Treatment options in patients with early breast cancer and BRCAmutations or family history of cancer

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1 PHARMACOTHERAPY 239 Treatment options in patients with early breast cancer and BRCAmutations or family history of cancer M-D. t Kint de Roodenbeke, MD 1, L. Buisserer, MD, PhD 2, M. Piccart-Gebhart, MD, PhD 1 SUMMARY Women diagnosed with BRCA1/2 mutation positive breast cancer have an increased lifetime risk of contralateral breast cancer and ovarian cancer. They benefit from risk-reducing surgical strategies such as mastectomy and salpingo-oophorectomy. For patients with BRCA mutations and hormone-receptor positive breast cancer, the option of combined bilateral annexectomy and hormonal therapy with Aromatase Inhibitor can be discussed with high-risk patients. For triple negative breast cancer with BRCA mutation, there is some evidence that adding platinum-agents in the neoadjuvant setting improves the pathologic complete response. Lastly, ongoing clinical trials testing the efficacy of poly (ADP-ribose) polymerase inhibitor therapy in patients with BRCA1/2 mutations will be determinant for the future guideline recommendations in determining best treatment options for these patients. (BELG J MED ONCOL 2018;12(5): ) INTRODUCTION Management of hereditary breast cancer (BC) cases requires specific handling and care concerning the available treatment options. Over the past two decades, significant progress has been made in the diagnosis, treatment, and prevention of BC. Identification and cloning of the BRCA1 and BRCA2 genes and their role in BC pathogenesis have improved treatment modalities and result in their successful clinical application. It is now well established that women inheriting mutations in the BC type 1 susceptibility protein (BRCA1) or BC type 2 susceptibility protein (BRCA2) genes have a homologous recombination DNA-repair deficiency caused by loss of the functioning wild-type BRCA1 or BRCA2 allele, elevating their lifetime risk for developing early invasive BC. 1 It was hypothesised early on that the inherent homologous recombination DNA-repair deficiencies in BC could be exploited to develop therapeutic modalities. BRCA1 and BRCA2 wild-type breast tumours exhibit differential chemosensitivity when compared to the BRCA1 and BRCA2 mutant positive BC. 2 In 2005, simultaneous publications by Bryant and colleagues and Farmer et al. demonstrated that BRCA1 or BRCA2 dysfunction resulted in the lack of homologous recombination and markedly sensitised the cancer cells to inhibition of poly (ADP-ribose) polymerase (PARP) enzymatic activity. 3,4 Inhibition of PARP enzymes is a potential synthetic lethal therapeutic strategy in cancers harbouring specific DNA-repair defects such as BRCA1 or BRCA2 mutations. PLATINUM-BASED CHEMOTHERAPY There has been a recent resurgence of interest in plati- 1 Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, 2 Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels. Please send all correspondence to: D. t Kint de Roodenbeke, MD, Rue Paul Héger 1, 1000 Bruxelles, Belgium, tel: 02/ , daphne.tkint@bordet.be. Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest. Keywords: BRCA, breast cancer, PARP inhibitors, TNBC and BRCA treatment. VOLUME12SEPTEMBER20185

2 240 Hereditary Breast Cancer 5-10% 15-20% Familial Breast Cancer 70-80% Sporadic Breast Cancer FIGURE 1. Breast cancer. num-based chemotherapy, including the use of platinum in patients with BRCA-associated BC, known for its germline deficiency in DNA-damage repair via homologous recombination (HR). The alkylating agent cisplatin, which induces DNA adducts and intra- and inter-strand crosslinks causing single and double strand DNA breaks, activation of DNA-damage response and eventually tumour cell apoptosis, has been used in the treatment of cancers of ovary, testis, lung and head and neck. In both early and advanced disease settings, response rates to platinum agents are influenced by BRCA1 and BRCA2 germ line mutation status, which has emerged as an important potential biomarker for platinum therapy. Several trials have evaluated platinum therapy including BRCA mutation carriers or those with homologous recombinant deficiency (HRD), as well as patients who are not selected by mutation status (Table 1). In the metastatic setting, three different trials evaluated cisplatin chemotherapy for BC from The phase II trial by Byrski et al., evaluating the effects of cisplatin in BRCA1 targeted population with metastatic BC, concluded that platinum-based therapy was highly effective in the target population. 5 Isakoff conducted a phase II trial in patients with metastatic triple-negative breast cancer (mtnbc) and concluded that platinum agents were active in TNBC, especially in patients with germ line BRCA1/2 mutations. 6 In the TNT phase III trial, women with metastatic or recurrent, locally advanced TNBC or BRCA1/2 mutation-associated BC have been evaluated for the efficacy of platinum treatment (carboplatin) against docetaxel. 7 Carboplatin was found superior only in the subgroup of BRCA mutation carriers. In the neoadjuvant setting, there are four studies evaluating the efficacy of platinum-based neoadjuvant therapy in combination with platinum agents (Table 1). While this therapeutic combination has been evaluated in patients with BRCA-associated BC and TNBC, the outcomes of platinum-based neoadjuvant chemotherapy are heterogeneous. Depending of the study observed, in one study approximately 60% of patients with BRCA1 and a stage I to III primary BC treated with neoadjuvant chemotherapy with cisplatin achieve a pathologic complete response (pcr), whereas a sizable percentage of such patients in an other do not (non-pcr). 8,9 The pcr to neoadjuvant chemotherapy, defined as ypt0 ypn0, is regarded as an independent predictive factor of the favourable clinical outcome and is considered as a suitable surrogate marker for the long term outcome in patients with TNBCs. 10 The positive therapeutic effect (pcr) of cisplatin treatment in BRCA1-associated cancers has been attributed to germ line BRCA1 mutation. The molecular mechanisms underlying pcr as a result of such treatment remain obscure. Using real-time PCR arrays the expression levels of 120 genes involved in the main mechanisms of DNA repair has been compared in 43 pretreatment biopsies of BRCA1-associated TNBCs exhibiting pcr and non-pcr and to the dysfunctional DNA-damage repair caused by HR gene alterations. 11 In the secondary analysis using a BRCA1-like signature in the I-SPY VOLUME12SEPTEMBER2018

3 PHARMACOTHERAPY 241 TABLE 1. Clinical trials including BRCA mutated patients. Trial Author Journal Patients (n) Phase Context Study Scheme Primary Objective Population targeted Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1- positive metastatic breast cancer TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer Byrski TNT trial Tutt Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients Breast Cancer Res 2012 Isakoff JCO 2015 Byrski Cancer Research 2015 Breast Cancer Res and treat 2014 PrECOG 0105 Telli JCO 2015 GEPAR SIXTO trial- secondary analysis by BRCA status. Hahnen Jama Oncol 2017 Platinum compounds Metastatic 20 II Metastatic Cispaltin 75mg/m² 3wq for 6 cycles ORR 80% BRCA (11BRCA+) 376 (29 BRCA+) II Metastatic Cispaltin 75mg/m² 3wq or Carboplatin AUC6 ORR 25,6% (54,5% BRCA+) TNBC III Metastatic Platinum compounds NeoAdjuvant Neo-Adjuvant 80 (19 BRCA+) 50 II Néo-Adjuvant subanalysis Néo-Adjuvant BrighTNess Geyer ASCO III Néo-Adjuvant PARP inhibitor treatment versus control in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers. Tutt De Bono The Lancet 2010 Cancer Discov PARP Inhibitors Metastatic setting 54 III Métastatic 71 total; 14 BC; BRCAm BROCADE II Han SABCS II Metastatic Either Carboplatin (AUC 6 q3wk) or Docetaxel (100mg/m2 q3wk) for 6-8 cycles (cross over to the alternative treatment on confirmed progression). Cispaltin 75mg/m² 3wq for 4 cycles, followed by mastectomy and conventional chemotherapy. Gemcitabine (1,000 mg/m²j1-j8), Carboplatin (AUC2 J1-J8), iniparib (5.6 mg/kg IV on D1, 4, 8, and 11) 3wq x 4or 6 cycles Paclitaxel 80 mg/m² 1wq, nonpegylated liposomal doxorubicin 20 mg/m² 1wq, and bevacizumab 15 mg/kg 3wq +/- Carboplatin AUC 2 1wq x 18. addition of Veliparib 50mg bid + Carboplatin AUC6 3wq or Carboplatin alone to neoadjuvant paclitaxel followed by doxorubicin + cyclophosphamide (AC). Olaparib 400mg b.i.d or Olaparib 100mg b.i.d 15% improvement in ORR with C >< to D BRCA+ ORR 68% for C >< 33,3% for D TNBC or BRCA+ pcr 63% BRCA1 + pcr 36% The high pcr rate observed in BRCA1 and BRCA2 mutation carriers[66.7%] was not increased further by adding carboplatin [65.4%]. pcr rate arm A 53.2%; arm B 57.5%, arm C 31%; I Metastatic Talazoparib 1mg/d ORR 50% Veliparib 40mg bid D1-D5. Veliparib + carboplatin AUC6 and paclitaxel vs placebo + carboplatin and paclitaxel vs veliparib plus temozolomide (cycle = 28d). TNBC / subanalysis BRCA1/2 + BRCA+ (subanalysis) TNBC (15% BRCA+) ORR 41% BRCA+ subgroup BRCA+ ORR 77,8% >< 61,3% BRCA+ OlympiaD Robson NEJM III Metastatic Olaparib 300mg, 2x/d PFS 7m >< 4,2m BRCA+ EMBRACA Litton SABCS III Metastatic Talazoparib 1mg daily PFS 8,6 >< 5,6m BRCA+ VOLUME12SEPTEMBER20185

4 242 EMA approval 2014 < monotherapy in maintenance treatment with BRCA mutated platine sensitive ovarian cancer Olaparib FDA approval 2014 < monotherapy with BRCA mutated advanced ovarian cancer Talazoparib Veliparib Rucaparib Niraparib FDA approval in December 2016 FDA approval in April 2017 FIGURE 2. Five key PARP inhibitors in clinical development. 2 trial in patients receiving the PARP inhibitor veliparib in combination with carboplatin (V-C) or standard chemotherapy alone, the expression of 25 genes involved in five different pathways of DNA-damage repair were significantly differentially expressed between the pcr and non-pcr groups in pre-treatment biopsies, confirming the heterogeneity in the expression of DNA-damage repair genes in BRCA1-associated TNBCs. 12 The downregulation of the set of these genes before the onset of neoadjuvant chemotherapy with cisplatin may partially explain the differences in pcr rate. While platinum agents have not been endorsed as a new standard of care for patients with TNBC by the CALGB investigators, the Alliance Breast Committee, NCCN and the St Gallen Consensus Panel, the impact of platinum agents on disease free survival (DFS) and overall survival (OS) rates and the potential benefits of additional therapy in the post-neoadjuvant setting are considered as pivotal clinical questions in current practice. 13 The presence of BRCA mutation or HRD are influencing many oncologists to prescribe a combination with platinum therapy in neoadjuvant setting. Meanwhile, the secondary analysis of the GeparSixto randomised clinical trial determined that the addition of carboplatin to patients without BRCA1 and BRCA2 germ line mutations provided added benefit, while patients with BRCA1 and BRCA2 mutations had superior response rates with no added benefit from carboplatin. 1 On the other hand, recent results from the BrighTNess trial show that the addition of veliparib to neoadjuvant carboplatin plus paclitaxel followed by AC did not increase pcr rate in stage II and III TNBC not selected for BRCA mutations, while addition of carboplatin significantly increased pcr rates as well as the toxicity. 14 These results confirm again that addition of carboplatin may now be considered as a reasonable option in good condition TNBC patients scheduled to receive neoadjuvant chemotherapy consisting of anthracyclines, taxanes and cyclophosphamide. PARP INHIBITORS PARP inhibitors (PARPi) are a promising treatment option in combination with the other cytotoxic agents presently used to combat cancer proliferation in BRCA1/2-deficient tumours. Several PARPi are currently under investigation (Table 2). This class of agents has tolerable toxicity profiles and can therefore be administered to patients over long periods of time. Clinical benefit of PARPi has been observed in patients with BRCA1/2 deficient tumours and BRCA-like phenotypes in germ line mutation-negative patients. 15 So far, PARPi have been shown to amplify the effect of chemotherapeutic agents when used in combination. 16 These observations suggest that PARPi have the potential to play an effective role in the maintenance of VOLUME12SEPTEMBER2018

5 PHARMACOTHERAPY 243 TABLE 2. Trials running with PARP inhibitors in breast cancer. Study name (NCT) Phase Setting Investigational arm(s) Comparator arm(s) Response (%) PFS Olaparib OLYMPIA (NCT ) PARTNER (NCT ) III ADJ Olaparib monotherapy Placebo IDFS R II/III NADJ Olaparib + carbo/taxol carbo/taxol pcr rate R Veliparib BROCADE (NCT ) II ADV Veliparib + (Temozolomide) or (CBDCA + PTX) Placebo + CBDCA + PTX PFS R (NCT ) III ADV Veliparib + CBDCA + PTX Placebo + CBDCA + PTX PFS R Talazoparib ABRAZO (NCT ) II ADV Talazoparib monotherapy Single arm study ORR R (NCT ) II NADJ Talazoparib monotherapy Single arm study Safety R Niraparib BRAVO (NCT ) III ADV Niraparib monotherapy Physician s choice CT PFS closed < toxicity Rucaparib (NCT ) II ADJ Rucaparib + Cisplatin Cisplatin 2y-DFS Ongoing but not recruiting patient ADJ: Adjuvant, ADV: Advanced, CBDCA: Carboplatin, CT: Chemotherapy, IDFS: Interval disease-free survival, NADJ: Neoadjuvant, NR: Not yet recruiting, ORR: Objective response rate, PFS: Progression-free survival, PTX: Paclitaxel, R: Recruiting, 2y-DFS: 2-year disease-free survival. currently used BC combating strategies. Since the development of first-generation PARPi, more than a decade ago, numerous clinical trials have been performed to validate their safety and efficacy, bringing us to the present status where their contribution as adjuvant therapy is being tested in large randomised clinical trials (such as OlympiA). Although the BROCADE 2 phase II trial demonstrated a significantly higher objective response rate and an improvement of symptoms when veliparib was added to carboplatin and paclitaxel, no significant improvements were observed for OS and PFS in patients with mtnbc and a BRCA1 or BRCA2 germ line mutation. 17,18 In neoadjuvant setting, it has been confirmed, with the recent results from the BrighTNess trial again, that the addition of veliparib to neoadjuvant carboplatin plus paclitaxel followed by AC did not increase pcr rate in early TNBC, including about 15% of women with BRCA1/2 germ line mutation, while addition of veliparib plus carboplatin or carboplatin alone to paclitaxel followed by AC did. The results of the BROCADE 3 trial will provide valuable clinical data on the effectiveness of the PARP inhibitor veliparib in BRCA1- or BRCA2-mutated metastatic BC, in combination with DNA-damaging therapies. 19 In the randomised phase III OlympiAD trial, the PARP inhibitor olaparib in monotherapy showed for the first time a gain of PFS by 2.8 months compared with standard chemotherapy in the metastatic setting for BRCA-mutated HER2- negative BC. 20 This result has been recently confirmed by the EMBRACA study presented in SABCS In this large randomised phase III trial, targeting the same population (metastatic BRCA-mutated HER-negative BC), the new dual mechanism PARP inhibitor, talazoparib, confirmed a significant gain of PFS by 3 months compared with the physician s choice of single agent chemotherapy. Although of modest magnitude, these results provide a proof of concept for PARP inhibition in BRCA-deficient BC and demonstrate a favourable therapeutic index in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. There is one additional phase-iii study evaluating the VOLUME12SEPTEMBER20185

6 244 Discuss prophylactic Annexectomy if therapeutic castration needed and > 35y Evaluate the addition of Platinumcompounds Discuss adjuvant PARP inhibitor in a clinical trial Discuss Mastectomy (and immadiate reconstruction if no radiotherapy needed) BRCA status Adapt Follow up FIGURE 3. Impact of BRCA status on today s management of early breast cancer. benefit of PARPi in the metastatic setting restricted to patients with BRCA1/2 mutations: BRAVO (niraparib, NCT ), actually closed for toxicity. Another clinical study will evaluate the efficacy of veliparib versus placebo in combination with carboplatin and paclitaxel in HER2-negative metastatic or locally advanced, unresectable, BRCA-associated BC (NCT ). There seems to be a clear benefit of the use of PARPi in BR- CA-mutated BC (see recent results of OlympiAD and EM- BRACA trials). As described in Table 3, there are two major ongoing trials testing olaparib either in addition to a neoadjuvant platinum-based chemotherapy for TNBC BRCA mutated (the PARTNER trial) or in the adjuvant setting for TNBC and RH+ BC BRCA mutated (the OlympiA trial, available in Belgium). IMMUNOTHERAPIES AND FUTURE PERSPECTIVES Tumour-infiltrating lymphocytes (TILs) levels are significantly higher in TNBC. 25 Moreover, following what has been previously demonstrated in high-grade serous ovarian cancer (HGSOC) supporting a link between BRCA1/2-mutation status, immunogenicity and survival, and suggesting that BRCA1/2-mutated HGSOCs may be more sensitive to PD-1/ PD-L1 inhibitors compared to HR-proficient HGSOCs further studies are evaluating the germ line BRCA1/2-mutation in TNBC and their correlation with a higher extent of the TILs, along with the expression of inhibitory immune checkpoint molecules. 26 Compare this, for example, with the DORA phase II study designed to explore the efficacy of olaparib or olaparib in combination with durvalumab in platinum-treated mutated TNBC independent of BRCA status (NCT ). We await the results of the ongoing investigations covering the theme of these promising individualised immunological therapies in the neoadjuvant or adjuvant setting. IMPACT OF BRCA STATUS ON THE MANAGEMENT OF EARLY BREAST CANCER Considering the important role of BRCA status in the decision making process for management of early breast cancer, it is pivotal to know the BRCA status of the patient soon after cancer diagnosis. Current management practices for early BC patients with inherited BRCA mutations require discussions with the patient regarding the option of total mastectomy instead of a classical conservative surgery, if possible. 22 Depending on the individual cases, the option of mastectomy, instead of tumorectomy, may be viable and often avoids the need for adjuvant radiotherapy and authorises immediate reconstruction. Furthermore, a contralateral prophylactic mastectomy has to be VOLUME12SEPTEMBER2018

7 PHARMACOTHERAPY 245 TABLE 3. Trials testing PARP-inhibitors in the (neo-)adjuvant setting for breast cancer. STUDY TRIAL DESCRIPTION DESIGN OLYMPIA USA / Europe /Asia EORTC-1324-BCG NCT PARTNER United Kingdom (Cambridge) NCT Neoadjuvant Talazoparib for Patients With a BRCA Deleterious Mutation. Texas, US. NCT A Randomised, Double-blind, Parallel Group, Placebo-controlled Multi-centre Phase III Study to Assess the Efficacy and Safety of Olaparib Versus Placebo as Adjuvant Treatment in Patients With gbrca1/2 Mutations and High Risk HER2 Negative Primary Breast Cancer Who Have Completed Definitive Local Treatment and Neoadjuvant or Adjuvant Chemotherapy. Randomised, Phase II/III, 3 Stage Trial to Evaluate the Safety and Efficacy of the Addition of Olaparib to Platinum-based Neoadjuvant Chemotherapy in Breast Cancer Patients With TNBC and/or gbrca. A Pilot Study of Talazoparib as a Neoadjuvant Study in Patients With a Diagnosis of Invasive Breast Cancer and a Deleterious BRCA Mutation. Olaparib orally twice daily (b.i.d.) at 300 mg or Placebo Paclitaxel 80mg/ m2 1wq, Carboplatin AUC 5 3wq +/- Olaparib oral 150mg twice daily, Day -2 to Day 10 3wq Talazoparib 1 mg PO daily x 6 cycles, (28 day cycles) Primary Objective Invasive Disease Free Survival (IDFS) Target Recruitement 1320 (Ratio 1:1) 1191 already recruited PHASE pcr 527 II/III Toxicity profile 20 II III discussed together with the different techniques of breast reconstruction, either immediately or at a future time point. For patients who opt for intensive screening instead of bilateral mastectomy, alternating MRI and mammography every six months is recommended. Patients should be actively involved in all management decisions. While patient s preferences must always be taken into account, any decision should be based on the clinicopathological features of the tumour as well as the general health, the life expectancy, the family history and the age of the patient. Considering the above, the possibility of a hereditary BC should be explored earlier in the treatment, and prophylactic procedures should be discussed following appropriate genetic counselling and testing of the patient. Recommendations regarding surgery have to include bilateral prophylactic annexectomy before 40 (BRCA1) and before 45 (BRCA2). 23 Fertility issues and guidance on fertility-preservation techniques must be discussed in younger pre-menopausal patients before the initiation of treatment and especially in specific populations known to have higher rates of infertility. 24 In pre-menopausal patients, it is important to recognise KEY MESSAGES FOR CLINICAL PRACTICE 1. While most cases of breast cancer are not hereditary, the cases where breast cancer is inherited mandate a highly specialised multidisciplinary care to assist in the decision making process regarding the best treatment options for these patients. 2. Deleterious mutations in BRCA1 or BRCA2 impair homologous recombination DNA repair, rendering cancers with such mutations uniquely sensitive to platinum and PARP inhibitor therapy. 3. Numerous PARP inhibitors are currently under evaluation in early as well as advanced phase III trials for several indications, including BRCA1/2-mutated breast cancer in early settings. The results of these trials will likely have a major influence on the management of early breast cancer. VOLUME12SEPTEMBER20185

8 246 that the removal of ovaries is a highly effective adjuvant endocrine therapy when given in combination with tamoxifen or exemestane, usually indicated for women at high risk of recurrence (TEXT and SOFT Trials). Lastly, an extended and close follow-up has to be organised for patients with mutant BRCA status based on the type of surgery performed (bilateral mastectomy vs tumorectomy) and age. Patients with BC who have these mutations may be offered specific therapies, such as platinum agents and PARPi in the plan for systemic treatment. As the management of BR- CA-mutation-associated BC is complex, involving multiple factors, future cancer risks must be weighed together when making treatment decisions. However, promising data from ongoing and future clinical trials regarding platinum agents and PARPi in the treatment of BRCA-mutation-associated BC may result in a change of paradigm in the current treatment modalities for BC. Furthermore, the differential effects of platinum agents and PARPi in BRCA1- and BRCA2-mutation-associated BC treatment outcomes need to be addressed to better understand and recommend the treatment options for early stage BC patients. REFERENCES 1. Hahnen E, et al. Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of the GeparSixto Randomized Clinical Trial. JAMA Oncol. 2017;3(10): Chalasani P, Livingston R. Differential chemotherapeutic sensitivity for breast tumors with BRCAness : A review. Oncologist. 2013;18(8): Bryant HE, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(adp-ribose) polymerase. Nature. 2005;434(7035): Farmer H, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035): Byrski T, et al. 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