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Prevalence of KRAS, BRAF, PI3K and EGFR mutations among Asian patients with metastatic colorectal cancer.

ABSTRACT: Mutations in oncogenes along the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the resistance to cetuximab in patients with metastatic colorectal cancer (mCRC). However, the relative significance of these mutations based on their frequencies of occurrence in the Singaporean population remains unclear. In the present study, the prevalence of Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF), phosphoinositide 3-kinase (PI3K) and EGFR somatic mutations were determined among Singaporean patients with mCRC. DNA extracted from 45 pairs of surgically resected tumor and normal mucosa samples was subjected to direct sequencing or restriction fragment length polymorphism. Associations of the genetic mutations with various clinicopathological parameters were further explored. Mutations in either codon 12 or 13 of KRAS were confirmed as prominent phenomena among the included Singaporean mCRC patients, at a prevalence comparable with that of Caucasian and patients of other Asian ethnicities [33.3% (90% confidence interval, 21.8-44.9%)]. KRAS mutation was not associated with clinicopathological features, including age, gender and ethnicity of patients, or the tumor site, differentiation and mucinous status. Conversely, the prevalence of BRAF (0%), PI3K (2.2%) and EGFR (0%) mutations were low. The results of the present study indicate that KRAS mutations are prevalent among the studied population, and confirm the low prevalence of BRAF, PI3K and EGFR mutations. KRAS should be prioritized as an investigational gene for future studies of predictive biomarkers of cetuximab response among Singaporean patients with mCRC.

SUBMITTER: Phua LC

PROVIDER: S-EPMC4579971 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Prevalence of KRAS, BRAF, PI3K and EGFR mutations among Asian patients with metastatic colorectal cancer.

Phua Lee Cheng LC Ng Hui Wen HW Yeo Angie Hui Ling AH Chen Elya E Lo Michelle Shu Mei MS Cheah Peh Yean PY Chan Eric Chun Yong EC Koh Poh Koon PK Ho Han Kiat HK

Oncology letters 20150803 4

Mutations in oncogenes along the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the resistance to cetuximab in patients with metastatic colorectal cancer (mCRC). However, the relative significance of these mutations based on their frequencies of occurrence in the Singaporean population remains unclear. In the present study, the prevalence of Kirsten rat sarcoma viral oncogene homolog (<i>KRAS</i>), v-Raf murine sarcoma viral oncogene homolog B (<i>BRAF</i>), ph ...[more]

PMID: 26622882

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Project description:To investigate the impact of thymidylate synthase (TYMS), KRAS and BRAF in the survival of metastatic colorectal cancer (mCRC) patients treated with chemotherapy.Clinical data were collected retrospectively from records of consecutive patients with mCRC treated with fluoropyrimidine-based chemotherapy from 1/2005 to 1/2007. Formalin-fixed paraffin-embedded tissues were retrieved for analysis. TYMS genotypes were identified with restriction fragment analysis PCR, while KRAS and BRAF mutation status was evaluated using real-time PCR assays. TYMS gene polymorphisms of each of the 3' untranslated region (UTR) and 5'UTR were classified into three groups according to the probability they have for high, medium and low TYMS expression (and similar levels of risk) based on evidence from previous studies. Univariate and multivariate survival analyses were performed.The analysis recovered 89 patients with mCRC (46.1% de novo metastatic disease and 53.9% relapsed). Of these, 46 patients (51.7%) had colon cancer and 43 (48.3%) rectal cancer as primary. All patients were treated with fluoropyrimidine-based chemotherapy (5FU or capecitabine) as single-agent or in combination with irinotecan or/and oxaliplatin or/and bevacizumab. With a median follow-up time of 14.8 mo (range 0-119.8), 85 patients (95.5%) experienced disease progression, and 63 deaths (70.8%) were recorded. The 3-year and 5-year OS rate was 25.4% and 7.7% while the 3-year progression-free survival rate was 7.1%. Multivariate analysis of TYMS polymorphisms, KRAS and BRAF with clinicopathological parameters indicated that TYMS 3'UTR polymorphisms are associated with risk for disease progression and death (P < 0.05 and P < 0.03 respectively). When compared to tumors without any del allele (genotypes ins/ins and ins/loss of heterozygosity (LOH) linked with high TYMS expression) tumors with del/del genotype (low expression group) and tumors with ins/del or del/LOH (intermediate expression group) have lower risk for disease progression (HR = 0.432, 95%CI: 0.198-0.946, P < 0.04 and HR = 0.513, 95%CI: 0.287-0.919, P < 0.03 respectively) and death (HR = 0.366, 95%CI: 0.162-0.827, P < 0.02 and HR = 0.559, 95%CI: 0.309-1.113, P < 0.06 respectively). Additionally, KRAS mutation was associated independently with the risk of disease progression (HR = 1.600, 95%CI: 1.011-2.531, P < 0.05). The addition of irinotecan in 1st line chemotherapy was associated independently with lower risk for disease progression and death (HR = 0.600, 95%CI: 0.372-0.969, P < 0.04 and HR = 0.352, 95%CI: 0.164-0.757, P < 0.01 respectively).The TYMS genotypes ins/ins and ins/LOH associate with worst prognosis in mCRC patients under fluoropyrimidine-based chemotherapy. Large prospective studies are needed for validation of our findings.

Project description:BackgroundTumors of the metastatic colorectal cancer (mCRC) patients that are wildtype (WT) for KRAS or NRAS mutations respond more favorably to anti-epidermal growth factor receptor (EGFR) treatments. Treatment guidelines now recommend that all mCRC patients have WT KRAS and NRAS tumor status confirmed prior to initiating anti-EGFR therapy. Evidence also suggests that BRAF mutations may predict lack of response to anti-EGFR therapy. As such, there is now a need for comprehensive data on the prevalence of KRAS, NRAS, and BRAF mutations among patients with mCRC.MethodsA systematic literature review was conducted among studies that described the prevalence of KRAS, NRAS, and BRAF gene mutations in mCRC patients. Observational cohort studies and standard of care arm of randomized clinical trials were included. Random effects meta-analysis models were used to create summary prevalence estimates for each of the mutation types. Subgroup analyses were also conducted to identify potential sources of heterogeneity. Exploratory analyses of overall and progression-free survival by mutation status were also conducted.ResultsThis systematic review and meta-analysis included 275 studies comprising 77,104 mCRC patients. The summary prevalence estimate was 35.9% for KRAS mutations, 7.1% for BRAF mutations, and 4.1% for NRAS mutations. Female patients had significantly more KRAS and BRAF mutations than males, and significant variation by study location was observed for both KRAS and BRAF mutation prevalence. Overall survival was significantly decreased for patients with KRAS, BRAF, and NRAS mutations compared to those with WT tumors. Progression-free survival was also significantly decreased among patients with KRAS and BRAF mutations.ConclusionsKRAS, NRAS, and BRAF mutation statuses in patients with mCRC are important predictors of treatment success and may also have prognostic value. In this paper we present the first systematic and comprehensive literature review and meta-analysis of the prevalence of KRAS, BRAF, and NRAS mutations and demonstrate the prognostic impact of mutation status on survival.

Dataset Information

Prevalence of KRAS, BRAF, PI3K and EGFR mutations among Asian patients with metastatic colorectal cancer.

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Prevalence of KRAS, BRAF, PI3K and EGFR mutations among Asian patients with metastatic colorectal cancer.

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