Colorectal Cancer (CRC) Tests

NEW CLINICAL STUDY FOR COLORECTAL CANCER PATIENTS-

 FWCC Bulletin - Patient Information Sheet

The uridine-diphosphoglucuronosyl transferase (UGT) superfamily is a detoxification pathway.  Single nucleotide polymorphisms (SNPs) have recently been identified in the UGT 1 subfamily, and specifically, the UGT 1A1 gene.  Polymorphisms in this gene lead to a reduced production of the enzymes necessary to metabolize certain compounds, thus, leaving the individual susceptible to toxicity from certain metabolites.  This is exactly the case in the widely used chemotherapeutic agent, Irinotecan (Camptosar, Pfizer), which is used in the treatment of colorectal cancer.

Iriniotecan has been best established as a treatment for metastatic colorectal cancer.  It is derived from a class of therapeutic agents, camptothecins, which interact specifically with the enzyme topoisomerase I and prevent religation of DNA single-strand breaks.  Often, irinotecan is used as a first line treatment option in combination with other drugs such as fluouracil and leucovorin.  It can also be used as a second line monotherapy.  There is sufficient data supporting irinotecan as an effective chemotherapeutic agent; however, it can also cause severe side effects, particularly, in individuals with a UGT1A1 polymorphism.  This polymorphism leads to a deficiency in the enzymes essential for the metabolism and excretion of the active metabolite of irinotecan, SN-38.  As a result, SN-38 is not inactivated in the liver.   When it becomes present in the small bowel, it often produces side effects, the most significant being severe diarrhea.

As much as 10% of the patients with colorectal cancer are homozygous for UGT1A1*28 polymorphism. Of this group, 50% are at risk of toxicity from treatment with irinotecan (reference).  In addition, 40% of these patients are heterozygous for the polymorphism, causing as many as 12.5% to be at risk.   The most at-risk population is the 10% who are homozygous and who are even more susceptible to severe, adverse and potentially life- threatening side effects.  A combination of severe diarrhea and neutropenia can lead to severe morbidity and toxic death.  Other symptoms accompanying the diarrhea may include cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping.

Pharmacogenomics has become increasingly important as new drug therapies rapidly become available on the market.  In reference to irinotecan, identifying colorectal cancer patient populations who have the UGT1A1 polymorphism is of significant importance.  Just recently, irinotecan labeling was updated to include dosing recommendations based on a patient’s UGT1A1 status.  Also, the starting dose in UGT1A1*28 homozygous individuals has been reduced by at least one level.  Hence, by screening for the UGT1A1 polymorphism, we can identify patients who are at increased risk for severe toxicity to the drug, and can subsequently select a safer, more appropriate chemotherapeutic dosage or alternative drug treatments.

      Our main objective is therefore to institute and utilize a patient screening process to identify patients who          are at risk of experiencing side effects from treatment with Irinotecan and stratify therapy for these patients. 

This research will be done through molecular chip technology on an automated platform for reproducible and sensitive results. 

The goal of this study is to address the following specific aims:

 

·        Identify patients who have the UGT1A1 polymorphism

·        Provide therapeutic counseling for these patients in an effort to offer the safest, most effective chemotherapeutic agent

·        Perform DNA mutation analysis for the UGT1A1 mutation using PCR and SNP detection

·        Retain DNA on candidate patients for larger spectrum UGT1A1 screening when available or other pharmacogenomic endpoints