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

Authors

  • Gilda da Cunha Santos MD, PhD,

    1. Department of Pathology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
    2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
    Search for more papers by this author
  • Neesha Dhani MD,

    1. Department of Medical Oncology and Hematology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
    Search for more papers by this author
  • Dongsheng Tu PhD,

    1. National Cancer Institute of Canada Clinical Trials Group and Queen's University, Kingston, Ontario, Canada
    Search for more papers by this author
  • Kayu Chin MSc,

    1. Department of Pathology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
    Search for more papers by this author
  • Olga Ludkovski MSc,

    1. Division of Applied Molecular Oncology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
    Search for more papers by this author
  • Suzanne Kamel-Reid PhD,

    1. Department of Pathology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
    2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
    3. Division of Applied Molecular Oncology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
    Search for more papers by this author
  • Jeremy Squire PhD,

    1. Division of Applied Molecular Oncology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
    Search for more papers by this author
  • Wendy Parulekar MD,

    1. National Cancer Institute of Canada Clinical Trials Group and Queen's University, Kingston, Ontario, Canada
    Search for more papers by this author
  • Malcolm J. Moore MD,

    1. Department of Medical Oncology and Hematology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
    2. Department of Medicine, University of Toronto, Toronto, Ontario, Canada
    Search for more papers by this author
  • Ming Sound Tsao MD

    Corresponding author
    1. Department of Pathology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
    2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
    3. Division of Applied Molecular Oncology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
    • Princess Margaret Hospital, 610 University Avenue, Toronto, ON Canada M5G 2M9
    Search for more papers by this author
    • Fax: (416) 340-5517


Abstract

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.

Ancillary