Genetic Breast Cancer Susceptibility Variants and Prognosis in the Prospectively Randomized SUCCESS A Study

Abstract

Large-scale genotyping studies have identified over 70 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. However, knowledge regarding genetic risk factors associated with the prognosis is limited. The aim of this study was therefore to investigate the prognostic effect of nine known breast cancer risk SNPs. BC patients (n = 1687) randomly sampled in an adjuvant, randomized phase III trial (SUCCESS A study) were genotyped for nine BC risk SNPs: rs17468277 (CASP8), rs2981582 (FGFR2), rs13281615(8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042(2q35), rs4973768 (SLC4A7), rs6504950 (COX11). Cox proportional hazards models were used to test the SNPs' association with overall survival (OS) and progression-free survival (PFS). Additional analyses were carried out for molecular subgroups. rs3817198 in LSP1 (lymphocyte-specific protein 1) was the only SNP that significantly influenced OS (p = 0.01) and PFS (p < 0.01) in the likelihood ratio test comparing the genetic survival model with the clinical survival model. In the molecular subgroups, triple-negative patients with two minor alleles in rs3817198 had a much better prognosis relative to OS (adjusted HR 0.03; 95% CI 0.002-0.279) and PFS (HR 0.09; 95% CI 0.02-0.36) than patients with the common alleles. The same effect on PFS was shown for patients with luminal A tumors (HR 0.19; 95% CI 0.05-0.84), whereas patients with luminal B tumors had a poorer PFS with two minor alleles (HR 2.13; 95% CI 1.02-4.40). The variant in rs3817198 has a prognostic effect particularly in the subgroup of patients with triple-negative BC, suggesting a possible link with immunomodulation and BC.