Genetic predictors of severe skin toxicity in patients with stage III colon cancer treated with cetuximab: NCCTG N0147 (Alliance)

Background: Cetuximab, an EGFR inhibitor used to treat multiple cancer types, including colon cancer, causes severe skin toxicity in 5%-20% of patients, leading to decreased quality of life and treatment delays. Our understanding of which patients have an increased risk of severe toxicities is limited. We conducted a genome-wide association study to identify germline variants predictive of cetuximab-induced severe skin toxicity. Methods: Our study included 1,209 patients with stage III colon cancer randomized to receive cetuximab plus 5-fluorouracil and oxaliplatin as part of the NCCTG N0147 (Alliance) clinical trial. Skin toxicity outcomes were collected using the Common Toxicity Criteria for Adverse Events version 3.0. We performed genotyping, evaluating approximately 10 million genetic variants. We used logistic regression to evaluate the association of each genetic variant and severe (grade ≥ 3) skin toxicity, adjusting for age, sex, and genetic ancestry. Genome-wide significance was defined as P < 5 × 10-⁸. Results: Participants were predominantly middle-aged white men; 20% (n ¼ 243) experienced severe skin toxicity. Two genetic variants in the retinoic acid receptor alpha (RARA) gene were significantly associated with severe skin toxicity [OR, 3.93; 95% confidence interval (CI), 2.47-6.25; P < 7.8 × 10-⁹]. Functional annotations indicate these variants are in the RARA promoter. Additional significantly associated variants were identified in chromosome 2 intergenic regions. Conclusions: Identified variants could represent a potential target for risk stratification of patients with colon cancer receiving cetuximab. Impact: Retinoids have shown promise in the treatment of cetuximab-induced skin toxicity, so follow-up work could evaluate whether individuals with the RARA variant would benefit from retinoid therapy.