Tumor Mutation Burden and Prognosis in Resected NSCLC
In a study reported in the Journal of Clinical Oncology, Devarakonda et al found that high nonsynonymous tumor mutation burden was associated with improved outcomes in patients undergoing resection for non–small cell lung cancer (NSCLC).
Study Details
The study (Lung Adjuvant Cisplatin Evaluation [LACE]-Bio-II study) analyzed data on next-generation sequencing and long-term outcomes from 908 patients (453 undergoing resection alone, 455 undergoing resection with adjuvant chemotherapy) with early-stage NSCLC in landmark adjuvant chemotherapy clinical trials. A targeted panel of 1,538 genes was used to assess outcomes associated with mutations in individual genes, DNA-repair pathways, and tumor mutation burden.
Tumor Mutation Burden and Outcomes
Nonsynonymous mutations were identified in 1,515 genes in 908 tumor samples. When tumors of all histologies were categorized into tertiles of low (≤ 4 mutations/Mb), intermediate (> 4 to ≤ 8 mutations/Mb), and high (> 8 mutations/Mb) tumor mutation burden, tumors with high nonsynonymous tumor mutation burden were associated with more favorable outcomes vs tumors with lower nonsynonymous tumor mutation burden; P values for trends were .007 for disease-free survival, .016 for overall survival, and .001 for lung cancer–specific survival. For example, for disease-free survival, compared with the middle tertile, the hazard ratio for patients with tumor mutation burden in the lowest tertile was 1.2 (95% confidence interval [CI] = 0.97–1.5) and that for patients in the highest tertile was 0.88 (95% CI = 0.70–1.1). An exploratory analysis using a splines model showed improved lung cancer–specific survival with increasing nonsynonymous tumor mutation burden; the model indicated that the beneficial effect of adjuvant chemotherapy was greatest in samples with lower nonsynonymous tumor mutation burden (≤ 4 mutations/Mb) and decreased with increasing nonsynonymous tumor mutation burden.
The presence of mutations in DNA-repair pathways, tumor-infiltrating lymphocytes, TP53 alteration subtype, and intratumor heterogeneity were not found to be prognostic or predictive of outcomes. High false-discovery rates made it difficult to discern statistically significant effects of mutations in individual genes.
The investigators concluded: “High nonsynonymous [tumor mutation burden] was associated with a better prognosis in patients with resected NSCLC. In addition, the benefit of adjuvant chemotherapy on [lung cancer–specific survival] was more pronounced in patients with low nonsynonymous [tumor mutation burdens]. Studies are warranted to confirm these findings.”
The study was supported by grants from the National Institutes of Health, Canadian Cancer Society Research Institute, and La Ligue Nationale Contre le Cancer.
Ramaswamy Govindan, MD, of the Division of Oncology, Washington University School of Medicine, is the corresponding author of the Journal of Clinical Oncology article.
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