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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.

Background Treatment strategies for metastatic breast cancer (MBC) have made great strides over the past 10 years. Real-world data allow us to evaluate the actual benefit of new treatments. ESME (Epidemio-Strategy-Medico-Economical)-MBC, a nationwide observational cohort (NCT03275311), gathers data of all consecutive MBC patients who initiated their treatment in 18 French Cancer Centres since 2008. Patients and methods We evaluated overall survival (OS) in the whole cohort (N = 20 446) and among subtypes: hormone receptor positive, human epidermal growth factor 2 negative (HR+/HER2−; N = 13 590), HER2+ (N = 3919), and triple-negative breast cancer (TNBC; N = 2937). We performed multivariable analyses including year of MBC diagnosis as one of the covariates, to assess the potential OS improvement over time, and we described exposure to newly released drugs at any time during MBC history by year of diagnosis (YOD). Results The median follow-up of the whole cohort was 65.5 months (95% CI 64.6-66.7). Year of metastatic diagnosis appears as a strong independent prognostic factor for OS [Year 2016 HR 0.89 (95% CI 0.82-0.97); P = 0.009, using 2008 as reference]. This effect is driven by the HER2+ subcohort, where it is dramatic [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. YOD had, however, no sustained impact on OS among patients with TNBC [Year 2016 HR 0.93 (95% CI 0.77-1.11); P = 0.41, using 2008 as reference] nor among those with HR+/HER2– MBC [Year 2016 HR 1.02 (95% CI 0.91-1.13); P = 0.41, using 2008 as reference]. While exposure to newly released anti-HER2 therapies appeared very high (e.g. >70% of patients received pertuzumab from 2016 onwards), use of everolimus or eribulin was recorded in less than one-third of HR+/HER2– and TNBC cohorts, respectively, whatever YOD. Conclusion OS has dramatically improved among HER2+ MBC patients, probably in association with the release of several major HER2-directed therapies, whose penetrance was high. This trend was not observed in the other subtypes, but the impact of CDK4/6 inhibitors cannot yet be assessed., Highlights • OS of HER2+ MBC patients keeps improving over time [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. • This effect seems timely related to the release of drugs demonstrated to improve survival in clinical trials. • OS gains observed in real life among HER2+ MBC patients are at least equivalent to those observed in clinical trials. • YOD had no sustained impact on OS among patients with TNBC and luminal MBC. • The impact of CDK4/6 inhibitors cannot yet be assessed in this cohort.

International audience; Background: Diagnosis of atypical breast lesions (ABLs) leads to unnecessary surgery in 75-90% of women. We have previously developed a model including age, complete radiological target excision after biopsy, and focus size that predicts the probability of cancer at surgery. The present study aimed to validate this model in a prospective multicenter setting.- methods: Women with a recently diagnosed ABL on image-guided biopsy were recruited in 18 centers, before wire-guided localized excisional lumpectomy. Primary outcome was the negative predictive value (NPV) of the model.Results: The NOMAT model could be used in 287 of the 300 patients included (195 with ADH). At surgery, 12 invasive (all grade 1), and 43 in situ carcinomas were identified (all ABL: 55/287, 19%; ADH only: 49/195, 25%). The area under the receiving operating characteristics curve of the model was 0.64 (95% CI 0.58-0.69) for all ABL, and 0.63 for ADH only (95% CI 0.56-0.70). For the pre-specified threshold of 20% predicted probability of cancer, NPV was 82% (77-87%) for all ABL, and 77% (95% CI 71-83%) for patients with ADH. At a 10% threshold, NPV was 89% (84-94%) for all ABL, and 85% (95% CI 78--92%) for the ADH. At this threshold, 58% of the whole ABL population (and 54% of ADH patients) could have avoided surgery with only 2 missed invasive cancers.Conclusion: The NOMAT model could be useful to avoid unnecessary surgery among women with ABL, including for patients with ADH.

Aim Real-world data inform the outcome comparisons and help the development of new therapeutic strategies. To this end, we aimed to describe the full characteristics and outcomes in the Epidemiological Strategy and Medical Economics (ESME) cohort, a large national contemporary observational database of patients with metastatic breast cancer (MBC). Methods Women aged ≥18 years with newly diagnosed MBC and who initiated MBC treatment between January 2008 and December 2016 in one of the 18 French Comprehensive Cancer Centers (N = 22,109) were included. We assessed the full patients’ characteristics, first-line treatments, overall survival (OS) and first-line progression-free survival, as well as updated prognostic factors in the whole cohort and among the 3 major subtypes: hormone receptor positive and HER2-negative (HR+/HER2−, n = 13,656), HER2-positive (HER2+, n = 4017) and triple-negative (n = 2963) tumours. Results The median OS of the whole cohort was 39.5 months (95% confidence interval [CI], 38.7–40.3). Five-year OS was 33.8%. OS differed significantly between the 3 subtypes (p Conclusions The ESME program represents a unique large-scale real-life cohort on MBC. This study highlights important situations of high medical need within MBC patients. Database registration clinicaltrials.gov Identifier NCT032753.

Background: The HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) demonstrated efficacy in heavily pretreated HER2-over- and HER2-low expressing ABC (1, 2). We aimed to assess the activity of T-DXd in HER2-over-, HER2-low and HER2-nul expressing ABC, to describe the drug mechanisms of action in the 3 cohorts and to identify biomarkers associated to drug response or resistance. Study Description: DAISY is a multicenter, open-label phase II trial designed to assess the efficacy of single agent T-DXd at 5.4 mg/kg dose in ABC with extensive biomarkers analysis. Three cohorts of patients were included: Cohort 1 (HER2 over-expressing: HER2 3+ on immunohistochemistry (IHC) or HER2 IHC2+/in situ hybridization [ISH]+), Cohort 2 (HER2 low-expressing: IHC1+ or IHC2+/ISH-) and cohort 3 (HER2-nul: IHC0+). Biopsy of metastatic sites was performed: at baseline, on treatment (mandatory for cohort 1, optional for cohort 2/3) and at tumor progression; blood samples for ctDNA were collected at baseline. The primary endpoint was the Best Overall Response (BOR) in each cohort, according to the investigator assessment. Secondary endpoints were BOR by central assessment, clinical benefit rate, duration of response (DOR), progression-free (PFS), overall survival (OS) and safety. Results:185 women and 1 man were enrolled between November 2019 and March 2021. Among the patients enrolled in the safety population (see Table 1), median (range) age was 55 (24-82) years, all received at least one prior line of therapy and 12 patients were TN. Table 2 shows investigator-reported T-Dxd activity in the 3 cohorts at a median follow-up of 10.1 months [95%CI: 9.2-11.1]. A total of 170 patients (95%) had at least one treatment-related toxicity. Key grade ≥3 treatment-related toxicities included neutropenia (10.6% of patients), fatigue (5.6%), leucopenia (4.5%), vomiting (4.5%) and anemia (3.4%). A total of 4 patients had drug-related interstitial lung disease or pneumonitis (grade 1 in 3 patients and grade 2 in 1 patient), 11 patients discontinued treatment due to treatment-related adverse events. No drug-related deaths occurred. Conclusions: T-DXd showed clinically meaningful activity in patients with HER2-overexpressing ABC and interestingly also in those with HER2low and HER2-nul ABC. Safety profile was consistent with previous reports. 1.Modi S et al N Engl J Med 2020 2.Mosi S et al J Clin Oncol 2020 Table 1.Analysis populationsTotalCohort 1 (HER2 over-expressing)Cohort 2 (HER2 low-expressing)Cohort 3 (HER2 non-detected)Enrolled population186727440Safety population*179687338 (including 12 TN)Full analysis Set**176687236TN: Triple Negative. *: safety population = enrolled population except 7 patients who did not receive at least one dose of study drug. **: Full Analysis Set = safety population except 3 patients (2 who did not have a valid first post-baseline assessment of disease status or who did not have progressive disease and 1 who did not have at least one radiologically measurable lesion according to RECIST v1.1) Table 2.T-DXd activity in the three cohorts according to investigator assessmentTotalCohort 1Cohort 2Cohort 3BOR confirmedn/N82/176 (46.6%)47/68 (69.1%)24/72 (33.3%)11/36 (30.6%)[95%CI][39.1; 54.2][56.7; 79.8][22.7; 45.4]16.3; 48.1]Median DORmonths7.69.97.66.8[95%CI][6.2; 9.7][5.4; NR][4.4; 8.7][2.8; 8.3]Median PFSmonths6.911.16.74.2[95%CI][6.7; 8.7][8.4; NR][4.6; 8.5][2.1; 6.9]NR: Not Reached Citation Format: Véronique Diéras, Elise Deluche, Amélie Lusque, Barbara Pistilli, Thomas Bachelot, Jean-Yves Pierga, Frédéric Viret, Christelle Levy, Laura Salabert, Fanny Le Du, Florence Dalenc, Christelle Jouannaud, Laurence Venat-Bouvet, Jean-Philippe Jacquin, Xavier Durando, Thierry Petit, Céline Mahier - Aït Oukhatar, Thomas Filleron, Maria Fernanda Mosele, Magali Lacroix-Triki, Agnès Ducoulombier, Fabrice André. Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: A phase II study with biomarkers analysis (DAISY) [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 PD8-02.

Background: The double blind randomized UNIRAD trial (NCT01805271) showed no evidence that adding Everolimus (EVE) to adjuvant endocrine therapy (EHT) for high-risk early breast cancer (BC) improved 3-year disease-free survival (iDFS) compared with EHT alone. In this trial, high risk was defined by any T and either ≥4N+, or ≥1N+ after neoadjuvant treatment, or ≥1N+ and EPclin high risk (EPCH) score ≥3.3. This sub analysis is aimed to verify prognostic added value of EndoPredict test results on outcomes in patients screened for the UNIRAD study.. Material and methods: From May 2015 to March 2020, 777 patients were screened with the EndoPredict test. Complete results were obtained for 767 of them. 662 pts were classified as EPCH and 429 were randomized in UNIRAD. 233 pts with EPCH and 105 pts with EPclin low risk (EPCL) were not randomized but followed up for iDFS. Statistical analysis: Kaplan-Meier estimates the association of the integrated molecular-clinico-pathologic EPclin score, and the 12-gene molecular EP score, with iDFS (primary endpoint) and dMFS (secondary endpoint). Independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics (Grade and T, N). A two-sided p-value less than 0.05 considered as statistically significant, 95% confidence intervals reported with HR. Results: Median follow-up of the cohort was 36.6 mo (0-69) since EndoPredict test. As for the whole population, there was no significant difference in iDFS between treatment arms in the randomized EPCH group. On the other hand, EPclin was an independent prognostic factor for iDFS. 36 mo relapse rate from testing for patients in the EPCL group and the EPCH group was 0% and 7%, respectively (HR supposing continuous EPclin score: 2.36, 95%CI: 1.7-3.3, p < .0001). This difference remained significant when assessed in a cox model with tumor size, number of positive nodes and tumor grade (HR: 1.96, 95%CI: 1.32-2.9, p=0.0008). Furthermore, EPclin results was independently correlated to distant metastatic free survival: 36 mo dMFS for patient in the EPCL and EPCH group was 100% and 94%, respectively (adjusted HR: 2.13, 95%CI:11.3-3.4, p = .0014). Of interest when assessing prognostic of patients within quartiles of EPclin Score ( Citation Format: Frederique Penault-Llorca, Florence Dalenc, Sylvie Chabaud, Paul Cottu, Djelila Allouache, David Cameron, Jean-Philippe Jacquin, Julien Grenier, Laurence Venat Bouvet, Apurna Jegannathen, Mario Campone, Francesco Del Piano, Marc Debled, Anne-Claire Hardy-Bessard, Sylvie Giacchetti, Philippe Barthelemy, Laure Kaluzinski, Audrey Mailliez, Marie-Ange Mouret-Reynier, Eric Legouffe, Anne Cayre, Mathilde Martinez, Catherine Delbaldo, Delphine Mollon-Grange, E. Jane Macaskill, Matthew Sephton, Laëtitia Stefani, Blaha Belgadi, Matthew Winter, Hubert Orfeuvre, Magali Lacroix-Triki, Herve Bonnefoi, Judith Bliss, Jean-Luc Canon, Jerome Lemonnier, Fabrice Andre, Thomas Bachelot. Prognostic value of EndoPredict test in patients screened for UNIRAD, a UCBG randomized, double blind, phase III international trial evaluating the addition of everolimus (EVE) to adjuvant hormone therapy (HT) in women with high risk HR+, HER2- early breast cancer (eBC) [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 PD9-08.

Oncogene-induced replication stress (RS) promotes cancer development but also impedes tumor growth by activating anti-cancer barriers. To determine how cancer cells adapt to RS, we have monitored the expression of different components of the ATR-CHK1 pathway in primary tumor samples. We show that unlike upstream components of the pathway, the checkpoint mediators Claspin and Timeless are overexpressed in a coordinated manner. Remarkably, reducing the levels of Claspin and Timeless in HCT116 cells to pretumoral levels impeded fork progression without affecting checkpoint signaling. These data indicate that high level of Claspin and Timeless increase RS tolerance by protecting replication forks in cancer cells. Moreover, we report that primary fibroblasts adapt to oncogene-induced RS by spontaneously overexpressing Claspin and Timeless, independently of ATR signaling. Altogether, these data indicate that enhanced levels of Claspin and Timeless represent a gain of function that protects cancer cells from of oncogene-induced RS in a checkpoint-independent manner., Oncogene-induced replication stress (RS) promotes cancer development. Here, the authors report that cancer cells adapt to oncogene-induced RS by overexpressing downstream components of ATR-CHK1 pathway, Claspin and Timeless, which have protective role at the replication forks independent of their checkpoint function.

The cyclin-dependent kinase 4 (CDK4)/6 inhibitor Palbociclib is a new standard treatment in hormone-receptor positive breast cancer patients. No predictive biomarkers have been identified and no pharmacodynamics has properly been described so far.Patients with early-breast cancer were randomized 3 : 1 to oral palbociclib 125 mg daily for 14 days until the day before the surgery versus no treatment. Primary objective was antiproliferative response defined as a natural logarithm of Ki67 expression at day 15 below 1. Secondary end points were subgroups analyses and safety. Exploratory analyses included search for predictive biomarkers. Immunostainings (Ki67, RB, pRB, p16, pAKT, pER, pCDK2, CyclinD1), FISH (CCND1) and gene expression (GE) arrays were carried out at baseline and at surgery. In addition, activating PIK3CA and AKT1 mutations were assessed at baseline.74 patients were allocated to palbociclib and 26 to control. Most patients (93%) were hormone-receptor (HR)-positive, whereas 8% were HER2-positive. Palbociclib led to significantly more antiproliferative responses when compared with control (58% versus 12%, P 0.001), and to a significantly higher Ki67 decrease (P 0.001). In the HR-positive/HER2-negative subgroup, this antiproliferative effect was even more marked in the palbociclib arm when compared with control (70% versus 9%, P 0.001). Palbociclib treatment led also to a significantly higher decrease from baseline in phospho-Rb when compared with control (P 0.001). Among treated patients, changes in Ki67 correlated with changes in phospho-Rb (Spearman rank r = 0.41, P 0.0001). GE analyses confirmed a major effect on proliferation and cell cycle genes. Among treated patients, CCNE2 expression was significantly more decreased in antiproliferative responders versus nonresponders (P = 0.006).Short-term preoperative palbociclib decreases Ki67 in early-breast cancer patients. Early decrease of Rb phosphorylation correlates with drug's effect on cell proliferation and could potentially identify patients with primary resistance.NCT02008734.

Background The 21-gene Recurrence Score (RS) result predicts outcome and chemotherapy benefit in node-negative and node-positive (N+), estrogen receptor-positive (ER+) patients treated with endocrine therapy. The purpose of this study was to evaluate the prognostic impact of RS results in N+, hormone receptor-positive (HR+) patients treated with adjuvant chemotherapy (6 cycles of FEC100 vs. 3 cycles of FEC100 followed by 3 cycles of docetaxel 100 mg/m2) plus endocrine therapy (ET) in the PACS-01 trial (J Clin Oncol 2006;24:5664-5671). Methods The current study included 530 HR+/N+ patients from the PACS-01 parent trial for whom specimens were available. The primary objective was to evaluate the relationship between the RS result and distant recurrence (DR). Results There were 209 (39.4%) patients with low RS (

Purpose:Incidence of LRs in patients (pts) treated for HR+ HER2- localized BC and distribution overtime have not been described in recent years after introduction of new generation of adjuvant therapies and more extensive use of radiotherapy. We evaluated the incidence and distribution overtime of LRs in pts with HR+ HER2- N+ BCs who entered PACS 01 and PACS04 trials. Patients and Methods: Data were analyzed from 2909 pts with HR+/HER2- BC out of 5008 included in both trials. Pts underwent mastectomy or lumpectomy plus axillary dissection for a localized N+ BC and, according to study design, were randomized to: 6 cycles of FE100C (standard arm) versus FE100C x 3 cycles followed by docetaxel 100 mg/m2 x 3 cycles (FEC-D) (PACS01) or 6 cycles of Epirubicin 75mg/m2 and Docetaxel 75 mg/m2 (ED75)(PACS04). Loco-regional radiotherapy was mandatory after lumpectomy and recommended in other cases. All pts received 5 years of hormone therapy (HT). A competing risk multivariate analysis was conduct using Fine and Gray model to identify risk factors associated to isolated LRs. Competing events were nodal recurrence, contralateral BC, distant metastasis and death. Cumulative incidence associated to each event was estimated by a Kablfleish-Prentice estimator. Results: Pts' median age was 50 (22-65); 67.2% underwent lumpectomy, 32.8% mastectomy; 67.6% had 1 to 3 N+, 32.4% more than 3 N+; 45.7% had lymphovascular invasion; 49.5% received FE100C, 35.8% ET75, 14.7% had FEC-D; while radiotherapy was given to 97.3% and HT to 92.2%, of whom 90.5% received tamoxifen. At a median follow-up of 9.1 years, 60 pts (2.1%) experienced LR as first event. The 5-year and 10-year cumulative incidence of LRs were 1.04% and 2.53%, respectively. The cumulative incidence of LRs increased from the 5th year, and the annual risk tended to remain constant over time. Multivariate analysis of competing risk showed that younger age, conservative surgery and omission of HT (not prescribed or non-adherence) were independently associated with risk of developing LRs. Table 1. Multivariate analysis on competing risk of predictors of LRsVariablesHR 95%CIP valueAge at entry ( 20mm, ≤20 mm0.68 [0.37; 1.24]0.203N+ >3, 1-31.73 [0.99; 3.02]0.055Grade II/III, I1.06 [0.50; 2.24]0.885PR+,PR-1.78 [0.70; 4.53]0.223Type of chemotherapy 3FEC-3D, 6FEC/6ET1.32 [0.65; 2.69]0.446Number of cycles 6, Conclusion: Our analysis showed that incidence of LRs in pts with HR+ N+ BCs treated within PACS trials were considerably lower as compared to earlier studies. These findings may reflect differences in treatment era, as the more extensive use of radiotherapy and new generation of adjuvant chemotherapy. Despite current adjuvant strategies, young age at diagnosis and omission of HT remain independent risk factors of LRs. Citation Format: Pistilli B, Filleron T, Mazouni C, Zingarello A, Lacroix-Triki M, Rivera S, Coudert B, Serin D, Canon J-L, Campone M, Bachelot T, Goncalves A, Levy C, Cottu P, Petit T, Eymard J-C, Tunon De Lara C, Roché H, Roca L, Lemonnier J, Delaloge S. Overtime distribution and predictors of local recurrences (LRs) in patients with hormone receptor positive (HR+) and node positive (N+) breast cancers (BCs): 10 -year follow-up analysis of UNICANCER-PACS 01 and PACS04 trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-07.

Objectives The current challenge for the various digital whole-slide imaging (WSI) systems is to be definitively validated for diagnostic purposes. We designed a concordance study between glass slide and digital slide diagnosis in real-life conditions, coupled with an ergonomic study. Methods Three senior pathologists evaluated, first in glass slides and then in digital slides, 119 biopsy cases, including 749 slides, with 332 H&E saffron stains and 417 additional techniques, mainly immunohistochemistry. Results All digital slides, including specially stained slides, were interpretable. Concordance between glass slides and digital slides was observed in 87.4% of cases. Minor discordances were observed in 12 (10.1%) cases and major discordances, with therapeutic impact, in three (2.5%), including one related to WSI. The satisfaction of participants was high and increased with time. Conclusions Our study confirms the feasibility and accuracy of WSI diagnosis, even for cases having multiple samples and requiring special staining techniques, such as immunohistochemistry and in situ hybridization.

Les cancers du sein sont subdivises selon leur degre d'expression des recepteurs hormonaux et du gene HER2 . La classification moleculaire a bouleverse cette conception simpliste en mettant en lumiere de multiples profils de pronostics differents. C'est dans ce contexte, et devant la necessite d'employer des traitements cibles que sont nees les signatures moleculaires. Bien qu'elles different par les methodes employees (qRT-PCR, microarray ou derives type n-counter ), elles ont les memes objectifs : calculer un score pronostique, fonde sur les niveaux d'expression de genes impliques dans la cancerogenese, et si possible predire la reponse au traitement. Applicables essentiellement aux tumeurs luminales RE+, elles ont prouve leur valeur pronostique dans de vastes essais prospectifs, et les experts souhaitent les integrer dans la decision therapeutique, actuellement etablie sur les criteres clinicopathologiques. Par ailleurs, comparativement aux couts d'une chimiotherapie, les signatures moleculaires apportent un reel benefice financier et permettent d'equilibrer la balance benefice/risque en diminuant le recours a des traitements agressifs parfois inefficaces.

Background: HEV are specialized blood vessels that function as portals of entry for lymphocytes into lymphoid organs and tumor tissues (Moussion and Girard, Nature 2011, 479:542-546; Girard et al, Nature Rev Immunol 2012, 12:762-773). We retrospectively considered HEV and CD8 as potential prognostic and/or predictive factors in a large randomized adjuvant trial of node positive breast cancer patients (PACS04). This trial included 3010 node positive patients randomized between anthracyclins alone or anthracyclins and docetaxel chemotherapy. Patients with HER2+ expressing tumors had a second randomization with or without trastuzumab given sequentially for one year. With 59.5 median follow-up, metastatic free interval (MFI), the first end-point, was 84.5% at 5 years for the whole population. Methods: 1660 tumor samples (9.7% triple negative, 67.5% HR+/HER2- and 22.8% HER2+) were collected and analyzed by immunostaining on full sections for HEV (MECA-79 mAb, BD Biosciences) and CD8 (C8/144B mAb, Dako). HEV densities were determined as previously described (Martinet et al., Cancer Res 2011, 71:5678-5687). CD8+ cells and tumor-infiltrating lymphocytes (TIL) were scored according to recently published guidelines. Univariate analyses were performed using cox proportional hazard model for continuous variable. Independent analyses for the predictive evaluation of trastuzumab outcome were performed in the HER2+ subgroup. Results: MFI and overall survival at 5 years for this series are respectively of 84.9% (TN: 77.4%, HR+/HER2-: 89%, HER2+:75.8%) and 91% not different with the total group. The table shows expression of the different markers according to the subgroup of tumors. Marker values according to sub molecular classification TNRH+/HER2-HER2+/RH-Number1601119378Metastatic events3411990HEV/mm2(median,range)0.51 (0, 7.73)0.13 (0, 10.23)0.38 (0, 13.63)CD8score (median, range)2 (0, 3)1 (0, 3)2 (0, 3)Table 1 No difference in univariate analysis was observed in TN and HR+/HER2- subgroups in terms of relationship between marker expression and outcomes. For the HER2+ group, HEV and CD8 were correlated to better outcome (HEV: HR=0.73, p =0.011; CD8: HR=0.64; p=0.006). For HER2+ patients not receiving trastuzumab (222 pts, 55 events), CD8 was predictive of metastasis risk (HR: 0.65, p=0.032), but not HEV (HR:0.82, p=0.09). Conversely, in the trastuzumab treated group (156 pts, 35 events), HEV was significantly correlated with a lower risk of relapse (HR: 0.45, p=0.02), but CD8 was not (HR:0.63, p=0.07). TIL counts are still ongoing and will be reported at time of presentation. Conclusions: HEV and CD8 are associated with better prognosis in the HER2+ tumor group. Interestingly, HEV presence in the tumor seems to be a significant predictive factor of trastuzumab efficacy. Citation Format: Roché HH, Lafouresse FF, Filleron T, Laffont R, Maisongrosse V, Pichery M, Le Guellec S, Penault-Llorca F, Lemonnier J, Lacroix-Triki M, Girard J-P. Prognostic and predictive values of high endothelial venules (HEV) and tumor infiltrating CD8+ lymphocytes (CD8) in tumors of patients included in the adjuvant PACS04 trial: HEV is predictive of outcome for HER2+ tumors exposed to trastuzumab [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-05.

With the major development of immunotherapies, evaluation of the immune response associated to cancer has become the new challenge for pathologists. In breast cancer, this perspective has been notably anticipated by the recent publication, in 2014, of international guidelines for assessment of tumor-infiltrating lymphocytes (TILs), on routine haematoxylin-eosin stains. This technical article aims at reviewing the main key points and different steps in evaluation of tumor-infiltrating lymphocytes, in order to allow an easy implementation of this putative biomarker in routine practice. Widespread diffusion of international guidelines is the key to development of a standardized and reproducible biomarker. This early learning phase is of particular importance, as immune response will probably play a major role as a prognostic and predictive biomarker, especially in triple-negative and HER2 positive breast cancer.

International audience; Predictive biomarkers for tumor response to neoadjuvant chemotherapy are needed in breast cancer. This study investigates the predictive value of 280 genes encoding proteins that regulate microtubule assembly and function. By analyzing 3 independent multicenter randomized cohorts of breast cancer patients, we identified 17 genes that are differentially regulated in tumors achieving pathological complete response (pCR) to neoadjuvant chemotherapy. We focused on the MTUS1 gene, whose major product, ATIP3, is a microtubule-associated protein down-regulated in aggressive breast tumors. We show here that low levels of ATIP3 are associated with an increased pCR rate, pointing to ATIP3 as a predictive biomarker of breast tumor chemosensitivity. Using preclinical models of patient-derived xenografts and 3-dimensional models of breast cancer cell lines, we show that low ATIP3 levels sensitize tumors to the effects of taxanes but not DNA-damaging agents. ATIP3 silencing improves the proapoptotic effects of paclitaxel and induces mitotic abnormalities, including centrosome amplification and multipolar spindle formation, which results in chromosome missegregation leading to aneuploidy. As shown by time-lapse video microscopy, ATIP3 depletion exacerbates cytokinesis failure and mitotic death induced by low doses of paclitaxel. Our results favor a mechanism by which the combination of ATIP3 deficiency and paclitaxel treatment induces excessive aneuploidy, which in turn results in elevated cell death. Together, these studies highlight ATIP3 as an important regulator of mitotic integrity and a useful predictive biomarker for a population of chemoresistant breast cancer patients.

International audience; Purpose: The identification of molecular biomarkers for classification of breast cancer is needed to better stratify the patients and guide therapeutic decisions. The aim of this study was to investigate the value of MAPRE1 gene encoding microtubule-end binding proteins EB1 as a biomarker in breast cancer and evaluate whether combinatorial expression of MAPRE1 and MTUS1 gene encoding EB1-negative regulator ATIP3 may improve breast cancer diagnosis and prognosis.Methods: Probeset intensities for MAPRE1 and MTUS1 genes were retrieved from Exonhit splice array analyses of 45 benign and 120 malignant breast tumors for diagnostic purposes. Transcriptomic analyses (U133 Affymetrix array) of one exploratory cohort of 150 invasive breast cancer patients and two independent series of 130 and 155 samples were compared with clinical data of the patients for prognostic studies. A tissue microarray from an independent cohort of 212 invasive breast tumors was immunostained with anti-EB1 and anti-ATIP3 antibodies.Results: We show that MAPRE1 gene is a diagnostic and prognostic biomarker in breast cancer. High MAPRE1 levels correlate with tumor malignancy, high histological grade and poor clinical outcome. Combination of high-MAPRE1 and low-MTUS1 levels in tumors is significantly associated with tumor aggressiveness and reduced patient survival. IHC studies of combined EB1/ATIP3 protein expression confirmed these results.Conclusions: These studies emphasize the importance of studying combinatorial expression of EB1 and ATIP3 genes and proteins rather than each biomarker alone. A population of highly aggressive breast tumors expressing high-EB1/low-ATIP3 may be considered for the development of new molecular therapies.

The aim of the current study was to conduct a pooled analysis of studies that have investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in early-stage triple negative breast cancer (TNBC)., SCOPUS: ar.j, info:eu-repo/semantics/published

The optimal management of patients with pathologically node-negative triple-negative breast cancer (pN0 TNBC) remains unclear. We hypothesized that lymph node irradiation (LNI; internal mammary chain/periclavicular irradiation) had an impact on outcomes of pN0 TNBC. A cohort of 126 consecutive patients with pN0 TNBC treated between 2007 and 2010 at a single institute were included. All radiotherapy (breast/chest wall, ±LNI) was delivered adjuvantly, following completion of surgery ± chemotherapy. Tumors were reviewed and histologic features were described. Tissue microarrays were constructed and tumors were assessed by immunohistochemistry using antibodies against ER, PR, HER2, Ki-67, cytokeratins 5/6, 14, epidermal growth factor receptor and androgen receptor. Patients were divided into two groups for statistical analysis: LNI (LNI+) or no LNI (LNI-). We focused on disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS). Fifty-seven and 69 patients received or not LNI, respectively. Median age was 52 (range [25-76]) and 55 (range [29-79]) in LNI+ and LNI- group (p = 0.23). LNI was associated with larger tumors (p = 0.033), central/internal tumors (33 versus 4, p 0.01) and more chemotherapy (86% versus 59.4% p 0.01). The median follow-up was 53.5 months. The rate of first regional relapse (associated or not with distant relapse) was low in both groups. There was no difference in 4-year DFS (82.2% versus 89.9%; p = 0.266), MFS (87.0% versus 91.1%; p = 0.286) and OS (85.8% versus 89.9%; p = 0.322) between LNI+ and LNI- group, respectively. In univariate analysis, only clinical size (T10 mm versus ≤10 mm), histologic size (pT10 mm versus ≤10 mm) and grade 3 (versus grade 2) were found to be significantly associated with shorter DFS. Omission of LNI in patients with pN0 TNBC does not seem to result in poorer outcome. Further studies are needed to specifically evaluate LNI in pN0 TNBC with histologic grade 3 and/or (p)T 10 mm.

Background: Ixabepilone, an epothilone B analog, has demonstrated single-agent activity in metastatic and neoadjuvant settings. The PACS08 trial aimed to compare adjuvant FEC100-Docetaxel regimen to FEC100-Ixabepilone in poor prognosis early breast cancer (BC) composed of patients presenting with triple-negative (TN) [i.e. estrogen receptor (ER)-/progesterone receptor (PR)-/HER2-] or ER+/PR-/HER2- tumor, which are subgroups significantly associated with worse prognosis. Patients and methods: Between 2007 and 2010, 762 patients with unilateral TNBC (n=592, 78%) or node-positive ER+/PR-/HER2- BC (n=170, 22%) were enrolled. Recruitment was interrupted due to BMS decision to stop ixabepilone development in adjuvant setting. Main inclusion criteria were: age Results: Main pts characteristics were well balanced between the 2 arms. As of September 2014, the median follow-up was 36 months. The safety profile indicates that Docetaxel is more often associated to significant haematological toxicities whereas both neurotoxicities and haematological toxicities are reported in Ixabepilone arm. Log-Rank tests indicate no difference between two arms in terms of both DFS and OS (HR=1.2, 95%CI (0.864-1.728), p=0.256 and HR=1.8, 95%CI (0.751-1.855), p=0.473, respectively). Pathological analysis of the PACS08 collection showed that TNBC displayed significantly higher proliferative activity as shown by mitotic count and Ki67 index (p Conclusions: Our results indicate that Ixabepilone doesn't show higher efficiency compared to Docetaxel in adjuvant setting in poor prognosis early breast cancer. We have an unusual biological collection associated to our clinical data which will allow us to correlate efficacy data to breast cancer subgroups. Other several translational researches are still ongoing. Citation Format: Campone M, Lacroix-Triki M, Roca L, Spielmann M, Wildiers H, Cottu P, Kerbrat P, Levy C, Mayer F, Bachelot T, Wiston T, Eymard J-C, Uwer L, Machiels J-P, Verhoeven D, Jaubert D, Facchini T, Orfeuvre H, Canon J-L, Asselain B, Lemonnier J, Roché H. UCBG intergroup: 3-years efficacy results of the Unicancer-PACS08 trial including poor prognosis patients treated with docetaxel or ixabepilone in adjuvant setting. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-12-06.

Background. Ductal carcinoma in situ (DCIS) of the breast is considered to be a non-obligatory precursor of invasive breast cancer. Its histopathological assessment is characterized by considerable inter-observer discordance. In a previous study, we performed post hoc dichotomization of multi-categorical variables to determine the ‘ideal’ cut-offs for dichotomous histopathological assessment. In the present multicenter study, inter-observer variability is evaluated among 39 pathologists who performed upfront dichotomous evaluation of a consecutive series of 149 DCIS. Methods. All participants were board-certified pathologists with a special interest in breast disease. The participants assessed at least 50 primary oncologic breast cancer resection specimens per year, in accordance with the EUSOMA criteria for dedicated breast pathologists. No training set was used. Instead, a written guideline with associated DCISion poster was provided, which contained all definitions of the histopathological features of interest. Representative digital slides of 149 DCIS were accessible via an online platform. All pathologists independently assessed the following histopathological features: nuclear atypia, necrosis, solid DCIS architecture, calcifications, stromal architecture and lobular cancerization. Stromal inflammation was assessed semi-quantitatively. Stromal tumor-infiltrating lymphocytes (TILs) were quantified as percentages and were also dichotomously assessed with a cut-off at 50%. Krippendorff’s alpha (KA), Cohen’s kappa (K) and intraclass correlation coefficient (ICC) were calculated for the appropriate variables. Results. Intraductal calcifications (KA 0,676) and solid DCIS architecture (KA 0,602) were characterized by the highest inter-observer concordance. Stromal inflammation (KA 0,564), dichotomously assessed TILs (KA 0,520) and comedonecrosis (KA 0,539) showed slightly higher inter-observer agreement. Lobular cancerization (KA 0,396), nuclear atypia (KA 0,422) and stromal architecture (KA 0,450) showed the lowest inter-observer concordance. Assessment of TILs as a percentage showed good overall agreement with a mean ICC of 0,821 (range 0,566 - 0,933). Semi-quantitative assessment of stromal inflammation (KA 0,564) resulted in somewhat lower inter-observer variability than upfront dichotomous TILs assessment (KA 0,520). High stromal inflammation corresponded best with dichotomously assessed TILs when the TILs cut-off was set at 10% (K 0,881). Nevertheless, a post hoc TILs cut-off set at 20% resulted in the highest inter-observer agreement (KA 0,669). Experience and time dedicated to breast pathology did not influence the degree of concordance. Conclusion. The DCSion study shows that, despite upfront dichotomous evaluation, the inter-observer variability remains considerable and is at most acceptable. Nevertheless, the discordance rate varies among the different histopathological features. Future studies should investigate its impact on DCIS risk stratification. Differences in prognostic value among the different methods to quantify TILs are of particular interest, since inter-observer variability may partly explain different outcomes among different studies. Artificial intelligence might be able to tackle this diagnostic challenge. Development of deep learning algorithms could result in more objective histopathological assessment. Although machine learning might represent the next “pathologist’s best friend”, we should be careful not to introduce inter-observer variability into these deep learning algorithms. The DCISion study therefore provides an excellent setting to investigate the value of such algorithms in rendering the final diagnosis more robust. Citation Format: Mieke Rosalie Van Bockstal, Hélène Dano, Serdar Altinay, Laurent Arnould, Noella Bletard, Cecile Colpaert, Franceska Dedeurwaerdere, Benjamin Dessauvagie, Valérie Duwel, Giuseppe Floris, Stephen Fox, Clara Gerosa, Shabnam Jaffer, Eline Kurpershoek, Magali Lacroix-Triki, Andoni Laka, Kathleen Lambein, Gaëtan Marie MacGrogan, Caterina Marchió, Dolores Martin Martinez, Sharon Nofech-Mozes, Dieter Peeters, Alberto Ravarino, Emily Reisenbichler, Erika Resetkova, Souzan Sanati, Anne-Marie Schelfhout, Vera Schelfhout, Abeer M Shaaban, Renata Sinke, Claudia Maria Stanciu-Pop, Claudia Stobbe, Carolien HM van Deurzen, Koen Van de Vijver, Anne-Sophie Van Rompuy, Stephanie Verschuere, Anne Vincent-Salomon, Hannah Wen, Caroline Bouzin, Christine Galant. Upfront dichotomous histopathological assessment of ductal carcinoma in situ of the breast to reduce inter-observer variability: The DCISion study [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 P5-02-04.

Salivary gland-like tumours are described in the breast but remain very rare and difficult to diagnose in this location. Only 37 cases of mucoepidermoid carcinoma have been described in the literature. We report the challenging diagnosis of a mucoepidermoid carcinoma sampled by core biopsy in a 51-year-old woman.

Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort.ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008-31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor-positive and HER2-negative (HR+/HER2-, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR-/HER2-, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts.Median OS of the whole cohort was 37.22 months (95% confidence interval [CI], 36.3-38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 [95% CI, 0.97-1.00], P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2-, HER2+ and HR-/HER2- subcohorts was, respectively, 42.12 (95% CI, 40.90-43.10), 44.91 (95% CI, 42.51-47.90) and 14.52 (95% CI, 13.70-15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 [95% CI, 0.88-0.94], P .001), but not in HR+/HER2- nor HR-/HER2- subcohorts (hazard ratio 1.00 [95% CI, 0.98-1.01], P = .80 and 1.00 [95% CI, 0.97-1.02], P = .90, respectively).The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes.

The current challenge for the various digital whole-slide imaging (WSI) systems is to be definitively validated for diagnostic purposes. We designed a concordance study between glass slide and digital slide diagnosis in real-life conditions, coupled with an ergonomic study.Three senior pathologists evaluated, first in glass slides and then in digital slides, 119 biopsy cases, including 749 slides, with 332 HE saffron stains and 417 additional techniques, mainly immunohistochemistry.All digital slides, including specially stained slides, were interpretable. Concordance between glass slides and digital slides was observed in 87.4% of cases. Minor discordances were observed in 12 (10.1%) cases and major discordances, with therapeutic impact, in three (2.5%), including one related to WSI. The satisfaction of participants was high and increased with time.Our study confirms the feasibility and accuracy of WSI diagnosis, even for cases having multiple samples and requiring special staining techniques, such as immunohistochemistry and in situ hybridization.

Purpose: UNICANCER-PACS08 compared adjuvant FEC (5-FU; epirubicin; cyclophosphamide) then docetaxel to FEC then ixabepilone in poor prognosis early breast cancer (BC). We evaluated whether replacing docetaxel with ixabepilone would increase 5-year disease-free survival (DFS). Patients and methods: Triple-negative breast cancer (TNBC) or oestrogen receptor (ER) +/progesterone receptor (PR) -/HER2- BC patients were randomised to receive standard FEC (3 cycles) followed by 3 cycles of either docetaxel (100 mg/m(2)) or ixabepilone (40 mg/m 2). Radiotherapy was mandatory after conservative surgery; ER+ patients received endocrine therapy. Results: Seven hundred sixty-two patients were enrolled between October 2007 and September 2010. Baseline characteristics were balanced between arms. Median follow-up was 66.7 months. Median DFS was not reached; 5-year DFS rate was 76% with docetaxel and 79% with ixabepilone (hazard ratio [HR] = 0.80; 95% confidence interval [CI] = 0.58-1.10; p = 0.175). Median overall survival (OS) was not reached; 5-year OS rate was 86% versus 84% (HR = 0.97; 95% CI = 0.66-1.42; p = 0.897). TNBC patients treated with ixabepilone had a 23% lower risk of relapse compared to docetaxel (HR for DFS = 0.77; 95% CI = 0.53-1.11; p = 0.168). DFS was longer with ixabepilone than docetaxel in patients with grade II-III lymphocytic infiltration (HR = 0.55; 95% CI = 0.29-1.05; p = 0.063). All patients experienced >= 1 adverse events (AEs): 75% reported grade III-IV AEs and two (

Luminal breast cancers (i.e. displaying œstrogen receptor expression) account for 70 to 80% of all breast cancers. It encompasses a heterogeneous population of tumors, differing by their clinical course, histopathological characteristics, phenotypes and molecular features. As a continuum of lesions, luminal breast tumors are critically challenged by the recent evolution in treatment decision making. Indeed, whilst about half of luminal breast cancers are associated with a very good prognosis (so-called luminal A tumors with regard to the intrinsic molecular classification), 20% of luminal tumors display a poor clinical outcome (i.e. luminal B tumors), the remaining tumors corresponding to intermediate lesions that are very difficult to accurately classify. Clearly, therapeutic issues are critical, since according to the vast majority of international consensus guidelines luminal A tumors are best treated by endocrine therapy, whilst an additional adjuvant chemotherapy will be proposed to patients harbouring luminal B breast cancer. By providing precise histopathological, phenotypic and molecular characterization of luminal breast tumors, the pathologist is actually the cornerstone of this therapeutic decision. Herein we aim to review the state-of-the-art knowledge on luminal breast carcinomas, with a perspective of routine clinical practice in 2015.

International audience; Breast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3β,5α,6β-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3β,5α-diol (OCDO) by 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2). 11βHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11βHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11βHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11βHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic pathway producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor (GR), the nuclear receptor of endogenous cortisol. Interestingly, high GR expression or activation correlates with poor therapeutic response or prognosis in many solid tumors, including BC. Targeting the enzymes involved in cholesterol epoxide and glucocorticoid metabolism or GR may be novel strategies to prevent and treat BC.

Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecological system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

International audience; Solid papillary carcinoma with reverse polarity is a rare breast cancer of favorable prognosis that can be difficult to diagnose. We report here nine additional cases of this tumor, and we describe its morphologic, immunohistochemical and molecular profile in comparison to other types of papillary and micropapillary lesions of the breast that are intraductal papilloma with usual ductal hyperplasia, encapsulated papillary carcinoma, solid papillary carcinoma and invasive micropapillary carcinoma. We studied nine cases of this special papillary tumor and six of each other types mentioned above. We found that solid papillary carcinoma with reverse polarity harbor specific morphologic features as cuboid or tall cells with abundant eosinophilic cytoplasms located at the basal pole giving the impression of reverse nuclear polarity. Nuclei were sometimes grooved. Immunohistochemistry demonstrated the lack of myoepithelial cells, as in encapsulated papillary carcinoma and solid papillary carcinoma, questioning their invasive nature. Seven of nine solid papillary carcinoma with reverse polarity showed a low Ki67 proliferative index (Ki67

International audience; De nouvelles recommandations internationales pour l’évaluation du statut HER2 dans les cancers du sein, basées sur plus de dix ans d’expérience et sur les résultats d’études cliniques et de concordance entre les différentes techniques de détection, viennent tout juste de voir le jour. Le présent article a pour objet de faire le point sur ces nouvelles recommandations, à la lumière de la publication récente du groupe de travail de l’American Society of Clinical Oncology (ASCO) et du Collège des pathologistes américains (CAP), adaptées à la pratique de la pathologie en France et revues par le groupe GEFPICS. À l’ère de la médecine personnalisée, la détermination du statut HER2 reste un élément phare dans le panel des biomarqueurs théranostiques des cancers du sein. Si l’interprétation du statut HER2 dans les cancers du sein est aisée dans la majorité des cas, un certain nombre de situations anatomocliniques est d’interprétation plus délicate, telles que la possibilité rare mais réelle de l’hétérogénéité intra-tumorale du statut de HER2, les formes à différenciation micropapillaire ou la ré-évaluation du statut des biomarqueurs lors de la rechute métastatique. Ces nouvelles recommandations abordent ces différentes questions, reprécisent les conditions pré-analytiques optimales et les critères d’interprétation (notamment des cas 2+), afin de réduire au maximum le risque de faux négatifs. Plus que jamais, la mobilisation de la spécialité d’anatomo-cytopathologie autour de la qualité des tests théranostiques témoigne de son implication dans la chaîne des soins en cancérologie., Summary International guidelines on HER2 determination in breast cancer have just been updated by the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), on the basis of more than ten-year practice, results of clinical trials and concordance studies. The GEFPICS group, composed of expert pathologists in breast cancer, herein presents these recommendations, adapted to the French routine practice. These guidelines highlight the possible diagnosis difficulties with regards to HER2 status determination, such as intra-tumor heterogeneity, special histological subtypes and biomarker re-evaluation during metastatic relapse. Pre-analytical issues and updated scoring criteria (especially for equivocal cases) are detailed, in order to decrease the occurrence of false negative cases. In the era of personalized medicine, pathologists are more than ever involved in the quality of oncotheranostic biomarker evaluation.]

Grâce aux avancees des technologies de biologie moleculaire, des progres majeurs ont ete accomplis ces dernieres annees dans la comprehension de la biologie tumorale. Si la cible premiere reste la cellule cancereuse, le microenvironnement est clairement indissociable de cette derniere et joue un role primordial dans la prise en charge diagnostique, a toutes les etapes du parcours clinique et histopathologique. L’analyse du microenvironnement fait en effet partie integrante non seulement du diagnostic histologique de tumeur (element essentiel permettant la classification histologique des tumeurs), mais aussi de l’evaluation pronostique de la maladie, et meme de la strategie therapeutique. Au cours des prochaines annees, de nouveaux biomarqueurs pronostiques et/ou predictifs, representatifs du stroma tumoral, seront certainement proposes et passeront les phases de validation clinique.

With the major development of immunotherapies, evaluation of the immune response associated to cancer has become the new challenge for pathologists. In breast cancer, this perspective has been notably anticipated by the recent publication, in 2014, of international guidelines for assessment of tumor-infiltrating lymphocytes (TILs), on routine haematoxylin-eosin stains. This technical article aims at reviewing the main key points and different steps in evaluation of tumor-infiltrating lymphocytes, in order to allow an easy implementation of this putative biomarker in routine practice. Widespread diffusion of international guidelines is the key to development of a standardized and reproducible biomarker. This early learning phase is of particular importance, as immune response will probably play a major role as a prognostic and predictive biomarker, especially in triple-negative and HER2 positive breast cancer.

Background Despite a growing number of studies exploring the underlying mechanisms, resistance to trastuzumab (TTZ) in HER2+ breast cancer (BC) remains elusive and an important issue in clinical practice. Among the proposed mechanisms, involvement of the PI3K/Akt/mTOR pathway is one of the best characterized. In a previous preclinical and clinical study (n = 54) (Bergé Y et al, SABCS 2009 and [1]), we have shown a significant correlation between eIF4E (a downstream effector of the PI3K/Akt/mTOR pathway) expression level as determined by immunohistochemistry (IHC) on initial tumor biopsy and pathological complete response (pCR) in patients with HER2+ BC treated with a neoadjuvant TTZ-containing regimen. The aim of this study was to validate these findings on an independent and larger cohort of HER2+ BC treated in neoadjuvant setting. Method In this multicenter (n = 9) study, 274 patients (pts) with HER2+ BC treated were included. All pts received neoadjuvant chemotherapy regimen containing TTZ, consisting mostly of 3-4 cycles of FEC (5FU, Epirubicin, Cyclophosphamid) followed by 3-4 cycles of TTZ–Docetaxel (n = 116). 74 pts received 6 cycles of TTZ–Docetaxel, 18 received 6 cycles of TTZ–Docetaxel-Cyclophosphamid, 12 received 6 cycles of TTZ–Docetaxel-carbolpatine, and the remaining 54 pts received other regimens. Pathological response was assessed according to Sataloff and Chevallier criteria. Unstained slides from the initial tumor biopsy were centrally collected for biomarkers analysis. Expression levels of eIF4E, p-4EBP1 and pS6 were determined by IHC. An immunoreactive score (IRS) combining the percentage of stained tumor cells and staining intensity was assessed by two pathologists. Results Median age at diagnosis was 50 years [range 22–84]. Most pts presented with T2 (52.6%), N1 (53.9%) stage, with a median tumor size of 40mm [range 0-150mm] as determined on clinical examination. Tumors were mainly invasive ductal of no special type (93.8%), of histological grade III (50%) and II (45%), ER+ (54.4%). Breast conserving surgery with free margins was achieved in 50.9% of pts. pCR (breast Sataloff TA) was observed in 53% of pts, and in 47.6% when considering both breast and lymph node response. Out of the 274 pts, 257 had sufficient tumor on the initial biopsy for biomarker analysis. Preliminary results showed a median eIF4E IRS of 6 [range 1-12], with 52.1% of cases displaying a low eIF4E expression level (IRS£6). The agreement for inter-observer assessment of eIF4E status was good (k = 0.618, 95% CI [0.523-0.713]). Scoring of p-4EBP1 and pS6 are ongoing and correlations of pCR with eIF4E/4EBP1 axis will be presented. Conclusion In this large multicentre retrospective study, the rate of pCR obtained in neoadjuvant setting of HER2+ BC is similar to those described in the literature. Thorough tumor collection allows biomarkers analysis, which has been specifically focused on downstream effectors of the PI3K/Akt/mTOR pathway. Reference[1] Zindy P, Bergé Y, Allal B et al. Formation of the eIF4F translation-initiation complex determines sensitivity to anticancer drugs targeting the EGFR and HER2 receptors. Cancer Res. 2011;71(12):4068-73. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-13.

Background The genomic grade index (GGI) completes the prognostic value of histological grade (HG). Other proliferation markers include the mitotic activity index (MAI) and the Ki67 immunohistochemistry (IHC) status. We compared the prognostic value of GGI, HG, MAI, Ki67 IHC and messenger RNA (mRNA) status in node-positive breast cancer (BC) patients treated with adjuvant anthracycline-based chemotherapy in the prospective PACS01 trial. Patients and methods The five proliferation-related parameters (GGI, Ki67 mRNA expression and centrally determined HG, MAI, and Ki67 IHC status) of tumours were available for 204 cases and analysed as continuous values. We compared the correlations of each one with the other proliferation-related parameters and with histoclinical variables including the disease-free survival (DFS). Results Expected correlations were observed between the five parameters and for each parameter with biological features (hormone-receptor and HER2 status, molecular subtypes), but the GGI displayed the strongest correlations. The GGI outperformed the prognostic performance of the four other proliferation-related parameters for the DFS in all 204 patients and in the 95 HG2 patients. In multivariate analysis including the classical prognostic factors, only GGI remained significant. Finally, the GGI outperformed the prognostic performance of MKI67 mRNA expression in a series of 1599 samples and 656 HG2 cases. Conclusions In this small pilot biomarker study ancillary to the PACS01 trial, the GGI outperforms the prognostic performance of centrally determined HG, MAI, Ki67 IHC status and mRNA expression. Further validation is warranted in larger series.

Background: The incidence of infra-centimetric breast cancer (BC) is increasing due to mass screening. The management remains controversial opposing locoregional treatment only based on low stage and potentially aggressive tumor biology (especially for triple negative and HER2 positive tumors). The objectives of the prospective multicenter ODISSEE study were i) to describe daily practice management of pT1ab BC, ii) to identify potential new biomarkers and iii) to describe long term outcome (10-year follow up). Methods: 616 patients with unifocal pT1a, b pN0M0 BC were included after surgery from May 2009 to March 2010 in 116 centers. Paraffin blocks were available for central pathology review in 350 patients. Due to the small tumor size, tissue microarray (TMA) construction was finally achieved for 287 cases. Collection of additional tumor blocks is ongoing. Review of the cases was performed independently by two pathologists and discordant cases were reviewed under a multihead microscope. Histological characteristics (histological type, tumor size and grade, presence of in situ component, presence of lymphovascular invasion) were assessed on whole tissue sections. Immunohistochemical detection of ER, PR, HER2, Ki67, EGFR, cytokeratin 5/6, Bcl-2 was performed on TMAs. Results: Clinicopathological characteristics of the 287 centrally reviewed cases were similar to those of the 616 patients included in the cohort. Median age: 60.1 years (range [31–89] years). Median tumor size: 7.8 mm (range [1–10] mm) with 11% pT1a and 89% pT1b. Histological types: 72% ductal, 11% lobular and 17% other types (among which 53% of tubular). Minor in situ component was found in 36% of the cases, and invasive carcinoma with an extensive in situ component in 1.9%. Most of tumors were histological grade I and II (52% and 40% respectively), 8% were grade III. Proliferation was low as assessed by mitotic count (low 82%, intermediate 13% and high 5%) or by Ki67 index ( Conclusions: The pT1a, bpN0M0 BC ODISSEE patients were mainly grade I or II, low proliferative HR+/HER2− tumors (i.e. the so-called luminal A subtype). Adjuvant treatment decision was mainly based on the presence of an aggressive phenotype such as HER2+ and triple negative tumors. A further exploration of ER/luminal pathway (FoxA1, GATA3, androgen receptor, Cox-2) and of PI3K/Akt/mTOR pathway (eIF4E, 4EBP, p70S6) is ongoing and will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-21-01.

Aims: HER2 gene amplification is observed in up to 15% of breast carcinomas. In a rare subset of breast cancers classified as HER2-positive by immunohistochemistry and in situ hybridisation, HER2 overexpression and gene amplification are restricted to a subset of >30% but not all cancer cells. Here we sought to characterise the repertoire of gene copy number aberrations and somatic mutations in the HER2-positive and HER2-negative components of cases with heterogeneous HER2 overexpression and gene amplification. Material and methods: Cases diagnosed as HER2 positive but with >30% but Results: Twelve cases yielded sufficient DNA for aCGH analysis. Tumours were preferentially ER positive (83%) and of histological grade 3 (67%). The HER2-positive and HER2-negative components of all cases shared most of the copy number aberrations. A pairwise comparison of the genomic profiles of the two components from each case revealed that in ten of the twelve cases, copy number aberrations in addition to 17q12 amplification encompassing the HER2 gene locus were restricted to one of the two components. Exome sequencing of two cases suggested that the HER2-positive and HER2-negative components from each case harboured >30 somatic mutations in common, including identical TP53 somatic mutations in both components of each case. The HER2-negative component of one of the cases displayed a somatic mutation in NRG2, an ERBB receptor ligand, and the HER2-negative component of the other case harboured a mutation in PTTG1IP, a proto-oncogene with putative oestrogen receptor elements. Conclusions: Our results demonstrate that in HER2-positive breast cancers with heterogeneous HER2 gene amplification, the HER2-positive and HER2-negative components are clonally related. The distinct genomic profiles of HER2-positive and HER2-negative components, however, suggest that, at least in some of these cases, HER2 amplification may constitute a relatively late event in tumour evolution. Exome sequencing revealed mutations restricted to the HER2-negative components of HER2-positive tumours with heterogeneous HER2 overexpression/gene amplification, which may constitute potential drivers in the absence of HER2 overexpression/gene amplification. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD05-08.

Background Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing. Methods and Findings Whole-exome sequencing was performed on 216 tumor–blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were more frequently mutated in mBC as compared to eBC (FDR < 0.01). ESR1 was identified both as a driver and as a metastatic gene (n = 22, odds ratio = 29, 95% CI [9–155], p = 1.2e-12) and also presented with focal amplification (n = 9) for a total of 31 mBCs with either ESR1 mutation or amplification, including 27 hormone receptor positive (HR+) and HER2 negative (HER2−) mBCs (19%). HR+/HER2− mBC presented a high prevalence of mutations on genes located on the mechanistic target of rapamycin (mTOR) pathway (TSC1 and TSC2) as compared to HR+/HER2− eBC (respectively 6% and 0.7%, p = 0.0004). Other actionable genes were more frequently mutated in HR+ mBC, including ERBB4 (n = 8), NOTCH3 (n = 7), and ALK (n = 7). Analysis of mutational signatures revealed a significant increase in APOBEC-mediated mutagenesis in HR+/HER2− metastatic tumors as compared to primary TCGA samples (p < 2e-16). The main limitations of this study include the absence of bone metastases and the size of the cohort, which might not have allowed the identification of rare mutations and their effect on survival. Conclusions This work reports the results of the analysis of the first large-scale study on mutation profiles of mBC. This study revealed genomic alterations and mutational signatures involved in the resistance to therapies, including actionable mutations., Fabrice Andre and colleagues describe the mutations occurring in a large group of patients with metastatic breast cancer., Author Summary Why Was This Study Done? Breast cancer often results in poor outcomes after it has metastasized to distant organs, but, while primary breast tumors have been extensively characterized at the molecular level, metastatic lesions are poorly understood. This study aims to characterize the mutational landscape of metastatic breast cancer by performing and analyzing whole-exome sequencing of a large collection of metastatic breast tumors and corresponding blood samples. Understanding of the mutational landscape of metastatic tumors should open new avenues for assessing resistance to therapy and developing better treatments. What Did the Researchers Do and Find? The authors generated a large collection of whole-exome sequencing data from the DNA of breast cancer metastases and from each patient’s corresponding unmutated DNA in order to identify mutations and gene copy number alterations specific to the tumors. The bioinformatics analyses identified recurrently mutated genes in metastatic tumors and revealed the genes specifically involved in metastatic disease by comparing their mutational frequency to those of primary breast tumors. The study allowed identification of the affected genes and of mutational signatures that were more prevalent in metastatic as compared with primary tumors and that may be involved in the resistance to therapies. What Do These Findings Mean? The identification of mutational and copy number alterations specifically involved in breast cancer metastasis demonstrated that tumors evolve under the pressure of therapy. Characterization of mutations and copy number alterations in metastatic lesions in addition to primary tumors should help to tailor treatment for patients, with the potential for improved clinical outcomes.

Background Most breast cancer (BC) tumors ≤10 mm have an excellent prognosis. The subgroups with a higher risk for distant recurrence requiring adjuvant systemic therapy are not precisely defined in current international guidelines. Patients and Methods The O BSERVATOIRE D ES PET I TS CANCER S DU SE IN H E R2 +/− (ODISSEE) study was a prospective, multicenter, cohort study that aimed to describe the daily adjuvant management and outcome of 616 patients with unifocal, invasive pT1a-b pN0 nonmetastatic BC who underwent surgery. Results At the time of diagnosis, the median age of patients was 61 years. Tumor was detected on imaging or during a screening program in 397 patients (64.6%). Most patients (96%) underwent conservative surgery with sentinel node biopsy (89%), completed with axillary lymph node dissection in 15%. At inclusion, 82% of tumors were pT1b, 73% were pN0 (i−), 53% were Scarff–Bloom–Richardson Grade I, 91% were estrogen receptor (ER)-positive, 5% overexpressed/amplified HER2, and 5% were triple negative (TNBC). Adjuvant treatments were radiotherapy (95%), hormone therapy (82%), chemotherapy (7%), and trastuzumab (3.5%). In patients with TNBC and HER2-positive BC, chemotherapy and trastuzumab (if needed) were administered in 45% and 68%, respectively. After 5 years of follow-up, 7 patients had contralateral BC, 7 had locoregional recurrence, and 1 had distant metastasis. At 5 years, overall survival, disease-free survival, and recurrence-free survival were: 98.4% (96.9%-99.1%), 94.7% (92.4%-96.3%), and 97.1% (95.2%-98.2%), respectively. Conclusion This prospective cohort study showed that in France, the routine practice in pT1a-b pN0 breast cancers follows international standard guidelines for practice including conservative surgery followed by radiotherapy and endocrine therapy for ER-positive patients. Adjuvant chemotherapy with or without trastuzumab was used but their benefit in breast cancer of ≤10 mm remains controversial.

Aims: Microglandular adenosis (MGA) is a proliferative breast lesion, which has been proposed to be a potential precursor of triple-negative breast cancers. The aims of this study were to determine whether MGAs harbour genetic alterations and if any such genetic aberrations found in MGAs are similar to those found in matched invasive carcinomas. Methods and results: Twelve cases of MGA and/or atypical MGA (AMGA), 10 of which were associated with invasive carcinoma, were evaluated. Immunohistochemical profiling revealed that all invasive carcinomas were of triple-negative phenotype and expressed S100, cytokeratins 8/18 and basal markers. The morphologically distinct components of each case (MGA, AMGA and/or invasive carcinoma) were microdissected and subjected to microarray comparative genomic hybridization. Apart from three typical MGAs, all samples harboured genetic alterations. The percentage of the genome affected by copy number aberrations in MGA/AMGA ranged from 0.5 to 61.9%, indicating varying levels of genetic instability. In three cases, MGA/AMGA displayed copy number aberrations similar to those found in matched invasive components, providing strong circumstantial evidence that MGA may constitute the substrate for the invasive carcinoma development. Conclusions: Our results support the contention that MGA can be a clonal lesion and non-obligate precursor of triple-negative breast cancer.

Background Personalized medicine has become a priority in breast cancer patient management. In addition to the routinely used clinicopathological characteristics, clinicians will have to face an increasing amount of data derived from tumor molecular profiling. The aims of this study were to develop a new gene selection method based on a fuzzy logic selection and classification algorithm, and to validate the gene signatures obtained on breast cancer patient cohorts. Methods We analyzed data from four published gene expression datasets for breast carcinomas. We identified the best discriminating genes by comparing molecular expression profiles between histologic grade 1 and 3 tumors for each of the training datasets. The most pertinent probes were selected and used to define fuzzy molecular grade 1-like (good prognosis) and fuzzy molecular grade 3-like (poor prognosis) profiles. To evaluate the prognostic performance of the fuzzy grade signatures in breast cancer tumors, a Kaplan-Meier analysis was conducted to compare the relapse-free survival deduced from histologic grade and fuzzy molecular grade classification. Results We applied the fuzzy logic selection on breast cancer databases and obtained four new gene signatures. Analysis in the training public sets showed good performance of these gene signatures for grade (sensitivity from 90% to 95%, specificity 67% to 93%). To validate these gene signatures, we designed probes on custom microarrays and tested them on 150 invasive breast carcinomas. Good performance was obtained with an error rate of less than 10%. For one gene signature, among 74 histologic grade 3 and 18 grade 1 tumors, 88 cases (96%) were correctly assigned. Interestingly histologic grade 2 tumors (n = 58) were split in these two molecular grade categories. Conclusion We confirmed the use of fuzzy logic selection as a new tool to identify gene signatures with good reliability and increased classification power. This method based on artificial intelligence algorithms was successfully applied to breast cancers molecular grade classification allowing histologic grade 2 classification into grade 1 and grade 2 like to improve patients prognosis. It opens the way to further development for identification of new biomarker combinations in other applications such as prediction of treatment response. Electronic supplementary material The online version of this article (doi:10.1186/s12920-015-0077-1) contains supplementary material, which is available to authorized users.

These past few years, neoadjuvant strategy has taken an increasing place in the management of breast cancer patients. This strategy is mainly indicated to obtain a tumour bulk regression allowing a breast conserving surgery in patients that otherwise would have undergone mastectomy. Of note, development of new chemotherapy agents and targeted therapies has critically helped in the progress of neoadjuvant strategy as it is currently associated with better pathological response rates. In this context, the pathologist is at the crossroad of this multidisciplinary process. First, he provides on the initial core needle biopsy the tumour pathological characteristics that are critical for the choice of treatment strategy, i.e. histological type, histological grade, proliferative activity (mitotic count and Ki67/MIB1 index labeling), hormone receptor status (oestrogen receptor and progesterone receptor) and HER2 status. Secondly, the pathologist evaluates the pathological response and the status of surgical margins with regards to the residual tumour on the surgical specimen after neoadjuvant treatment. These parameters are important for the management of the patient, since it has been shown that complete pathological response is associated with improved disease free survival. Several grading systems are used to assess the pathological response in breast and axillary lymph nodes. The most frequently used in France are currently the systems described by Sataloff et al. and Chevallier et al. In this review, we detail the different steps involving the pathologist in neoadjuvant setting, with special regards to the quality process and future perspectives such as emerging predictive biomarkers.

Aberrant β-catenin expression as determined by assessment of its subcellular localization constitutes a surrogate marker of Wnt signalling pathway activation and has been reported in a subset of breast cancers. The association of β-catenin/Wnt pathway activation with clinical outcome and the mechanisms leading to its activation in breast cancers still remain a matter of controversy. The aims of this study were to address the distribution of β-catenin expression in invasive breast cancers, the correlations between β-catenin expression and clinicopathological features and survival of breast cancer patients, and to determine whether aberrant β-catenin expression is driven by CTNNB1 (β-catenin encoding gene) activating mutations. Immunohistochemistry was performed on a tissue microarray containing 245 invasive breast carcinomas from uniformly treated patients, using two anti-β-catenin monoclonal antibodies. Selected samples were subjected to CTNNB1 exon 3 mutation analysis by direct gene sequencing. A good correlation between the two β-catenin antibodies was observed (Spearman's r >0.62, P

The juvenile papillomatosis is a rare entity. We shall systematically check for a cancer. A 20-year-old woman patient without any familial medical history of breast carcinoma, was presenting a voluminous nodule of the left breast. A core needle biopsy allowed to diagnose papilloma. A conservative surgical treatment was proposed and realized despite any possibility of complete resection. Histological examination of the surgical specimen concluded to a juvenile papillomatosis. A closed follow-up was proposed to the patient. This case illustrates the difficulty of a voluminous tumor surgery on a young woman. The main problem is to combine the cosmetic constraints with oncology risk.

Wnt signalling pathway is known to have a critical role in carcinogenesis and in epithelial-to-mesenchymal transition. Upon Wnt activation, β-catenin is translocated from the membrane to the cytoplasm and nucleus, where it interacts with transcriptional activators. It has been suggested that various spindle cell lesions of the breast may harbour Wnt pathway activation. Given that β-catenin nuclear localization constitutes a good surrogate marker of Wnt canonical pathway activation, we have investigated the distribution of β-catenin in spindle cell lesions of the breast and whether it could be employed in the differential diagnosis of these lesions. A total of 52 metaplastic breast carcinomas, eight fibromatoses and 23 phyllodes tumours were retrieved from our institutions' archives. We performed immunohistochemistry using two anti-β-catenin antibodies. In all, three fibromatoses and 21 metaplastic breast carcinomas were subjected to CTNNB1 (β-catenin encoding gene) mutation analysis by direct gene sequencing. A good correlation between the two antibodies was observed (Spearman's r0.82, P0.001). All fibromatoses and 23% of metaplastic breast carcinomas expressed nuclear β-catenin. In fibromatosis, β-catenin was more often diffusely expressed, whereas in metaplastic breast carcinomas, expression was more frequently focal. Membranous β-catenin expression was significantly lower in spindle cell carcinomas than in other subtypes of metaplastic breast carcinomas. In phyllodes tumours, stromal cells of benign and malignant subtypes displayed nuclear β-catenin expression in 94 and 57% of cases, respectively. No CTNNB1 mutation was identified in any of the 21 metaplastic carcinomas analysed, whereas the mutations 45SS/P and 41TT/A were found in samples of fibromatosis. In conclusion, β-catenin nuclear expression is a common feature in fibromatoses and in the stromal component of phyllodes tumours, but may also be observed in metaplastic breast carcinomas. β-catenin nuclear expression should not be used as a single marker to differentiate fibromatosis from other spindle cell tumours of the breast.

International audience; En Europe, les patientes atteintes d’un cancer du sein invasif susceptibles de recevoir un traitement ciblé anti-HER2sont actuellement sélectionnées sur la base d’un test immunohistochimique (IHC). Les techniques d’hybridation in situ (HIS) doivent être utilisées pour l’évaluation des cas IHC ambigus (2+) et pour l’étalonnage de la technique IHC. Les patientes éligibles au traitement ciblant HER2présentent un statut HER2positif défini par un test IHC 3+ ou un test 2+ amplifié. Une détection correcte du statut HER2est indispensable à une utilisation optimale des thérapeutiques ciblées puisque leur efficacité est limitée aux patientes surexprimant HER2. Il est capital que l’évaluation du statut HER2soit optimisée et fiable. Ces recommandations du groupe d’étude des facteurs pronostiques IHC dans le cancer du sein (GEFPICS) détaillent et commentent les différentes étapes des techniques IHC et HIS, les contrôles utilisables et les règles générales de l’apprentissage de la lecture. Une fois acquis, ce savoir-faire doit être pérennisé par l’observation de règles de bonnes pratiques techniques (utilisation rigoureuse de témoins internes et externes et participation régulière à des programmes d’Assurance qualité [AQ])., Summary In Europe, patients who may benefit from an HER2 targeted drug are currently selected by immunohistochemistry (IHC). In situ hybridization (ISH) techniques should be used for complementary assessment of ambiguous 2+ IHC cases and for the calibration of the IHC technique. Eligibility to an HER2 target treatment is defined by an HER2 positive status being IHC test 3+ or 2+ amplified. Reliable detection of HER2 status is essential to the appropriate usage of HER2 targeted drugs because its specificity is limited to tumors overexpressing HER2. It is essential that the IHC evaluation of the HER2 status of a mammary carcinoma is optimized and reliable. This GEFPICS’ guidelines look over the different steps of the IHC technique, the controls and, the rules for interpretation. Once acquired, this knowledge must be perpetuated by the observation of rules of good technical practice (internal and external controls, quality assurance programs).