Prognostic Differences of Adjuvant Radiotherapy in Breast Cancer Cohorts Based on Genotypes, Expression, and Transcriptional Network Regulation.

Prolactin receptor (PRLR) signaling affects breastfeeding and potentially breast cancer treatment response. The prognostic impact of 20 single nucleotide polymorphisms (SNPs) in relation to adjuvant treatment groups in patients with primary breast cancer ( = 1701, 2002-2016, Sweden) was evaluated. Genomic DNA was genotyped on Illumina OncoArray, and survival analyses with up to 15-year follow-up were performed. Interaction models, adjusted for potential confounders, were created with different adjuvant treatment modalities: chemotherapy, radiotherapy, tamoxifen, and aromatase inhibitors. Five SNPs (rs7734558, rs6860397, rs2962101, rs7732013, and rs4703503) showed interactions with radiotherapy and were utilized to create seven combined genotypes: six unique and one 'rare'. Patients carrying combined genotype AG/GG/TT/CC/TC or 'rare' combinations derived greater benefits from radiotherapy than other patient groups (both HR ≤ 0.29, Bonferroni-adjusted ≤ 0.039). Expression Quantitative Trait Loci (eQTL) analysis revealed that three SNPs were associated with decreased expression. To explore potential SNP-associated effects, gene expression and transcriptional networks were analyzed in the METABRIC cohort and indicated that -low tumors were associated with reduced DNA repair signaling and enhanced anti-tumoral immunity. PRLR merits further evaluation as a putative pharmacogenomic biomarker in relation to radiotherapy for breast cancer patients.