Effects of Co-occurring Genomic Alterations on Outcomes in Patients withKRAS-Mutant Non–Small Cell Lung Cancer

Abstract

mutations occur in approximately 25% of patients with non-small cell lung cancer (NSCLC). Despite the uniform presence of mutations, patients with-mutant NSCLC can have a heterogeneous clinical course. As the pattern of co-occurring mutations may describe different biological subsets of patients with -mutant lung adenocarcinoma, we explored the effects of co-occurring mutations on patient outcomes and response to therapy. We identified patients with advanced -mutant NSCLC and evaluated the most common co-occurring genomic alterations. Multivariate analyses were performed incorporating the most frequent co-mutations and clinical characteristics to evaluate association with overall survival as well as response to platinum-pemetrexed chemotherapy and immune checkpoint inhibitors. Among 330 patients with advanced -mutant lung cancers, the most frequent co-mutations were found in (42%), (29%), and/ (27%). In a multivariate analysis, there was a significantly shorter survival in patients with co-mutations in / [HR, 1.96; 95% confidence interval (CI), 1.33-2.92; ≤ 0.001]. (HR, 1.3; = 0.22) and (HR 1.11, = 0.58) co-mutation statuses were not associated with survival. Co-mutation in/ was also associated with shorter duration of initial chemotherapy (HR, 1.64; 95% CI, 1.04-2.59; = 0.03) and shorter overall survival from initiation of immune therapy (HR, 3.54; 95% CI, 1.55-8.11; = 0.003). Among people with -mutant advanced NSCLC,, and / are the most commonly co-occurring somatic genomic alterations. Co-mutation of and/ is an independent prognostic factor, predicting shorter survival, duration of response to initial platinum-based chemotherapy, and survival from the start of immune therapy..

Quantitative in vivo analyses reveal a complex pharmacogenomic landscape in lung adenocarcinoma

“…This analysis confirmed that mutation of KEAP1 correlated with a shorter time-to-next-treatment, which is consistent with our Tuba-seq results as well as a previous study on the impact of KEAP1/NRF2 -pathway alterations on platinum responses ( Fig. 2j, k ) 22, 23 . Our in vivo pharmacogenomic platform, in which the responses of tumors with defined genotypes can be quantified, establishes direct causal relationships between genotype and treatment responses and enables accurate interpretation of patient data.…”

K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways

“…14 There is growing evidence for genetic heterogeneity of KRAS-mutated NSCLC. 15 Kinase inhibitors targeting molecules downstream of KRAS-like MEK inhibitors have shown modest efficacy, with response rates of 11% for selumetinib 16 and 12% for trametinib. 17 Obviously, the RAF-MEK-ERK pathway is not the only pathway controlled by KRAS, 18 which is supported by findings demonstrating enhanced efficacy of combining MEK inhibitors with phosphoinositide 3-kinase inhibitors in NSCLC models.…”

“…22 In addition, different KRAS proteins have been described as exerting different effects on transformation of downstream signal transduction pathways. 23 Recent work has revealed co-occurring kelch like ECH associated protein 1 gene (KEAP1)/ nuclear factor erythroid 2, like 2 gene (NFE2L2) mutations as an independent negative prognostic factor regarding survival and response to platinum-based chemotherapy 15,24 and leading to dependence on glutaminolysis, whereas co-occurrence of serine/threonine kinase 11 deficiency promotes activation of proinflammatory cytokine production. 25 For the G12C mutation, specific inhibitors have shown preclinical activity and are under clinical evaluation.…”

Identification of Subsets of Genetic Alterations in KRAS-mutant Lung Cancer using Association Rule Mining

“…Concurrent mutations in KRAS and KEAP1 in lung cancer is associated with a more aggressive disease [48]. The KEAP1 gene encodes for Kelch-like ECH associated protein 1 which is a negative modulator of NFE2L2, a master transcriptional regulator of the antioxidant response.…”

“…However, there are conflicting reports on the effects of alterations in STK11 in KRAS-mutant tumors. Some researchers reported that concurrent STK11 and KRAS mutations did not affect the aggressiveness of the disease in patients [48,63]. Findings from other studies show that STK11 can potentiate tumor progression in KRAS-mutant tumors in mouse models [64] and was associated with a more aggressive disease [36].…”