Abstract P5-08-24: Evaluation of single nucleotide polymorphisms (SNPs) as predictive factors of progression (PFS) and metastatic (MFS) free survival in adjuvant breast cancer (BC)
Authors: Ducoulombier A , Dumont A , Revillion F , Bonneterre J , Peyrat J-P 
Published: May 2016

Abstract
Background: Adjuvant chemotherapy (ACT) using anthracyclines and taxanes is a standard treatment for BC. Usual criteria as age, SBR grade, HER2 or hormonal status (HS), estrogen receptor (ER), triple negative BC, histological type, lymphovascular invasion (LVI), Ki67, tumor size and lymph node involvement are not yet sufficient for ACT decision. As SNPs located in genes involved in metabolism or transport of cytotoxic drugs may affect efficacy of ACT, we investigated the potential of 49 SNPs to predict response to ACT in BC.
Methods: From 01/2008 to 01/2012, 418 patients (pts) with BC treated with ACT were included. 309 pts received FEC100-Docetaxel regimen (cohort 1), and 109 pts with HER2 overexpression FEC100-Docetaxel-Trastuzumab regimen (cohort 2). Genotyping of 49 SNPs was performed on germline DNA using real time PCR with SNPType (Fluidigm) or Taqman probes (Life technologies) on BioMark Platform (Fluidigm). PFS, MFS and overall survival (OS) were estimated by Kaplan-Meier method. Association of clinicopathologic features (CPF) with PFS/MFS was evaluated by log-Rank test. After ensuring Hardy-Weinberg equilibrium was respected, PFS/MFS were correlated to CPF and genotypes, using univariate and multivariate Cox logistic regression. A prognostic score was established.
Results: PFS, MFS and OS rates were respectively 81.8%, 83.4% and 87.3% in cohort 1 (3.4 years of median follow up (FU)) and 90.1%, 90% and 93.8% in cohort 2 (4 years of FU). In cohort 1, univariate analysis revealed that 5 SNPs, SLCO1B3 (rs11045585), NOS3 (rs1799983), CYB2B6 (rs2279345), BRCA1 (rs799917) and CYP2D6 (rs3892097) were associated with MFS. Genotypes, HR, 95%CI and p value are as follows: SLCO1B3 GG 7.73 (1.83-32.7) p=0.001, NOS3 GT 0.32 (0.14-0.76) p=0.006, CYB2B6 TT 2.29 (1.02-5.13) p=0.04, BRCA1 CT 0.41 (0.19-0.89) p=0.02, and CYP2D6 AG 2.14 (1.05-4.36) p=0.03. Multivariate analysis revealed that 4 SNPs remained associated with metastatic risk: CYB2B6; TT 2.38 (1.05-5.41) p=0.038, NOS3; GG-TT 3.11 (1.33-7.27) p=0.009, BRCA1; CC-TT 2.21 (1.01-4.85) p=0.047, CYP2D6; AG 2.14(1.04-4.40) p=0.039. No CPF was associated with survival. Prognostic model revealed a metastatic risk of 10.25 (1.29-81.31) if these four adverse genotypes coexist. In cohort 2, subject to limited number of events, age (p=0.03), HS (p=0.06), ER (p=0.05), LVI (p=0.02) tumor size (p=0.003) and 2 SNPs were associated in univariate with PFS: CYB2B6 (rs2279345); CT 5.73 (1.22-27) p=0.01, MTHFR (rs1801133); CT 4.61 (0.98-21.7) p=0.03. Multivariate analysis showed unfavorable PFS for heterozygous patients for CYB2B6 or for MTHFR: 9.67 (1.82-51.28) p=0.008 and 5.62(1.19-26.59) p=0.03 respectively and if tumor size was ≥T2 10.78 (2.12-54.90) p=0.004.
Conclusion: SNPs of genes involved in oxidative stress (NOS3 rs1799983; GG-TT), docetaxel transport (SLCO1B3 rs11045585; GG) cyclophosphamide (CYB2B6 rs2279345; TT in cohort 1 ou CT in cohort 2) and 5FU metabolism (MTHFR rs1801133; CT), or DNA repair (BRCA1rs799917; CC-TT) are associated with survival in pts treated with ACT. BRCA1, CYB2B6 and SLCO1B3 represent potential attractive tools for guiding ACT indication.
Citation Format: Ducoulombier A, Dumont A, Revillion F, Bonneterre J, Peyrat J-P. Evaluation of single nucleotide polymorphisms (SNPs) as predictive factors of progression (PFS) and metastatic (MFS) free survival in adjuvant breast cancer (BC). [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 P5-08-24.