Clinical significance of the BRAFV600E mutation in Asian patients with colorectal cancer
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To investigate the clinicopathological features and prognostic significance of the BRAFV600E mutation in Asian patients with colorectal cancer.
We retrospectively reviewed the medical records of 1969 patients with colorectal cancer admitted to Taipei Veterans General Hospital for surgical treatment between 2000 and 2013. The measured endpoint was overall survival after surgery. The prognostic value of the BRAFV600E mutation was analyzed using the log-rank test and Cox regression analysis.
The BRAFV600E mutation was detected in 106 (5.4%) patients and associated with female gender, abnormal cancer antigen (CA)19-9 at diagnosis, microsatellite status, right-sided primary tumors, mucinous histology, poor differentiation, and lymphovascular invasion. Metastatic patterns were more common in non-regional lymph node metastasis (20.8 vs. 7.4%, p = 0.06) and peritoneal seeding (41. vs. 21.2%, p = 0.04). Mutations were not prognostic in the overall survival of the entire study group but only in specific patients: age < 65, normal carcinoembryonic antigen at diagnosis, and stage IV disease.
The BRAFV600E mutation was associated with distinct clinicopathological features and metastatic patterns. The overall survival rate was lower in selected colorectal patients with the BRAFV600E mutation.
KeywordsBRAF mutation Colorectal cancer Stage IV Survival Metastatic pattern
Study conception and design: Hou-Hsuan Cheng and Shih-Ching Chang.
Data acquisition: Jen-Kou Lin, Shung-Haur Yang, Wei-Shone Chen, Jeng-Kai Jiang, and Shih-Ching Chang.
Data analysis and interpretation: Hou-Hsuan Cheng and Shih-Ching Chang.
Drafting of manuscript: Hou-Hsuan Cheng and Shih-Ching Chang.
Critical revision of manuscript: Jen-Kou Lin, Shung-Haur Yang, Wei-Shone Chen, and Jeng-Kai Jiang.
This research was funded by grants from the Taipei Veterans General Hospital (V101E2-005), Ministry of Science and Technology, Taiwan (105-2314-B-075-010-MY2), and Department of Health, Taipei City Government (10401-62-031; 10601-62-059).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
- 1.Ministry of Health and Welfare (2016) Taiwan Cancer Registry annual report, 2013. In: Ministry of Health and WelfareGoogle Scholar
- 6.O’Brien MJ, Yang S, Mack C et al (2006) Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am J Surg Pathol [Internet] 30(12):1491–1501CrossRefGoogle Scholar
- 17.Roth AD, Tejpar S, Delorenzi M et al (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol Off J Am Soc Clin Oncol 28:466–474. https://doi.org/10.1200/JCO.2009.23.3452 CrossRefGoogle Scholar
- 19.Pai RK, Jayachandran P, Koong AC et al (2012) BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: an aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features. Am J Surg Pathol 36:744–752. https://doi.org/10.1097/PAS.0b013e31824430d7 CrossRefPubMedGoogle Scholar
- 21.Sinicrope FA, Mahoney MR, Smyrk TC, Thibodeau SN, Warren RS, Bertagnolli MM, Nelson GD, Goldberg RM, Sargent DJ, Alberts SR (2013) Prognostic impact of deficient DNA mismatch repair in patients with stage iii colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol 31:3664–3672. https://doi.org/10.1200/JCO.2013.48.9591 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Yokota T, Ura T, Shibata N, Takahari D, Shitara K, Nomura M, Kondo C, Mizota A, Utsunomiya S, Muro K, Yatabe Y (2011) BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer 104:856–862. https://doi.org/10.1038/bjc.2011.19 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Modest DP, Ricard I, Heinemann V, Hegewisch-Becker S, Schmiegel W, Porschen R, Stintzing S, Graeven U, Arnold D, von Weikersthal LF, Giessen-Jung C, Stahler A, Schmoll HJ, Jung A, Kirchner T, Tannapfel A, Reinacher-Schick A (2016) Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group. Ann Oncol 27:1746–1753. https://doi.org/10.1093/annonc/mdw261 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Gonsalves WI, Mahoney MR, Sargent DJ, Nelson GD, Alberts SR, Sinicrope FA, Goldberg RM, Limburg PJ, Thibodeau SN, Grothey A, Hubbard JM, Chan E, Nair S, Berenberg JL, McWilliams R, Alliance for Clinical Trials in Oncology (2014) Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147. JNCI: J Natl Cancer Inst 106. https://doi.org/10.1093/jnci/dju106
- 25.Price TJ, Hardingham JE, Lee CK, Weickhardt A, Townsend AR, Wrin JW, Chua A, Shivasami A, Cummins MM, Murone C, Tebbutt NC (2011) Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J Clin Oncol 29:2675–2682. https://doi.org/10.1200/JCO.2010.34.5520 CrossRefPubMedGoogle Scholar
- 26.Seligmann JF, Fisher D, Smith CG, Richman SD, Elliott F, Brown S, Adams R, Maughan T, Quirke P, Cheadle J, Seymour M, Middleton G (2016) Investigating the poor outcomes of BRAF -mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials. Ann Oncol mdw645. https://doi.org/10.1093/annonc/mdw645
- 27.Benedix F, Kube R, Meyer F et al (2010) Colon/Rectum Carcinomas (Primary Tumor) Study Group. Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum 53:57–64. https://doi.org/10.1007/DCR.0b013e3181c703a4. CrossRefPubMedGoogle Scholar
- 33.Taieb J, Zaanan A, Le Malicot K et al (2016) Prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without cetuximab: a post hoc analysis of the PETACC-8 trial. JAMA Oncol 2:643. https://doi.org/10.1001/jamaoncol.2015.5225 CrossRefGoogle Scholar
- 39.Hara M, Kanemitsu Y, Hirai T, Komori K, Kato T (2008) Negative serum carcinoembryonic antigen has insufficient accuracy for excluding recurrence from patients with Dukes C colorectal cancer: analysis with likelihood ratio and posttest probability in a follow-up study. Dis Colon Rectum 51:1675–1680. https://doi.org/10.1007/s10350-008-9406-1 CrossRefPubMedGoogle Scholar
- 42.Barault L, Charon-Barra C, Jooste V, de la Vega MF, Martin L, Roignot P, Rat P, Bouvier AM, Laurent-Puig P, Faivre J, Chapusot C, Piard F (2008) Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. Cancer Res 68:8541–8546. https://doi.org/10.1158/0008-5472.CAN-08-1171 CrossRefPubMedGoogle Scholar
- 43.Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, Taylor G, Barrett JH, Quirke P (2009) KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 27:5931–5937. https://doi.org/10.1200/JCO.2009.22.4295 CrossRefPubMedGoogle Scholar
- 44.Dahlin AM, Palmqvist R, Henriksson ML, Jacobsson M, Eklof V, Rutegard J, Oberg A, van Guelpen BR (2010) The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status. Clin Cancer Res 16:1845–1855. https://doi.org/10.1158/1078-0432.CCR-09-2594 CrossRefPubMedGoogle Scholar
- 45.Tie J, Gibbs P, Lipton L, Christie M, Jorissen RN, Burgess AW, Croxford M, Jones I, Langland R, Kosmider S, McKay D, Bollag G, Nolop K, Sieber OM, Desai J (2011) Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAFV600E mutation. Int J Cancer 128:2075–2084. https://doi.org/10.1002/ijc.25555 CrossRefPubMedGoogle Scholar
- 46.Tian S, Simon I, Moreno V, Roepman P, Tabernero J, Snel M, van’t Veer L, Salazar R, Bernards R, Capella G (2013) A combined oncogenic pathway signature of BRAF , KRAS and PI3KCA mutation improves colorectal cancer classification and cetuximab treatment prediction. Gut 62:540–549. https://doi.org/10.1136/gutjnl-2012-302423 CrossRefPubMedGoogle Scholar
- 47.Lochhead P, Kuchiba A, Imamura Y, Liao X, Yamauchi M, Nishihara R, Qian ZR, Morikawa T, Shen J, Meyerhardt JA, Fuchs CS, Ogino S (2013) Microsatellite instability and BRAF mutation testing in colorectal Cancer prognostication. JNCI: Journal of the National Cancer Institute 105:1151–1156. https://doi.org/10.1093/jnci/djt173 CrossRefPubMedPubMedCentralGoogle Scholar
- 48.Li HT, Lu YY, An YX et al (2011) KRAS, BRAF and PIK3CA mutations in human colorectal cancer: relationship with metastatic colorectal cancer. Oncol Rep. https://doi.org/10.3892/or.2011.1217
- 49.Nakanishi R, Harada J, Tuul M, Zhao Y, Ando K, Saeki H, Oki E, Ohga T, Kitao H, Kakeji Y, Maehara Y (2013) Prognostic relevance of KRAS and BRAF mutations in Japanese patients with colorectal cancer. Int J Clin Oncol 18:1042–1048. https://doi.org/10.1007/s10147-012-0501-x CrossRefPubMedGoogle Scholar