Mutant-allele dispersion correlates with prognosis risk in patients with advanced non-small cell lung cancer.

Abstract

Intra-tumor heterogeneity (ITH) contributes to lung cancer progression and resistance to therapy. To evaluate ITH and determine whether it may be employed as a predictive biomarker of prognosis in patients with advanced non-small cell lung cancer (NSCLC), we used a novel algorithm called mutant-allele dispersion (MAD). In the study, 103 patients with advanced NSCLC were enrolled. Using a panel of 425 cancer-related genes, next-generation sequencing (NGS) was performed on tumor specimens that had been collected. From NGS data, we derived MAD values, and we next looked into their relationships with clinical variables and different mutation subtypes. The median MAD among 103 NSCLC patients was 0.73. EGFR mutation, tyrosine kinase inhibitor (TKI) therapy, radiotherapy, and chemotherapy cycles were all substantially correlated with the MAD score. In patients with lung adenocarcinoma (LUAD), correlation analysis revealed that the MAD score was substantially linked with Notch pathway mutation (P = 0.021). A significant relationship between high MAD and shorter progression-free survival (PFS) was found (HR = 2.004, 95%CI 1.269-3.163, P = 0.003). In patients with advanced NSCLC, histological type (P = 0.004), SMARCA4 mutation (P = 0.038), and LRP1B mutation (P = 0.006) were all independently associated with prognosis. The disease control rate was considerably greater in the low MAD group compared to the high MAD group in 19 LUAD patients receiving immunotherapy (92.9% vs. 40%, P = 0.037). TKI-PFS was longer in 37 patients with low MAD who received first-line TKI therapy (P = 0.014). Our findings suggested that MAD is a practical and simple algorithm for assessing ITH, and populations with high MAD values are more likely to have EGFR mutations. MAD can be used as a potential biomarker to predict not only the prognosis of NSCLC but also the efficacy of immunotherapy and TKI therapy in patients with advanced NSCLC.