Genomic Profiling Reveals Novel Predictive Biomarkers for Chemo-Radiotherapy Toxicity and Efficacy in Non-Small-Cell Lung Cancer.

Purpose/objective(s) Chemo-radiotherapy (CRT) remains the main treatment modality for non-small-cell lung cancer (NSCLC). However, its clinical efficacy is largely limited by individual variations in radio-sensitivity and risk of radiation-induced thoracic toxicity (RITT). There is an urgent need to identify genetic determinants that can explain patients' likelihood to develop recurrence and RITT following CRT. Materials/methods We performed comprehensive genomic profiling, using a 474-cancer and radiotherapy-related gene panel, on pretreatment biopsy samples from patients with unresectable stage III NSCLCs who underwent definitive CRT. Patients' clinical and genomic features were correlated with progression-free survival (PFS), overall survival (OS), and high-grade RITT development, after CRT. Results A total of 122 patients were enrolled (median age, 62 years; 87% males). Of these, the majority (n = 84, 69%) had squamous cell carcinoma (SCC) and the remaining 38 (31%) were adenocarcinoma (ADC). Median PFS and OS of the cohort were 11.4 and 34.6 months, respectively. No clear survival difference was seen between the histological subtypes or other clinical features, other than an association between smoking history and an unfavorable outcome (PFS HR = 1.89 [95% CI, 1.11-3.21], P = 0.02; OS HR = 1.59 [0.80-3.16], P = 0.19). Genetic association analysis identified alterations in NOTCH2, KEAP1, FGFR1/3 alterations as potential risk factors of CRT resistance, with reduced PFS and OS compared with patients carrying the respective wild-type genes. The rates of grade 2 or higher (high-grade) radiation-induced pneumonitis and esophagitis were 32% and 13%, respectively. Polymorphisms in the DNA repair-associated XRCC5 (rs3835) and XRCC1 (rs25487) were associated with an increased risk of high-grade esophagitis and pneumonitis, respectively. Moreover, XRCC5 (rs3835) was also associated with an earlier occurrence of high-grade esophagitis. MTHFR (rs1801133) and NQO1 (rs1800566) were additional risk alleles associated with an increased susceptibility to RITT overall. Conclusion Our results provide a set of clinically usable predictive biomarkers for chemo-radiotherapy toxicity and efficacy. These findings suggest that pre-treatment testing for a combination of genetic variants, which likely act together to confer resistance or toxicity after CRT, might be clinically useful.