative circadian datasets of mRNA and protein expression together with timing-dependent irinotecan cytotoxicity data. The model also discriminates time-dependent toxicity between the different cells, suggesting that treatment can be optimized according to their cellular clock. Our results show that the time-dependent degradation of the protein mediating irinotecan activation, as well as an oscillation in the death rate may play an important role in the circadian variations of drug toxicity. In the future, this model can be used to support personalized treatment scheduling by predicting optimal drug timing based on the patient's gene expression profile., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give patients, health professionals, managers and policymakers a guide to essential care throughout the patient journey. Pancreatic cancer is an increasing cause of cancer mortality and has wide variation in treatment and care in Europe. It is a major healthcare burden and has complex diagnosis and treatment challenges. Care must be carried out only in pancreatic cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals detailed here. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Treatment of extremity rhabdomyosarcomas (RMS) includes chemotherapy, surgery, and radiotherapy. Lymph node irradiation is recommended in the presence of regional node involvement at diagnosis. The aim of this study was to analyze the correlation between the pattern of relapse of non-metastatic extremity RMS and the initial therapies delivered., Methods: All patients with localized extremity RMS prospectively treated in France in the MMT-95 and RMS-05 protocols were selected. Extent of disease and pattern of relapse were evaluated by clinical examination and imaging., Results: We identified 59 patients with clinical characteristics corresponding to unfavorable prognostic factors. Twenty patients (34%) were considered to have lymph node involvement at diagnosis. Regional node biopsy was performed in 32 patients (54%) and modified the lymph node stage in 8 of the 59 patients (14%). Seventy-three percent of patients received radiotherapy. Fifty-two patients achieved first remission. Overall, 26 patients underwent complete tumor resection, 17 had R1 margins, and 5 were not operated due to early tumor progression. With a median follow-up of 82 months (range: 5-287), 18 relapses had occurred, at least locoregional in 12 cases. The 5‑year local and nodal control rates were 73% (63-86%) and 86% (77-95%), respectively. Five-year progression-free and overall survival were 57% (95%CI [45-72%]) and 70% (95%CI [58-84%]), respectively., Conclusion: The main sites of extremity RMS relapse are locoregional. Nodal failures in non-irradiated fields are not uncommon. We recommend systematic biopsy of in-transit nodes, especially in alveolar RMS and/or RMS with regional positive nodes at diagnosis to ensure their negativity., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Low-income and middle-income countries (LMICs) have a disproportionately high burden of cancer and cancer mortality. The unique barriers to optimum cancer care in these regions necessitate context-specific research. The conduct of research in LMICs has several challenges, not least of which is a paucity of formal training in research methods. Building capacity by training early career researchers is essential to improve research output and cancer outcomes in LMICs. The International Collaboration for Research methods Development in Oncology (CReDO) workshop is an initiative by the Tata Memorial Centre and the National Cancer Grid of India to address gaps in research training and increase capacity in oncology research. Since 2015, there have been five CReDO workshops, which have trained more than 250 oncologists from India and other countries in clinical research methods and protocol development. Participants from all oncology and allied fields were represented at these workshops. Protocols developed included clinical trials, comparative effectiveness studies, health services research, and observational studies, and many of these protocols were particularly relevant to cancer management in LMICs. A follow-up of these participants in 2020 elicited an 88% response rate and showed that 42% of participants had made progress with their CReDO protocols, and 73% had initiated other research protocols and published papers. In this Policy Review, we describe the challenges to research in LMICs, as well as the evolution, structure, and impact of CReDO and other similar workshops on global oncology research., Competing Interests: Declaration of interests IT served as Chair of a data and safety monitoring committee (DSMC) for a trial by Roche Genentech, Chair of a DSMC for a trial by Janssen, and member of a DSMC for a trial by Bayer, outside of the submitted work. MK reports personal fees from Merck Sharpe & Dohme, outside of the submitted work. MRS reports grants from Astellas, Amgen, AstraZeneca, Bayer, Bionomics, Bristol Myers Squibb, Celgene, Medivation, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, and Tilray, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Prolonged Covid-19 is an emerging issue for patients with lymphoma or immune deficiency. We aimed to examine prolonged length of in-hospital stay (LOS) due to Covid-19 among patients with lymphoma and assess its determinants and outcomes. Adult patients with lymphoma admitted for Covid-19 to 16 French hospitals in March and April, 2020 were included. Length of in-hospital stay was analyzed as a competitor vs death. The study included 111 patients. The median age was 65 years (range, 19-92). Ninety-four patients (85%) had B-cell non-Hodgkin lymphoma. Within the 12 months prior to hospitalization for Covid-19, 79 patients (71%) were treated for their lymphoma. Among them, 63 (57%) received an anti-CD20 therapy. Fourteen patients (12%) had relapsed/refractory disease. The median LOS was 14 days (range, 1-235). After a median follow-up of 191 days (3-260), the 6-month overall survival was 69%. In multivariable analyses, recent administration of anti-CD20 therapy was associated with prolonged LOS (subdistribution hazard ratio 2.26, 95% confidence interval 1.42-3.6, p < 0.001) and higher risk of death (hazard ratio 2.17, 95% confidence interval 1.04-4.52, p = 0.039). An age ≥ 70 years and relapsed/refractory lymphoma were also associated with prolonged LOS and decreased overall survival. In conclusion, an age ≥ 70 years, a relapsed/refractory lymphoma and recent administration of anti-CD20 therapy are risk factors for prolonged LOS and death for lymphoma patients hospitalized for Covid-19. These findings may contribute to guide the management of lymphoma during the pandemic, support evaluating specific therapeutic approaches, and raise questions on the efficacy and timing of vaccination of this particular population., (© 2021 Wiley Periodicals LLC.)

Over the past century, epidemiologic changes and implementation of screening may have had an impact on tumor doubling time in breast cancer. Our study was designed to evaluate changes in tumor doubling time in breast cancer over the past 80 years. A systematic review of published literature and meta-regression analysis was performed. An online electronic database search was undertaken using the PubMed platform from inception until June 2020. All studies that measured tumor doubling time in breast cancer were included. A total of 151 publications were retrieved. Among them, 16 full-text articles were included in the qualitative analysis. An exponential growth model was used for quantitative characterization of tumor growth rate. Tumor doubling time has remained stable over the past 80 years. Recent studies have not only identified "fast growing tumor" (grade 3, human epidermal growth factor receptor 2-positive, triple-negative, or tumor with an elevated Ki-67) but also "inactive breast cancer" feeding the ongoing debate of overdiagnosis due to screening programs. The stability of tumor doubling time over the past 80 years, despite increasing and changing risk factors, supports the validity for our screening guidelines. Prospective studies based on more precise measurement of tumor size and adjustment for tumor characteristics are necessary to more clearly characterize the prognostic and predictive impact of tumor doubling time in breast cancer., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: In BRAF V600MUT metastatic melanoma, cyclin D-CDK4/6-INK4-Rb pathway alterations are involved in resistance to MAPK inhibitors, suggesting a clinical benefit of cyclin-dependent kinase 4 (CDK4) inhibitors. In this phase I-II study, we aimed to establish the MTD of palbociclib when added to vemurafenib., Patients and Methods: Patients with BRAF V600E/KMUT metastatic melanoma harboring CDKN2A loss and RB1 expression were included and stratified into two groups according to previous BRAF inhibitor treatment (no:strata 1; yes:strata 2). Treatment comprised palbociclib once daily for 14 days followed by a 7-day break + continuous dosing of vemurafenib. The primary endpoint was the occurrence of dose-limiting toxicity (DLT), and the secondary endpoints included the best response, survival, pharmacokinetics, and tumor molecular profiling., Results: Eighteen patients were enrolled, with 15 in strata 2. Characteristics at inclusion were American Joint Committee on Cancer stage IVM1c ( N = 16; 88.9%), high lactate dehydrogenase ( N = 9; 50.0%), and median number of previous treatments of 2. One and 5 patients experienced DLT in strata 1 and 2, respectively, defining the MTD at palbociclib 25 mg and vemurafenib 960 mg in strata 2. No significant evidence for drug-drug interactions was highlighted. The median progression-free survival was 2.8 months, and 5 (27.8%) patients showed a clinical response. The baseline differential mRNA expression analysis and in vitro data revealed the role of CHEK2 in the response to palbociclib., Conclusions: Although the combination of palbociclib + fixed-dose vemurafenib did not allow an increased palbociclib dosage above 25 mg, a significant clinical benefit was achieved in pretreated patients with melanoma. An association between the transcriptomic data and clinical response was highlighted., (©2021 American Association for Cancer Research.)

Breast cancer is increasingly prevalent in older adults and is a substantial part of routine oncology practice. However, management of breast cancer in this population is challenging because the disease is highly heterogeneous and there is insufficient evidence specific to older adults. Decision making should not be driven by age alone but should involve geriatric assessments plus careful consideration of life expectancy, competing risks of mortality, and patient preferences. A multidisciplinary taskforce, including members of the European Society of Breast Cancer Specialists and International Society of Geriatric Oncology, gathered to expand and update the previous 2012 evidence-based recommendations for the management of breast cancer in older individuals with the endorsement of the European Cancer Organisation. These guidelines were expanded to include chemotherapy toxicity prediction calculators, cultural and social considerations, surveillance imaging, genetic screening, gene expression profiles, neoadjuvant systemic treatment options, bone-modifying drugs, targeted therapies, and supportive care. Recommendations on geriatric assessment, ductal carcinoma in situ, screening, primary endocrine therapy, surgery, radiotherapy, adjuvant systemic therapy, and secondary breast cancer were updated., Competing Interests: Declaration of interests LB reports personal fees from AstraZeneca, Eisai, Lilly, Pierre Fabre, and Daiichi Sankyo; grants, personal fees, and non-financial support from Celgene, Ipsen, and Pfizer; grants and personal fees from Genomic Health and Novartis; and personal fees and non-financial support from Roche, outside the submitted work. NLMB reports grants and personal fees from Pfizer and grants from Genomic Health, outside the submitted work. HW reports that his institution (University Hospitals Leuven, Leuven, Belgium) received consulting fees and honoraria from AstraZeneca, Biocartis, Lilly, Novartis, Pfizer, PUMA Biotechnology, Roche, Sirtex, and Daiiji; the institution received unrestricted research grants from Roche and Novartis; and HW received travel support from Roche and Pfizer. MSA reports personal fees and non-financial support from the Multinational Association for Supportive Care in Cancer, European Society of Medical Oncology, and European CanCer Organisation; grants and personal fees from Helsinn, Sandoz; and personal fees from Tesaro, Merck, Vifor, Pfizer, Taiho, and Kyowa Kirin, outside the submitted work. EGCB reports personal fees from Pfizer, Roche, Samsung, Pierre Fabre, Novartis, AstraZeneca, TLC PharmaChem, Clinigen, Mylan, and G1 Therapeutics; and grants and personal fees from Bristol Myers Squibb, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Vulvar carcinomas represent 4% of all gynaecological cancers with 838 new cases in France in 2018. The precursor lesions of vulvar carcinomas are differentiated vulvar intraepithelial lesion (dVIN) in a context of lichen sclerosus and vulvar high-grade squamous intraepithelial lesion (HSIL) link to human papillomavirus (HPV) infection. Three typical clinical forms of HSIL are described: the Bowenoid papulosis, the Bowen's disease and the confluent VIN. Histopathology cannot differentiate effectively these two types of lesions. P16 and P53 immunostaining are valuable tools to respectively assess HPV infection and divide different types of dVIN. However, P53 immunostaining is still lacking sensibility to detect dVIN. First line therapies are medical treatment excluding the cases with a doubt of invasion. The gold standard treatment for dVIN and vulvar HSIL are respectively topical corticosteroids and imiquimod. Primary prevention for vulvar HSIL and dVIN are respectively HPV vaccination and early treatment of lichen sclerosus. Destructive therapy can be used in case of medical treatment failure such as CO2 laser, cryotherapy, dynamic phototherapy. Surgical indications should be carefully assessed between the risk of recurrence, the spread of the lesions, the aesthetic and functional aspect. Surgical procedures consist in either superficial vulvectomy or radical vulvectomy with or without flap reconstruction. Recurrence rate after surgery is around 20%., (Copyright © 2020. Published by Elsevier Masson SAS.)

We assessed long-term associations of Granulocyte-Colony Stimulating Factors (G-CSF) use with patient-reported outcomes (PROs) and hematologic toxicity among chemotherapy-treated, early-stage breast cancer patients in CANTO (NCT01993498). Among 2920 patients longitudinally followed-up until year-4 after diagnosis, 49% used G-CSF. In multivariable-adjusted mixed-models, EORTC QLQ-C30 pain and summary score were not substantially different between groups (overall adjusted mean difference, use vs no-use [95%CI]: +1.27 [-0.33 to +2.87] and -1.01 [-1.98 to -0.04], respectively). PROs were slightly worse at year-4 among patients receiving G-CSF, although differences were of trivial clinical significance. No major differences were observed in leukocyte or platelet count over time., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Chemoradiotherapy (CRT) is the standard of care for patients diagnosed with locally advanced cervical cancer (LACC), a human papillomavirus (HPV)-related cancer that relapses in 30%-60% of patients. This study aimed to (i) design HPV droplet digital PCR (ddPCR) assays for blood detection (including rare genotypes) and (ii) monitor blood HPV circulating tumor DNA (HPV ctDNA) levels during CRT in patients with LACC., Methods: We analyzed blood and tumor samples from 55 patients with HPV-positive LACC treated by CRT in a retrospective cohort (n = 41) and a prospective cohort (n = 14). HPV-ctDNA detection was carried out by genotype-specific ddPCR., Results: HPV ctDNA was successfully detected in 69% of patients (n = 38/55) before CRT for LACC, including nine patients with a rare genotype. HPV-ctDNA level was correlated with HPV copy number in the tumor (r = 0.41, P < 0.001). HPV-ctDNA positivity for HPV18 (20%, n = 2/10) was significantly lower than for HPV16 (77%, n = 27/35) or other types (90%, n = 9/10, P = 0.002). HPV-ctDNA detection (positive versus negative) before CRT was associated with tumor stage (P = 0.037) and lymph node status (P = 0.02). Taking into account all samples from the end of CRT and during follow-up in the prospective cohort, positive HPV-ctDNA detection was associated with lower disease-free survival (DFS) (P = 0.048) and overall survival (OS) (P = 0.0013)., Conclusion: This is one of the largest studies to report HPV-ctDNA detection before CRT and showed clearance of HPV ctDNA at the end of treatment in most patients. Residual HPV ctDNA at the end of CRT or during follow-up could help to identify patients more likely to experience subsequent relapse., Competing Interests: Disclosure The authors have declared no conflicts of interest. Data sharing The data that support the findings of this study are available from Institut Curie but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Institut Curie., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Leptomeningeal metastasis (LM) is a rare complication of metastatic breast cancer (MBC), with high morbidity/mortality rates. Our study aimed to describe the largest-to-date real-life population of MBC patients treated with intrathecal (IT) therapy and to evaluate prognostic models., Methods: The Epidemiological Strategy and Medical Economics (ESME) MBC database (NCT03275311) includes all consecutive patients who have initiated treatment for MBC since 2008. Overall survival (OS) of patients treated with IT therapy was estimated using the Kaplan-Meier method. Prognostic models were constructed using Cox proportional hazards models. Performance was evaluated using C-index and calibration plots., Results: Of the 22 266 patients included in the database between 2008 and 2016, 312 received IT therapy and were selected for our analysis. Compared with non-IT-treated patients, IT-treated patients were younger at MBC relapse (median age: 52 years versus 61 years) and more often had lobular histology (23.4% versus 12.7%) or triple-negative subtype (24.7% versus 13.3%) (all P < 0.001). Median OS was 4.5 months [95% confidence interval (CI) 3.8-5.6] and 1-year survival rate was 25.6%. Significant prognostic factors associated with poorer outcome on multivariable analysis were triple-negative subtype (hazard ratio 1.81, 95% CI 1.32-2.47), treatment line ≥3 (hazard ratio 1.88, 95% CI 1.30-2.73), ≥3 other metastatic sites (hazard ratio 1.33, 95% CI 1.01-1.74) and IT cytarabine or thiotepa versus methotrexate (hazard ratio 1.68, 95% CI 1.28-2.22), while concomitant systemic therapy was associated with better OS (hazard ratio 0.47, 95% CI 0.35-0.62) (all P < 0.001). We validated two previously published prognostic scores, the Curie score and the Breast-graded prognostic assessment, both with C-index of 0.57., Conclusions: MBC patients with LM treated with IT therapy have a poor prognosis. We could identify a subgroup of patients with better prognosis, when concomitant systemic therapy and IT methotrexate were used., Competing Interests: Disclosure MCapone reports personal fees (consulting, advisory) from Lilly, Novartis, GT1, Daiichi Sankyo and fees to the institution from AstraZeneca, Sanofi, Servier and AbbVie, outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the first report of such an association.Family description: The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer. She was tested for several genes associated with hereditary breast cancer., Results: A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified., Conclusion: This complex situation is challenging for genetic counselling and management of at-risk individuals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Acquired perineal hernia is a rare complication following extensive pelvic surgery. Radiotherapy is also a predisposing factor. Perineal hernia can cause chronic perineal pain, bowel obstruction, urinary disorders and a cosmetically disfiguring defect. The treatment of perineal hernia is surgical, usually consisting of mesh repair via an abdominal or perineal approach., Case Presentation: We present a case report and a surgical video of a 42-year-old woman with history of a squamous cell carcinoma. This patient had 3 recurrences since the diagnosis and a symptomatic perineal hernia. Complete regression of the recurrent malignancy allowed us to treat the perineal hernia. We performed laparoscopic repair with prosthetic mesh in this patient who had undergone multiple surgeries and radiotherapy, while preserving the omental flap that was used to reconstruct the posterior part of the vagina., Conclusion: There is no consensus concerning the preferred surgical approach, perineal or laparoscopic, as no study has demonstrated the superiority of either of these approaches. Laparoscopic repair for an acquired perineal hernia is safe and feasible. However, further studies including randomized trials are required to precisely evaluate the best surgical approach and type of mesh.

Objectives: To compare brain MRI findings in progressive multifocal leukoencephalopathy (PML) associated to rituximab and natalizumab treatments and HIV infection., Materials and Methods: In this retrospective, multicentric study, we analyzed brain MRI exams from 72 patients diagnosed with definite PML: 32 after natalizumab treatment, 20 after rituximab treatment, and 20 HIV patients. We compared T2- or FLAIR-weighted images, diffusion-weighted images, T2*-weighted images, and contrast enhancement features, as well as lesion distribution, especially gray matter involvement., Results: The three PML entities affect U-fibers associated with low signal intensities on T2*-weighted sequences. Natalizumab-associated PML showed a punctuate microcystic appearance in or in the vicinity of the main PML lesions, a potential involvement of the cortex, and contrast enhancement. HIV and rituximab-associated PML showed only mild contrast enhancement, punctuate appearance, and cortical involvement. The CD4/CD8 ratio showed a trend to be higher in the natalizumab group, possibly mirroring a more efficient immune response., Conclusion: Imaging features of rituximab-associated PML are different from those of natalizumab-associated PML and are closer to those observed in HIV-associated PML., Key Points: • Nowadays, PML is emerging as a complication of new effective therapies based on monoclonal antibodies. • Natalizumab-associated PML shows more inflammatory signs, a perivascular distribution "the milky way," and more cortex involvement than rituximab- and HIV-associated PML. • MRI differences are probably related to higher levels of immunosuppression in HIV patients and those under rituximab therapy.

Comprehensive understanding of molecular principles in cancer and the diversification of oncological therapy promise individual therapeutic concepts, which have not yet found their way into urogenital cancer therapy. In March 2019 the International Society of Urogenital Pathology (ISUP) therefore held a consensus conference on recommendations for molecular diagnostics of genitourinary tumors, which were published in five separate manuscripts and are summarized in this article.In preparation for the conference, a comprehensive survey of current practices for molecular testing of urogenital tumors was carried out by members of the ISUP. At the conference, the results and the corresponding background information were presented by five working groups and recommendations for action for diagnostics were developed. An agreement between 66% of the conference participants was defined as consensus.

Introduction: Immune checkpoint inhibitors (ICIs) have proved to be an effective treatment for up to 40% of muscle-invasive bladder cancer (MIBC), but there is still a need for better performing biomarkers allowing to improve prediction of response to ICI. Response to immunotherapy in soft-tissue sarcoma, melanoma and renal cell carcinoma have been recently linked to the presence of tertiary lymphoid structures (TLS) in the tumour. TLS are organised aggregates of T, B and dendritic cells, participating in adaptive antitumor immune response. The chemokine CXCL13 is involved in the formation of TLS, and is reported as a reliable transcriptomic marker of TLS., Objectives: In this study, we sought to assess whether CXCL13 transcript expression can be a prognostic biomarker for ICI-treated MIBC patients and also investigated whether it can serve a biomarker of TLS in MIBC., Methods: We analysed transcriptomic data from three publicly available MIBC cohorts and evaluated pathological slides from the TCGA-BLCA cohort for TLS presence and stage of maturation., Results: We showed that CXCL13 was independently associated with both prolonged survival (HR = 0.8, 95% CI [0.68-0.94]) and objective response (p < 0.0001) in patients treated with ICI, at the difference of others immunological signatures. However, it was not a predictor for non-ICI-treated MIBC, suggesting a predictive effect of ICI efficacy. Finally, we validated that CXCL13 expression was correlated with tumour TLS in TCGA data set (p < 0.001), and can serve as a marker of TLS in bladder cancer., Conclusion: These results support that CXCL13 expression, as a surrogate for tumour TLS, is a relevant candidate predictive biomarker of response to ICI for patients with advanced-stage bladder cancer., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Enhancers are cis-regulatory sequences that fine-tune expression of their target genes in a spatiotemporal manner. They are recognized by sequence-specific transcription factors, which in turn recruit transcriptional coactivators that facilitate transcription by promoting assembly and activation of the basal transcriptional machinery. Their functional importance is underscored by the fact that they are often the target of genetic and nongenetic events in human disease that disrupt their sequence, interactome, activation potential, and/or chromatin environment. Dysregulation of transcription and addiction to transcriptional effectors that interact with and modulate enhancer activity are common features of cancer cells and are amenable to therapeutic intervention. Here, we discuss the current knowledge on enhancer biology, the broad spectrum of mechanisms that lead to their malfunction in tumor cells, and recent progress in developing drugs that efficaciously target their dependencies.

Background: Team-based and timely integrated palliative care is a gold standard of care in oncology, but issues concerning its optimal organization remain. Palliative Care in Day-Hospital (PCDH) could be one of the most efficient service model of palliative care to deliver interdisciplinary and multidimensional care addressing the complex supportive care needs of patients with advanced cancer. We hypothesize that, compared to conventional outpatient palliative care, PCDH allows the clinical benefits of palliative care to be enhanced., Methods/design: This study is a multicentre parallel group trial with stratified randomization. Patient management in PCDH will be compared to conventional outpatient palliative care. The inclusion criteria are advanced cancer patients referred to a palliative care team with an estimated life expectancy of more than 2 months and less than 1 year. The primary endpoint is health-related quality of life with deterioration-free survival based on the EORTC QLQ-C30 questionnaire. The secondary objectives are the following: increase in patient satisfaction with care using the EORTC PATSAT-C33 and OUT-PATSAT7 questionnaires, better understanding of the prognosis using the PTPQ questionnaire and advance care planning; decrease in the need for supportive care among relatives using the SCNS-P&C-F questionnaire, and reduction in end-of-life care aggressiveness. Patients will complete one to five questionnaires on a tablet before each monthly visit over 6 months and will be followed for 1 year. A qualitative study will take place, aiming to understand the specificity of palliative care management in PCDH. Cost-effectiveness, cost-utility and, an additional economic evaluation based on capability approach will be conducted from a societal point of view., Discussion: The first strength of this study is that it combines the main relevant outcomes assessing integrated palliative care; patient quality of life and satisfaction; discussion of the prognosis and advance care planning, family well-being and end-of-life care aggressiveness. The second strength of the study is that it is a mixed-method study associating a qualitative analysis of the specificity of PCDH organization, with a medical-economic study to analyse the cost of care., Trial Registration: Name of the registry: IDRCB 2019-A03116-51 Trial registration number: NCT04604873 Date of registration: October 27, 2020 URL of trial registry record.

Expression of hormone receptor (HR) for estrogens (ER) and progesterone (PR) and HER2 remains the cornerstone to define the therapeutic strategy for breast cancer patients. We aimed to compare phenotypic profiles between matched primary and metastatic breast cancer (MBC) in the ESME database, a National real-life multicenter cohort of MBC patients. Patients with results available on both primary tumour and metastatic disease within 6 months of MBC diagnosis and before any tumour progression were eligible for the main analysis. Among the 16,703 patients included in the database, 1677 (10.0%) had available biopsy results at MBC diagnosis and on matched primary tumour. The change rate of either HR or HER2 was 27.0%. Global HR status changed (from positive = either ER or PR positive, to negative = both negative; and reverse) in 14.2% of the cases (expression loss in 72.5% and gain in 27.5%). HER2 status changed in 7.8% (amplification loss in 45.2%). The discordance rate appeared similar across different biopsy sites. Metastasis to bone, HER2+ and RH+/HER2- subtypes and previous adjuvant endocrine therapy, but not relapse interval were associated with an HR discordance in multivariable analysis. Loss of HR status was significantly associated with a risk of death (HR adjusted = 1.51, p = 0.002) while gain of HR and HER2 discordance was not. In conclusion, discordance of HR and HER2 expression between primary and metastatic breast cancer cannot be neglected. In addition, HR loss is associated with worse survival. Sampling metastatic sites is essential for treatment adjustment.