UGT1A1 Biomarker

The UGT1A1 gene is present in each of the cells in our body. The UGT1A1 gene provides instructions for making a protein called UDP glucuronosyltransferases. The normal (wild type) protein is an enzyme that is most active in the liver and breaks down irinotecan.

Irinotecan is a chemotherapy drug commonly used to treat metastatic colorectal cancer, either alone or in combination as FOLFIRI, FOLFIRINOX, or with cetuximab. Irinotecan is converted in the body to a toxic molecule that kills cancer cells. If the active, toxic molecule is not removed from the body fast enough, it will attack normal healthy cells and could destroy the liver and other tissues. Patients with a UGT1A1 mutation cannot convert irinotecan’s active and toxic ingredient to a non-toxic form which can be eliminated. This can lead to severe toxicity (especially liver toxicity). The most common and studied mutation, UGT1A1*28, is only 30% active compared to the normal enzyme.

Testing for UGT1A1 mutations is not required. Patients usually get tested after experiencing severe toxicity during treatment with FOLFIRI, FOLFIRINOX, or irinotecan alone. Warnings about toxicity can be found on the FDA-approved drug label.

Every treatment has the potential to cause some side effects. Some people may be more sensitive to a drug than others. If you are experiencing severe side effects during treatment with irinotecan, FOLFIRI, or FOLFIRINOX, call your doctor immediately. You should discuss pharmacogenetic testing with your doctor. Results will show if you have a UGT1A1 gene mutation that puts you at risk for severe toxicity or side effects.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend dose reduction based on the type of UGT1A1 mutation or enzyme activity. Some patients may have mutations in both DPYD and UGT1A1. If you have mutations in both genes, you and your doctor can decide the best treatment plan that will be effective and safe for you.

Every treatment has the potential to cause some side effects. Some people may be more sensitive than others to a particular drug. It also depends on your other treatments, medications, vitamins and herbal supplements. For example, side effects could be worse if you are treated with radiation at the same time. Your cancer drugs may also interact with vitamins and herbal supplements, which means it is dangerous to take them together. Tell your doctor and pharmacist about all of your medications, vitamins, and treatments. Call your doctor immediately if you are experiencing severe symptoms.

For more on side effects of other chemotherapy regimens, click here.