Although most estrogen receptor (ER)-positive breast cancer patients benefit from endocrine therapies, a significant proportion do not. Our aim was to identify inherited genetic variations that might predict survival among patients receiving adjuvant endocrine therapies.

We performed a meta-analysis of two genome-wide studies; Helsinki Breast Cancer Study, 805 patients, with 240 receiving endocrine therapy and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer, 536 patients, with 155 endocrine therapy-patients, evaluating 486,478 single nucleotide polymorphisms (SNPs). The top four associations from the endocrine treatment subgroup were further investigated in two independent datasets totalling 5011 patients, with 3485 receiving endocrine therapy.

A meta-analysis identified a common SNP rs8113308, mapped to 19q13.41, associating with reduced survival among endocrine treated patients (hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.37-2.07, P = 6.34 ×10-7) and improved survival among ER-negative patients, with a similar trend in ER-positive cases not receiving endocrine therapy. In a multivariate analysis adjusted for conventional prognostic factors, we found a significant interaction between the rs8113308 and endocrine treatment indicating a predictive, treatment-specific effect of the SNP rs8113308 on breast cancer survival, with the per-allele HR for interaction 2.16 (95% CI 1.30 - 3.60, Pinteraction = 0.003) and HR=7.77 (95% CI 0.93 - 64.71) for the homozygous genotype carriers. A biological rationale is suggested by in silico functional analyses.

Our findings suggest carrying the rs8113308 rare allele may identify patients who will not benefit from adjuvant endocrine treatment.