Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer

We address the prognostic and predictive value of KRAS, PIK3CA and BRAF mutations for clinical outcomes in response to active agents in the treatment of metastatic colorectal cancer (mCRC). We determined KRAS, BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC at two institution...

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Bibliographic Details
Published in:British journal of cancer 2009-08, Vol.101 (3), p.465-472
Main Authors: SOUGLAKOS, J, PHILIPS, J, FREED, E, MEYERHARDT, J. A, SARIDAKI, Z, GEORGOULIAS, V, FINKELSTEIN, D, FUCHS, C. S, KULKE, M. H, SHIVDASANI, R. A, WANG, R, MARWAH, S, SILVER, M, TZARDI, M, SILVER, J, OGINO, S, HOOSHMAND, S, KWAK, E
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal - therapeutic use
Antibodies, Monoclonal, Humanized
Biological and medical sciences
Cancer research
Cancer therapies
Cetuximab
Chemotherapy
Class I Phosphatidylinositol 3-Kinases
Clinical outcomes
Colorectal cancer
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
Colorectal Neoplasms - mortality
Colorectal Neoplasms - pathology
Female
Gastroenterology. Liver. Pancreas. Abdomen
Growth factors
Hospitals
Humans
Male
Medical prognosis
Medical research
Medical sciences
Metastasis
Middle Aged
Molecular Diagnostics
Mutation
Neoplasm Metastasis
Oncology
Pathology
Patients
Phosphatidylinositol 3-Kinases - genetics
Predictive Value of Tests
Prognosis
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins B-raf - genetics
Proto-Oncogene Proteins p21(ras)
ras Proteins - genetics
Salvage Therapy
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Tumors
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Summary:We address the prognostic and predictive value of KRAS, PIK3CA and BRAF mutations for clinical outcomes in response to active agents in the treatment of metastatic colorectal cancer (mCRC). We determined KRAS, BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC at two institutions. All patients received 5-FU-based first-line chemotherapy and treatment outcome was analysed retrospectively. KRAS, BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%) cases, respectively. Multivariate analysis uncovered BRAF mutation as an independent prognostic factor for decreased survival (hazard ratio (HR) 4.0, 95% confidence interval (CI) 2.1-7.6). In addition, patients with BRAF-mutant tumours had significantly lower progression-free survival (PFS: HR 4.0, 95% CI 2.2-7.4) than those whose tumors that carried wild-type BRAF. Among 92 patients treated using chemotherapy and cetuximab as salvage therapy, KRAS mutation was associated with lack of response (P=0.002) and shorter PFS (P=0.09). BRAF (P=0.0005) and PIK3CA (P=0.01) mutations also predicted reduced PFS in response to cetuximab salvage therapy. These results underscore the potential of mutational profiling to identify CRCs with different natural histories or treatment responses. The adverse significance of BRAF mutation should inform patient selection and stratification in clinical trials.
ISSN:0007-0920
1532-1827
DOI:10.1038/sj.bjc.6605164