Actionable Mutation Profiles of Non-Small Cell Lung Cancer patients from Vietnamese population

Abstract

Comprehensive profiling of actionable mutations in non-small cell lung cancer (NSCLC) is vital to guide targeted therapy, thereby improving the survival rate of patients. Despite the high incidence and mortality rate of NSCLC in Vietnam, the actionable mutation profiles of Vietnamese patients have not been thoroughly examined. Here, we employed massively parallel sequencing to identify alterations in major driver genes (EGFR, KRAS, NRAS, BRAF, ALK and ROS1) in 350 Vietnamese NSCLC patients. We showed that the Vietnamese NSCLC patients exhibited mutations most frequently in EGFR (35.4%) and KRAS (22.6%), followed by ALK (6.6%), ROS1 (3.1%), BRAF (2.3%) and NRAS (0.6%). Interestingly, the cohort of Vietnamese patients with advanced adenocarcinoma had higher prevalence of EGFR mutations than the Caucasian MSK-IMPACT cohort. Compared to the East Asian cohort, it had lower EGFR but higher KRAS mutation prevalence. We found that KRAS mutations were more commonly detected in male patients while EGFR mutations was more frequently found in female. Moreover, younger patients (<61 years) had higher genetic rearrangements in ALK or ROS1. In conclusions, our study revealed mutation profiles of 6 driver genes in the largest cohort of NSCLC patients in Vietnam to date, highlighting significant differences in mutation prevalence to other cohorts. Lung cancer is the most common malignancy and the leading cause of cancer related deaths worldwide (18.4% of total cancer deaths), with non-small cell lung cancer (NSCLC) being the most common subtype, accounting for approximately 85% of all diagnosed cases 1,2. The majority of NSCLC patients display advanced disease when diagnosed and thus have poor prognosis 2,3. It is well established that acquired genetic alterations in certain driver genes result in tumour growth and invasiveness, and that patients harboring certain mutations may benefit from targeted therapies 4,5. Indeed, a randomized clinical trial reported that advanced NSCLC patients harboring activating mutations in EGFR, one of the major driver genes of NSCLC, exhibited longer progression-free period when treated with a tyrosine kinase inhibitor (TKI), gefitinib, compared to those treated with standard platinum based chemotherapy 6. However, those who were treated with TKI drugs can acquire secondary resistant mutations, in which case a new treatment regimen is needed to maintain therapeutic effect 7,8. In addition to EGFR, NSCLC patients carrying ALK or ROS1 rearrangement were shown to respond well to a different TKI drug,

Ultra-Deep Massive Parallel Sequencing of Plasma Cell-Free DNA Enables Large-Scale Profiling of Driver Mutations in Vietnamese Patients With Advanced Non-Small Cell Lung Cancer

“…Recently, liquid biopsy, genetic testing of plasma cfDNA shed by tumor cells into the blood stream, has been suggested as a promising approach not only to offer noninvasive testing to advanced stage patients but also to provide more comprehensive picture of mutation profiles due to its unbiased sampling of ctDNA in the blood stream (10,13). In this study, we evaluated the application of liquid biopsy in a large-scale profiling of population-specific mutation profile by comparing the mutation profiles of six driver genes of 265 Vietnamese patients with advance stage NSCLC defined by sequencing of cfDNA to the existing tissue based sequencing data generated from an independent cohort consisting of 285 patients with similar race, histology and treatment status (7).…”

“…Previous mutation analysis of tumor tissue samples reported significant associations between certain clinical features among Vietnamese NSCLC patients and the prevalence of EGFR and KRAS mutations (7). Here, we sought to examine whether cfDNA testing is able to detect such features.…”

“…The second cohort, hereafter called ttDNA cohort, comprised of 285 tissue samples from Vietnamese NSCLC selected to match the tumor stages and treatment status of the cfDNA cohort. The mutation profiles of this cohort were retrieved from our previously published study (7). Descriptive statistics of these two cohorts showed that, in addition to tumor stages and treatment status, they were also comparable with respect to male-to-female ratio and median age (Table S1).…”

“…The ttDNA cohort comprised of tissue samples from 285 Vietnamese NSCLC patients selected from our previous study (7). All patients in ttDNA cohort are naïve to treatment and diagnosed with advanced NSCLC at the time of hospital admission.…”

“…However, it has been reported that 20-50% of patients with advanced metastatic NSCLC are not fit for tumor biopsy testing (8,19), thus making a large-scale comparison between matched plasma and tissue samples a challenge, both logistically and ethically. In this study, we performed liquid biopsy on a large cohort of Vietnamese NSCLC patients to examine whether it can accurately represent the mutation profiles previously obtained by direct analysis of tumor derived DNA (7).…”