Abstract
Radiation therapy (RT)-induced pneumonitis and esophagitis are commonly developed side effects in non-small cell lung cancer (NSCLC) patients treated with definitive RT. Identifying patients who are at increased risk for these toxicities would help to maximize treatment efficacy while minimizing toxicities. Here, we systematically investigated single nucleotide polymorphisms (SNPs) within double-strand break (DSB) repair pathway as potential predictive markers for radiation-induced esophagitis and pneumonitis. We genotyped 440 SNPs from 45 genes in DSB repair pathways in 250 stage I–III NSCLC patients who received definitive radiation or chemoradiation therapy, followed by internal validation in 170 additional patients. We found that 11 SNPs for esophagitis and 8 SNPs for pneumonitis showed consistent effects between discovery and validation populations (same direction of OR and reached significance in meta-analysis). Among them, rs7165790 in the BLM gene was significantly associated with decreased risk of esophagitis in both discovery (OR = 0.59, 95% CI: 0.37–0.97, p = 0.037) and validation subgroups (OR = 0.45, 95% CI: 0.22–0.94, p = 0.032). A strong cumulative effect was observed for the top SNPs, and gene-based tests revealed 12 genes significantly associated with esophagitis or pneumonitis. Our results support the notion that genetic variations within DSB repair pathway could influence the risk of developing toxicities following definitive RT in NSCLC.
Highlights
Radiation therapy (RT) is the primary care for locally advanced non-small cell lung cancer (NSCLC)
No statistically significant difference was observed between patients in the discovery and validation phases in terms of age, gender, smoking pack year, performance status, pulmonary function, planning tumor volume (PTV) volume, mean esophagus dose or proportion of radiation-induced esophagitis
Patients in the validation phase had slightly lower mean lung dose (16 vs. 18 Gy), were less likely to receive concurrent chemoradiation therapy (35% vs. 74%), more patients treated by IMRT, and less treated by 3D-CRT technique (41% vs. 23%) compared to the discovery phase
Summary
Radiation therapy (RT) is the primary care for locally advanced non-small cell lung cancer (NSCLC). Occurred RT-induced toxicities have limited the planed dose and compromised the efficiency of local and/or regional control and negatively influence patients’ prognosis. Cancers 2016, 8, 23 personalized dosimetric design, and maximize treatment effect while minimizing potential toxicities. The risk of RT-induced toxicities were assessed based on clinical-based factors, including physical characteristics of the radiation beam; treatment dose, fractionation and time; volume and type of normal tissue receiving radiation; radiosensitizer usage; and comorbidities [2]. Large variation exists in patients with similar clinical parameters. It suggests a potential role of host genetic factors in determining an individual’s response to RT and susceptibility of developing
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