No association between polygenic risk scores for cancer and development of radiotherapy toxicity

Abstract

Purpose: To test whether updated polygenic risk scores (PRS) for susceptibility to cancer affect risk of radiotherapy toxicity. Experimental design: Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from XXXX and XXXX Consortia cohorts. Patients underwent potentially curative radiotherapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with non-typed SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, 24 lung. Weighted PRS were generated using log odds ratios for cancer susceptibility. Standardized total average toxicity (STAT) scores at 2 and 5 years (breast, prostate) or 6 to 12 months (lung) quantified toxicity. Primary analysis tested late STAT, secondary analyses investigated acute STAT, and individual endpoints and SNPs using multivariable regression. Results: Increasing PRS did not increase risk of late toxicity in patients with breast (OR 1.000, 95%CI 0.997-1.002), prostate (OR 0.99, 95%CI 0.98-1.00; weighted PRS OR 0.93, 95%CI 0.83-1.03) or lung (OR 0.93, 95%CI 0.87-1.00; weighted PRS OR 0.68, 95%CI 0.45-1.03) cancer. Similar results were seen for acute toxicity. Secondary analyses identified rs138944387 associated with breast pain (OR=3.05; 95%CI 1.86- 5.01; P=1.09 × 10-5) and rs17513613 with breast oedema (OR=0.94; 95%CI 0.92- 0.97; P=1.08 × 1 0-5). Conclusions: Patients with increased polygenic predisposition to breast, prostate or lung cancer can safely undergo radiotherapy with no anticipated excess toxicity risk. Some individual SNPs increase likelihood of a specific toxicity endpoint warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.