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

Background: Prolactin receptor (PRLR) signaling affects breastfeeding and potentially breast cancer treatment response. Methods: The prognostic impact of 20 PRLR single nucleotide polymorphisms (SNPs) in relation to adjuvant treatment groups in patients with primary breast cancer (n = 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. Results: 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_adj ≤ 0.29, Bonferroni-adjusted P_int ≤ 0.039). Expression Quantitative Trait Loci (eQTL) analysis revealed that three PRLR SNPs were associated with decreased PRLR expression. To explore potential SNP-associated effects, gene expression and transcriptional networks were analyzed in the METABRIC cohort and indicated that PRLR-low tumors were associated with reduced DNA repair signaling and enhanced anti-tumoral immunity. Conclusions: PRLR merits further evaluation as a putative pharmacogenomic biomarker in relation to radiotherapy for breast cancer patients.