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Abstract
Pharmacogenomic testing may have clinical value in the treatment of patients with gastrointestinal malignancies such as colorectal and pancreatic cancer. These types of cancer are often treated with combination chemotherapy regimens. These regimens can lead to severe adverse effects in patients with diminished drug tolerability potentially due to certain genetic variants in the enzymes involved in the metabolism of the chemotherapies. Genetic variants resulting in decreased enzymatic activity of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and dihydropyrimidine dehydrogenase (DPD) are known to increase irinotecan and 5-fluorouracil-related toxicity, respectively. We report a case of a patient with pancreatic adenocarcinoma who was found to be not only homozygous for the UGT1A1∗28 allele, but also heterozygous for a DPYD variant through pharmacogenomic testing. Potentially severe adverse effects were prevented in this patient’s case by implementing preemptive dose reductions. On the basis of the significant implications of chemotherapy-related toxicity in this and other similar cases, we report on the clinical value of integrating pharmacogenomic testing into clinical practice to allow for preemptive and/or point-of-care dose reductions in patients potentially at risk for increased toxicity. This is even more important in an era where combinatorial triplet chemotherapies are increasingly being used.
Highlights
Pharmacogenomic testing can have significant implications for patients with gastrointestinal cancers by reducing toxicity in combination chemotherapy regimens
Combination regimens with 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin, such as FOLFIRINOX for pancreatic cancer or FOLFOXIRI for colorectal cancer, are standard of care being used by many clinicians for patients with advanced or metastatic pancreatic or colorectal cancer with good performance status (Balaban et al, 2016; Leal et al, 2017)
The dosing adjustments were implemented to prevent potentially serious toxicity-related adverse effects from 5FU and irinotecan while we awaited the results from the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and DPYD genotyping tests, which we have recently integrated into our clinical practice as a quality improvement initiative
Summary
Pharmacogenomic testing can have significant implications for patients with gastrointestinal cancers by reducing toxicity in combination chemotherapy regimens. We report a case of a patient with pancreatic adenocarcinoma who was found to be a carrier of deleterious polymorphisms in both UGT1A1 and DPYD during our recently implemented preemptive and/or point-of-care pharmacogenomics-based genetic testing platform, placing him at increased risk for chemotherapy-related toxicity. The dosing adjustments were implemented to prevent potentially serious toxicity-related adverse effects from 5FU and irinotecan while we awaited the results from the UGT1A1 and DPYD genotyping tests, which we have recently integrated into our clinical practice as a quality improvement initiative. Prior to administration of cycle 2 of the dose-adjusted FOLFIRINOX, we received the pharmacogenomic test results, which indicated that the patient is homozygous for the UGT1A1∗28 allele and an heterozygous carrier of a DPYD variant identified as c.536dupC, a no-activity allele. Clinical course so far indicates both response to the treatment and tolerability despite the deleterious polymorphisms in UGT1A1 and DPYD and the implemented dose adjustments
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