Cancer du sein et BRCA Adaptation de la stratégie thérapeutique en cas de gène de prédisposition

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1 Cancer du sein et BRCA Adaptation de la stratégie thérapeutique en cas de gène de prédisposition Dr Cristian Villanueva CHRU de Besançon

2 HBOC HIGH RISK BRCA 1 BRCA 2 HIGH PENETRANCE OC MODERATE RISK LOWER PENETRANCE RAD51C BRIP1 MMR HIGH RISK BC HIGH PENETRANCE LOWER PENETRANCE TP53 (Li-Fraumeni) PTEN (Cowden synd) PALB2 MODERATE RISK CDH1 (Gastric synd) CHEK2 ATM NF1

3 «23andMe se rapproche de la FDA pour proposer un produit répondant aux critères fixés par l'agence. Un coup de maître qui lui vaut de relancer son «Personal Genome Service» avec un tampon officiel «FDA approval» en 2015 qui fait office de garantie pour les utilisateurs. La FDA «appréciant le fait que le grand public puisse obtenir des informations sur son génome et ses risques de développer des maladies afin de les responsabiliser sur certains aspects de leur santé et d'en apprendre plus sur les risques génétiques».»

4 Genetic RiskHereditary Breast and Ovarian Cancer Syndrome (BRCA1- and BRCA2- Related, Selected Mutations) Hereditary Hemochromatosis (HFE-Related) Inherited Thrombophilia (Factor V Leiden- and Prothrombin-Related) Factors Inherited DPD G6PD Deficiency Conditions Drug Fluorouracil Toxicity Response Traits Breast Morphology

5 1- BASAL-LIKE 1 2- BASAL-LIKE 2 3- IMMUNOMODULATORY 4- MESENCHYMAL-LIKE 5- MESENCHYMAL STEM- LIKE 6- LUMINAL AR Brian D Lehmann et al. JCInvest 2011

6 The relationship between RCB index and the 7 subtypes. Masuda H et al. Clin Cancer Res 2013;19: by American Association for Cancer Research

7 CANCER DU SEIN CUADRUPLE NEGATIF QUADRUPLE-NEGATIVE BREAST CANCER

8 Chirurgie conservatrice ou mastectomie Mastectomie controlatérale Ovariectomie prophylactique Chimiothérapie Thérapie ciblé. Anti-PARP

10 Is the breast-conserving treatment with radiotherapy appropriate in BRCA1/2 mutation carriers? Long-term results and review of the literature Ipsilateral recurrence rate: a BRCA1/2 mutation carriers versus non-carriers versus sporadic controls, b BRCA1/2 mutation carriers versus their matched sporadic controls Clinical TrialBreast Cancer Research and Treatment February 2010, Volume 120, Issue 1, pp

11 (A) Overall in-breast tumor recurrence in BRCA1/2[r] mutation carriers and sporadic controls. Lori J. Pierce et al. JCO 2006;24: by American Society of Clinical Oncology

12 Cumulative incidence of IBTR (including local or loco-regional relapse). Five- and 10-year cumulative incidence in carriers vs. controls, respectively: 15% vs. 4%, and 27% vs. 4%. Ipsilateral-breast tumor recurrence (IBTR); Hazard Ratio (HR); Confidence Interval (CI) Garcia-Etienne C et al. Breast Oncology Annal of Surgical Oncology December 2009, Volume 16(12), pp

14 Cumulative risk of second primary contralateral breast cancer in BRCA1/BRCA2 mutation carriers with a first breast cancer: A systematic review and meta-analysis Fig. 2. Meta-analysis of CBD cumulative risk by time after diagnosis of the first primary breast cancer. A) Cumulative risk at 5 years after the diagnosis in BRCA1 (A1), BRCA2 (A2), BRCA1/2 (A3) mutation carriers and non-carriers (A4). B) Cumulative risk at Esther Molina-Montes, Beatriz Pérez-Nevot, Marina Pollán, Emilio Sánchez-Cantalejo, Jaime Espín, María-José Sánchez The Breast, Volume 23, Issue 6, 2014,

15 Cumulative risk of second primary contralateral breast cancer in BRCA1/BRCA2 mutation carriers with a first breast cancer: A systematic review and meta-analysis Fig. 2. Meta-analysis of CBD cumulative risk by time after diagnosis of the first primary breast cancer. A) Cumulative risk at 5 years after the diagnosis in BRCA1 (A1), BRCA2 (A2), BRCA1/2 (A3) mutation carriers and non-carriers (A4). B) Cumulative risk at Esther Molina-Montes, Beatriz Pérez-Nevot, Marina Pollán, Emilio Sánchez-Cantalejo, Jaime Espín, María-José Sánchez The Breast, Volume 23, Issue 6, 2014,

16 Metcalfe K et al. BJM 2014

17 Fig 2 Survival from 10 to 20 years after breast cancer, by contralateral mastectomy Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis BMJ. 2014; 348 Published online 2014 Feb 11 Kelly Metcalfe et al

18 Metcalfe K et al. BJM 2014

19 Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis. Heemskerk-Garritsen BA et al Int J Cancer 2015 Feb 1;136(3): Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. Dutch multicentre cohort, we selected 583 BRCA-associated Survival analyses were performed using Cox models, with CRRM as a time-dependent covariate. The median follow-up after PBC diagnosis was 11.4 years. In the CRRM group, 2% against 19% in the surveillance group (p < 0.001). The mortality was lower in the CRRM group than in the surveillance group (9.6 and 21.6 per 1000 person-years of observation, respectively; adjusted HR 0.49 ( 95% CI

21 From: Effect of Oophorectomy on Survival After Breast Cancer in BRCA1 and BRCA2 Mutation Carriers JAMA Oncol. 2015;1(3): doi: /jamaoncol Table Title: Hazard Ratios (HRs) Associated With Oophorectomy by Gene (BRCA1 vs BRCA2), by Various Subgroups Date of download: 1/21/2016 Copyright 2016 American Medical Association. All rights reserved.

22 From: Effect of Oophorectomy on Survival After Breast Cancer in BRCA1 and BRCA2 Mutation Carriers JAMA Oncol. 2015;1(3): doi: /jamaoncol Table Title: Annual Mortality (of Breast Cancer Death) by Time From Diagnosis, Oophorectomy vs No Oophorectomy, BRCA1 Carriers Only Date of download: 1/21/2016 Copyright 2016 American Medical Association. All rights reserved.

23 Indication de CT adjuvante CX Tumorectomie CT A A T RT CX (12 mois) MB + RMD OB University LOGO

24 Indication de traitement neoadjuvant CT neo T A Cx Tumorectomie RT CX (12 mois) MB + RMD OB University LOGO

25 Traitement neo-adjuvant CT neo T A Cx MB +RMI OB University LOGO

27 TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer (A) Progression-free survival and (C) overall survival estimates for all 86 enrolled patients. Steven J. Isakoff et al. JCO 2015;33: by American Society of Clinical Oncology

28 The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012) A. Tutt et al., S3-01

29 Essai TNT : Design Eligibilité CSM ou Récidivant /localement avancée Mesurable ER-, PR-/?, HER2- ou BRCA1/2 mutée Pas de taxanes adjuvant < 12 mois Pas de platine préalable Pas de CT préalable pour CSM sauf anthracyclines Carboplatin (C) AUC 6 q3w, 6 cycles On progression, crossover if appropriate Docetaxel (D) 100 mg/m 2 q3w, 6 cycles On progression, crossover if appropriate Docetaxel (D) 100 mg/m 2 q3w, 6 cycles Carboplatin (C) AUC 6 q3w, 6 cycles A. Tutt et al., SABCS 2014, S3-01

30 Essai TNT : Carboplatine vs Docetaxel dans les CSM TPN ou BRCAmut Réponse objective (critère de jugement principal) Randomised treatment All patients (n=376) % with OR at cycle 3 or 6 (95% CI) Carboplatin Docetaxel 59/188 (31,4%) 67/188 (35,6%) Absolute difference (C-D) -4,2% (95% CI -13,7 to 5,3) Exact p=0,44 Crossover treatment All patients (n=182) Carboplatin (Crossover=Docetaxel) Docetaxel (Crossover=Carboplatin) Absolute difference (D-C) -2,8% (95% CI -15,2 to 9,6) Exact p=0,73 *Denominator excludes those with no first progression and those not starting crossover treatment Pas de différence A. Tutt et al., SABCS 2014, S3-01

31 % patients alive Survie globale Essai TNT : Carboplatine vs Docetaxel dans les CSM TPN ou BRCAmut OS Carboplatin Docetaxel Median time (mo) 12,4 12,3 (95% CI) 10,4 to 15,3 10,5 to 13,6 Restricted mean survival to 15 months 10,7 10,8 Absolute difference: -0,2 (95% CI -1,1 to 0,8) p=0, Carboplatin = 152/188 Docetaxel = 151/ N o events/at risk: C 0/188 D 0/ /165 11/ Months from randomisation 18/141 20/151 24/114 35/ /89 19/ /71 23/ /44 16/39 A. Tutt et al., SABCS 2014, S3-01 Pas de différence

32 Essai TNT : Carboplatine vs Docetaxel dans les CSM TPN ou BRCAmut Analyse selon le statut mutationnel Germline BRCA 1/2 Mutation (n=43) Carboplatin Docetaxel No Germline BRCA 1/2 Mutation (n=273) % with OR at cycle 3 or 6 (95% CI) /25 (68,0%) 6/18 (33,3%) Absolute difference (C-D) 34,7% (95% CI 6,3 to 63,1) Exact p=0, Carboplatin Docetaxel 36/128 (28,1%) 53/145 (36,6%) Absolute difference (C-D) -8,5% (95% CI -19,6 to 2,6) Exact p=0,16 A. Tutt et al., SABCS 2014, S3-01 Interaction: randomised treatment & BRCA ½ status: p=0,01 Carboplatine supérieur chez les patientes mutées BRCA1/2

33 % patients progression free Essai TNT : Carboplatine vs Docetaxel dans les CSM TPN ou BRCAmut Analyse selon le statut mutationnel PFS Carboplatin + BRCA1/2 Docetaxel+ BRCA1/2 Mutated Not mutated Mutated Not mutated Median time (mo) 6,8 3,1 4,8 4,6 (95% CI) 4,4 to 8,1 2,4 to 4,2 2,2 to 7,2 4,2 to 5, / /128 17/18 141/ Months from randomisation Interaction significative entre traitement et status BRCA1/2 (p=0,03) A. Tutt et al., SABCS 2014, S3-01

34 ESO-ESMO 3nd international consensus guidelines for advanced breast cancer (ABC3) 2015 Proposition: Chez les patientes ayant un cancer du sein muté BRCA triplenégatif ou hormonorésistant préalablement traité par une anthracycline et un taxane (en adjuvant ou en métastatique), un schéma avec un sel de platine est l option préférentielle si la patiente n en a jamais reçu et qu aucun essai clinique adapté n est disponible. Niveau de preuve: 1A OUI 86,4 % NON:4,5 % ABST9,1 % VOTE n 44

35 Cisplatin in Preop Setting in Patients With BRCA1- Related Breast Cancer Frequency of pathologic complete response (pcr) Cisplatine 75 mg /m2 x 4 cycles N=107 A pcr was observed in 65 of the 107 patients (61 %) Byrski, T. et al., Breast Cancer Res Treat, 2014 SEPT

36 Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB (Alliance) Schema of randomized phase II CALGB (Cancer and Leukemia Group B) trial. ddac, dose-dense doxorubicin plus cyclophosphamide. William M. Sikov et al. JCO 2015;33: by American Society of Clinical Oncology

37 (A) Pathologic complete response (pcr) breast (ypt0/is); (B) pcr breast/axilla (ypt0/is N0); 95% CIs shown in parentheses. William M. Sikov et al. JCO 2015;33: by American Society of Clinical Oncology

38 Étude GeparSixto - GBG 66 (1) 19 Essai de phase II randomisé évaluant l addition du carboplatine à la chimiothérapie néo-adjuvante dans les cancers du sein HER2+ ou triple-négatifs Cancer du sein TN ou HER2+ confirmé (n = 595) Initialement ASC 2 réduit à 1,5 par l amendement 1 après inclusion de 330 patientes Paclitaxel 80 mg/m 2 /sem. R PM PMCb Doxorubicine liposomale non pégylée 20 mg/m 2 /sem. Carboplatine ASC 1,5*/sem. C H I R U R G I E HER2+ : Trastuzumab 6 à 8 mg/kg/3 sem. (pour 1 an) Lapatinib 750 mg/j 18 sem. TNBC Bévacizumab 15 mg/kg/3 sem. Von Minckwitz G et al., Lancet Oncology 15(7) 2014:

39 20 Étude GeparSixto - GBG 66 (2) 100 % Réponse complète histologique par sous-types ypt0 ypn0 80 p < 0,05 NS 60 58,7 % 40 37,9 % 36,3 % 33,1 % 20 0 PM (n = 157) PMCb (n = 158) PM (n = 136) PMCb (n = 137) TN HER2 + Von Minckwitz G et al., Lancet Oncology 15(7) 2014:

41 Fig 1. Loss of functional BRCA1 or BRCA2 affects the choice of DNA double-strand break (DSB) repair pathway Ashworth, A. J Clin Oncol; 26: Copyright American Society of Clinical Oncology

42 Phase III Study of Iniparib Plus Gemcitabine and Carboplatin Versus Gemcitabine and Carboplatin in Patients With Metastatic Triple- Negative Breast Cancer Joyce O Shaughnessy et al JCO 2014

43 SOLTI NeoPARP: A Phase 2 Randomized Study of 2 Schedules of Iniparib plus Paclitaxel and Paclitaxel Alone as Neoadjuvant Therapy in Patients with Triple Negative Breast Cancer RC p Paclitaxel Paclitaxel + Iniparib QW Paclitaxel + Iniparib BIW Llombart A 1, Lluch A 2, Villanueva C 3 Breast Cancer Res Treat Nov;154(2):351-7.

44 Tutt A. et al. Lancet 2010 Phase II trial of Olaparib in BRCA-deficient advanced breast cancer To assess the efficacy and tolerability of oral olaparib in BRCA1/ BRCA2 mutation carriers with breast cancer Multicenter proof-of-concept phase II study, single-arm sequential cohort design Confirmed BRCA1 or BRCA2 mutation Advanced refractory breast cancer (stage IIIB/IIIC/IV) after failure of 1 prior chemotherapy for advanced disease Cohort 1 (enrolled first) Olaparib 400 mg po bid (MTD) 28-day cycles; n=27 Cohort 2 * Olaparib 100 mg po bid 28-day cycles; n=27 * Following an interim review of the emerging efficacy of each cohort, patients ongoing in 100 mg bid cohort were permitted to crossover to receive the 400 mg bid dose

45 Freedom from progression (%) Progression-free survival PFS (days) Median PFS (95% CI) Olaparib 400 mg: 5.7 ( ) months Olaparib 100 mg: 3.8 ( ) months NB: Non-randomized sequential cohorts No. of patients at risk 400 mg: mg: Tutt A. et al. Lancet 2010

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48 TESARO PR C (BRAVO TRIAL) PHASE III Cancers du sein metastatique RH - HER2- BRCA muté 3ème ligne ou plus NIRAPARIB Physician s choice Sequençage ADN BRCA 1-2 MYRIAD : 15 jours

49 SOLTI/BIG 6-13/GEICAM: OLYMPIA PHASE III Neo-Olympia Cancers du sein adjuvante RH - HER2- BCRA muté Traitement par CT standard OLAPARIB PLACEBO Sequençage ADN BRCA 1-2: 15 jours Objetif principale: DFS

50 Conclusions Chirurgie conservatrice ou mastectomie Mastectomie controlatérale Ovariectomie prophylactique Chimiothérapie standard. Platines post anthracyclynes-taxanes en CSM Thérapie ciblé. Anti-PARP. Essais en cours