Prospective Study to Identify Molecular Mechanisms of Clinical Resistance to Standard First-line Therapy in Patients With Metastatic Colorectal Cancer
The major obstacle to the cure of cancer by pharmacological agents is resistance to these
agents. Clinical responses of metastatic cancers to the most advanced chemotherapeutic
agents usually range from 15 to 40%, indicating that intrinsic resistance, and acquired
resistance occurs almost inevitably in those tumors that do respond. In patients with
metastatic colorectal cancer, clinical resistance to a particular treatment is a clear
endpoint (tumor growth), and is usually observed within 6-12 months of any given therapy.
Thus, drug resistance and selecting appropriate therapeutic alternatives for drug-resistant
cancer remain major dilemmas for oncologists.
The current first-line treatment for metastatic colorectal cancer in Quebec and much of
North America is a combination called FOLFOX (the fluoro-pyrimidine 5-FU given as a 46-hour
infusion, folinic acid and oxaliplatin) in combination with bevacizumab (Avastin®). An
alternative regimen of cytotoxic drugs, also used with Avastin®, is FOLFIRI, which simply
replaces oxaliplatin with the topoisomerase inhibitor irinotecan. In the metastatic setting,
studies have not demonstrated significant differences between the two regimens, such that
decision-making lacks definitive tools.
The objective of this study is to identify, in clinical samples, the molecular signature of
clinically resistant colorectal cancer (CRC) patients for the most current and commonly used
therapeutic agents. The goals of this study are two-fold. First, to build a biobank of blood
and tissue specimens, prior to starting chemotherapy and at a determined time-point
(progression of disease), from patients undergoing the same standard and well established
first-line treatments (FOLFOX/bevacizumab or FOLFIRI/bevacizumab) for metastatic colorectal
cancer. Second, to use state-of-the-art approaches by various collaborating laboratories to
correlate clinical outcomes with molecular events that can be used to predict and
Observational Model: Case-Only, Time Perspective: Prospective
Changes in biomarkers in patients that have acquired clinical resistance.
Liver needle core biopsies are obtained pre-treatment and at progression of disease from all patients. These are used to discover exploratory biomarkers of resistance to FOLFOX/bevacizumab.
Gerald Batist, MD
Jewish General Hospital, Segal Cancer Center
Canada: Health Canada