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The majority of breast cancers are driven by the female hormone oestrogen via oestrogen receptor (ER) alpha. ER-positive patients are commonly treated with adjuvant endocrine therapy, however, resistance is a common occurrence and aside from ER-status, no unequivocal predictive biomarkers are currently in clinical use. In this study, we aimed to identify constitutional genetic variants influencing breast cancer survival among ER-positive patients and specifically, among endocrine-treated patients. We conducted a meta-analysis of three genome-wide association studies comprising in total 3,136 patients with ER-positive breast cancer of which 2,751 had received adjuvant endocrine therapy. We identified a novel locus (rs992531 at 8p21.2) associated with reduced survival among the patients with ER-positive breast cancer ( P = 3.77 × 10 -8 ). Another locus (rs7701292 at 5q21.3) was associated with reduced survival among the endocrine-treated patients ( P = 2.13 × 10 -8 ). Interaction analysis indicated that the survival association of rs7701292 is treatment-specific and independent of conventional prognostic markers. In silico functional studies suggest plausible biological mechanisms for the observed survival associations and a functional link between the putative target genes of the rs992531 and rs7701292 (RHOBTB2 and RAB9P1, respectively). We further explored the genetic interaction between rs992531 and rs7701292 and found a significant, treatment-specific interactive effect on survival among ER-positive, endocrine-treated patients (hazard ratio = 6.97; 95% confidence interval, 1.79-27.08, P  interactio n   = 0.036). This is the first study to identify a genetic interaction that specifically predicts treatment outcome. These findings may provide predictive biomarkers based on germ line genotype informing more personalized treatment selection.

Meta-analysis of three genome-wide association studies identifies two loci that predict survival and treatment outcome in breast cancer