Study Finds Predictive Biomarkers for Chemo-Radiotherapy Toxicity, Efficacy in NSCLC

Several biomarkers identified by comprehensive genomic profiling were found to predict efficacy and toxicity of chemo-radiotherapy in patients with non–small cell lung cancer (NSCLC), with progression-free survival and overall survival outcomes associated with some of the identified genes.

Several predictive biomarkers may be leveraged to determine toxicity and efficacy of chemo-radiotherapy (CRT) in patients with non–small cell lung cancer (NSCLC), according to study findings published in the International Journal of Radiation Oncology, Biology, Physics.

As the main treatment modality for NSCLC, clinical efficacy of CRT was noted by researchers to be limited by individual variations in radiosensitivity and risk of radiation-induced thoracic toxicity (RITT). Although identifying these genetic variants could improve treatment considerations in NSCLC, the standard of care for these patients solely includes genetic testing for EGFR, ALK, and ROS1 mutations.

In fact, a prior study showed that the use of comprehensive genomic profiling (CGP) to assist in matching patients with NSCLC with targeted therapies and clinical trials was associated with significant improvements in progression-free survival (PFS) and overall survival (OS).

“There is an urgent need to identify genetic determinants that can explain patients’ likelihood to develop recurrence and RITT following CRT,” said the study authors.

They used CGP to assess a 474-cancer and radiotherapy-related gene panel, which included pretreatment biopsy samples from patients with unresectable stage 3 NSCLC who underwent definitive CRT (N = 122; median age, 62 years; 87% male). In the study, patients’ clinical and genomic features after CRT were correlated with PFS, OS, and high-grade RITT development, indicated as rates of grade 2 or higher.

Of the patient cohort, the majority were found to have squamous cell carcinoma (n = 84 [69%]), with the remaining patients diagnosed with adenocarcinoma (n = 38 [31%]). Moreover, the median PFS and OS of the cohort were 11.4 and 34.6 months, respectively.

No clear survival difference was observed between the histological subtypes or other clinical features, noted the researchers, other than an association between smoking history and an unfavorable outcome in PFS and OS (PFS: HR, 1.89; 95% CI, 1.11-3.21; P = .02; OS: HR, 1.59; 95% CI, 0.80-3.16; P = .19).

After applying CGP, alterations in NOTCH2, KEAP1, and FGFR1/3 were identified as potential risk factors of CRT resistance, with reduced PFS and OS outcomes observed in patients with these genetic variants compared with those without. “Rates of high-grade radiation-induced pneumonitis and esophagitis were 32% and 13%, respectively,” added the study authors.

Researchers further found that polymorphisms in the DNA repair-associated XRCC5 (rs3835) and XRCC1 (rs25487) were associated with an increased risk of high-grade esophagitis and pneumonitis, with XRCC5 also associated with an earlier occurrence of high-grade esophagitis.

Increased susceptibility to RITT was additionally associated with the alleles of MTHFR (rs1801133) and NQO1 (rs1800566).

“Our results provide a set of clinically usable predictive biomarkers for chemo-radiotherapy toxicity and efficacy,” concluded the study authors. “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.”

Reference

He K, Zhang S, Pang J, et al. Genomic profiling reveals novel predictive biomarkers for chemo-radiotherapy toxicity and efficacy in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. Published online November 1, 2021. doi:10.1016/j.ijrobp.2021.07.1240