Abstract
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, Pinteraction = 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.
Highlights
Oestrogen receptor (ER) positive breast cancer is driven by oestrogen signalling and accounts for approximately 70% of all breast cancers [1]
Genome-wide association studies (GWASs) have investigated single nucleotide polymorphism (SNPs) associating with breast cancer survival [4], including our previous research investigating 10-year disease free survival among all breast cancer cases based on a meta-analysis of two GWAS studies [5]
We have previously investigated association of genetic variants with 10-year overall survival among chemotherapy-treated patients [7], and based on a two-study GWAS meta-analysis, we identified a locus 19q13.41 associating with 10-year breast cancer specific survival after endocrine treatment [8]
Summary
Oestrogen receptor (ER) positive breast cancer is driven by oestrogen signalling and accounts for approximately 70% of all breast cancers [1]. No biomarkers that identify such nonresponders are currently in clinical use Both somatic mutations and germ-line variants are likely to contribute to breast cancer survival, e.g. by influencing tumour progression, host-tumour interactions, or pharmacogenomical mechanisms. We have previously investigated association of genetic variants with 10-year overall survival among chemotherapy-treated patients [7], and based on a two-study GWAS meta-analysis, we identified a locus 19q13.41 associating with 10-year breast cancer specific survival after endocrine treatment [8]. Our goal was to identify prognostic and predictive SNPs among patients with ER-positive tumours To this end, we conducted a meta-analysis of SNP data from three independent GWAS studies
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