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Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer
National Cancer Institute of Canada Clinical Trials Group Study PA.3
Article first published online: 7 SEP 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 24, pages 5599–5607, 15 December 2010
How to Cite
da Cunha Santos, G., Dhani, N., Tu, D., Chin, K., Ludkovski, O., Kamel-Reid, S., Squire, J., Parulekar, W., Moore, M. J. and Tsao, M. S. (2010), Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer. Cancer, 116: 5599–5607. doi: 10.1002/cncr.25393
- Issue published online: 3 DEC 2010
- Article first published online: 7 SEP 2010
- Manuscript Accepted: 23 MAR 2010
- Manuscript Revised: 6 MAR 2010
- Manuscript Received: 3 DEC 2009
- pancreatic neoplasms;
- protein kinase inhibitors;
- epidermal growth factor receptor genes;
- DNA mutational analysis;
- in situ hybridization;
National Cancer Institute of Canada Clinical Trials Group PA.3 (NCIC CTG PA.3) was a phase 3 study (n = 569) that demonstrated benefits for overall survival and progression-free survival with the addition of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib to gemcitabine in patients with advanced pancreatic carcinoma (APC). Mutation status of the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and EGFR gene copy number (GCN) were evaluated as predictive markers in 26% of patients who had tumor samples available for analysis.
KRAS mutation status was evaluated by direct sequencing of exon 2, and EGFR GCN was determined by fluorescence in situ hybridization (FISH) analysis. The results were correlated with survival, which was the primary endpoint of the trial.
KRAS analysis was successful in 117 patients, and EGFR FISH analysis was successful in 107 patients. KRAS mutations were identified in 92 patients (78.6%), and EGFR amplification or high polysomy (FISH-positive results) was identified in 50 patients (46.7%). The hazard ratio of death between gemcitabine/erlotinib and gemcitabine/placebo was 0.66 (95% confidence interval [CI], 0.28-1.57) for patients with wild-type KRAS and 1.07 (95% CI, 0.68-1.66) for patients with mutant KRAS (P value for interaction = .38), and the hazard ratio was 0.6 (95% CI, 0.34-1.07) for FISH-negative patients and 0.90 (95% CI, 0.49-1.65) for FISH-positive patients (P value for interaction = .32).
In a molecular subset analysis of patients from NCIC CTG PA.3, EGFR GCN and KRAS mutation status were not identified as markers predictive of a survival benefit from the combination of erlotinib with gemcitabine for the first-line treatment of APC. Cancer 2010. © 2010 American Cancer Society.