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Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer
Author(s) -
da Cunha Santos Gilda,
Dhani Neesha,
Tu Dongsheng,
Chin Kayu,
Ludkovski Olga,
KamelReid Suzanne,
Squire Jeremy,
Parulekar Wendy,
Moore Malcolm J.,
Tsao Ming Sound
Publication year - 2010
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.25393
Subject(s) - kras , erlotinib , hazard ratio , medicine , gemcitabine , oncology , pancreatic cancer , gefitinib , polysomy , cancer , erlotinib hydrochloride , fluorescence in situ hybridization , epidermal growth factor receptor , tyrosine kinase inhibitor , confidence interval , biology , colorectal cancer , genetics , gene , chromosome
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.