Visceral crisis in a patient with pancreatic ductal adenocarcinoma with DPYD and UGT1A1 gene mutations: case report, literature review, and viewpoint

Introduction

Pancreatic cancer is currently the third leading cause of cancer related deaths in the United States (1,2). Pancreatic ductal adenocarcinoma (PDAC) is the most common type, accounting for approximately 90% of all diagnosed cases of pancreatic cancer (3). The vast majority of patients present with advanced stage disease at the time of diagnosis, largely attributable to a paucity of available strategies for early detection and high metastatic risk (4). The most common site of distant metastases from PDAC is the liver.

Current National Comprehensive Cancer Network guidelines recommend modified FOLFIRINOX (mFFX) as first line treatment of metastatic PDAC in patients with good Eastern Cooperative Oncology Group (ECOG) performance status. The mFFX regimen consists of a combination of folinic acid (leucovorin) with three chemotherapy agents: 5-fluorouracil (5-FU), irinotecan, and oxaliplatin, without the fluorouracil bolus, in order to decrease the incidence and severity of adverse events (AEs) while maintaining treatment efficacy (5,6). Indeed, a recent meta-analysis showed that the pooled rates of grade III/IV AEs were lower in the mFFX group compared to the FFX cohort (7). In this study, the reported rates of grade III/IV hematologic AEs on the mFFX regimen were as follows: neutropenia 23.1%, febrile neutropenia 4.8%, thrombocytopenia 4.8%, and anemia 5.7%. mFFX for the treatment of metastatic PDAC is typically administered in the outpatient setting. While mFFX has been the mainstay of treatment for metastatic PDAC for several years, recent data from the NAPOLI-3 trial show promising results with NALIRIFOX, which consists of liposomal irinotecan, 5-FU, leucovorin, and oxaliplatin. In this study, NALIRIFOX demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) when compared to gemcitabine and nab-paclitaxel (8). A meta-analysis and systematic review in 2024 revealed similar OS and PFS with FOLFIRINOX and NALIRIFOX as first line treatment for advanced PDAC (9). Here, we present a unique case of a patient diagnosed with metastatic PDAC complicated by visceral crisis (VC) who was urgently treated with mFFX and subsequently developed severe pancytopenia and acute encephalopathy in the setting of dihydropyrimidine dehydrogenase (DPYD) and UDP-glucuronosyltransferase 1 (UGT1A1) gene mutations. We present this case in accordance with the CARE reporting checklist (available at https://apc.amegroups.com/article/view/10.21037/apc-24-15/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

A 56-year-old Caucasian man with no smoking history and a past medical history of obesity, hyperlipidemia, and obstructive sleep apnea presented to the emergency department with shoulder pain, abdominal bloating, and fatigue for 2–3 weeks. He denied abdominal pain, nausea, vomiting, weight loss, and symptoms of obstructive jaundice. Physical exam was unremarkable. In the emergency department, he was noted to have elevated liver function tests (LFTs) with total bilirubin 1.4 mg/dL, alkaline phosphatase 242 U/L, aspartate aminotransferase (AST) 218 U/L, and alanine aminotransferase (ALT) 135 U/L. Side-by-side diagnostic and restaging imaging studies are shown in Figures 1,2. A computed tomography (CT) scan of the abdomen and pelvis revealed an ill-defined hypo-enhancing mass in the pancreatic tail measuring approximately 4.5 cm × 4.0 cm (Figure 1A) and innumerable hypodense hepatic lesions throughout the liver, with the largest lesion measuring 6.4 cm (Figure 2A).

Figure 1 CT scan of the abdomen with contrast showing a pancreatic tail mass. (A) CT scan at diagnosis showing an ill-defined hypo-enhancing mass in the pancreatic tail measuring approximately 4.5 cm × 4.0 cm (red arrows). (B) Three-month follow-up CT scan of the abdomen status post treatment with modified FOLFIRINOX demonstrates a decrease in size of the pancreatic tail mass. CT, computed tomography.

Figure 2 Staging and 3-month follow-up CT scans of the abdomen (A,B) and chest (C,D). Initial staging CT notable for (A) innumerable hypodense hepatic lesions throughout the liver and (C) multiple pulmonary nodules in bilateral lungs. Three-month follow-up CT scan status post treatment with modified FOLFIRINOX demonstrates reduction in the size and number of (B) hepatic lesions and (D) pulmonary nodules. CT, computed tomography.

An endoscopic ultrasound-guided core biopsy of the pancreatic tail mass revealed a diagnosis of moderately to poorly differentiated adenocarcinoma. Carbohydrate antigen (CA) 19-9 was elevated at 4,809 U/mL. Staging CT scan of the chest showed numerous bilateral pulmonary nodules suspicious for metastatic disease (Figure 2C). Over the next 2 days, the patient began to experience new onset severe right upper quadrant pain. Laboratory studies demonstrated rapidly rising LFTs with total bilirubin notably increased to 2.4 times the upper limit of normal without evidence of biliary tract obstruction or history of Gilbert syndrome. These findings, along with significantly high metastatic disease burden in the liver, raised suspicion for VC. The patient was promptly started on first line mFFX in the inpatient setting.

On Cycle 1 Day 7 of mFFX, the patient became acutely encephalopathic with persistent pancytopenia out of proportion to what is typically expected with mFFX induced myelosuppression (Table 1). A magnetic resonance imaging (MRI) of the brain was normal. Given the rapid development of hematologic abnormalities with unexplained and abrupt neurologic changes, there was high clinical suspicion for a thrombotic microangiopathy (TMA) syndrome such as thrombotic thrombocytopenic purpura (TTP). Empiric treatment for TTP was initiated with therapeutic plasma exchange and glucocorticoids. The patient completed five sessions of plasma exchange with clinical improvement, however, ADAMTS13 activity returned at 22% with a negative inhibitor screen, excluding TTP. In addition, metabolic testing for DPYD and UGT1A1 gene mutations were obtained when the patient became acutely encephalopathic with severe pancytopenia. The results revealed that the patient has a heterozygous variant of the DPYD gene and is homozygous positive for the UGT1A1*28 decreased function allele, leading to delayed metabolism and heightened toxicity of 5-FU and irinotecan, respectively. The patient improved clinically with count recovery, and he was eventually discharged in stable condition with outpatient follow-up. In the outpatient setting, 5-FU was dose reduced to 50% and irinotecan to 60% in subsequent cycles of mFFX.

The patient continued treatment with dose reduced mFFX. At his 3-month follow-up visit, he reported feeling better overall with improvement in appetite and stable weight. Follow up CT scan of the chest, abdomen, and pelvis showed a decrease in size of the pancreatic tail mass (Figure 1B) as well as reduced hepatic and pulmonary metastases (Figure 2B,2D). Informed consent was obtained from the patient to publish this case report.

Discussion

In our patient case scenario, he was found to have a pancreatic tail mass with extensive liver lesions suspicious for and eventually confirmed to be metastatic PDAC. In addition, the development of right upper quadrant pain and rapidly rising LFTs raised concern for VC. VC has been well described and studied in metastatic breast cancer, but seldomly reported in gastrointestinal malignancies (10,11). According to the 5^th European School of Oncology-European Society for Medical Oncology (ESO-ESMO) guidelines, VC is defined as “severe organ damage, as assessed by signs and symptoms, laboratory studies, and rapid progression of disease that causes organ compromise leading to a clinical indication for the most rapidly efficacious therapy” (12). Presence of VC confers a poor prognosis and significantly lower OS (13). Thus, early recognition and prompt initiation of systemic therapy is of utmost importance (14). In our case, the patient was immediately started on inpatient mFFX given the life-threatening nature of VC.

The patient tolerated mFFX well until Cycle 1 Day 7, when he became acutely altered with pancytopenia out of proportion to what is typically expected with myelosuppression in the setting of recent mFFX administration. Overall, the incidence of grade III/IV cytopenia with mFFX was fairly low. One study showed that approximately 16.4% of patients with solid tumors undergoing chemotherapy experienced grade III/IV thrombocytopenia (15). Initially, there was high clinical suspicion for TTP, possibly induced by oxaliplatin (16). He was empirically started on therapeutic plasma exchange and completed a total of five sessions with clinical improvement. However, ADAMTS13 activity returned at 22% with a negative inhibitor screen, which was inconsistent with TTP.

Given the degree of pancytopenia status post mFFX, another diagnostic consideration was the presence of metabolic deficiencies that can lead to increased toxicity with certain chemotherapy regimens. Dihydropyridimine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolic pathway of 5-FU and is encoded by the DPYD gene (Figure 3A) (17,18). It is well documented that DPD deficiency can lead to severe toxicities in patients who receive 5-FU (19), including mucositis, granulocytopenia, neuropathy, ataxia, and diarrhea. In one study, up to 43% of patients who experienced toxicity following treatment with 5-FU were found to be deficient in the DPYD gene (19). Symptoms associated with DPD deficiency have been described as a pharmacogenetic syndrome with significant phenotypic variability. Mental status and neurologic changes have been documented as the most prominent feature (20). Patients with DPD deficiency can present with acute encephalopathy and should be a diagnostic consideration in patients who develop altered mental status after receiving 5-FU. Saif et al. presented a case describing a patient with metastatic PDAC who developed severe thrombocytopenia, coagulopathy, and neurologic complications and was subsequently found to have DPD deficiency (21). Another well-known mutation that affects chemotherapy metabolism is seen in the UGT1A1 enzyme, which inactivates the active metabolite of irinotecan (Figure 3B). The presence of a polymorphism in UGTIA1, specifically UGT1A1*28, UGT1A1*93, and UGT1A1*6, have been shown to harbor a greater susceptibility to gastrointestinal and bone marrow toxicities in patients receiving irinotecan (22,23).

Figure 3 Schematic of DPD and UGT1A1 metabolism. (A) Schematic of 5-FU metabolism in normal DPD and DPD deficiency. During normal 5-FU metabolism, DPD breaks down the majority of 5-FU via the catabolic pathway with only a small portion of 5-FU being shunted towards the uracil anabolism pathway. In the case of DPD deficiency, the majority of 5-FU undergoes uracil anabolism, which leads to increased DNA and RNA damage and severe toxicities. (B) Schematic of irinotecan metabolism in the case of normal UGT1A1 and mutated UGT1A1. Irinotecan is metabolized into its active metabolite SN-38 by CES. SN-38 is subsequently inactivated into its glucuronide conjugate, SN-38G, by UGT1A1. When UGT1A1 is mutated, SN-38 and irinotecan build up and results in severe cytotoxicity. DPD, dihydropyridimine dehydrogenase; 5-FU, 5-fluorouracil; FdUMP, 5-fluorodeoxyuridine monophosphate; UGT1A1, UDP-glucuronosyltransferase 1; CES, carboxylesterases; SN-38, 7-ethyl-10hydroxycamptothecin.

Remarkably, our patient harbored both a heterozygous variant of the DPYD gene and was homozygous positive for the UGT1A1*28 decreased function allele. Thus, it is likely that the presence of these mutations delayed metabolism of 5-FU and irinotecan, leading to increased AEs. Our patient experienced significant tumor reduction in his 3-month follow-up CT scans status post treatment (Figures 1,2). This striking response was likely due to simultaneous drug metabolism defects and delayed clearance of chemotherapy. Metabolic deficiencies should be considered in the differential diagnosis in patients who develop altered mental status, AEs out of proportion to what is expected with a chemotherapy regimen, and/or significant myelosuppression.

Due to the clinical impact of metabolic deficiencies, clinicians have long debated the utility in screening prior to the administration of chemotherapy (24,25). In the United States, current guidelines do not recommend routine screening prior to initiation of chemotherapy. Current Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide fluoropyrimidine drug dosing recommendations for normal, intermediate, and poor metabolizers of DPYD based on the DPYD activity score (26). Poor metabolizers with a gene activity score of zero are recommended to avoid 5-FU agents and prodrugs while intermediate metabolizers with a gene activity score of 1–1.5 typically receive a 50% reduction of the standard dose (23,24). Similarly, several studies have evaluated tolerable doses of irinotecan in patients harboring UGT1A1 gene mutations. A recent retrospective study in Japan involving 63 patients with metastatic colorectal cancer revealed that a dose reduction of irinotecan by 20% was safe and efficacious in patients with a homozygous mutation in UGT1A1 genes (27). In a multicenter, prospective study evaluating UGT1A1 genotype-guided dosing of irinotecan, patients who were homozygous variant carriers and poor metabolizers of UGT1A1 received an initial 30% dose reduction of irinotecan, resulting in a significant decrease in the incidence of febrile neutropenia while maintaining therapeutic effectiveness (28). Despite extensive research on metabolite deficiencies, well-defined dosing guidelines and recommendations have not yet been established.

Guidelines for routine, pre-treatment metabolite deficiency testing vary. In Europe, it is standard of care to obtain DPD deficiency testing prior to the initiation of chemotherapy. In 2020, the European Medicines Agency (EMA) recommended pre-treatment DPD testing using either phenotyping with endogenous uracil concentrations or genotyping for DPYD risk variant alleles in patients who will receive 5-FU or other fluoropyrimidine regimens (29,30). In the United States, it is not standard of practice to screen for metabolite deficiencies prior to initiation of chemotherapy. Nonetheless, a subset of patients should be considered for initial metabolite testing. Prior to initiation of mFFX, it is important to query a patient’s history of hyperbilirubinemia, as this can be an indicator of Gilbert syndrome and potential sensitivity to irinotecan (31). In addition, a history of drug sensitivity can be another indicator of metabolite deficiency. Drawing from the experience with our patient, we recommend obtaining metabolic deficiency testing during the first cycle of treatment for any chemotherapy-related AEs out of proportion to what is typically expected. Furthermore, any Grade 2 or 3 cytopenia and neutropenia refractory to growth factor administration should alert practitioners to consider metabolite deficiency testing. For a list of facilities that perform testing, visit the National Institutes of Health (NIH)’s Genetic Testing Registry. To date, the registry lists 68 facilities that perform DPYD deficiency testing and 62 facilities that perform UGT1A1 genetic testing in the United States (32).

Conclusions

In summary, we present a unique case of a previously healthy patient who was found to have metastatic PDAC complicated by hepatic VC with acute encephalopathy and severe myelosuppression following urgent inpatient chemotherapy in the setting of DPYD and UGT1A1 gene mutations. Our case emphasizes the importance of early and prompt administration of chemotherapy in VC due to high risk for progression to fulminant organ failure. In addition, our case highlights the impact of metabolic deficiencies in patients who experience hematologic toxicities out of proportion to what is typically expected with a chemotherapy regimen.

Acknowledgments

The authors would like to thank the patient for his kindness and permission to report his case.

Funding: This work was supported by the National Institutes of Health (grant No. K08 CA259456) and a Conquer Cancer Foundation ASCO Career Development Award.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://apc.amegroups.com/article/view/10.21037/apc-24-15/rc

Peer Review File: Available at https://apc.amegroups.com/article/view/10.21037/apc-24-15/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-24-15/coif). A.O. serves as an unpaid section editor for Annals of Pancreatic Cancer from May 2023 to April 2025. D.O. has been compensated for two advisory boards (one through Pfizer and one through Johnson & Johnson) and is on the speakers bureau for Johnson & Johnson. All of these activities are in relation to his experience treating patients with drugs used for multiple myeloma. While this manuscript is not related to multiple myeloma, both companies manufacture medications used in pancreatic ductal adenocarcinoma, which is the topic of this manuscript. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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