The prevalence RAS and BRAF mutations among patients in the Middle East and Northern Africa with metastatic colorectal cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 598-598
Author(s):  
Tamer Garawin ◽  
Kimberly Lowe ◽  
George Kafatos ◽  
Samuel Murray
Keyword(s):  
Colorectal Cancer ◽  
Saudi Arabia ◽  
Middle East ◽  
Wild Type ◽  
Braf Mutations ◽  
Real World Data ◽  
Exon 2 ◽  
Ras Mutation ◽  
Exon 4 ◽  
Kras Exon

598 Background: Anti-EGFR therapies are recommended for metastatic colorectal cancer (mCRC) patients with confirmed wild-type RAS (exons 2, 3, 4 of KRAS and NRAS) status. There is limited published information on the prevalence of RAS mutations using real world data. The objective of this study was estimate the prevalence of RAS and BRAF mutations among patients with mCRC in the Middle East and Northern Africa (MENA) in an effort to inform the rationale for biomarker testing and treatment choice. Methods: The study included 1,669 patients from August 2013 to July 2015 with mCRC from Algeria, Bahrain, Egypt, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Qatar, Saudi Arabia, and the United Arab Emeritus. Information on RAS mutation status was obtained from one pathology lab using High Resolution Melting Analysis. Extended RAS analysis was conducted in a subset of patients, including: overall RAS (exon 2, 3, 4 of KRAS and NRAS; n = 750), KRAS exon 2 (n = 750), KRAS exon 3 and 4 (n = 507), NRAS exon 2, 3, and 4 (n = 507), and BRAF exon 15 (n = 78). The proportion of patients with each mutation was summarized. Results: The overall RAS mutation in the full sample was 35.3% (n = 589/1669). The observed mutation for KRAS exon 2 in a subset of patients with extended RAS analysis (n = 750) was 32.4% (243/750). Out of the subjects with wild-type exon 2 (n = 507), the observed mutations rates were as follows: KRAS exon 4 (20/507 = 3.9%), KRAS exon 3 (13/507 = 2.6%), NRAS exon 2 (7/507 = 1.4%), NRAS exon 3 (6/507 = 1.2%), and NRAS exon 4 (0%). The prevalence of BRAF exon 15 was 3.8% (3/78). The most robust data on specific RAS mutations was obtained from Algeria, Egypt, and Saudi Arabia. The prevalence of KRAS exon 2 mutations in these countries was as follows: Algeria (n = 33/86 = 38.4%), Egypt (n = 83/303 = 27.4%), Saudi Arabia (n = 85/245 = 34.7%). Conclusions: To our knowledge, this is the first study to evaluate the prevalence of RAS and BRAF mutations in the Middle East using real world data. The results of this descriptive study illustrate that there is variation in the prevalence of RAS and BRAF mutations in MENA.

FOLFOX4 plus cetuximab administered weekly or every two weeks in first-line treatment of patients with KRAS and NRAS wild-type (wt) metastatic colorectal cancer (mCRC).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. LBA391-LBA391 ◽  
Author(s):  
Thomas Brodowicz ◽  
Damir Vrbanec ◽  
Klaus Kaczirek ◽  
Tudor-Eliade Ciuleanu ◽  
Regina Knittelfelder ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibody ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Wild Type ◽  
First Line ◽  
Braf Mutations ◽  
Exon 2 ◽  
The Impact ◽  
Kras Exon

LBA391^ Background: Efficacy and safety of first-line FOLFOX4 plus either cetuximab (weekly or every two weeks) have been reported to be similar in 152 patients with KRAS exon 2 wt mCRC within the randomized phase II CECOG/CORE2 study. Recent analyses have shown that also mutations in KRAS exons 3/4 and NRAS (exons 2, 3, and 4) are associated with an inferior PFS and OS with EGFR-targeted monoclonal antibody containing therapy. The impact of these additional mutations on the reported findings in the CECOG/CORE2 study were investigated. Methods: Tumor samples of 148 randomized KRAS exon 2 wild-type metastatic colorectal cancer patients were available for testing of additional mutations by conventional Sanger sequencing. Objective response rate (ORR), PFS and OS were compared in patients with KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4) wild-type tumors [RAS wt] versus patients with mutations in KRAS (exons 3 and 4) or NRAS (exons 2, 3 and 4) [RAS mt]. Patients with BRAF mutations were excluded from this comparison. The Cochran-Mantel-Haenszel procedure was used to compare the ORR. Kaplan-Meier methods, log-rank test and Cox proportional hazard methods were used to analyze PFS and OS. Results: Of the 148 KRAS exon 2 wt patients 124 patients had RAS and BRAF wt tumors, 10 patients had RAS mutations only and 14 had only BRAF mutations. In the RAS wt and the RAS mt groups ORR was 61.3% (95% CI 52.1-69.9) and 40% (95%CI 12.2-73.8), (Odds ratio 0.43, p=0.1966). Median PFS was 9.7 months (95% CI 8.9-11.2) versus 7.2 months (95% CI 6.7-10.8) (hazard ratio HR=0.56, p=0.1135). Median OS was 28.5 months (95% CI 24.0-31.3) versus 16.3 months (95% CI 15.9-20.7), (HR=0.43, p=0.0199). The difference in OS remained statistically significant in the Cox model, if adjusted for significant confounding factors. ORR, PFS, and OS in BRAF mt and RAS mt patients were similar. Conclusions: RAS wt patients treated with cetuximab and FOLFOX4 experience a significant prolongation of OS as compared to RAS mt patients. This analysis supports the findings of other trials that RAS mutational analyses in metastatic CRC disease is recommended prior to initiation of an EGFR-targeted monoclonal antibody therapy. Clinical trial information: NCT00479752.

scholarly journals A phase 2 study of panitumumab with irinotecan as salvage therapy in chemorefractory KRAS exon 2 wild-type metastatic colorectal cancer patients

2019 ◽  
Vol 121 (5) ◽  
pp. 378-383 ◽  
Author(s):  
Elena Elez ◽  
Carles Pericay ◽  
Manuel Valladares-Ayerbes ◽  
Inmaculada Bando ◽  
Maria Jose Safont ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Salvage Therapy ◽  
Phase 2 ◽  
Wild Type ◽  
Exon 2 ◽  
Phase 2 Study ◽  
Colorectal Cancer Patients ◽  
Kras Exon

scholarly journals Sequential cetuximab/bevacizumab therapy is associated with improved outcomes in patients with wild‐type KRAS exon 2 metastatic colorectal cancer

2019 ◽  
Vol 8 (7) ◽  
pp. 3437-3446 ◽  
Author(s):  
Hung‐Chih Hsu ◽  
Yu‐Chun Liu ◽  
Chuang‐Wei Wang ◽  
Wen-Chi Chou ◽  
Yu-Jen Hsu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Wild Type ◽  
Exon 2 ◽  
Improved Outcomes ◽  
Kras Exon

Expanded KRAS and NRAS assays increase detection of mutations that predict for resistance to therapy in colorectal cancer patients.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 519-519
Author(s):  
Garrett Larson ◽  
Anna Israyelyan ◽  
Heinz-Josef Lenz ◽  
Stephanie H. Astrow
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Targeted Therapies ◽  
Kinase Inhibitor ◽  
Meta Analysis ◽  
Screening Strategy ◽  
Nras Mutation ◽  
Braf Mutations ◽  
Exon 2 ◽  
Exon 4

519 Background: The selection of targeted therapies is guided by the analysis of somatic mutations. The identification of RAS activating mutations can be used to examine tyrosine kinase inhibitor therapeutic eligibility and prognosis. Beyond known mutations in RAS exon 2 (codons 12 and 13), the identification of additional mutations in RAS exons 3 and 4 (codons 61, 117 and 146) also predict for resistance to EGFR therapy in colorectal cancer (CRC). Meta-analysis supports screening for these additional mutations in any screening strategy prior to administration of EGFR mAb therapy in metastatic CRC patients (Sorich, MJ, et al., Ann Oncol, Aug 12, 2014). Methods: We expanded our existing allele-specific KRAS and sequencing-based NRAS assays to include codons 61, 117, and 146 and analytically validated these assays to CAP/CLIA standards. DNA, from microdissected colon tumor tissue that was wild-type for RAS exon 2, was tested for exon 3 and 4 mutations and included over 15 additional mutations. Results: Forty-two (9.1%) samples were identified as bearing either an exon 3 or 4 KRAS mutation amongst 461 colon cancer specimens. Exon 4 codon 146 mutations were more prevalent than three of the commonly screened exon 2 mutations: G12A, G12R, and G12S. Five (1.8%) of samples were identified as carrying exon 3 or 4 NRAS mutations amongst 272 colon cancer specimens. This included a single codon 146 mutation in exon 4. As is seen with exon 2, RAS mutations at exons 3 and 4 were mutually exclusive of activating BRAF mutations with ~10% of patients harboring V600E. The collection of additional data studying KRAS and NRAS mutation status is currently ongoing. Conclusions: The KRAS expanded coverage contributed an additional 5.5% to overall burden of specimens bearing mutations. The NRAS expanded coverage contributed an additional 1.8% to the mutational burden. These analyses in clinical cohorts support the observations made in a trial population (Douillard JV, et al. NEJM 369:1023-34, 2013). The expanded RAS coverage identifies additional patients unlikely to respond to EGFR-targeted therapies that would otherwise have been assessed as “no mutation detected” in using assays restricted to RAS exon 2.

scholarly journals Phase II trial of biweekly cetuximab and irinotecan as third‐line therapy for pretreated KRAS exon 2 wild‐type colorectal cancer

2018 ◽  
Vol 109 (8) ◽  
pp. 2567-2575 ◽  
Author(s):  
Hiroki Osumi ◽  
Eiji Shinozaki ◽  
Tetsuo Mashima ◽  
Takeru Wakatsuki ◽  
Mitsukuni Suenaga ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Wild Type ◽  
Exon 2 ◽  
Line Therapy ◽  
Third Line Therapy ◽  
Third Line ◽  
Kras Exon
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