Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy?

Abstract

In patients with metastatic colorectal cancer, the predictive value of KRAS mutational status in the selection of patients for treatment with anti-epidermal growth factor (EGFR) monoclonal antibodies is established. In patients with non-small-cell lung cancer (NSCLC), the utility of determining KRAS mutational status to predict clinical benefit to anti-EGFR therapies remains unclear. This review will provide a brief description of Ras biology, provide an overview of aberrant Ras signaling in NSCLC, and summarize the clinical data for using KRAS mutational status as a negative predictive biomarker to anti-EGFR therapies. Retrospective investigations of KRAS mutational status as a negative predictor of clinical benefit from anti-EGFR therapies in NSCLC have been performed; however, small samples sizes as a result of low prevalence of KRAS mutations and the low rate of tumor sample collection have limited the strength of these analyses. Although an association between the presence of KRAS mutation and lack of response to EGFR tyrosine kinase inhibitors (TKIs) has been observed, it remains unclear whether there is an association between KRAS mutation and EGFR TKI progression-free and overall survival. Unlike colorectal cancer, KRAS mutations do not seem to identify patients who do not benefit from anti-EGFR monoclonal antibodies in NSCLC. The future value of testing for KRAS mutational status may be to exclude the possibility of an EGFR mutation or anaplastic lymphoma kinase translocation or to identify a molecular subset of patients with NSCLC in whom to pursue a drug development strategy that targets the KRAS pathway.

• Authors: Patrick J Roberts, Thomas E Stinchcombe, Channing J Der, Mark A Socinski
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 28 Issue 31 Pg. 4769-77 (Nov 01 2010) ISSN: 1527-7755 [Electronic] United States
• PMID: 20921461 (Publication Type: Journal Article, Review)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Biomarkers, Tumor
• Cell Cycle Proteins
• KRAS protein, human
• Microtubule-Associated Proteins
• Proto-Oncogene Proteins
• Quinazolines
• Deoxycytidine
• Carboplatin
• Erlotinib Hydrochloride
• ALK protein, human
• Anaplastic Lymphoma Kinase
• ErbB Receptors
• Protein-Tyrosine Kinases
• Receptor Protein-Tyrosine Kinases
• EML4 protein, human
• Serine Endopeptidases
• Proto-Oncogene Proteins p21(ras)
• ras Proteins
• Paclitaxel
• Cetuximab
• Cisplatin
• Gefitinib
• Gemcitabine

Topics

• Anaplastic Lymphoma Kinase
• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (pharmacology, therapeutic use)
• Biomarkers, Tumor (genetics, metabolism)
• Carboplatin (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism, mortality)
• Cell Cycle Proteins (genetics)
• Cetuximab
• Cisplatin (pharmacology)
• Clinical Trials as Topic
• Deoxycytidine (analogs & derivatives, pharmacology)
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Erlotinib Hydrochloride
• Gefitinib
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism, mortality)
• Microtubule-Associated Proteins (genetics)
• Mutation
• Paclitaxel (pharmacology)
• Patient Selection
• Precision Medicine
• Predictive Value of Tests
• Protein-Tyrosine Kinases (genetics)
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins p21(ras)
• Quinazolines (pharmacology)
• Receptor Protein-Tyrosine Kinases
• Serine Endopeptidases (genetics)
• Signal Transduction
• Survival Analysis
• Translocation, Genetic
• ras Proteins (genetics, metabolism)
• Gemcitabine