Devarakonda S, et al. - Given that adjuvant chemotherapy provides modest survival benefit in patients with resected stage II-III non–small-cell lung cancer (NSCLC), researchers evaluated the prognostic impact of mutations in individual genes, DNA repair pathways, and tumor mutation burden (TMB). They used a targeted gene panel in the Lung Adjuvant Cisplatin Evaluation (LACE)-Bio-II study, wherein next-generation sequencing and long-term outcomes data from > 900 patients with early-stage NSCLC, treated prospectively in adjuvant landmark clinical trials, was analyzed. In patients with resected NSCLC, a better prognosis was observed in relation to high nonsynonymous TMB. Additionally, patients with low nonsynonymous TMBs showed more pronounced benefit of adjuvant chemotherapy on lung cancer-specific survival (LCSS).

Methods

• Researchers used a targeted panel of 1,538 genes to sequence a total of 908 unmatched, formalin-fixed, paraffin-embedded, resected lung cancer tumor specimens.
• Exclusion of germline variants and artifacts related to formalin fixation was accomplished by applying stringent filtering criteria.
• Using Cox models stratified by trial and adjusted for treatment, age, sex, performance score, histology, type of surgery, and stage, the evaluation of disease-free survival, overall survival, and lung cancer-specific survival (LCSS) was carried out.

Results

• They identified nonsynonymous mutations in 1,515 genes in 908 tumor samples.
• In patients with resected NSCLC, high nonsynonymous TMB (> 8 mutations/Mb) was found to be prognostic for favorable outcomes (ie, overall survival, disease-free survival, and LCSS).
• Patients with low nonsynonymous TMBs (≤ 4 mutations/Mb) showed a more pronounced LCSS benefit with adjuvant chemotherapy.
• Presence of mutations in DNA repair pathways, tumor-infiltrating lymphocytes, TP53 alteration subtype, and intratumor heterogeneity was shown to have neither prognostic nor predictive utility.
• High false-discovery rates resulted in difficulty in determining the statistically significant effect of mutations in individual genes.