UGT1A1 Gene Polymorphisms in Patients with Small Cell Lung Cancer Treated with Irinotecan-Platinum Doublet Chemotherapy and Their Association with Gastrointestinal Toxicity and Overall Survival

Abstract

Background. Irinotecan (CPT11) is an important drug for small cell lung cancer (SCLC) chemotherapy (CTx). UDPglucuronosyltransferase 1A1 (UGT1A1) polymorphisms can influence CPT11-related toxicity. This study aimed to assess prevalence of UGT1A1 polymorphisms and their association with clinical outcomes in patients with SCLC on CPT11-CTx. Methods. An observational cohort of treatment-naïve patients with SCLC was given CPT11-platinum doublet at a referral center in North India over 3 years. Clinical outcomes assessed were hematological and gastrointestinal toxicity (Common Terminology Criteria for Adverse Events, version 3.0), response rates (RECIST), and overall survival (OS). Peripheral blood was drawn from all enrolled patients just prior to CPT11-CTx initiation, and genomic DNA was isolated. Genotyping was done by polymerase chain reaction (PCR)-restriction fragment length polymorphism for UGT1A1*7, UGT1A1*6, and UGT1A1*27 and by PCR-DNA sequencing for UGT1A1*28. Patients were classified as homozygous wild-type (WT/WT), heterozygous mutant (WT/M), or homozygous mutant (M/M) for each polymorphism assessed. Results. Of 140 patients enrolled, no mutant alleles were found for UGT1A1*27 or UGT1A1*7. Frequency of UGT1A1*6 polymorphisms (n = 111) was 89.2% for WT/WT, 8.1% for WT/M, and 2.7% for M/M. For UGT1A1*28 (n = 102), this was 41.2% for WT/WT, 43.1% for WT/M, and 15.7% for M/M. UGT1A1*6 WT/WT patients tolerated >95% predicted CPT11 dose more frequently (59.6% vs. 25.0% in WT/M-M/M combined group; p = .026). The UGT1A1*6 WT/M-M/M group also experienced severe (grade ≥3) diarrhea (41.7% vs. 17.2% in WT/WT; p = .044) and mucositis (41.7% vs. 8.1% in WT/WT; p = .005) more frequently. On multivariate logistic regression analysis, UGT1A1*6 WT/M-M/M status was the only variable associated with occurrence of both mucositis (odds ratio [OR], 10.4) and severe diarrhea (OR, 4.8). UGT1A1*28 WT/M-M/M patients had better OS (320 days [95% confidence interval, 203-437] vs. 216 days [95% confidence interval, 140-292] in WT/WT group; p = .047). On multivariate Cox proportional hazards analysis, UGT1A1*28 WT/M-M/M status was independently associated with better OS (hazard ratio, 0.35), whereas lack of objective radiological response, moderate/heavy smoking, and increasing age were associated with worse OS. Conclusion. UGT1A1*6 and UGT1A1*28 polymorphisms were associated with increased gastrointestinal toxicity and improved OS, respectively, in North Indian patients with SCLC receiving CPT11-CTx. The Oncologist 2021;9999:• • Implications for Practice: UGT1A1 gene polymorphisms are known to influence irinotecan-related toxicity. In this prospective cohort study of patients with small cell lung cancer receiving first-line irinotecan-platinum chemotherapy, the prevalence of UGT1A1*6 polymorphisms was found to be 10.8% UGT1A1*6 and 58.8% UGT1A1*28 homo/heterozygous mutant,

Association of UGT1A1*6, UGT1A1*28, or ABCC2 c.3972C>T genetic polymorphisms with irinotecan‐induced toxicity in Asian cancer patients: Meta‐analysis

“…Applying the exclusion criteria, 195 articles were removed and the remaining 105 full‐text articles were assessed in depth in line with the predetermined eligibility criteria. Finally, 42 articles were included in the meta‐analysis for assessing the associations of UGT1A1*6/UGT1A1*28 or ABCC2 c.3972C>T with irinotecan‐induced severe toxicities 12,14,21–24,26–31,34,35,48–75 . The complete selection process for the articles following PRISMA guidelines is shown in Figure 1.…”

SARS-CoV-2 infection dysregulates the expression of clinically relevant drug metabolizing enzymes in Vero E6 cells and membrane transporters in human lung tissues

“…Additionally, caution needs to be taken when administering drugs to COVID-19 patients especially the patient population with comorbidities to mitigate clinically relevant disease–drug interactions. For example, UGT1A1 is highly polymorphic and can impact irinotecan (a prodrug used for small cell lung cancer chemotherapy) metabolite related-toxicity ( Bandyopadhyay et al, 2021 ). Given that UGT1A1 mRNA expression was significantly downregulated in SARS-CoV-2-infected Vero E6 cells and patients with lung cancer have a greater than 7-fold higher risk of SARS-CoV-2 infection ( Rolfo et al, 2022 ), further investigation is required to determine the effect of prescribing UGT1A1 candidate drugs to COVID-19 patients, especially the UGT1A1 poor metabolizers which accounts for about 10% of North Americans ( Dean, 2018 ).…”