Use of a High-Throughput Genotyping Platform (OncoMap) for RAS Mutational Analysis to Predict Cetuximab Efficacy in Patients with Metastatic Colorectal Cancer
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Purpose Cetuximab demonstrates improved efficacy outcomes in patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS exon 2. Resistance to cetuximab is mediated by activating less frequent mutations in the RAS genes beyond KRAS exon 2. We performed extended RASmutational analysis using a high -throughput genotyping platform (OncoMap) and evaluated extended RAS analysis for predicting cetuximab efficacy in patients harboring wild-type KRAS exon 2 tumors following Sanger sequencing. Materials and Methods Extended RAS analysis was performed on 227 wild-type KRAS exon 2 mCRC patients who received cetuximab as salvage treatment using OncoMap ver. 4.0. Targeted genes included exon 2, exon 3, and exon 4, both in KRAS and NRAS, and included BRAF exon 15. We assessed efficacy by the new RAS mutation status. Results The OncoMap detected 57 additional mutations (25.1%): 25 (11%) in KRAS exon 2 and 32 (14.1%) beyond KRAS exon 2. Survival differences were observed after dividing patients into the wild-type RAS group (n=170) and mutant RAS group (n=57) using OncoMap. Progression-free survival was 4.8 months versus 1.8 months (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.32 to 0.61), and overall survival was 11.9 months versus 8.4 months (HR, 0.65; 95% CI, 0.47 to 0.88). Conclusion Sanger sequencing is not sufficient for selecting candidates for cetuximab treatment. High - throughput extended RAS genotyping is a feasible approach for this purpose and identifies patients who might benefit from cetuximab treatment.
Abstract
Purpose Cetuximab demonstrates improved efficacy outcomes in patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS exon 2. Resistance to cetuximab is mediated by activating less frequent mutations in the RAS genes beyond KRAS exon 2. We performed extended RASmutational analysis using a high -throughput genotyping platform (OncoMap) and evaluated extended RAS analysis for predicting cetuximab efficacy in patients harboring wild-type KRAS exon 2 tumors following Sanger sequencing. Materials and Methods Extended RAS analysis was performed on 227 wild-type KRAS exon 2 mCRC patients who received cetuximab as salvage treatment using OncoMap ver. 4.0. Targeted genes included exon 2, exon 3, and exon 4, both in KRAS and NRAS, and included BRAF exon 15. We assessed efficacy by the new RAS mutation status. Results The OncoMap detected 57 additional mutations (25.1%): 25 (11%) in KRAS exon 2 and 32 (14.1%) beyond KRAS exon 2. Survival differences were observed after dividing patients into the wild-type RAS group (n=170) and mutant RAS group (n=57) using OncoMap. Progression-free survival was 4.8 months versus 1.8 months (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.32 to 0.61), and overall survival was 11.9 months versus 8.4 months (HR, 0.65; 95% CI, 0.47 to 0.88). Conclusion Sanger sequencing is not sufficient for selecting candidates for cetuximab treatment. High - throughput extended RAS genotyping is a feasible approach for this purpose and identifies patients who might benefit from cetuximab treatment.
참고문헌 (19)
- 정규원, "Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2012", Cancer Research and Treatment, 47(2), pp.127~141 (2015), 대한암학회[DOI]
- Di Fiore F, "Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy", Br J Cancer, 96, pp.1166~1169 (2007)
- Khambata-Ford S, "Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab", J Clin Oncol, 25, pp.3230~3237 (2007)
- Ciardiello F, "Uptake of KRAS mutation testing in patients with metastatic colorectal cancer in Europe, Latin America and Asia", Target Oncol, 6, pp.133~145 (2011)
- Heinemann V, "FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer(FIRE-3) : a randomised, open-label, phase 3 trial", Lancet Oncol, 15, pp.1065~1075 (2014)
- Douillard JY, "Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer", N Engl J Med, 369, pp.1023~1034 (2013)
- Schwartzberg LS, "PEAK : a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin(mFOLFOX6)or bevacizumab plus mFOLFOX6in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer", J Clin Oncol, 32, pp.2240~2247 (2014)
- Peeters M, "Analysis of KRAS", NRAS mutations in a phase III study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer, 2015, pp.21, 5469~5479
- Van Cutsem E, "Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer", J Clin Oncol, 33, pp.692~700 (2015)
- Bokemeyer C, "FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer", Eur J Cancer, 51, pp.1243~1252 (2015)
- Tsiatis AC, "Comparison of Sanger sequencing, pyrosequencing, and melting curve analysis for the detection of KRAS mutations : diagnostic and clinical implications", J Mol Diagn, 12, pp.425~432 (2010)
- MacConaill LE, "Profiling critical cancer gene mutations in clinical tumor samples", PLoS One, 4, pp.e7887~ (2009)
- Kim YM, "Analysis and comparison of somatic mutations in paired primary and recurrent epithelial ovarian cancer samples", PLoS One, 9, pp.e99451~ (2014)
- Atreya CE, "Expanded RAS : refining the patient population", J Clin Oncol, 33, pp.682~685 (2015)
- Sohn BS, "The role of KRAS mutations in predicting the efficacy of cetuximab-plus-irinotecan therapy in irinotecan-refractory Korean metastatic colorectal cancer patients", Oncology, 77, pp.224~230 (2009)
- Hecht JR, "Extended RAS analysis for anti-epidermal growth factor therapy in patients with metastatic colorectal cancer", Cancer Treat Rev, 41, pp.653~659 (2015)
- Bokemeyer C, "Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer : pooled analysis of the CRYSTAL and OPUS randomised clinical trials", Eur J Cancer, 48, pp.1466~1475 (2012)
- Sommeijer DW, "The relationship between rash, tumour KRAS mutation status and clinical and quality of life outcomes in patients with advanced colorectal cancer treated with cetuximab in the NCIC CTG", AGITG CO.17, 2014, pp.53, 877~884
- Peeters M, "Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer", Clin Cancer Res, 19, pp.1902~1912 (2013)