Journal Article

Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability and CIMP status: Prognostic implications and response to chemotherapy

Zapater, Pedro, Castells, Antoni, Yuste, Ana, Alustiza, Miren, Alenda, Cristina, Mangas-Sanjuan, Carolina, Clofent, Joan, Bujanda, Luís, Jover, Rodrigo, Castillejo, Adela, Hernández-Illán, Eva, Giner-Calabuig, Mar, Juárez, Míriam, Egoavil, Cecilia, Barberá, Víctor, Murcia, Oscar, Llor, Xavier, Rodríguez-Soler, María, Andreu, Montserrat

2018

Overview

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. 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). 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). 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Aged / Antimetabolites, Antineoplastic - therapeutic use / Biology and life sciences / Biomarkers, Tumor - genetics / Biomarkers, Tumor - metabolism / Cancer / Cancer therapies / Care and treatment / Chemotherapy / Classification / Clinical medicine / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - classification / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Colorectal Neoplasms - metabolism / CpG Islands / Deoxyribonucleic acid / DNA / DNA Methylation / Female / Fluorouracil - therapeutic use / Gastroenterology / Gene expression / Gene mutation / Genetic aspects / Genotype & phenotype / Hospitals / Humans / K-Ras protein / Laboratories / Male / Medical prognosis / Medicine and Health Sciences / Microsatellite Instability / Microsatellites / Middle Aged / Multivariate analysis / Mutation / Neoplasm Staging / Observational studies / Patients / Phenotypes / Physical Sciences / Population studies / Prognosis / Proto-Oncogene Proteins B-raf - genetics / Proto-Oncogene Proteins p21(ras) - genetics / Research and Analysis Methods / Retrospective Studies / Sex / Stability / Systematic review / Tumors