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

Abstract

Simple Summary FOLFIRINOX, which is a first-line chemotherapy for metastatic pancreatic cancer, has become one of the high-risk regimens related to developing febrile neutropenia (FN). Although UGT1A1 polymorphisms are associated with the metabolism of irinotecan, their role as surrogate markers for FOLFIRINOX-induced neutropenia has not been confirmed. In this retrospective study, a total of 154 patients (FN group (n = 31) vs. non-FN group (n = 123)) were divided into three groups based on the predicted UGT1A1 phenotype (extensive metabolizer (EM) vs. intermediate metabolizer (IM) vs. poor metabolizer (PM)). The Cox regression analysis showed that female sex (hazard ratio (HR): 2.20; p = 0.031), ECOG PS = 1 (HR: 2.83; p = 0.008), UGT1A1 IM (HR: 4.30; p = 0.004), and UGT1A1 PM (HR: 4.03; p = 0.028) were independent risk factor of FN. We propose UGT1A1 as the strongest predictive factor for FN and the need for UGT1A1 screening prior to chemotherapy. FOLFIRINOX (oxaliplatin, leucovorin, irinotecan, and 5-fluorouracil) is a first-line chemotherapy for metastatic pancreatic cancer (PC). Chemotherapy-induced neutropenia is one of the most serious adverse events associated with advanced PC. Although UGT1A1 polymorphisms are associated with the metabolism of irinotecan, their role as surrogate markers for FOLFIRINOX-induced neutropenia has not been confirmed. We investigated risk factors for FN-in particular, UGT1A1 polymorphisms-in PC patients receiving FOLFIRINOX, using a single-center cohort registry. To investigate the association between UGT1A1 polymorphisms and FN, we divided patients into three groups based on the predicted UGT1A1 phenotype: extensive metabolizer (EM) vs. intermediate metabolizer (IM) vs. poor metabolizer (PM). A total of 154 patients (FN group (n = 31) vs. non-FN group (n = 123)) receiving first-line FOLFIRINOX were identified between December 2017 and July 2020. The Cox regression analysis showed that female sex (HR: 2.20; p = 0.031), Eastern Cooperative Oncology Group performance status = 1 (HR: 2.83; p = 0.008), UGT1A1 IM (HR: 4.30; p = 0.004), and UGT1A1 PM (HR: 4.03; p = 0.028) were statistically significant risk factors for FN. We propose that UGT1A1 is the strongest predictive factor for FN and that this gene should be screened prior to the administration of chemotherapy.