UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

Abstract

Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments.

Impact of UGT1A1 Polymorphisms on Febrile Neutropenia in Pancreatic Cancer Patients Receiving FOLFIRINOX: A Single-Center Cohort Study

“…EMs were found in 46.1% of patients. Our data are generally in accordance with those reported by the CPIC guidelines, which showed that the prevalence of PMs, IMs, and EMs is 8%, 42%, and 50%, respectively, in East Asians [22].…”

Real-World Evaluation of Universal Germline Screening for Cancer Treatment-Relevant Pharmacogenes

“…Consistent with the expected American/European population frequency, UGT1A1 variants were common (157/291, 54%). UGT1A1 genotype status impacts irinotecan metabolism, often indicated for front-line treatment of gastrointestinal malignancies [ 14 , 15 ]. Over half (45/86, 52.3%) of the patients who could potentially receive irinotecan as a component of an NCCN “preferred” regimen harbored a UGT1A1 variant.…”

“…Though variant-associated toxicity is established for TPMT [ 17 ], UGT1A1 [ 15 ], and DPYD [ 16 ] intermediate and poor metabolizers, testing is not routinely performed and clinical management guidelines for dosing are inconsistent. This is likely related to logistical barriers, lack of clinical utility, and cost associated with routine pharmacogenomic screening [ 7 , 11 ].…”

“…The oncology community has hesitated to initiate lower fluoropyrimidine doses for patients with DPYD variants and lower irinotecan doses for UGT1A1 intermediate metabolizers because not all poor and intermediate metabolizers experience toxicity [ 15 , 16 , 24 ] and treating with a lower dose may decrease the drug’s therapeutic efficacy [ 24 ]. In fact, recent research demonstrated genotype-directed irinotecan dosing resulted in improved pathologic complete responses and decreased irinotecan-related toxicity for UGT1A1 intermediate metabolizers (*1/*28) undergoing neoadjuvant chemoradiation for locally advanced rectal cancer [ 25 ].…”

Cancer Pharmacogenetics: perspective on newly discovered and implemented predictive biomarkers

“…A similar mechanism has been also observed for pazopanib, a TKI for patients with advanced renal cell carcinoma. UGT1A1*28 patients should be monitored for higher adverse reaction risk(26). The same drug treatment can promote deregulation of liver enzymes levels in patients carrying the HLB*5701 variant and should carefully followed-up…”