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APCgermline pathogenic variants result in predisposition to familial adenomatous polyposis and extraintestinal tumours such as desmoid fibromatosis, medulloblastomas and thyroid cancers. They have also been recently involved in ovarian microcystic stromal tumours.APCinactivation has been described at the tumour level in epithelial ovarian cancers (EOCs). Here, we report the identification ofAPCgermline pathogenic variants in two patients diagnosed with premenopausal EOC in early 30s, with no other pathogenic variant detected in the known ovarian cancer predisposing genes. Subsequent tumour analysis showed neither a second hit ofAPCinactivation nor β-catenin activation. Both tumours did not have a homologous recombination (HR) deficiency, pointing towards the implication of other genes than those involved in HR.APCmay contribute to the carcinogenesis of EOC in a multifactorial context. Further studies are required to clarify the role ofAPCin predisposition to EOC.

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.

The last international guidelines on HER2 determination in breast cancer have been updated in 2018 by the American Society of Clinical Oncology and College of American Pathologists, on the basis of a twenty-year practice and results of numerous clinical trials. Moreover, the emerging HER2-low concept for 1+ and 2+ non amplified breast cancers lead to refine French practices for HER2 status assessment. The GEFPICS group, composed of expert pathologists, herein presents the latest French recommendations for HER2 status evaluation in breast cancer, taking into account the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, HER2 status assessment remains one of the most important biomarkers in breast cancer and its quality guaranties the optimal patients' care. French pathologists' commitment in theranostic biomarker quality is more than ever required to provide the most efficient cares in oncology.

Neoadjuvant therapy is an increasing treatment option in the management of breast cancer. The tumor response to neoadjuvant therapy, especially the pathological complete response, is a validated endpoint frequently used in clinical trials. However, there is still a lack of standardization for the surgical specimen management in the neoadjuvant setting. This leads to heterogeneity in the specimen handling and might lead to significant bias for the prognostic assessment of patients or in clinical trials. The GEFPICS group, composed of expert breast cancer pathologists, herein presents guidelines for the management of breast and axillary specimen before treatment (management of biopsy, items of the pathological report) and after neoadjuvant therapy (specimen handling, histological assessment of response, items of the pathological report and response grading systems).

Background: We explored, within the EORTC10994 study, the outcomes for patients with molecular apocrine (MA) breast cancer, and defined immunohistochemistry (IHC) as androgen-receptor (AR) positive, oestrogen (ER) and progesterone (PR) negative. We also assessed the concordance between IHC and gene expression arrays (GEA) in the identification of MA cancers. Methods: Centrally assessed biopsies for AR, ER, PR, HER2 and Ki67 by IHC were classified into six subtypes: MA, triple-negative (TN) basal-like, luminal A, luminal B HER2 negative, luminal B HER2 positive and “other”. The two main objectives were the pCR rates and survival outcomes in the overall MA subtype (and further divided by HER2 status) and the remaining five subtypes. Results: IHC subtyping was obtained in 846 eligible patients. Ninety-three (11%) tumours were classified as the MA subtype. Both IHC and GEA data were available for 64 patients. In this subset, IHC concordance was 88.3% in identifying MA tumours compared with GEA. Within the MA subtype, pCR was observed in 33.3% of the patients (95% CI: 29.4–43.9) and the 5-year recurrence-free interval was 59.2% (95% CI: 48.2–68.6). Patients with MA and TN basal-like tumours have lower survival outcomes. Conclusions: Irrespective of their HER2 status, the prognosis for MA tumours remains poor and adjuvant trials evaluating anti-androgens should be considered., SCOPUS: ar.j, info:eu-repo/semantics/published

We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in bothA large deletion ofThis complex situation is challenging for genetic counselling and management of at-risk individuals.

Background Neoadjuvant endocrine therapy (NET) has shown efficacy in terms of clinical response and surgical outcome in postmenopausal patients with estrogen receptor-positive / HER2-negative breast cancer (ER+/HER2- BC) but monitoring of tumor response is challenging. The aim of the present study was to investigate the value of an early metabolic response compared to morphological and pathological responses in this population. Methods This was an ancillary study of CARMINA 02, a phase II clinical trial evaluating side-by-side the efficacy of 4 to 6 months of anastrozole or fulvestrant. Positron Emission Tomography/Computed Tomography using 2-deoxy-2-[18F]fluoro-D-glucose (FDG-PET/CT) scans were performed at baseline (M0), early after 1 month of treatment (M1) and pre-operatively in 11 patients (74.2 yo ± 3.6). Patients were classified as early “metabolic responders” (mR) when the decrease of SUVmax was higher than 40%, and “metabolic non-responders” (mNR) otherwise. Early metabolic response was compared to morphological response (palpation, US and MRI), variation of Ki-67 index, pathological response according to the Sataloff classification and also to Preoperative Endocrine Prognostic Index (PEPI) score. It was also correlated with overall survival (OS) and recurrence-free survival (RFS). Results Tumor size measured on US and on MRI was smaller in mR than mNR, with the highest statistically significant difference at M1 (p = 0.01 and 7.1 × 10− 5, respectively). No statistically significant difference in the variation of tumor size between M0 and M1 assessed on US or MRI was observed between mR and mNR. mR had a better clinical response: no progressive disease in mR vs 2 in mNR and 2 partial response in mR vs 1 partial response in mNR. One patient with a pre-operative complete metabolic response had the best pathological response. Pathological response did not show any statistically significant difference between mR and mNR. mR had better OS and RFS (Kaplan-Meier p = 0.08 and 0.06, respectively). All cancer-related events occurred in mNR: 3 patients died, 2 of them from progressive disease. Conclusions FDG-PET/CT imaging could become a “surrogate marker” to monitor tumor response, especially as NET is a valuable treatment option in postmenopausal women with ER+/HER2- BC.

Background Few data are available on survival and predictive factors in early breast cancer (BC) patients treated with neoadjuvant endocrine therapy (NET). Methods This is a pooled analysis of two multicentre, randomised non-comparative phase 2 clinical trials evaluating neoadjuvant anastrozole and fulvestrant efficacy for postmenopausal HR+/HER2- breast cancer patients: HORGEN (NCT00871858) and CARMINA02 (NCT00629616) studies. Results In total, 236 patients were included in CARMINA02 and HORGEN trials. Modified intention-to-treat analysis was available for 217 patients. Median follow-up was 65.2 months. Relapse-free survival (RFS) and overall survival (OS) at 5 years were 83.7% (95% CI: 77.9–88) and 92.7% (95% CI: 88.2–95.6), respectively, with no difference between treatment arms. On univariate analysis, tumour staging (T2 vs T3–4; p = 0.0001), Ki-67 at surgery (≤10% vs >10%; p = 0.0093), pathological tumour size (pT1–2 vs pT3–4; p = 0.0012) and node status (pN negative vs positive; p = 0.007), adjuvant chemotherapy (p = 0.0167) and PEPI score (PEPI group I + II vs III; p = 0.0004) were associated with RFS. No events were observed in patients with pathological response according to the Sataloff classification. Multivariate analysis showed that preoperative endocrine prognostic index (PEPI) group III was associated with significantly worse RFS (p = 0.0069, hazard ratio = 3.33 (95% CI: 1.39–7.98)). Conclusions Postmenopausal HR+/HER2- breast cancer patients receiving NET generally have a favourable outcome. The PEPI score identifies a subset of patients of poorer prognosis who are candidates for further additional treatment.

To ensure their high proliferation rate, tumor cells have an iron metabolic disorder causing them to have increased iron needs, making them more susceptible to iron deprivation. This vulnerability could be a therapeutic target. In breast cancers, the development of new therapeutic approaches is urgently needed for patients with triple-negative tumors, which frequently relapse after chemotherapy and suffer from a lack of targeted therapies. In this study, we demonstrated that deferasirox (DFX) synergises with standard chemotherapeutic agents such as doxorubicin, cisplatin and carboplatin to inhibit cell proliferation and induce apoptosis and autophagy in triple-negative breast cancer (TNBC) cells. Moreover, the combination of DFX with doxorubicin and cyclophosphamide delayed recurrences in breast cancer patient-derived xenografts without increasing the side-effects of chemotherapies alone or altering the global iron storage of mice. Antitumor synergy of DFX and doxorubicin seems to involve downregulation of the phosphoinositide 3-kinase and nuclear factor-κB pathways. Iron deprivation in combination with chemotherapy could thus help to improve the effectiveness of chemotherapy in TNBC patients without increasing toxicity. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Ovarian cancer is mostly diagnosed at advanced stage. Better survival is achieved through complete debulking surgery and chemotherapy. Historically, neoadjuvant chemotherapy (NAC) has been introduced for unresectable disease to decrease tumor load and perform a unique complete surgery. Four randomized control trials have compared primary debulking surgery to NAC, but there is still controversy about the use of neoadjuvant chemotherapy and questions about its modalities. Areas covered: We made a review of knowledge on benefits of NAC compared to primary debulking chemotherapy, in terms of survival and morbidity, methods of administration, new drugs in early and late phase trials, the selection of patients. Similar survival was observed after NAC and interval debulking surgery or primary debulking surgery. Morbidity of surgery was decreased after interval debulking compared primary debulking surgery. Conventional drugs are carboplatin and paclitaxel. Safety of bevacizumab was evaluated in phase 2 trials associated with conventional drugs. Immunotherapy trials are enrolling patients in phase 1 study. Expert commentary: NAC followed by debulking surgery is the best treatment for patients with advanced ovarian cancer.

Few studies evaluated the prognostic value of the presence of lymphovascular invasion (LVI) after neoadjuvant chemotherapy (NAC) for breast cancer (BC). The association between LVI and survival was evaluated in a cohort of BC patients treated by NAC between 2002 and 2011. Five post-NAC prognostic scores (ypAJCC, RCB, CPS, CPS + EG and Neo-Bioscore) were evaluated and compared with or without the addition of LVI. Out of 1033 tumors, LVI was present on surgical specimens in 29.2% and absent in 70.8% of the cases. Post-NAC LVI was associated with impaired disease-free survival (DFS) (HR 2.54; 95% CI 1.96–3.31; P

Centrosome amplification has been described as a common feature of human cancers and it is known to promote tumorigenesis when induced in animals. However, little is known about the real status of centrosome numbers in human cancers and whether numerical alterations are solely associated with poor prognosis. To address this question, we have analyzed a large cohort of human epithelial ovarian cancers (EOCs) from 100 patients using state-of-the-art microscopy to determine the Centrosome-Nucleus Index (CNI) of each tumor. We found that EOCs are highly heterogeneous, with infrequent but strong centrosome amplifications leading to higher CNI than in healthy tissues. Strikingly, while a correlation between CNI and genomic alterations, such as aneuploidy or chromosome rearrangements could not be established, we found that high CNI correlates with increased patient survival and sensitivity to chemotherapy. Using ovarian cancer cellular models to manipulate centrosome numbers and Patient-Derived Xenografts (PDXs), we found that higher CNIs can positively impact the response to chemotherapy and inhibit cell dissemination. Our findings highlight a novel paradigm linking centrosome amplification to the inhibition of tumor progression.

// Sandrine Tury 1 , Veronique Becette 2 , Franck Assayag 3 , Sophie Vacher 1 , Camille Benoist 1 , Maud Kamal 4 , Elisabetta Marangoni 3 , Ivan Bieche 1 , Florence Lerebours 4 , Celine Callens 1 1 Pharmacogenomic Unit, Genetics Laboratory, Institut Curie, Paris, France 2 Department of Pathology, Institut Curie, Hopital Rene Huguenin, Saint-Cloud, France 3 Laboratory of Preclinical Investigations, Translational Research Department, Institut Curie, Paris, France 4 Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France Correspondence to: Celine Callens, email: celine.callens@curie.fr Keywords: breast cancer, PIK3CA, celecoxib, prognosis, predictive biomarker Received: April 29, 2016 Accepted: October 26, 2016 Published: November 08, 2016 ABSTRACT COX-2 expression level and prognostic value are still a matter of debate in breast cancer (BC). We addressed these points in the context of PIK3CA mutational status. Based on an interesting study of aspirin efficacy in colorectal cancer, we hypothesized that celecoxib antitumoral activity may be restricted to PIK3CA mutated BC. COX-2 mRNA expression was analyzed in 446 BC samples and in 61 BC patient-derived xenografts (PDX) using quantitative RT-PCR. The prognostic impact of COX-2 expression level was assessed independently and according to PIK3CA mutational status in our cohort and in a validation set of 817 BC. The antitumoral activity of celecoxib was tested in two triple-negative (TN) PDX with a PIK3CA wild-type (wt) or mutated genotype. COX-2 mRNA was overexpressed in 2% of BC and significantly associated with TN subtype. Metastasis-free survival (MFS) was significantly better in patients with high COX-2 expression level, the prognosis of whom was similar to patients with PIK3CA mutations. TCGA validation cohort confirmed that patients with low COX-2 expression PIK3CA wt tumors had the worse disease-free survival (DFS) compared to all other subgroups. Celecoxib had a significant antitumoral effect in PIK3CA mutated PDX only. Celecoxib antitumoral activity involved S6 ribosomal protein and AKT phosphorylation. Low expression of COX-2 has a significant negative impact on the MFS/DFS of BC patients. Antitumoral effect of celecoxib is restricted to PIK3CA mutated PDX. These results suggest that PIK3CA mutation may be a new predictive biomarker for celecoxib efficacy.

Background: Cyclooxygenase-2 (COX2) is responsible for the synthesis of prostaglandins from arachidonic acid. This enzyme is weakly expressed in normal tissues and implicated in oncogenic and inflammatory processes. Treatment with a COX2 inhibitor (aspirin) increases overall survival of patients with colorectal cancer only for PIK3CA mutated tumors confirming an interaction between COX2 and the PI3K/AKT pathway. PIK3CA gene mutations are detected in 10-40% of BC depending on the molecular subtype. We hypothesized that COX inhibition could have an impact in Breast Cancer (BC) treatment. Methods: COX2 mRNA expression levels were analyzed in 446 BC samples and 61 patient-derived xenografts (PDX) using qRT-PCR. Protein expression of COX2 was studied by immunohistochemistry (IHC) in 26 BC and 14 PDX. The prognostic impact of COX2 expression level according to PIK3CA mutation status was also analyzed in BC patients. The activity of celecoxib, a selective COX2 inhibitor, was tested in two PDX of triple-negative BC: the HBCx50 PDX (PIK3CA wild-type, expressing COX2) and the HBCx4B PDX (PIK3CA mutated, expressing COX2). Results: COX2 transcript was under-expressed in 74% and overexpressed in 2% of the BC samples. COX2 overexpression is significantly associated with triple-negative subtype (11%, 7/68 cases, p Conclusion: In BC, COX2 underexpression is frequent and impact prognosis. BC overexpressing COX2 are rare and mainly belong to the triple-negative subtype. In vivo PDX studies show that the antitumoral effect of celecoxib may be restricted to BC expressing COX2 with PIK3CA mutation. Analyses of signaling pathways, expression levels of COX2 and its target proteins, tumor proliferation and apoptosis induction are ongoing on tumors and serum of mice to elucidate the antitumoral effect of celecoxib. This work could help to identify a subgroup of BC patients who may benefit from celecoxib especially as COX2 immunostaining and PIK3CA mutation status could routinely be used as COX2 inhibitor sensitivity biomarkers. These results need to be validated in a phase II clinical trial. Citation Format: Tury S, Becette V, Assayag F, Vacher S, Marangoni E, Bièche I, Lerebours F, Callens C. Prognostic and predictive value of COX2 in breast cancer, correlation with PIK3CA mutations. [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 P4-09-03.

Resume Objectifs Nous rapportons notre experience de preservation de la fertilite chez cinq patientes jeunes atteintes d’un cancer du col de plus de 2 cm. Methodes Entre juillet 2012 et fevrier 2014, cinq patientes presentant des carcinomes du col uterin de plus de 2 cm (IB1 > 2 cm) (23–35) ont ete prises en charge en vue d’un traitement conservateur. Une stadification ganglionnaire par curage pelvien bilateral et lombo-aortique cœlioscopique a ete realisee chez toutes les patientes. En l’absence d’atteinte ganglionnaire, les patientes ont beneficie d’une chimiotherapie neoadjuvante suivie d’un traitement chirurgical conservateur. Resultats Quatre des cinq patientes ont recu une chimiotherapie neoadjuvante a base de sels de platine suivie d’une chirurgie conservatrice : 3 trachelectomies elargies et une trachelectomie simple. Une patiente presentait une atteinte ganglionnaire et a beneficie d’un traitement par chimiotherapie puis radiochimiotherapie concomitante. Une patiente a presente une toxicite hematologique pendant la chimiotherapie (grade 3) necessitant un changement de chimiotherapie. On retrouvait une reponse histologique complete a la chimiotherapie neoadjuvante chez deux patientes et une reponse partielle chez deux patientes. Apres un suivi moyen de 20,5 mois (14–33), aucune recidive n’a ete observee. Aucune grossesse n’a ete obtenue a ce jour. Conclusion Apres stadification ganglionnaire, la chimiotherapie neoadjuvante suivie d’une trachelectomie elargie pour les cancers du col de plus de 2 cm pN0 semble etre une option oncologiquement satisfaisante pour les patientes ayant un desir de grossesse et refusant le traitement radical.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The most common subtype of EOC is high-grade serous (HGSOC), which responds at least initially to chemotherapy but has a worse overall prognosis. Genomic, transcriptomic, and proteogenomic profiling of HGSOC suggested a whole spectrum of molecular diversity, including homologous recombination pathway deficiencies (HRD). The centrosome is the main microtubule (MT)-organizing center of animal cells. It facilitates the accuracy of chromosome segregation during mitosis and influences cell polarity and migration. The presence of more than two centrosomes in a cell, centrosome amplification, has long been associated with tumorigenesis. However, little is known about the real status of centrosome numbers in human cancers and whether numerical alterations are solely associated with poor prognosis. We screened 100 samples of primary EOCs including 88 HGSOC, using immunofluorescence and state-of-the-art microscopy, to determine the centrosome-nucleus index (CNI). We integrated these data with genomic alterations, HRD status, and patient outcome. We found that EOCs are highly heterogeneous, with infrequent but strong centrosome amplifications leading to higher CNI than in healthy tissues. Strikingly, while a correlation between CNI and genomic alterations, such as aneuploidy or chromosome rearrangements, could not be established, we found that high CNI correlates with increased patient survival and sensitivity to chemotherapy, independently of HRD status. Using ovarian cancer cellular models to manipulate centrosome numbers and patient-derived xenografts (PDXs), we found that higher CNIs can positively impact the response to chemotherapy and inhibit peritoneal cell dissemination. Citation Format: Jean-Philippe Morretton, Aurelie Herbette, Camille Cosson, Bassirou Mboup, Aurelien Latouche, Pierre Gestraud, Tatiana Popova, Marc-Henri Stern, Fariba Nemati, Didier Decaudin, Guillaume Bataillon, Veronique Becette, Didier Meseure, Andre Nicolas, Odette Mariani, Claire Bonneau, Jorge Barbazan, Anne Vincent-Salomon, Fatima Mechta-Grigoriou, Sergio Roman-Roman, Roman Rouzier, Xavier Sastre-Garau, Oumou Goundiam, Renata Basto. Centrosome amplification favors survival and impairs ovarian cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A43.

Background Postmenopausal women with large, hormone receptor (HR)-positive/HER2-negative and low-proliferative breast cancer derived a benefit from neoadjuvant endocrine therapy (NET) in the CARMINA02 trial. This study was designed to correlate gene expression and mutation profiles with both response to NET and prognosis. Methods Gene expression profiling using RNA sequencing was performed in 86 pre-NET and post-NET tumor samples. Targeted next-generation sequencing of 91 candidate breast cancer-associated genes was performed on DNA samples from 89 patients. Molecular data were correlated with radiological response and relapse-free survival. Results The transcriptional profile of tumors to NET in responders involved immune-associated genes enriched in activated Th1 pathway, which remained unchanged in non-responders. Immune response was confirmed by analysis of tumor-infiltrating lymphocytes (TILs). The percentage of TILs was significantly increased post-NET compared to pre-NET samples in responders (p = 0.0071), but not in non-responders (p = 0.0938). Gene expression revealed that lipid metabolism was the main molecular function related to prognosis, while PPARγ is the most important upstream regulator gene. The most frequently mutated genes were PIK3CA (48.3%), CDH1 (20.2%), PTEN (15.7%), TP53 (10.1%), LAMA2 (10.1%), BRCA2 (9.0%), MAP3K1 (7.9%), ALK (6.7%), INPP4B (6.7%), NCOR1 (6.7%), and NF1 (5.6%). Cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway were altered significantly more frequently in non-responders than in responders (p = 0.0017 and p = 0.0094, respectively). The average number of mutations per sample was significantly higher in endocrine-resistant tumors (2.88 vs. 1.64, p = 0.03), but no difference was observed in terms of prognosis. ESR1 hotspot mutations were detected in 3.4% of treatment-naive tumors. Conclusions The Th1-related immune system and lipid metabolism appear to play key roles in the response to endocrine therapy and prognosis in HR-positive/HER2-negative breast cancer. Deleterious somatic mutations in the cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway may be relevant for clinical management. Trial registration This trial is registered with ClinicalTrials.gov (NCT00629616) on March 6, 2008, retrospectively registered. Electronic supplementary material The online version of this article (10.1186/s13045-018-0670-9) contains supplementary material, which is available to authorized users.

The treatment of epithelial ovarian cancer (EOC) is narrowly focused despite the heterogeneity of this disease in which outcomes remain poor. To stratify EOC patients for targeted therapy, we developed an approach integrating expression and genomic analyses including the BRCAness status. Gene expression and genomic profiling were used to identify genes recurrently (>5%) amplified and overexpressed in 105 EOC. The LST (Large-scale State Transition) genomic signature of BRCAness was applied to define molecular subgroups of EOC. Amplified/overexpressed genes clustered mainly in 3q, 8q, 19p and 19q. These changes were generally found mutually exclusive. In the 85 patients for which the genomic signature could be determined, genomic BRCAness was found in 52 cases (61.1%) and non-BRCAness in 33 (38.8%). A striking mutual exclusivity was observed between BRCAness and amplification/overexpression data. Whereas 3q and 8q alterations were preferentially observed in BRCAness EOC, most alterations on chromosome 19 were in non-BRCAness cases. CCNE1 (19q12) and BRD4 (19p13.1) amplification/overexpression was found in 19/33 (57.5%) of non-BRCAness cases. Such disequilibrium was also found in the TCGA EOC data set used for validation. Potential target genes are frequently amplified/overexpressed in non-BRCAness EOC. We report that BRD4, already identified as a target in several tumor models, is a new potential target in high grade non-BRCAness ovarian carcinoma.

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.]

Resume La description semiologique des masses en mammographie s’appuie sur le referentiel BI-RADS de l’American College of Radiology. Le contour est le critere morphologique le plus discriminant entre masses benignes et malignes. Les masses circonscrites sont majoritairement benignes. Toutefois, du fait de caracteristiques histologiques particulieres, certaines lesions a risque ou malignes peuvent se presenter en mammographie sous cette forme faussement rassurante. Un contour non circonscrit en mammographie est un critere de suspicion necessitant un prelevement histologique. La valeur predictive positive de malignite varie selon la morphologie du contour, plus faible pour les contours microlobules, elle augmente pour les masques, puis indistincts, jusqu’a atteindre 96 % pour les contours spicules. Certaines lesions benignes peuvent cependant, dans de rares cas, se manifester sous forme de masses spiculees. Dans ces cas particuliers, une correlation du resultat histologique avec les donnees de l’imagerie est essentielle, afin de ne pas meconnaitre une lesion maligne sous-jacente que le prelevement biopsique aurait sous-estimee.

Background Few data are available on survival of breast cancer (BC) patients (pts) treated with neoadjuvant endocrine therapy (NET). Understanding how tumor response to NET is related to relapse risk would help clinicians make decisions about additional treatments for these pts. Methods The primary objective was to assess 5-years relapse-free survival (RFS) in previously published two sister phase II studies evaluating anastrozole and fulvestrant as NET in post-menopausal HR-positive/HER2-negative BC pts (CARMINA02 NCT00629616 ; HORGEN NCT00871858 ). Prognostic factors of RFS were explored by pooling the two databases : age ( 70), tumor and node staging, histological type and grade, clinical response, pathological response according to the Sataloff classification, baseline and surgical ER Allred score and Ki-67 expression, treatment arm, preoperative endocrine prognostic index (PEPI) score, adjuvant chemotherapy. The factor study (Horgen vs. Carmina02) was also introduced in the model as covariate. Univariate and multivariate Cox regression analysis (covariates from univariate model with P-value Results Intention-to-treat analysis is available for 217 of 236 pts included in the two trials. Post-menopausal pts with T2–T4, N0–N1, M0, HR-positive/HER2-negative BC were randomized to receive anastrozole (PO, 1 mg daily) or fulvestrant (IM, 500 mg on D1, D15 and D29 and then every 4 weeks) for 4 to 6 months before surgery. Mean age at diagnosis was 71.2 years. Baseline tumor characteristics were : 73.7 % T2, mean tumor size 44.3 mm, 66.4 % N0, 19.4 % SBR grade 1, 98.6 % ER Allred score 6-8, mean Ki67 score 17.5 % with Ki67 > 20 % in 29.5 % of cases. A clinical response (complete or partial) was observed in 50.2 % of pts and pathological response rate defined as TA or TB and NA or NB was 15.7 %. Mean Ki67 at surgery was 8.8 % (11.4 % of cases > 20 %). Among the pts, 12.4 % were classified in PEPI risk group I (risk score 0), 35.5 % in group II (score 1–3) and 30.4 % in group III (score > 4) (PEPI not available for 21.7 % of pts) ; 21.7 % of pts received adjuvant chemotherapy. Median follow-up is 65.2 months. RFS and overall survival at 5 years are 83.7 % [95 % CI : 77.9–88 %] and 92.7 [95 % CI : 88.2–95.6 %] respectively. On univariate analysis, tumor staging (T3–4 versus T2, P = 0.0001) and PEPI score (I + II versus III, P = 0.0004) are associated with RFS. So far, no relapses/death have been observed in pts with pathological response (n = 34, 15.7 %). Multivariate analysis (T, baseline Ki67, ER Allred score at surgery, PEPI and study) shows that PEPI group III is associated with significantly worse RFS (P = 0.0014, HR : 3.9 [95 % CI : 1.7–9.0]). Conclusion Post-menopausal HR-positive/HER2-negative BC pts receiving NET have a very favorable outcome. Within this population eligible for NET, the PEPI score identifies a subset of pts of poorer prognosis who are candidate for further additional treatment like chemo/or targeted therapies. The PEPI may be a tool routinely used for individualization of adjuvant treatment in NET setting. According to recent published studies, further analysis will be performed with Ki67 > 10 % and PEPI risk (group I versus groups II–III).

Purpose : Lymphovascular invasion (LVI) is a poor prognosis factor in breast cancer (BC), but data on its value in the neoadjuvant setting is scarce. This study evaluates the relationships between post-NAC LVI and prognosis in BC. Methods: We identified 1197 patients with primary BC receiving NAC +/- trastuzumab between 2002 and 2011. Information on LVI in post-NAC surgical specimen was retrieved from review of medical charts. Univariate and multivariate analyses were performed to assess the association of clinical, pathological factors with disease free survival (DFS) and overall survival (OS) was assessed using a cox proportional hazard model. Results: On 1197 tumors, 528 were luminal (44.1%), 375 were triple negative breast cancer (TNBC) (31.3%) and 294 were HER2-positive (24.6%). On post-NAC surgical specimens, LVI was present in 302 (25.2%), absent in 531 (44.4%), and was not mentionned in 364 cases (30.4%). The presence of post-NAC LVI was associated with an impaired DFS (HR=2.17, 95 CI [1.65 - 2.86], p Table 1 Univariate analysis and multivariate analysis on DFS (whole population) Univariate Multivariate VariableClassHRClpHRCIpAge< 451 0.35 45-550.82[0.62 - 1.08] >550.87[0.64 - 1.19] Menopausal statuspremenopausal1.04[0.81 - 1.34]0.75 postmenopausal1 BMI class19-251 < 191.24[0.75 - 2.05]0.41 > 251.36[1.06 - 1.75]0.01 Tumor sizeT1-T21 T31.77[1.38 - 2.27]201.54[1.06 - 2.22]0.02 Mitotic index≤221 >221.18[0.9 - 1.53]0.23 DCIS componentno1 yes1.33[0.88 - 2.01]0.18 Pre-NAC LVIno1 yes1.35[0.88 - 2.01]0.09 ER statusnegative1 positive0.72[0.56 - 0.91] Post-NAC LVI was an independent predictor of poor DFS, that overwhelmed the prognostic impact of pathological complete response in all 3 BC subtypes. Post-NAC LVI was also an independent predictor of poor OS in the whole cohort and in all BC subtypes. Table 1 resumes univariate and multivariate analysis on DFS in whole population. Conclusion: Post-NAC LVI is a strong independent prognostic factor associated with poor DFS and OS, that (i) should be systematically mentioned in pathological reports following NAC and (ii) could be used to select high risk patients candidates to second line trials in the post-neoadjuvant window. Citation Format: Hamy-Petit A-S, Lam G-T, Laas E, Darrigues L, Balezeau T, Guerin J, Livartowski A, Sadacca B, Pierga J-Y, Vincent-Salomon A, Bidard F-C, Lerebours F, Brain E, Becette V, Rouzier R, Lae M, Reyal F. Lymphovascular invasion in breast carcinoma following neodjuvant chemotherapy is a strong prognosis factor [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 P2-03-04.

International audience; BACKGROUND:Treatment strategies for locally advanced breast cancer in elderly patients too frail to receive neoadjuvant chemotherapy and the introduction of new classes of drugs in the early 2000s have led to the consideration of endocrine therapy as a neoadjuvant treatment for younger hormone receptor (HR)-positive, postmenopausal patients not eligible for primary breast-conserving surgery (BCS).METHODS:This was a multicenter, phase 2, randomized trial designed to evaluate as its primary objective the clinical response rate after up to 6 months of neoadjuvant endocrine therapy (NET) alone in HR-positive/human epidermal growth factor receptor 2 (HER2)-negative patients with 1 mg of anastrozole (arm A) or 500 mg of fulvestrant (arm B). Secondary objectives included the BCS rate, tumor response assessment (breast ultrasound and magnetic resonance imaging), pathological response (Sataloff classification), safety profile, relapse-free survival (RFS), and predictive markers of responses and outcomes.RESULTS:From October 2007 to April 2011, 116 women (mean age, 71.6 years) with operable infiltrating breast adenocarcinoma (T2-T4, N0-N3, M0) were randomized to receive anastrozole or fulvestrant. The clinical response rates at 6 months were 52.6% (95% confidence interval [CI], 41%-64%) in arm A and 36.8% (95% CI, 25%-49%) in arm B. BCS was performed for 57.6% of arm A patients and 50% of arm B patients. The RFS rates at 3 years were 94.9% in arm A and 91.2% in arm B. The Preoperative Endocrine Prognostic Index status was significantly predictive of RFS. Both treatments were well tolerated.CONCLUSIONS:Both drugs are effective and well tolerated as NET in postmenopausal women with HR-positive/HER2-negative breast cancer. NET could be considered a treatment option in this subpopulation. Cancer 2016;122:3032-3040. © 2016 American Cancer Society.

International audience; Specific human papillomavirus genotypes are associated with most ano-genital carcinomas and a large subset of oro-pharyngeal carcinomas. Human papillomavirus DNA is thus a tumour marker that can be detected in the blood of patients for clinical monitoring. However, data concerning circulating human papillomavirus DNA in cervical cancer patients has provided little clinical value, due to insufficient sensitivity of the assays used for the detection of small sized tumours. Here we took advantage of the sensitive droplet digital PCR method to identify circulating human papillomavirus DNA in patients with human papillomavirus-associated carcinomas. A series of 70 serum specimens, taken at the time of diagnosis, between 2002 and 2013, were retrospectively analyzed in patients with human papillomavirus-16 or human papillomavirus-18-associated carcinomas, composed of 47 cases from the uterine cervix, 15 from the anal canal and 8 from the oro-pharynx. As negative controls, 18 serum samples from women with human papillomavirus-16-associated high-grade cervical intraepithelial neoplasia were also analyzed. Serum samples were stored at -80 degrees C (27 cases) or at -20 degrees C (43 cases). DNA was isolated from 200 mu l of serum or plasma and droplet digital PCR was performed using human papillomavirus-16 E7 and human papillomavirus-18 E7 specific primers. Circulating human papillomavirus DNA was detected in 61/70 (87%) serum samples from patients with carcinoma and in no serum from patients with cervical intraepithelial neoplasia. The positivity rate increased to 93% when using only serum stored at -80 degrees C. Importantly, the two patients with microinvasive carcinomas in this series were positive. Quantitative evaluation showed that circulating viral DNA levels in cervical cancer patients were related to the clinical stage and tumour size, ranging from 55 +/- 85 copies/ml (stage I) to 1774 +/- 3676 copies/ml (stage IV). Circulating human papillomavirus DNA is present in patients with human papillomavirus-associated invasive cancers even at sub-clinical stages and its level is related to tumour dynamics. Droplet digital PCR is a promising method for circulating human papillomavirus DNA detection and quantification. No positivity was found in patients with human papillomavirus-associated high grade cervical intraepithelial neoplasia.

Resume Objectif Connaitre l’aspect clinique et radiologique d’une lesion rare, la fibromatose mammaire. Patients et methode Il s’agit d’une etude retrospective colligeant la totalite des cas diagnostiques entre 1993 a 2010. L’ensemble des dossiers cliniques, d’imagerie et de pathologie a ete revu. Resultats Onze dossiers, neuf femmes (dont un cas bilateral) et un homme ont ete identifies. Les patients etaient âges de 21 a 78 ans et comportaient tous une anomalie cliniquement decelable. Dans 50 % des cas, l’anomalie etait visible en mammographie, sous forme de masse spiculee (75 %), parfois d’asymetrie focale de densite (25 %). La lesion etait toujours visualisable en echographie avec un aspect suspect dans 80 % des cas. Il existait une prise de contraste significative de la lesion dans 83 % des cas en TDM/IRM. La taille moyenne des lesions en imagerie est de 26 mm. La microbiopsie au pistolet automatique 14 Gauge evoquait le diagnostic dans tous les cas (5/5), et l’affirmait dans trois cas avant l’exerese. Un seul cas de recidive a ete observe durant le recul clinique qui est de trois a huit ans (moyenne), les patientes ayant ensuite ete perdues de vue. Conclusion La fibromatose mammaire est souvent de presentation clinique et radiologique suspecte. La microbiopsie est importante car elle permet d’orienter le diagnostic en preoperatoire, avant exerese chirurgicale.

Background: CARMINA02 is a non-comparative multicenter phase II randomized trial evaluating the clinical response rate after up to 6 months of neoadjuvant endocrine therapy (NET) in HR+/HER2- patients with 1 mg anastrozole (Arm A) or 500 mg fulvestrant (Arm B). Secondary objectives included predictive markers of response and outcome. Between 2007 and 2011, 116 women with operable infiltrating breast adenocarcinoma T2-T4 N0-N3 M0 were randomized. Clinical response rates at 6 months (RECIST criteria) were 52.6% [95%CI 41-64%] in Arm A and 36.8% [95%CI 25-49%] in Arm B (Cancer 2016, in press). We aimed to identify the molecular predictive markers of resistance or sensitivity common to both treatments. Methods: Ninety tumor RNA from clinical responder (n=34) and resistant patients (n=23) treated in arms A or B have been sequenced with Illumina Hiseq2500 technology leading to 2x100-nt paired-end RNA-seq reads. These samples are from pre-treatment (29 in arm A, 28 in arm B) and post-treatment tumors (6 months after, 17 in arm A and 16 in arm B). Alignment was performed with Tophat_2.0.6. Differential gene expression was analyzed with the Differential Expression analysis for Sequence count data package. Gene fusion was detected with ChimeraScan, TophatFusion and DeFuse tools. Variant calling including variations, insertions and deletions was processed following GATK recommendations for RNAseq datas. Quantitative RT-PCR experiments were done to confirm RNA-seq expression results in patient samples not selected for RNA-seq analysis (validation cohort). Results: We first analyzed differentially expressed genes (DEGs) between responders and non-responders in pre-treatment or post-treatment samples to select potential predictive markers of response. We identified 51 DEGs before treatment common to anastrozole and fulvestrant. Among these 51 genes, SGK2 was the only gene more intensely expressed in responders than in non-responders. Then we compared DEGs between pre and post-treatment samples for responders or non-reponders for both treatment arms. SGK2 expression remains stable after treatment. Furthermore we identified 7 DEGs specific to responders and 11 DEGs specific to non-responders. Concerning genes fusion detection predicted by at least 2 tools, none was specific to a response type. We noted a higher number of fusions in non-responders samples. Variants detected by RNA-Seq are being confirmed by DNA-Seq using a home-made next-generation sequencing panel including 95 genes frequently mutated in breast cancers (analysis ongoing). Conclusion:High expression of SGK2, encoding a kinase induced in response to signals that activate PI3kinase, may represent a predictive marker of sensitivity to NET. DEGs associated with NET response or resistance belong to cell cycle, DNA replication and repair, cell death and drug metabolism. Ongoing DNA-seq datas will complete this genomic analysis. This research was conducted with support from AstraZeneca and Institut Curie. Citation Format: Callens C, Bessoltane N, Ngo C, Chemlali W, Becette V, Bernard V, Delattre O, Lemonnier J, Mouret-Reynier M-A, Andre F, Bieche I, Lerebours F. Genomic analysis to evaluate response to neoadjuvant anastrozole and fulvestrant in post-menopausal ER-positive HER2-negative breast cancer patients included in the UCBG CARMINA02 trial [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 P3-04-09.

Purpose: Atypical columnar cell hyperplasia (ACCH) is a borderline lesion that might represent an early stage in the development of certain low-grade carcinomas in situ (CIS) and invasive cancers. There are no guidelines on its management. Our objectives were to determine the upgrade to malignancy rate and identify a subpopulation of patients that might undergo just mammographic surveillance. Methods: We retrospectively reviewed the data for 271 ACCH cases among 5555 breast core biopsies obtained over a 7-year period (Jan. 2003 — Jan. 2010). We collated clinical data (age, history of cancer, menopausal status), radiological data (lesion type, size, Bi-Rads category), technical data (number of biopsies, needle gauge, excision quality) and histological data and sought correlations between these factors and upgrade rate. Results: The 271 ACCH comprised 128 cases of pure ACCH, 135 cases of ACCH + atypical ductal hyperplasia, and 8 cases of ACCH + atypical lobular hyperplasia. Overall, 184 patients underwent surgery and 46 mammographic surveillance. Surgery detected 34 cases of malignancy (23 CIS, 7 invasive cancers, and 4 mixed cases) giving a 15% upgrade rate. Quality of excision was the only factor associated with under-diagnosis. Conclusion: The presence of ACCH at biopsy warrants surgery. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-13.

Flat epithelial atypia (FEA) is a borderline lesion that might represent an early stage in the development of certain low-grade carcinomas in situ and invasive cancers. There are no guidelines on its management. Our objectives were to determine the upgrade to malignancy rate and identify a subpopulation of patients that might undergo just mammographic surveillance. We retrospectively reviewed the data for 271 FEA cases among 5,555 breast core biopsies obtained over a 7-year period (January 2003-2010). We collated clinical data (age, history of cancer, menopausal status), radiological data (lesion type, size, Bi-Rads category), technical data (number of biopsies, needle gauge, excision quality) and histological data and sought correlations between these factors and upgrade rate. The 271 FEA comprised 128 cases of pure FEA, 135 cases of FEA + atypical ductal hyperplasia, and 8 cases of FEA + atypical lobular hyperplasia. Overall, 184 patients underwent surgery and 46 mammographic surveillance. Surgery detected 34 cases of malignancy (23 CIS, 7 invasive cancers, and 4 mixed cases) giving a 15% upgrade rate. Quality of excision was the only factor associated with under-diagnosis. The presence of FEA at biopsy warrants surgery.

Among pre-invasive breast diseases, the lesion of flat epithelial atypia has a level of risk that remains unclear. The clinical significance of these lesions and how to behave during their diagnostic biopsy (monitoring vs. surgery) are still uncertain, because few studies (including monitoring) are available and because of the polymorphic spectrum of lesions and their many denominations across the studies in the literature. This article aims to update our knowledge and provide elements for the management of these lesions diagnosed on breast biopsy.

TP53 has a crucial role in the DNA damage response. We therefore tested the hypothesis that taxanes confer a greater advantage than do anthracyclines on breast cancers with mutated TP53 than in those with wild-type TP53.In an open-label, phase 3 study, women (age71 years) with locally advanced, inflammatory, or large operable breast cancers were randomly assigned in a 1:1 ratio to either a standard anthracycline regimen (six cycles of intravenous fluorouracil 500 mg/m², epirubicin 100 mg/m², and cyclophosphamide 500 mg/m² every 21 days [FEC100], or fluorouracil 600 mg/m², epirubicin 75 mg/m², cyclophosphamide 900 mg/m² [tailored FEC] starting on day 1 and then every 21 days) or a taxane-based regimen (three cycles of docetaxel 100 mg/m², intravenously infused over 1 h on day 1 every 21 days, followed by three cycles of intravenous epirubicin 90 mg/m² and docetaxel 75 mg/m² on day 1 every 21 days [T-ET]) at 42 centres in Europe. Randomisation was by use of a minimisation method that stratified patients by institution and initial tumour stage. The primary endpoint was progression-free survival (PFS) according to TP53 status. Analysis was by intention to treat. This is the final analysis of this trial. The study is registered with ClinicalTrials.gov, number NCT00017095.928 patients were enrolled in the FEC group and 928 in the T-ET group. TP53 status was not assessable for 183 (20%) patients in the FEC group and 204 (22%) patients in the T-ET group mainly because of low tumour-cell content in the biopsy. 361 primary endpoint events were recorded in the FEC group and 314 in the T-ET group. In patients with TP53-mutated tumours, 5-year PFS was 59·5% (95% CI 53·4-65·1) in the T-ET group (n=326) and 55·3% (49·2-60·9) in the FEC group (n=318; hazard ratio 0·84, 98% CI 0·63-1·14; p=0·17). In patients with TP53 wild-type tumours, 5-year PFS was 66·8% (95% CI 61·4-71·6) in the T-ET group (n=398) and 64·7% (59·6-69·4) in the FEC group (n=427; 0·89, 98% CI 0·68-1·18; p=0·35). For all patients, irrespective of TP53 status, 5-year PFS was 65·1% (95% CI 61·6-68·3) in the T-ET group and 60·8% (57·3-64·2) in the FEC group (0·85, 98% CI 0·71-1·02; p=0·035). At the sites using FEC100 versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (75 [9%] of 803 vs 173 [21%] of 809, respectively), and neutropenia (653 [81%] vs 730 [90%], respectively). At the sites using tailored FEC versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (ten [8%] of 118 vs 26 [22%] of 116, respectively), and neutropenia (100 [85%] vs 115 [99%], respectively). Two patients died of toxicity during or within 30 days of chemotherapy completion and without disease relapse (one in each group).Although TP53 status was prognostic for overall survival, it was not predictive of preferential sensitivity to taxanes. TP53 status tested by use of the yeast assay in this patient population cannot be used to select patients for an anthracycline-based chemotherapy versus a taxane-based chemotherapy.US National Cancer Institute, La Ligue Nationale Contre le Cancer, European Union, Pharmacia, and Sanofi-Aventis.

Neo-adjuvant chemotherapy of breast cancer provides an opportunity to evaluate predictive factors at initial tumor biopsy. We evaluated these factors on cell blocks obtained by diagnostic fine-needle cytopuncture (FNC), with respect to tumor regression and outcome. A prospective study (1996–2003, median follow-up 82 months) involved 163 patients with breast carcinoma (T2 ≥3 cm, T3, T4 noninflammatory) diagnosed by means of FNC. Malignancy, cytologic grade, and the presence of lymphocytes were determined on cytologic smears. Ki67, estrogen receptor (ER), progesterone receptor (PgR), HER2, and p53 expression was assessed on cell blocks by means of immunohistochemistry. All the patients received anthracycline-based chemotherapy. A combined clinical and pathologic tumor regression score was calculated. Twelve cases (7.5%) showed a complete regression, 72 cases (44%) a partial regression and 79 cases (48.5%) no regression. Factors predictive of regression were high grade, presence of lymphocytes, pN0, high Ki67 expression, hormone receptor negativity, and the “triple negative” phenotype. In univariate analysis 5-year metastasis-free survival rate (MFS) correlated with cytologic grade, pN, ER, and p53 status, while overall survival (OS) correlated with cytologic grade, type of surgery, pN, and ER status. In multivariate analysis, MFS was significantly influenced by the regression score, Ki67, age, ER status, pN, HER2, and initial tumor size. Except for age, the same parameters correlated with OS. FNC with the cell block technique is a rapid, minimally invasive, reliable, and inexpensive method for analyzing predictive biomarkers, and may thus be useful in the management of breast cancer patients requiring neo-adjuvant chemotherapy.

To better understand the relationship between tumor-host interactions and the efficacy of chemotherapy, we have developed an analytical approach to quantify several biological processes observed in gene expression data sets. We tested the approach on tumor biopsies from individuals with estrogen receptor-negative breast cancer treated with chemotherapy. We report that increased stromal gene expression predicts resistance to preoperative chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC) in subjects in the EORTC 10994/BIG 00-01 trial. The predictive value of the stromal signature was successfully validated in two independent cohorts of subjects who received chemotherapy but not in an untreated control group, indicating that the signature is predictive rather than prognostic. The genes in the signature are expressed in reactive stroma, according to reanalysis of data from microdissected breast tumor samples. These findings identify a previously undescribed resistance mechanism to FEC treatment and suggest that antistromal agents may offer new ways to overcome resistance to chemotherapy.

BACKGROUND Fine-needle aspiration generally produces results that are not as good for lobular carcinoma as the results for ductal carcinoma of the breast. In this study, the authors evaluated their team's performance in cytologic diagnosis of lobular carcinoma over 11 years and analyzed the reasons for diagnostic failure. METHODS Cytologic findings were analyzed in 555 consecutive fine-needle cytopuncture specimens from women with palpable, invasive lobular carcinoma of the breast. The authors also examined the influence of the cytologist's experience, the clinical tumor size, the histologic subtype, and the histologic grade on diagnostic performance. All negative samples were re-examined, along with all samples that had been obtained during the last year of the study, to refine the morphologic description of lobular carcinoma. RESULTS Malignancy was diagnosed in 68.8% of specimens overall. The individual pathologists diagnosed malignancy in from 44.4% to 81.1% of specimens, depending on their experience. Diagnostic performance was correlated with clinical tumor size, histologic grade, and histologic subtype, and correct diagnoses were significantly more frequent in pleomorphic subtypes than in “classic” types. Re-examination of all 32 negative specimens reduced the false-negative rate from 5.8% to 3.8%. CONCLUSIONS Despite the pitfalls associated with lobular carcinoma of the breast, fine-needle cytopuncture remains a useful diagnostic tool before treatment. Failures can be reduced through experience and by better knowledge of cytologic features. Cancer (Cancer Cytopathol) 2008. © 2008 American Cancer Society.

We report our experience on fertility sparing treatment in young women affected by cervical cancer of more than 2cm.Between July 2012 and February 2014, five patients presenting cervical tumors larger than 2cm (IB12cm) (23-35) and wishing to preserve fertility have been treated at our institution. Laparoscopic pelvic and para-aortic lymphadenectomy was performed for all patients. When lymph nodes were free of disease, patients had neoadjuvant chemotherapy followed by surgical conservative treatment.Four patients underwent a cisplatin based neoadjuvant chemotherapy before conservative surgery: radical trachelectomy or simple trachelectomy. One patient with nodal involvement underwent a 3cycle chemotherapy followed by concurrent radiochemotherapy. Hematologic toxicity grade 3 was observed in one patient leading to a change of chemotherapy. Two patients showed complete disappearance of tumor and two a partial response to neoadjuvant treatment. After a mean follow up of 20.5months (14-33), no relapse was observed. To date, no pregnancy was obtained.Lymph node staging followed by neoadjuvant chemotherapy and radical trachelectomy seems to be a promising treatment scheme for patients with cervical tumors IB12cm pN0 seeking parenthood.

The treatment of epithelial ovarian cancer (EOC) is narrowly focused despite the heterogeneity of this disease in which outcomes remain poor. To stratify EOC patients for targeted therapy, we developed an approach integrating expression and genomic analyses including the BRCAness status. Gene expression and genomic profiling were used to identify genes recurrently (5%) amplified and overexpressed in 105 EOC. The LST (Large-scale State Transition) genomic signature of BRCAness was applied to define molecular subgroups of EOC. Amplified/overexpressed genes clustered mainly in 3q, 8q, 19p and 19q. These changes were generally found mutually exclusive. In the 85 patients for which the genomic signature could be determined, genomic BRCAness was found in 52 cases (61.1%) and non-BRCAness in 33 (38.8%). A striking mutual exclusivity was observed between BRCAness and amplification/overexpression data. Whereas 3q and 8q alterations were preferentially observed in BRCAness EOC, most alterations on chromosome 19 were in non-BRCAness cases. CCNE1 (19q12) and BRD4 (19p13.1) amplification/overexpression was found in 19/33 (57.5%) of non-BRCAness cases. Such disequilibrium was also found in the TCGA EOC data set used for validation. Potential target genes are frequently amplified/overexpressed in non-BRCAness EOC. We report that BRD4, already identified as a target in several tumor models, is a new potential target in high grade non-BRCAness ovarian carcinoma.

Previous microarray studies on breast cancer identified multiple tumour classes, of which the most prominent, named luminal and basal, differ in expression of the estrogen receptor alpha gene (ER). We report here the identification of a group of breast tumours with increased androgen signalling and a 'molecular apocrine' gene expression profile. Tumour samples from 49 patients with large operable or locally advanced breast cancers were tested on Affymetrix U133A gene expression microarrays. Principal components analysis and hierarchical clustering split the tumours into three groups: basal, luminal, and a group we call molecular apocrine. All of the molecular apocrine tumours have strong apocrine features on histological examination (P = 0.0002). The molecular apocrine group is androgen receptor-positive (AR+) and contains all of the ER-negative tumours outside the basal group. Kolmogorov-Smirnov testing indicates that oestrogen signalling is most active in the luminal group, and androgen signalling is most active in the molecular apocrine group. ERBB2 amplification is more common in the molecular apocrine group than the other groups. Genes that best split the three groups were identified by the Wilcoxon test. Correlation of the average expression profile of these genes in our data with the expression profile of individual tumours in four published breast cancer studies suggest that molecular apocrine tumours represent 8–14% of tumours in these studies. Our data show that it is possible with microarray data to divide mammary tumour cells into three groups based on steroid receptor activity: luminal (ER+ AR+), basal (ER-AR-) and molecular apocrine (ER- AR+).

Quantitative reverse transcription-polymerase chain reaction (RT-PCR) used to detect minor changes in specific mRNA concentrations may be associated with poor reproducibility. Stringent quality control is therefore essential at each step of the protocol, including the PCR procedure. We performed inter-laboratory quality control of quantitative PCR between two independent laboratories, using in-house RT-PCR assays on a series of hormone-related target genes in a retrospective consecutive series of 79 breast tumors. Total RNA was reverse transcribed in a single center. Calibration curves were performed for five target genes (estrogen receptor (ER)α, ERβ, progesterone receptor (PR), CYP19 (aromatase) and Ki 67) and for two reference genes (human acidic ribosomal phosphoprotein PO (RPLPO) and TATA box-binding protein (TBP)). Amplification efficiencies of the calibrator were determined for each run and used to calculate mRNA expression. Correlation coefficients were evaluated for each target and each reference gene. A good correlation was observed for all target and reference genes in both centers using their own protocols and kits (P < 0.0001). The correlation coefficients ranged from 0.90 to 0.98 for the various target genes in the two centers. A good correlation was observed between the level of expression of the ERα and the PR transcripts (P < 0.001). A weak inverse correlation was observed in both centers between ERα and ERβ levels, but only when TBP was the reference gene. No other correlation was observed with other parameters. Real-time PCR assays allow convenient quantification of target mRNA transcripts and quantification of target-derived nucleic acids in clinical specimens. This study addresses the importance of inter-laboratory quality controls for the use of a panel of real-time PCR assays devoted to clinical samples and protocols and to ensure their appropriate accuracy. This can also facilitate exchanges and multicenter comparison of data.

Resume Comment diminuer le taux d’echecs des macrobiopsies mammaires percutanees ? Les macrobiopsies mammaires assistees par aspiration representent une alternative efficace a la chirurgie diagnostique des anomalies mammographiques suspectes non palpables. Bien que le taux d’echec soit faible, nous aborderons chaque etape de la procedure en essayant de lister les differentes sources possibles d’echec et en proposant un certain nombre de moyens permettant de les prevenir ou de les limiter.

Introduction: Tumor cells present an iron metabolic disorder with high proliferation rate, increased iron storage (ferritin and Labile Iron Pool - LIP) and high sensibility to iron deprivation, which could be a therapeutic target. Anticancer effect of iron chelators deferoxamine (DFO) and deferasirox (DFX) has been revealed in several types of cancers. In breast cancer (BC), the development of new therapeutic approaches is urgently needed for triple negative (TN) subtype which presents poor prognosis and lacks targeting therapy. We investigated the therapeutic potential of iron chelators combined with chemotherapeutic agents in TNBC cell lines and patient-derived xenografts (PDX). Methods: Anticancer effects of iron chelators combined with chemotherapeutic agents (doxorubicin, cisplatin or carboplatin) were evaluated in vitro in 4 TNBC cell lines by MTT assay, annexin V/PI staining and assessment of caspase 3/7 activity. Assessment of LIP, transferrin receptor 1 (TfR1) expression level, Reactive Oxygen Species (ROS) production and mitochondrial membrane potential variations were performed by flow cytometry, and ELISA assay for ferritin level. The activity of DFX alone or combined with doxorubicin/cyclophosphamide (AC) was tested in the HBCx-10 TNBC PDX selected because of its relapse to AC. Iron homeostasis, hypoxia and PI3K pathway were analyzed by immunohistochemistry (IHC) and Western-blot in both cell lines and PDX tumors. In DFX+/-AC treated and untreated tumors, induction of apoptosis was performed by TUNEL assay and a transcriptome analysis is ongoing. Results: Iron chelators acted in synergy effect with three chemotherapies in all cell lines which were tested to inhibit cell proliferation and induce apoptosis. Chelators increased cytotoxicity until 60% compared to chemotherapies alone. In all cell lines, chelators treatment increased TfR1 expression level and decreased LIP and ferritin. Furthermore, down-regulation of PI3K pathway, hypoxia, mitochondrial membrane potential, and the production increasing of ROS were observed. In HBCx-10 PDX, a trend for antitumoral activity of DFX alone was observed (p=0.09) at the end of the experiment (day 81). A significant difference of Relative Tumor Volume (RTV) was observed since day 18 between the AC group and the DFX+AC group (tumor growth inhibition: 37 to 61%, tumor growth delay: 10 to 14 days, 0.005 Conclusions: Iron chelators may increase the effectiveness of conventional chemotherapies for TNBC treatments. This antitumoral synergy involves PI3K pathway downregulation, ROS production and decrease mitochondrial membrane potential. Citation Format: Sandrine Tury, Sophie Vacher, Véronique Becette, Franck Assayag, Sophie Chateau-Joubert, Jean-Luc Servely, Elisabetta Marangoni, Ivan Bièche, Céline Callens. Antitumoral synergy of iron chelators and chemotherapies in triple-negative breast cancer cell lines and patient-derived xenograft [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2031. doi:10.1158/1538-7445.AM2017-2031

Background: Neaodjuvant endocrine therapy (NET) has demonstrated efficacy in terms of clinical response and outcome in hormone-receptor positive (HR+) post-menopausal patients (pts) with breast cancer (BC) not eligible for primary breast conservative surgery (BCS). However, the monitoring of tumor response to NET is challenging and clinical response is the current gold standard. The aim of the present study was to investigate the contribution of the early metabolic response (eMR) at one month in FDG-PET/CT in a NET setting for post-menopausal pts with HR+, HER2- BC compared to morphological and pathological responses. We also aimed to evaluate the prognostic value of eMR. Methods: This was a prospective and ancillary study of CARMINA 02, UCBG0609 (Cancer in press), a phase II clinical trial evaluating the efficacy of 4 to 6 months neoadjuvant anastrozole or fulvestrant. FDG-PET/CT exams were performed at baseline (M0), after 1 month of treatment (M1: eMR) and pre-Op (late metabolic response: lMR) in 11 pts (74.2 years ± 3.6) from 2007 to 2010. Pts were classified “metabolic responders” (mR) if SUVmax values decrease was ≥ 40% at M1 and “non-metabolic responders” (mNR) if otherwise; lMR was also assessed in mR and mNR groups defined at M1. We compared eMR to morphological response (clinical, breast US and MRI) at M1 and pre-op, to the pathological response according to Sataloff classification and to Ki67 score variation during treatment. Early metabolic response was also correlated with the PEPI (Preoperative Endocrine Prognostic Index) score and survival (overall survival, OS and relapse free survival, RFS). Results: Main results are summarized in Table I. There was a significant difference between mR and mNR pts at M1 (eMR) and pre-op (lMR). One patient with a complete metabolic response at pre-op had the best pathological response (Sataloff TB). Also, mR pts had a better clinical response: 2 partial response (PR) in mR vs 1 in mNR group and 2 mNR patients were classified PD (progressive disease). There was a trend toward better survival for mR pts in OS and RFS (Kaplan-Meier p=0.18 and 0.06, respectively) and all the pejorative events occurred in the mNR group: 3 deaths and 3 metastatic progressions. Besides, no difference in eMR was observed regarding the histological subtype (ductal or lobular; p>0.05) nor the treatment group (p>0.05). Table I: Metabolic, morphological and pathological response at M1, Pre-Op and on the surgical specimen. MR : 5ptsmNR : 6ptsP valueM1SUVmax2.6±1.13.9±1.40.00017 Clinical size42.5mm±11.951.7mm±7.50.19 US size22.6mm±6.334.2mm±2.40.02 MRI size21.2mm±4.239.7mm±4.79.16 E-5 Ki 673.6%±1.98.2%±80.19Pre-OpSUVmax2±1.33.3±1.40.018 Clinical size31mm±12.448.3mm±10.80.035 US size18.5mm±7.331.3mm±9.50.07 MRI size17.9mm±7.134.8mm±7.70.003Surgical SpecimenSataloff (TA+TB vs TC+TD)20% vs 80%0 vs 100%1 PEPI score (I+II vs III)80% vs 20%33 vs 67%0.048 Ki 678.6%±9.812.3%±7.90.41 Conclusions: These preliminary results showed the value of the early metabolic response in FDG- PET/CT in a NET setting compared to the morphological or the pathological responses alone. Early metabolic responders patients had better OS, RFS and PEPI scores. Citation Format: Boughdad S, Champion L, Becette V, Cherel P, Fourme E, Edeline V, Lemonnier J, Lerebours F, Alberini JL. Predictive value of FDG-PET/CT after neoadjuvant endocrine treatment in breast cancer [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 P4-01-03.

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.