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

• Published in: Journal of clinical oncology Vol. 28; no. 3; pp. 466 - 474
• Main Authors: ROTH, Arnaud D, TEJPAR, Sabine, ARANDA, Enrique, NORDLINGER, Bernard, CISAR, Laura, LABIANCA, Roberto, CUNNINGHAM, David, VAN CUTSEM, Eric, BOSMAN, Fred, DELORENZI, Mauro, PU YAN, FIOCCA, Roberto, KLINGBIEL, Dirk, DIETRICH, Daniel, BIESMANS, Bart, BODOKY, György, BARONE, Carlo
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 20.01.2010
• Subjects: Adenocarcinoma - diagnosis; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adolescent; Adult; Aged; Biological and medical sciences; Colonic Neoplasms - diagnosis; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Male; Medical sciences; Middle Aged; Mutation; Prognosis; Prospective Studies; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Young Adult; Prognosis; Surgical resection; Early stage; Malignant tumor; Genetic translation; Colonic disease; K ras Gene; BRAF Gene; Colon cancer; Cancerology; Treatment; Surgery; C-Onc gene; Digestive diseases; Intestinal disease; Clinical trial; Locally advanced stage; Protooncogene; Cancer; European Organization for Research and Treatment of Cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2009.23.3452

Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting. Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models. KRAS and BRAF tumor mutation rates were 37.0% and 7.9%, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P < 10(-4)). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003). In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.