The prevalence and prognostic value of KRAS co-mutation subtypes in Chinese advanced non-small cell lung cancer patients.

Cai D1,2, Hu C1,2, Li L1,2, Deng S1,2, Yang J1,2, Han-Zhang H3, Li M1,2,4,5.

Author information

1: Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
2: National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
3: Burning Rock Biotech, Guangzhou International Biotech Island, Guangzhou, China.
4: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
5: Key Laboratory of Molecular Radiation Oncology of Hunan Province, Changsha, Hunan, China.

Abstract

OBJECTIVE:

KRAS mutation plays a critical role in the initiation and development of non-small cell lung cancer (NSCLC). KRAS-mutant patients exhibit diverse response to chemotherapy. KRAS co-mutation subtypes and their prognosis value in advanced Chinese NSCLC patients remain largely elusive.

METHODS:

A total of 1126 Chinese advanced NSCLC patients from Xiangya hospital were screened by capture-based ultra-deep sequencing for KRAS mutation between January 2015 and December 2016. Survival analyses were performed using Kaplan-Meier analysis.

RESULTS:

Among the patients screened, 84 cases were detected with KRAS mutation (7.5%). All of them were non-squamous NSCLC and received pemetrexed plus platinum as the first-line treatment. The most frequent KRAS co-mutation genes were TP53 (29%), TP53/LKB1 (19%), and LKB1 (14%). Our data revealed that patients with KRAS co-mutation had poorer prognosis in comparison with those harboring single KRAS mutation. Furthermore, patients with KPL (KRAS mutated with TP53 and LKB1) subtype, which was a novel subtype, had the shortest progression-free survival (PFS) in all types of KRAS co-mutation patients (P < .0001). The PFS and overall survival (OS) of patients with KRASG12D mutation were inferior than those with KRASG12C mutation or KRASG12V mutation. Patients in KRASG>T type had significantly longer survival than those in KRASG>C type or KRASG>A type.

CONCLUSION:

Our study revealed that concurrent genomic alterations can further stratify KRAS-mutant lung adenocarcinoma patients into various subgroups with distinctive therapeutic responses and differential survival outcomes. The KPL is a novel and less responsive subtype among KRAS-mutated NSCLC, and further investigation of effective treatment for this subtype is warranted.