Identification of SNPs Associated to Response of Breast Cancer Patients to Neo-Adjuvant Chemotherapy in the EORTC-10994 / BIG1-00 Randomised Phase III Trial

Abstract

Background: Gene polymorphisms may be associated to response to chemotherapy. Using cell line panels we identified single nucleotide polymorphisms (SNPs) in MDM2 and CYP1B1 genes associated with chemosensitivity; for MDM2 (T309G) the association was strictly dependent upon the p53 status (Br J Cancer 2009; 101: 350‐6); for CYP1B1 (V432L), the association was only observed for DNA‐damaging agents (Mol Cancer Ther 2010; 9: 3315‐21). To validate these findings in the clinical setting, we genotyped a subset of patients of the EORTC10994 neoadjuvant trial (Lancet Oncol 2011; 12: 527‐39) to explore the relationship between these SNPs and the pathological response to chemotherapy (pCR) as a function of treatment received and TP53 status as assessed by a functional assay. Methods: We genotyped uninvolved lymph nodes removed at definitive surgery in 243 patients, using a customised Illumina platform for the assessment of 384 selected SNPs. A stepwise analysis was conducted to preserve statistical power: first, only five selected polymorphisms, including MDM2 T309G and CYP1B1 V432L, were tentatively associated with pCR, PFS and OS. In the second step, all SNPs present on the chip were considered for possible associations with clinical outcome. At both steps, a Benjamini‐Hochberg correction for multiple testing was applied and only corrected p values are shown below. Since the rate of pCR could vary independently by treatment arm and p53 status, interaction tests were performed by logistic regression. Results: The CYP1B1 polymorphism interacted only on pCR with treatment received (p = 0.032), the MDM2 one only with p53 status (p = 0.031). No significant relationship with DFS or OS was found. In contrast, for the complete SNP panel, there was a significant association between OS and a SNP of alcohol dehydrogenase 3, ADH1C R272Q (corrected p value = 0.0023). A multivariate analysis showed that only ADH1C genotype and p53 status were significantly associated with OS (p < 0.001 and p = 0.012 respectively). Conclusion: SNPs in CYP1B1 and MDM2 could be markers of response to chemotherapy in breast cancer while a SNP in ADH1C may have a prognostic interest that needs be further validation.