Associations between skin rash, treatment outcome, and single nucleotide polymorphisms in head and neck cancer patients receiving the EGFR-inhibitor zalutumumab: results from the DAHANCA 19 trial

PURPOSE: To study the associations between development of moderate to severe skin rash, clinical outcome, and single nucleotide polymorphisms (SNPs) in candidate genes in head and neck cancer patients from the DAHANCA 19 trial receiving the EGFR-inhibitor zalutumumab concurrently with radiation treatment.

MATERIAL AND METHODS: 310 patients were included from the zalutumumab-arm of the DAHANCA 19 study. Nine SNPs in the candidate genes EGFR, EGF, AREG, FCGR2A, FCGR3A, and CCND1 were successfully determined in 294 patients. Clinical endpoints were moderate to severe skin rash within the first 3 weeks of treatment, loco-regional failure (LRF), disease-specific survival (DSS), and overall survival (OS).

RESULTS: During the first 3 weeks of treatment, 86% of the patients experienced any grade of rash and 17% experienced a moderate to severe rash. Development of moderate to severe rash was not associated with LRF or DSS but was associated with improved OS, HR 0.40 (95% CI: 0.19-0.82). The effect was similar for patients with p16-negative or p16-positive tumors (p = .90). After adjustment for comorbidity and performance status, the minor alleles of SNPs rs9996584 and rs13104811 located near the AREG gene were significantly associated with increased risk of moderate to severe rash with per-allele odds ratios of 1.61 (1.01-2.54) and 1.56 (1.00-2.44). SNP rs11942466 located close to rs9996584 had a borderline significant association, and none of the other SNPS were significantly associated with risk of skin rash.

CONCLUSIONS: Moderate to severe skin rash after zalutumumab during radiation treatment was associated with improved OS, independent of HPV/p16-status. Genetic variants in AREG (member of the EGF family) may be associated with increased risk of skin rash.