Mutant KRAS Codon 12 and 13 Alleles in Patients With Metastatic Colorectal Cancer: Assessment As Prognostic and Predictive Biomarkers of Response to Panitumumab
- 20 February 2013
- journal article
- research article
- Published by American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology
- Vol. 31 (6), 759-765
- https://doi.org/10.1200/jco.2012.45.1492
Abstract
Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has demonstrated significant improvements in progression-free survival (PFS) in patients with wild-type KRAS metastatic colorectal cancer (mCRC) in studies 20050203 (first line), 20050181 (second line), and 20020408 (monotherapy). Mutations in KRAS codons 12 and 13 are recognized biomarkers that predict lack of response to anti-EGFR antibody therapies. This retrospective analysis of three randomized phase III studies assessed the prognostic and predictive impact of individual mutant KRAS codon 12 and 13 alleles. Patients were randomly assigned 1:1 to FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) in study 20050203, FOLFIRI (fluorouracil, leucovorin, and irinotecan) in study 20050181, or best supportive care in study 20020408 with or without panitumumab 6.0 mg/kg once every 2 weeks. In all, 441 (20050203), 486 (20050181), and 126 (20020408) patients with mutant KRAS codon 12 or 13 alleles were included in the analysis. No mutant KRAS allele in patients treated on the control arm emerged as a consistent prognostic factor for PFS or overall survival (OS). In addition, no mutant KRAS allele was consistently identified as a predictive factor for PFS or OS in patients receiving panitumumab treatment. Significant interactions for individual mutant KRAS alleles were observed only in study 20050203 with G13D negatively and G12V positively associated with OS in the panitumumab-containing arm. Pooled analysis indicated that only G12A was associated with a negative predictive effect on OS. In this retrospective analysis, results across three treatment regimens suggest that patients with mutant KRAS codon 12 or 13 mCRC tumors are unlikely to benefit from panitumumab therapy. Currently, panitumumab therapy should be limited to patients with wild-type KRAS mCRC.Keywords
This publication has 29 references indexed in Scilit:
- KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patientsBritish Journal of Cancer, 2011
- Randomized Phase III Study of Panitumumab With Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) Compared With FOLFIRI Alone As Second-Line Treatment in Patients With Metastatic Colorectal CancerJournal of Clinical Oncology, 2010
- Randomized, Phase III Trial of Panitumumab With Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) Versus FOLFOX4 Alone As First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME StudyJournal of Clinical Oncology, 2010
- Molecular Mechanisms of Resistance to Cetuximab and Panitumumab in Colorectal CancerJournal of Clinical Oncology, 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 TrialJournal of Clinical Oncology, 2010
- Biomarkers Predicting Clinical Outcome of Epidermal Growth Factor Receptor–Targeted Therapy in Metastatic Colorectal CancerJNCI Journal of the National Cancer Institute, 2009
- High Concordance of KRAS Status Between Primary Colorectal Tumors and Related Metastatic Sites: Implications for Clinical PracticeThe Oncologist, 2008
- Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal CancerJournal of Clinical Oncology, 2008
- Expression of Epiregulin and Amphiregulin and K-ras Mutation Status Predict Disease Control in Metastatic Colorectal Cancer Patients Treated With CetuximabJournal of Clinical Oncology, 2007
- Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal CancerJournal of Clinical Oncology, 2007