Impact of heterozygous UGT1A1*28 genotype on toxicity, dose-intensity and treatment compliance in pancreatic cancer patients receiving FOLFIRINOX/mFOLFIRINOX.

Abstract

698 Background: Pancreatic cancer remains the deadliest solid tumor because of late-stage presentation, intrinsic chemoresistance and rapid tumor doubling time. FOLFIRINOX/mFOLFIRINOX regimens improve outcomes, but are limited by frequent hematologic, neurologic and gastrointestinal toxicities. Irinotecan (CPT-11), a key drug, is inactivated by hepatic glucuronidation through UGT1A1; common polymorphisms reduce enzymatic activity, prompting dose reductions in patients with biallelic loss of function. Current clinical practice recommends full-dose CPT-11 for heterozygous carriers, yet the safety profile of this subgroup remains unclear. Methods: We retrospectively analyzed 137 pancreatic cancer patients treated with FOLFIRINOX/mFOLFIRINOX from 2011 to 2024 in our center. Only 47 had documented UGT1A1*28 status (2 homozygous for UGT1A1*28 – ultimately not included in the final analysis, 32 heterozygous, 13 wild-type). Toxicities (nausea, neutropenia, anemia, thrombocytopenia, diarrhea, neurotoxicity) were graded per NCI-CTCAE v5.0; dose-intensity for each drug during the first four cycles was calculated. Association between categorical variables was assessed by Fisher-exact test and χ² test. Association between numerical and categorical variables was assessed by Mann-Whitney test (two-tailed p < 0.05). Results: CPT-11 exposure was significantly lower in heterozygous patients (median dose 113 mg/m²) than in wild-type ones (median dose 147 mg/m²) (p = 0.0074). No significant differences were observed for 5-fluorouracil (p = 0.86) or oxaliplatin (p = 0.84) dose-intensity. Trends towards earlier toxicity onset were noted in heterozygous patients for diarrhea, neurotoxicity, anemia, neutropenia and thrombocytopenia, though these did not reach statistical significance. However, a statistically significant association between UGT1A1*28 status and the worst-grade anemia observed (χ² = 12.229, df = 3, p = 0.0066) was demonstrated, with a significant trend toward higher anemia grades in heterozygous patients (χ² for trend = 10.769, df = 1, p = 0.0010). Specifically, all heterozygous patients presented anemia, ranging from grades 1 to 3, whereas wild-type patients exhibited either normal serum hemoglobin values or anemia limited to grades 1–2. Conclusions: Even in the absence of homozygous for UGT1A1*28 patients, heterozygous UGT1A1*28 carriers showed significantly reduced CPT-11 dose-intensity, a significantly higher burden of anemia severity and a trend toward an overall earlier onset of toxicities. These findings might encourage prospective dose-adjustment algorithms to incorporate heterozygous UGT1A1 genotypes to improve tolerability without compromising efficacy. Prospective evaluation in larger cohorts is prompted.