Abstract S5-06: BRCA mutations, therapy response and prognosis in the neoadjuvant GeparQuinto study

Abstract

Background: Mutations in BRCA1 and BRCA2 influence the molecular pathogenesis of breast cancer. However, little is known about the association between mutations, response to therapy, and prognosis. We therefore analysed these associations in triple negative breast cancer (TNBC) patients in the neoadjuvant GeparQuinto Study. Methods: The GeparQuinto study recruited 1956 patients with HER2 negative disease including a prespecified group of 671 TNBC patients with untreated breast cancer. Patients were randomized to receive four cycles EC (90/600 mg/m2; q3w) followed by four cycles docetaxel (100 mg/m2; q3w), with or without bevacizumab (15 mg/kg). Here we present the analysis for both randomization arms combined. Sufficient blood was available of 482 TNBC patients. BRCA1 and BRCA2 genotyping was successful in 469 patients with available germline DNA and was conducted by SureSelect custom capture and sequencing on HiSeq 2500. Mutation status was correlated with pathological complete response rates (pCR) and disease free survival (DFS). Results: A total of 74 (15.8%) mutations in BRCA1 (n=61) and BRCA2 (n=13) were detected after initial sequencing. A pCR (ypT0/ypN0) was observed in 50% (n=37) of mutation carriers but only 31.1% (n=123) of patients without mutations (p=0.002). Similar results were observed for pCR (pT0is/pN0) (52.7% vs. 36.5%; p=0.010). pCR (ypT0/ypN0) was predictive of disease free survival (DFS) in all patients (Hazard Ratio, HR=0.23; 95%CI: 0.15-0.37; p<0.001) and in patients without BRCA mutations pCR (ypT0/ypN0) (HR= 0.20; 95%CI: 0.11-0.34; p<0.001). However in mutation carriers this effect was reduced (HR=0.48; 95%CI: 0.18 1.27; p=0.129). Conclusion: TNBC Patients with BRCA mutations showed a higher frequency of pCR than patients without BRCA mutations after treatment with epirubicin, cyclophosphamide and docetaxel (+/ bevacizumab), suggesting that BRCA mutations may influence pCR in response to treatment regimens that do not include platin chemotherapy. pCR as a surrogate marker for DFS was also confirmed in patients without BRCA mutations. In addition, the effect of pCR on prognosis seemed to be smaller among the mutation carriers, although the number of mutation carriers was too low to test for differences between mutation carriers and wildtype patients. The project has partly been funded within NIH-NIGMS U19 GM61388 and the Breast Cancer Research Foundation. Citation Format: Fasching PA, Loibl S, Eidtmann H, Tesch H, Untch M, Hilfrich J, Schem C, Rezai M, Gerber B, Costa SD, Blohmer JU, Fehm TN, Huober J, Liedtke C, Müller V, Nekljudova V, Weber K, Rack B, Rübner M, Wang L, Ingle JN, Weinshilboum RM, von Minckwitz G, Couch F. BRCA mutations, therapy response and prognosis in the neoadjuvant GeparQuinto study. [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 S5-06.

Efficacy of anthracycline/taxane-based neo-adjuvant chemotherapy on triple-negative breast cancer inBRCA1/BRCA2mutation carriers

“…The pCR rates reported in previous studies that evaluated the efficacy of anthracycline as neo‐adjuvant chemotherapy for these cancers varied widely (Table ). Two such studies revealed findings with values close to ours, whereas two others reported higher pCR rates with similar treatments …”

“…However, while researchers concentrate on the development of these therapies, the few studies that have focused on the efficacy of neo‐adjuvant systemic therapy (NST) using standard regimens drugs report a wide range of 36%‐68% pCR rate in TNBC of BRCA1 mutations carriers . Furthermore, there is a relative paucity of data concerning the prognosis of BRCA triple‐negative breast cancer.…”

“…7,8 However, while researchers concentrate on the development of these therapies, the few studies that have focused on the efficacy of neo-adjuvant systemic therapy (NST) using standard regimens drugs report a wide range of 36%-68% pCR rate in TNBC of BRCA1 mutations carriers. [9][10][11][12] Furthermore, there is a relative paucity of data concerning the prognosis of BRCA triple-negative breast cancer. This is what motivated us to obtain further information about the results obtained with current neo-adjuvant therapy using anthracycline or an anthracycline-taxane doublet.…”

Triple-negative breast cancer: treatment challenges and solutions

“…Interestingly, the GeparQuinto trial showed a statistically higher pCR rate with a classical sequential anthracycline–taxane regimen and a trend for better disease-free survival (hazard ratio 0.64, P =0.06) in the subgroup of patients with BRCA mutations (82 of 471 patients). 59 These results suggest higher chemosensitivity and better prognosis in patients with germ-line BRCA mutations, even without platinum compounds. Participation in clinical trials is recommended in the neoadjuvant and postneoadjuvant setting in the absence of pCR to better define the optimal standard systemic therapy for TNBC ( Table 3 ).…”

Targeted Therapy of HER2-Negative Breast Cancer

“…Fasching et al [18] have shown that tumors with BRCA1 or BRCA2 mutations have a higher sensitivity to chemotherapy in general. Higher rates of pathological complete response are more common in mutation carriers.…”