Schem, Christian

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.

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression‐free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2‐negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre‐planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF‐A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49–3.75), 1.20 (95% CI, 0.88–1.64) and 0.61 (95% CI, 0.34–1.12). Notably, some SNPs in VEGF‐A exhibited a more pronounced effect in the triple‐negative subgroup. Several SNPs in VEGF‐A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.