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.
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.
da Cunha Santos
Gilda
G
Department of Pathology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
Dhani
Neesha
N
Tu
Dongsheng
D
Chin
Kayu
K
Ludkovski
Olga
O
Kamel-Reid
Suzanne
S
Squire
Jeremy
J
Parulekar
Wendy
W
Moore
Malcolm J
MJ
Tsao
Ming Sound
MS
D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor / Q000032:analysis*; D002170:Canada; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D018628:Gene Dosage; D006801:Humans; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage*; D016896:Treatment Outcome; D018631:ras Proteins / Q000032:analysis / Q000235:genetics; D000093542:Gemcitabine
D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000093542:Gemcitabine