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Resume Introduction Chez les femmes considerees a haut risque de cancer du sein, la mastectomie est une alternative a la surveillance rapprochee. La chirurgie mammaire de reduction du risque (CMRR) presente des benefices et des risques, dont l’evaluation est particulierement importante car sa realisation depend du choix de la patiente. L’objectif de cette etude etait d’etudier les pratiques de la CMRR dans un centre francais de lutte contre le cancer et notamment d’evaluer la morbidite et le risque de decouverte fortuite de cancer. Methodes Il s’agit d’une etude retrospective, descriptive s’etendant de 2007 a 2017. Les dossiers de toutes les patientes ayant beneficie d’une CMRR bilaterale ou controlaterale ont ete analyses. Resultats Soixante-dix-neuf patientes ont ete operees sur la periode d’etude dont 58,2 % d’une mastectomie controlaterale. Le critere de recevabilite de la demande de mastectomie etait l’existence d’une mutation genetique dans 86,1 % des cas. Une complication postoperatoire est survenue chez 43,0 % des patientes et une reintervention a ete necessaire dans 72,1 % des cas. A l’analyse anatomopathologique, un cancer a ete decouvert dans 11,4 % des cas ; il s’agissait dans deux cas (2,5 %) d’un carcinome infiltrant de type triple negatif. Discussion La CMRR reste a ce jour la mesure la plus efficace de prevention du cancer du sein en France. Chaque femme doit, avant d’y recourir, etre clairement informee de la balance benefice–risque, en particulier de la forte probabilite de presenter une complication, de la necessite de plusieurs temps operatoires et de l’existence d’un risque de decouvrir un cancer a l’analyse anatomopathologique. L’accompagnement preoperatoire doit etre optimise afin de guider au mieux ces femmes dans leur processus decisionnel.

Background: Young breast cancer patients (pts) carrying a germline BRCA mutation (mBRCA) have similar outcomes as non-carriers. However, there is currently lack of evidence regarding the impact of mBRCA type and hormone receptor status on clinical behavior and outcomes of mBRCA breast cancer. We aim to address these questions in the largest dataset to date of young mBRCA breast cancer pts. Methods: This was an international, multicenter, hospital-based, retrospective cohort study. Women harboring deleterious germline mBRCA1 or mBRCA2 that received a diagnosis of stage I-III invasive early breast cancer at age ≤40 years between January 2000 and December 2012 were included. Baseline pts, tumor, and treatment characteristics, pattern and risk over time of disease-free survival (DFS) events, and survival outcomes (DFS, distant recurrence-free interval [DRFI] and overall survival [OS]) were compared between mBRCA1 and mBRCA2 pts overall and by hormone receptor status. Multivariate Cox proportional hazard models were used to compare hazard rates (HRs). Results: 1,236 young mBRCA breast cancer pts were included. Among 808 and 428 pts with mBRCA1 or mBRCA2, respectively, 191 (23.6%) and 356 (83.2%) had hormone receptor-positive tumors while 617 (76.4%) and 72 (16.8%) hormone receptor-negative disease (p Conclusions: In this large unique dataset, young mBRCA1 breast cancer pts had worse DFS than those with mBRCA2 mostly due to higher rates of second primary malignancies. Hormone receptor positivity had no positive prognostic value in young mBRCA breast cancer pts with a trend towards worse DRFI in those with hormone receptor-negative disease. These results provide important information for counseling young mBRCA breast cancer pts regarding treatment, prevention and follow-up care strategies. Citation Format: Matteo Lambertini, Marcello Ceppi, Anne-Sophie Hamy, Olivier Caron, Philip D. Poorvu, Estela Carrasco, Albert Grinshpun, Kevin Punie, Christine Rousset-Jablonski, Alberta Ferrari, Shani Paluch-Shimon, Angela Toss, Claire Senechal, Fabio Puglisi, Katarzyna Pogoda, Jose Alejandro Pérez-Fidalgo, Laura De Marchis, Riccardo Ponzone, Luca Livraghi, Maria Del Pilar Estevez-Diz, Cynthia Villarreal-Garza, Maria Vittoria Dieci, Florian Clatot, Francois P. Duhoux, Rossella Graffeo, Luis Teixeira, Octavi Córdoba, Amir Sonnenblick, Arlindo R. Ferreira, Ann H. Partridge, Antonio Di Meglio, Claire Saule, Fedro A. Peccatori, Marco Bruzzone, Lucia Del Mastro, Lieveke Ameye, Judith Balmaña, Hatem A. Azim, Jr. Clinical behavior and outcomes of BRCA-mutated breast cancer in young patients according to type of BRCA mutation and hormone receptor status: Results from an international cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-06.

PURPOSE Young women with germline BRCA mutations have unique reproductive challenges. Pregnancy after breast cancer does not increase the risk of recurrence; however, very limited data are available in patients with BRCA mutations. This study investigated the impact of pregnancy on breast cancer outcomes in patients with germline BRCA mutations. PATIENTS AND METHODS This is an international, multicenter, hospital-based, retrospective cohort study. Eligible patients were diagnosed between January 2000 and December 2012 with invasive early breast cancer at age ≤ 40 years and harbored deleterious germline BRCA mutations. Primary end points were pregnancy rate, and disease-free survival (DFS) between patients with and without a pregnancy after breast cancer. Pregnancy outcomes and overall survival (OS) were secondary end points. Survival analyses were adjusted for guarantee-time bias controlling for known prognostic factors. RESULTS Of 1,252 patients with germline BRCA mutations ( BRCA1, 811 patients; BRCA2, 430 patients; BRCA1/2, 11 patients) included, 195 had at least 1 pregnancy after breast cancer (pregnancy rate at 10 years, 19%; 95% CI, 17% to 22%). Induced abortions and miscarriages occurred in 16 (8.2%) and 20 (10.3%) patients, respectively. Among the 150 patients who gave birth (76.9%; 170 babies), pregnancy complications and congenital anomalies occurred in 13 (11.6%) and 2 (1.8%) cases, respectively. Median follow-up from breast cancer diagnosis was 8.3 years. No differences in DFS (adjusted hazard ratio [HR], 0.87; 95% CI, 0.61 to 1.23; P = .41) or OS (adjusted HR, 0.88; 95% CI, 0.50 to 1.56; P = .66) were observed between the pregnancy and nonpregnancy cohorts. CONCLUSION Pregnancy after breast cancer in patients with germline BRCA mutations is safe without apparent worsening of maternal prognosis and is associated with favorable fetal outcomes. These results provide reassurance to patients with BRCA-mutated breast cancer interested in future fertility.

BACKGROUND: Young breast cancer (BC) survivors are at risk of infertility. Ovarian stimulation for fertility preservation before (neo)adjuvant chemotherapy is standard of care. Research efforts have shown no negative prognostic effect of pregnancy following BC therapy, also among BRCA carriers. Currently, poor evidence is available on the safety to undergo ART following BC treatment, with no data in carriers of germline BRCA pathogenic variants. To provide evidence on the safety of fertility treatments in this specific population, we assessed the outcomes of a cohort of BRCA-mutated BC survivors who had a pregnancy after prior BC history by comparing the group of patients who underwent ART to achieve pregnancy to the group with spontaneous pregnancy. METHODS: We conducted a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤ 40 years with stage I-III BC, between January 2000 and December 2012, bearing germline BRCA1/2 pathogenic variants. Survivors with a pregnancy (any outcome) after BC, with no disease-free survival (DFS) event before pregnancy, were assigned to the ART and non-ART group if their pregnancy was achieved through ART or spontaneously, respectively. ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), and embryo transfer under hormonal replacement therapy (HRT). RESULTS: Of 1,424 patients registered in the study, 168 with a pregnancy after BC were included in the present analysis. A total of 22 patients were included in the ART group and 146 in the non-ART group. Before BC diagnosis, 18.2% patients in the ART group had at least one child, compared to 38.4% in the non-ART group (P=0.030). Patients had a median age at BC diagnosis of 33.0 vs 30.2 years old in the ART group and in the non-ART group, respectively (P=0.004); 45.4% and 17.1% had grade 1-2 tumors, respectively (P=0.008), and 59.1% vs 31.5% had hormone receptor-positive tumors, respectively (P=0.016). Both cohorts had similar tumor size and nodal stage characteristics. Type and duration of endocrine therapy were comparable between groups. The type of ART was not specified in 5 survivors (22.7%). Ovulation induction was used in 1 patient (4.5%), ovarian stimulation in 7 patients (31.8%), embryo transfer under HRT following oocyte donation in 5 patients (22.7%), and embryo transfer under HRT following oocyte and/or embryo cryopreservation for fertility preservation in 4 patients (18.2%). Median age at conception among survivors was 39.7 years in the ART group versus 35.4 years in the non-ART group (P Citation Format: Margherita Condorelli, Marco Bruzzone, Marcello Ceppi, Alberta Ferrari, Albert Grinshpun, Anne-Sophie Hamy, Evandro de Azambuja, Estela Carrasco, Fedro A. Peccatori, Antonio Di Meglio, Shani Paluch-Shimon, Philip D. Poorvu, Marta Venturelli, Christine Rousset-Jablonski, Claire Senechal, Luca Livraghi, Riccardo Ponzone, Laura De Marchis, Katarzyna Pogoda, Amir Sonnenblick, Cynthia Villarreal-Garza, Octavi Córdoba, Luis Teixeira, Florian Clatot, Kevin Punie, Rossella Graffeo Galbiati, Maria Vittoria Dieci, Alejandro Pérez-Fidalgo, Francois P. Duhoux, Fabio Puglisi, Arlindo R. Ferreira, Eva Blondeaux, Tamar Peretz-Yablonski, Olivier Caron, Claire Saule, Lieveke Ameye, Judith Balmaña, Ann H. Partridge, Hatem A. Azim, Jr, Isabelle Demeestere, Matteo Lambertini. Safety of assisted reproductive technologies (ART) following treatment completion in young women with germline BRCA pathogenic variants having a pregnancy after breast cancer [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 PD5-06.

Càncer de mama; Genètica del càncer Cáncer de mama; Genética del cáncer Breast cancer; Cancer genetics Young breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR−]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I–III invasive early BC at age ≤40 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P

Introduction: Five to 10% of breast cancers (BCs) occur in a genetic predisposition context (mainly BRCA pathogenic variant). Nevertheless, little is known about immune tumor infiltration, response to neoadjuvant chemotherapy (NAC), pathologic complete response (pCR) and adverse events according to BRCA status. Material and Methods: Out of 1199 invasive BC patients treated with NAC between 2002 and 2012, we identified 267 patients tested for a germline BRCA pathogenic variant. We evaluated pre-NAC and post-NAC immune infiltration (TILs). Response to chemotherapy was assessed by pCR rates. Association of clinical and pathological factors with TILs, pCR and survival was assessed by univariate and multivariate analyses. Results: Among 1199 BC patients: 46 were BRCA-deficient and 221 BRCA-proficient or wild type (WT). At NAC completion, pCR was observed in 84/266 (31%) patients and pCR rates were significantly higher in BRCA-deficient BC (p = 0.001), and this association remained statistically significant only in the luminal BC subtype (p = 0.006). The interaction test between BC subtype and BRCA status was nearly significant (Pinteraction = 0.056). Pre and post-NAC TILs were not significantly different between BRCA-deficient and BRCA-proficient carriers, however, in the luminal BC group, post-NAC TILs were significantly higher in BRCA-deficient BC. Survival analysis were not different between BRCA-carriers and non-carriers. Conclusions: BRCA mutation status is associated with higher pCR rates and post-NAC TILs in patients with luminal BC. BRCA-carriers with luminal BCs may represent a subset of patients deriving higher benefit from NAC. Second line therapies, including immunotherapy after NAC, could be of interest in non-responders to NAC.

IntroductionFive to 10% of breast cancers (BCs) occur in a genetic predisposition context (mainly BRCA pathogenic variant). Nevertheless, little is known about immune tumor infiltration, response to neoadjuvant chemotherapy (NAC), pathologic complete response (pCR) and adverse events according to BRCA status.Material and methodsOut of 1199 invasive BC patients treated with NAC between 2002 and 2012, we identified 267 patients tested for a germline BRCA pathogenic variant. We evaluated pre-NAC and post-NAC immune infiltration (TILs). Response to chemotherapy was assessed by pCR rates. Association of clinical and pathological factors with TILs, pCR and survival was assessed by univariate and multivariate analyses.ResultsAmong 1199 BC patients: 46 were BRCA-deficient and 221 BRCA-proficient or wild type (WT). At NAC completion, pCR was observed in 84/266 (31%) patients and pCR rates were significantly higher in BRCA-deficient BC (p= 0.001), and this association remained statistically significant only in the luminal BC subtype (p= 0.006). The interaction test between BC subtype and BRCA status was nearly significant (Pinteraction=0.056). Pre and post-NAC TILs were not significantly different between BRCA-deficient and BRCA-proficient carriers; however, in the luminal BC group, post-NAC TILs were significantly higher in BRCA-deficient BC. Survival analysis were not different between BRCA-carriers and non-carriers.ConclusionBRCA mutation status is associated with higher pCR rates and post-NAC TILs in patients with luminal BC. BRCA-carriers with luminal BCs may represent a subset of patients deriving higher benefit from NAC. Second line therapies, including immunotherapy after NAC, could be of interest in non-responders to NAC.Translational relevanceHigh lymphocytic infiltration (TILs) seem to reflect favorable host antitumor immune responses. In breast cancer, the variation of TILs before and after neoadjuvant chemotherapy (NAC) according to BRCA status has been poorly described. Little data is available on their value after treatment. We investigated TIL levels before and after NAC and response to treatment in 267 paired biopsy and surgical specimens.In our study, luminal BCs were associated with pathologic complete response (pCR) and higher TIL levels after chemotherapy completion in patients with BRCA pathogenic mutations. Our data supports that (i) NAC should be reconsidered in luminal BCs with BRCA pathogenic mutation, (ii) TILs could be a biomarker for response to immune checkpoint blockade in luminal BCs with BRCA pathogenic variant who did not achieve a pCR and (iii) exploiting the antitumor immune response in luminal BCs could be an area of active research.

Young women with germlineThis is an international, multicenter, hospital-based, retrospective cohort study. Eligible patients were diagnosed between January 2000 and December 2012 with invasive early breast cancer at age ≤ 40 years and harbored deleterious germlineOf 1,252 patients with germlinePregnancy after breast cancer in patients with germline

Background Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants. Patients and methods This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy. Results Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group. Conclusion This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing., Highlights • No data exist on safety of assisted reproductive techniques (ART) in BRCA-mutated breast cancer patients. • This study investigated outcomes of patients with a post-treatment pregnancy achieved through ART use or naturally. • 2 (9.1%) and 40 (27.4%) patients in the ART and non-ART groups experienced a disease-free survival event. • This study provides encouraging safety data on ART use in BRCA-mutated breast cancer survivors. • ART is feasible when natural conception fails or when survivors opt for carrying out preimplantation genetic testing.

In France, women carrying BRCA1/2 mutation, at an identified high risk of breast cancer are recommended to undergo breast MRI screening. That screening does not however prevent the risk of developing a breast cancer. The only alternative to breast cancer screening available in France is surgical prevention by prophylactic mastectomy. An interesting option for women who wish to reduce their breast cancer risk, but are unready for prophylactic mastectomy is a preventive hormonal treatment by aromatase inhibitors, or selective estrogens receptor modulators (SERMs). Reliable clinical trials show the efficiency of tamoxifen, raloxifen, exemestane, and anastrozole especially, in reducing breast cancer incidence by 33%, 34%, 65% and 53% respectively. This article tries to sum up the main published trials of breast cancer prevention with hormonal treatment, and presents the latest American and English clinical guidelines concerning hormonal prevention for women at high risk of breast cancer, and starts thinking about the possibilities of hormonoprevention, especially among women carrying a BRCA1/2 mutation in France.

Context: The majority of BRCA mutation carriers diagnosed with breast cancer (BC) are treated with chemotherapy. The effectiveness of standard neoadjuvant chemotherapy (NAC) in BRCA associated BC compared to noncarriers has been poorly explored. Objectives: To assess whether the BRCA mutation status modifies the immune infiltration, chemosensitivity, and prognosis of breast cancer. Methods: We retrospectively identified in our institutional database all consecutive patients with BRCA germline mutation status available treated with NAC between 2002 and 2012. Microbiopsy specimens and paired surgical samples were evaluated for pre-NAC and post-NAC immune infiltration (stromal TILs, str TILs; intratumoral TILs, IT TILs). Response to chemotherapy was assessed by pathological complete response (pCR) rates. Association of clinical and pathological factors with pCR, overall survival (OS), and relapse free survival (RFS) was assessed by univariate and multivariate analyses. Results: Overall, 267 patients were included in this study (46 BRCA carriers and 221 BRCA noncarriers). The median age at BC diagnosis was 40 years old, and most of the patients (n=227, 85%) were premenopausal. Patients repartition by subtype was as follows: luminal (n=90, 33.7%), TNBC (n=110, 41.2%), HER2-positive (n=67, 25.1%). BRCA mutation carriers were likely to have familial history of BC (73.9% vs. 52.3%, p = 0.012), and be diagnosed with TNBC (58.7% vs 37.6%; p = 0.006), than noncarriers. No pattern was significantly different between BRCA mutation subgroups regarding age, body mass index, histology, tumor size, grade or Ki67. TIL levels were available in 192 patients. Neither pre-NAC stromal TIL levels nor IT TILs were significantly different by BRCA status in the whole population, nor in each BC subtype. PCR rates were significantly higher in BRCA mutation carriers (p= 0.035), and this association remained statistically significant only in the luminal BC subtype (p=0.006) after stratification by BC subtype (Pinteraction= 0.056). After multivariate analysis, only BC subtype and pre-NAC str TILs were independent predictors of pCR. Post-NAC stromal and intra-tumoral TIL levels were significantly higher luminal subtype (p=0.009 and p=0.019, respectively). After a median follow-up of 90 months, RFS and OS were not different between BRCA carriers and noncarriers, neither in the whole population nor after stratification by BC subtype. Discussion: In our study, BRCA status was associated with an enhanced response to standard NAC, particularly in luminal BC patients, in addition to higher post-NAC TIL levels. Whether patients with luminal BC and BRCA mutation derive benefit from second line immunotherapy after NAC completion remains to determine. Citation Format: Beatriz Grandal, Clémence Evrevin, Eric Daoud, Elise Dumas, Nadir Sella, Clara Sebbag, Sonia Rozette, Isabelle Jardin, Lucie Laot, Florence Coussy, Claire Saule, Dominique Stoppa-Lyonnet, Sophie Franck, Claire Sénéchal, Enora Laas, Marick Lae, Diane De Croze, Fabien Reyal, Anne-Sophie Hamy. Impact of BRCA mutation status on immune infiltration, chemosensitivity, and prognosis of breast cancer patients treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-10.

Faced to an undetermined ovarian mass on ultrasound, an MRI is recommended and the ROMA score (combining CA125 and HE4) can be proposed (grade A). In case of suspected early stage ovarian or fallopian tube cancer, omentectomy (at least infracolonic), appendectomy, multiple peritoneal biopsies, peritoneal cytology (grade C) and pelvic and para-aortic lymphadenectomy are recommended (grade B) for all histological types, except for the expansive mucinous subtype where lymphadenectomy may be omitted (grade C). Minimally invasive surgery is recommended for early stage ovarian cancer, if there is no risk of tumor rupture (grade B). Adjuvant chemotherapy with carboplatin and paclitaxel is recommended for all high-grade ovarian or Fallopian tube cancers, stage FIGO I-IIA (grade A). In case of ovarian, Fallopian tube or primitive peritoneal cancer of FIGO III-IV stages, thoraco-abdomino-pelvic CT scan with injection (grade B) is recommended. Laparoscopic exploration for multiple biopsies (grade A) and to evaluate carcinomatosis score (at least using the Fagotti score) (grade C) are recommended to estimate the possibility of a complete surgery (i.e. no macroscopic residue). Complete medial laparotomy surgery is recommended for advanced cancers (grade B). It is recommended in advanced cancers to perform para-aortic and pelvic lymphadenectomy in case of clinical or radiological suspicion of metastatic lymph node (grade B). In the absence of clinical or radiological lymphadenopathy and in case of complete peritoneal surgery during an initial surgery for advanced cancer, it is possible not to perform a lymphadenectomy because it does not modify the medical treatment and the overall survival (grade B). Primary surgery is recommended when no tumor residue is possible (grade B). After a complete first surgery, it is recommended to deliver 6 cycles of intravenous (grade A) or to propose intraperitoneal (grade B) chemotherapy, to be discussed with patient, according to the benefit/risk ratio. After a complete interval surgery for a FIGO III stage, the hyperthermic intra peritoneal chemotherapy (HIPEC) can be proposed in the same conditions of the OV-HIPEC trial (grade B). In case of tumor residue after surgery or FIGO stage IV, chemotherapy associated with bevacizumab is recommended (grade A).

Resume En France, le cancer de l’endometre est au premier rang des cancers gynecologiques, avant les cancers de l’ovaire et du col uterin. Le nombre de cas incidents pour l’annee 2012 etait estime a 7275 ; le nombre de deces imputables au cancer de l’endometre a 2025. Il s’agit d’un cancer hormono-dependant et les principaux facteurs de risque « environnementaux » correspondent aux situations d’hyperestrogenie endogene et exogene (contraception estroprogestative, traitement hormonal de la menopause) pour les deux grands types des cancers de l’endometre : type 1 ou adenocarcinomes de type endometrioide de bas grade ; type 2, correspondant a tous les autres types de tumeurs epitheliales : adenocarcinomes endometrioides de haut garde, adenocarcinomes papillaires sereux ou a cellules claires, carcinosarcomes et tumeurs malignes mixtes mulleriennes (MMMT). La surcharge ponderale, le diabete et le traitement par tamoxifene sont d’autres facteurs de risque demontres du cancer de l’endometre. Les facteurs genetiques peuvent egalement intervenir dans la genese des cancers de l’endometre. Il peut s’agir soit de facteurs mineurs de predisposition genetique (facteurs de susceptibilite) largement meconnus aujourd’hui, mais rendant compte de l’augmentation demontree du risque chez les apparentees de femmes atteintes de cancers de l’endometre ; soit de facteurs majeurs de predisposition, dans le cadre du syndrome de Lynch, maladie hereditaire a transmission autosomique dominante. La connaissance des elements cliniques evocateurs du syndrome de Lynch et de la strategie diagnostique est essentielle compte tenu des risques lies a la meconnaissance de ce diagnostic tant pour le cas index que pour ces apparentees. L’objectif de cette synthese est de decrire les principaux facteurs de risque de cancer de l’endometre en soulignant les acquisitions recentes et de faire le point sur les modalites de surveillance et prise en charge des femmes a risque eleve.

It is estimated that 15–20 % of ovarian carcinomas arise in women carrying a monoallelic germline cancer-predisposing gene mutation. The two main known hereditary forms of ovarian carcinoma are hereditary breast/ovarian cancer (HBOC) linked to BRCA1 or BRCA2 mutations, genes involved in DNA double-strand break repair by homologous recombination (HR), and Lynch syndrome linked to mutations in genes involved in DNA mismatch repair (MMR): MLH1, MSH2, MSH6 or PMS2. The contribution of BRCA1/BRCA2 mutations is at least tenfold higher than that of MMR genes. Identification of a cancer-predisposing mutation is useful for the prevention of breast, ovarian or colon cancers in affected women and their relatives and is now becoming a major part of the treatment of women with ovarian carcinoma, as poly-ADP-ribose-polymerase (PARP) inhibitors have been demonstrated to be useful in HBOC syndrome. New perspectives are opening up in Lynch syndrome with immunotherapy targeting Lynch syndrome-related cancers, characterised by their immunogenicity. Other genes involved in the HR pathway (PALB2, RAD51, ATM) are good candidates to be associated with an increased risk of ovarian and breast cancers that would be expected to be also sensitive to PARP inhibitors. As the identification of women harbouring germline or tumour inactivation of HR genes and probably, in the near future, MMR gene mutations is now becoming essential for their treatment, increasing test demands and the need for rapid and complete analyses are going to modify current genetic counselling and testing practices.

Introduction: AdjuvantOnline is a web-based application designed to provide 10 years survival probability patients with breast cancer. Few validation studies have underlined some limitations, particularly an overestimation of the prognosis among certain subgroups of patients. Moreover, several predictors such as HER2 over expression status and proliferation markers have not been assessed in Adjuvant! original study. We provide the validation of AdjuvantOnline algorithm on two breast cancer datasets collected from two large European cancer centres, and we determined whether the accuracy of AdjuvantOnline is improved by others well known prognostic factors. Material and Methods: The French data set is composed of 456 women with early breast cancer, treated at the Institut Curie between 1995 and 1996. The dutch data set is composed of 295 women less that 52 years treated at the Netherlands Cancer Institute between 1984 and 1995. Agreement between observation and Adjuvant! prediction was checked by testing that the calibration slope was equal to 1. Logistic models were performed to evaluate whether risk factors adds significant prognostic information, including AdjuvantOnline a priori information as an offset. Results: Ten years survival status was known for 383 patients in the French data set and 247 patients in the Dutch data set. Adjuvant! prediction was globally well calibrated in the French data set (observed survival 86%, predicted survival 85%), but was overestimated in high grade, HER2 positive and Ki67 > 20% subgroups. HER2 status, Mitotic Index, Ki67 and treatment type were strongly associated with 10-year survival, even considering AdjuvantOnline a priori information. In the Dutch data set, the overall 10-year survival was overestimated by AdjuvantOnline (observed 66%, predicted 79%), particularly in patients less than 40 years old. Conclusion: AdjuvantOnline needs to be updated to adjust overoptimistic results in young and high grade patients, and should consider candidates, such as Ki67, HER2 and Mitotic Index. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-13.

Background: Recent studies have indicated the prognostic value of tumour subtype and pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). However these results were reported after a short follow-up and using a standard Cox model which could be unsatisfactory for time-dependent factors. In the present study, we identified the prognostic factors for long-term outcome after NAC, considering that they could have an inconstant impact over time. Methods: Prognostic factors from 956 consecutive breast cancer patients treated with NAC were identified and associated with long-term outcomes. We estimated survival by a time function multivariate Cox model regression and stratified by follow-up length. Results: The prognostic value of tumour histological grade and hormone receptors status varied as distant recurrence-free interval (DRFI) increased. The multivariate analysis identified the following significant prognostic factors: tumour size, N stage, clinical and pathological response to NAC, hormone receptors (HR) status and histological tumour grade. The ‘prognostic benefit' of low-grade and positive-HR status decreased over the years. Thus, in the early years after cancer diagnosis, the hazard ratio of distant recurrences in patients with positive-HR status increased from 0.26 (95% CI 0.1–0.4) at 6 months to 2.2 (95% CI 1.3–3.7) at 120 months. The histological tumour grade followed a similar trend. The hazard ratio of grade III patients compared with grade I was 1.83 (95% CI 1.1–2.8) at 36 months and diminished over time to 0.70 (95% CI 0.4–1.3) at 120 months. This indicates that the risk of recurrence for positive-HR patients was 74% lower at 6 months compared with the negative-hormone receptor group, but 30% higher at 5 years and more than double at 10 years. High-grade tumours presented a risk of 83% in the earlier years decreasing to 30% at 10 years versus the low-grade group. Conclusion: From the present study, we conclude the importance of identifying time-dependent prognostic factors. Distant recurrence-free interval within women who receive NAC are influenced by achieving pCR and breast cancer subtype. Tumours with more aggressive biology have poorer survival during the first 5 years, but if they exceed this point their prognostic impact is no longer significant. Conversely, positive-HR patients remain at risk for distant recurrence for many years.

Background Adjuvant! Online is a web-based application designed to provide 10 years survival probability of patients with breast cancer. Several predictors have not been assessed in the original Adjuvant! Online study. We provide the validation of Adjuvant! Online algorithm on two breast cancer datasets, and we determined whether the accuracy of Adjuvant! Online is improved with other well-known prognostic factors. Patients and Methods The French data set is composed of 456 women with early breast cancer. The Dutch data set is composed of 295 women less than 52 years of age. Agreement between observation and Adjuvant! Online prediction was checked, and logistic models were performed to estimate the prognostic information added by risk factors to Adjuvant! Online prediction. Results Adjuvant! Online prediction was overall well-calibrated in the French data set but failed in some subgroups of such high grade and HER2 positive patients. HER2 status, Mitotic Index and Ki67 added significant information to Adjuvant! Online prediction. In the Dutch data set, the overall 10-year survival was overestimated by Adjuvant! Online, particularly in patients less than 40 years old. Conclusion Adjuvant! Online needs to be updated to adjust overoptimistic results in young and high grade patients, and should consider new predictors such as Ki67, HER2 and Mitotic Index.

11506 Background: Very limited data are available on the safety of pregnancy and reproductive outcomes in mBRCA pts with prior BC history. We report the results of the largest study to date addressing these questions. Methods: This international, multicenter, hospital-based, retrospective cohort study included consecutive pts with invasive early BC (stage I-III) diagnosed between Jan-2000 and Dec-2012 at the age of ≤40 years and carrying a deleterious germline mBRCA. Primary endpoints were pregnancy rate and disease-free survival (DFS); overall survival (OS) and pregnancy outcomes were secondary endpoints. To account for guarantee-time bias, we performed two survival analyses: 1) Case-control approach matching pregnant and non-pregnant (1:3) pts for classic prognostic factors (each non-pregnant control had a disease-free interval ≥ than the time elapsing between BC diagnosis and date of pregnancy of the matched pregnant case); 2) Extended Cox model with time-varying covariates including all pts. Results: 1,252 mBRCA BC pts (811 mBRCA1, 430 mBRCA2, 11 mBRCA1&2) were included from 30 centers worldwide, of whom 195 pts had a pregnancy (pregnancy rate = 16% [95% CI 14-18]) after a median 4.5 years (range 3.1-6.7 years) following BC diagnosis. Pregnant pts were younger and had more ER-negative tumors (all p < 0.01). 16 (8.2%) and 20 (10.3%) pts had an induced and spontaneous abortion, respectively. Among the 150 (76.9%) pts who conceived (n = 170 babies), pregnancy complications and congenital anomalies were described in 13 (11.6%) and 2 (1.8%) cases, respectively. Median follow-up was 8.3 years (range 8.1-8.7 years). In the case-control analysis, pregnant pts had better DFS (HR 0.71; 95% CI 0.51-0.99; p = 0.045), with no difference in OS (HR 0.86; 95% CI 0.44-1.67; p = 0.65). Subgroup analysis suggested that the superior outcome was restricted to mBRCA1 pregnant pts (p-interaction < 0.01). Similar results were obtained in the second supportive analysis. Conclusions: Pregnancy following BC is safe in mBRCA pts, particularly mBRCA1, with no detrimental impact on maternal prognosis or fetal outcomes . These findings are of paramount importance for fertility counseling in young mBRCA BC pts.