A new study published in JCO Precision Oncology has identified a relatively simple method to predict the cancer patients most likely to develop severe toxicities from chemotherapy. If doctors can identify patients who have a genetic profile suggesting they will experience toxic side effects from chemotherapy, they can alter the prescription course to balance the anti-cancer efficacy and onset of treatment-related side effects.
The study included 225 patients with gastrointestinal (GI) malignancies, such as colorectal or pancreatic cancer. Patients had received treatment with one of three chemotherapies: fluorouracil, capecitabine, or irinotecan. As fluorouracil and capecitabine come from the same class of chemotherapy, fluoropyrimidine (FP), the researchers classified these patients as receiving the same treatment.
The genetic testing process was straightforward, involving the screening for the presence of two genes. The tests included screening for dihydropyrimidine dehydrogenase (DPYD), the gene that codes for the enzyme that metabolizes FPs, and UDP glucuronosyltransferase family 1 member A1 (UGT1A1). Individuals who carry a genetic mutation in UGT1A1 experience severe toxicities from irinotecan.
Eleven patients carried a mutation in DPYD, 8 of whom received an FP. The genetic screen also revealed that 39 patients had deficiencies in metabolizing UGT1A1, and 11 of these patients received irinotecan treatment.
The feasibility of running such a genetic screen before initiating treatment was assessed, and the results were promising. The researchers calculated the turnaround time from testing until receiving results, with an average of ten days. Importantly, in more than half of the cases, results came before the first cycle of chemotherapy began, enabling early treatment adjustments.
The study uncovered promising data regarding drug-gene interaction (DGI), an instance where an individual’s genetic profile impacts how they will respond to a particular medication. In the study cohort, 16 participants had a DGI, and 11 of these patients received their results before starting chemotherapy. Importantly, this allowed 69% of patients with a DGI to have their therapeutic dose reduced to optimize the chemotherapeutic effects.
The identification of patients with a DGI significantly improved outcomes for these patients. When compared to a control cohort, the prospective DGI group experienced 27% fewer severe treatment-related adverse events. Also, patients in the prospective DGI group had to discontinue their treatment less often than those in the comparison group. This reduction in treatment discontinuation is a significant step towards improving patient outcomes and positivly impacting quality of life in cancer survivors. Finally, significantly fewer treatment modifications occurred in those identified as having a DGI.
This prospective study demonstrates the feasibility of testing for DPYD and UGT1A1 before chemotherapy, and further, shows that this screening can occur in time for doctors to modify treatment dosing appropriately. Thus, this approach for genetic testing could help inform doctors and patients on personalized and precise chemotherapy prescriptions. Optimizing doses and scheduling of chemotherapy administration could significantly impact survivorship in patients with GI cancers.
Sources: JCO Prec Oncol