Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability and CIMP status: Prognostic implications and response to chemotherapy
Por:
Murcia, O, Juarez, M, Rodriguez-Soler, M, Hernandez-Illan, E, Giner-Calabuig, M, Alustiza, M, Egoavil, C, Castillejo, A, Alenda, C, Barbera, V, Mangas-Sanjuan, C, Yuste, A, Bujanda, L, Clofent, J, Andreu, M, Castells, A, Llor, X, Zapater, P and Jover, R
Publicada:
6 sep 2018
Ahead of Print:
6 sep 2018
Resumen:
Objective
The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype's response to chemotherapy.
Design
This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS).
Results
Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P < 0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05-2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P < 0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24-3.44, P = 0.005).
Conclusion
We confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy.
Filiaciones:
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Hosp Gen Univ Alicante, Inst Invest Sanitaria ISABIAL, Serv Med Digest, Alicante, Spain
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Hosp Gen Univ Alicante, Unidad Invest, Inst Invest Sanitaria ISABIAL, Alicante, Spain
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Hosp Gen Univ Alicante, Inst Invest Sanitaria ISABIAL, Serv Med Digest, Alicante, Spain
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Hosp Gen Univ Alicante, Unidad Invest, Inst Invest Sanitaria ISABIAL, Alicante, Spain
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Hosp Gen Univ Alicante, Unidad Invest, Inst Invest Sanitaria ISABIAL, Alicante, Spain
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Hosp Gen Univ Alicante, Unidad Invest, Inst Invest Sanitaria ISABIAL, Alicante, Spain
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Hosp Gen Univ Alicante, Unidad Invest, Inst Invest Sanitaria ISABIAL, Alicante, Spain
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Hosp Gen Univ Elche, Mol Genet Lab, Inst Invest Sanitaria ISABIAL, Alicante, Spain
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Hosp Gen Univ Alicante, Dept Pathol, Inst Invest Sanitaria ISABIAL, Alicante, Spain
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Hosp Gen Univ Elche, Mol Genet Lab, Inst Invest Sanitaria ISABIAL, Alicante, Spain
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Hosp Gen Univ Alicante, Inst Invest Sanitaria ISABIAL, Serv Med Digest, Alicante, Spain
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Hosp Gen Univ Alicante, Oncol Dept, Inst Invest Sanitaria ISABIAL, Alicante, Spain
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Univ Basque Country, UPV EHU, Gastroenterol Unity, Hosp Donostia,Inst Biodonostia,CIBERehd, San Sebastian, Spain
Clofent, J:
Hosp Sagunto, Gastroentyerol Unit, Sagunto, Spain
Andreu, M:
Hosp del Mar, Gastroenterol Unit, IMIM Inst Hosp del Mar Invest Med, Barcelona, Spain
Castells, A:
Univ Barcelona, Hosp Clin, Gastroenterol Unit, IDIBAPS,CIBERehd, Barcelona, Spain
Llor, X:
Yale Univ, Sect Digest Dis, Yale New Haven Hosp, New Haven, CT USA
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Hosp Gen Univ Alicante, Inst Invest Sanitaria ISABIAL, Clin Pharmacol Dept, Alicante, Spain
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Hosp Gen Univ Alicante, Inst Invest Sanitaria ISABIAL, Serv Med Digest, Alicante, Spain
gold, Green Published, Green Submitted
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