UGT1A1 gene polymorphisms and clinical outcomes in small cell lung cancer (SCLC) patients treated with irinotecan-platinum chemotherapy: The first study from north India.

Abstract

e20024 Background: Irinotecan(CPT11) is an important drug for SCLC chemotherapy(CTx). UDP-glucuronosyl-transferase1A1(UGT1A1) polymorphisms can influence CPT11-related toxicity. This study aimed to assess incidence of UGT1A1 polymorphisms and their association with clinical outcomes in SCLC patients on CPT11-CTx. Methods: Observational cohort of treatment-naïve SCLC patients given CPT11-platinum doublet at a referral centre in North India over 3-yrs(January 2013-December 2015). Clinical outcomes assessed were hematological & gastrointestinal toxicity(CTC-AE v3.0), response rates by RECIST & overall survival(OS). Peripheral blood was drawn from all enrolled patients just prior to CPT11-CTx initiation & genomic DNA isolated. Genotyping was done by PCR-RFLP for UGT1A1*7, UGT1A1*6 & UGT1A1*27 & 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% WT/WT, 8.1% WT/M & 2.7% M/M. For UGT1A1*28(n = 102), this was 41.2% WT/WT, 43.1% WT/M & 15.7% M/M. For UGT1A1*6, 60% WT/WT patients tolerated > 95% predicted CPT11 dose (vs. 25% in WT/M-M/M combined group;p = 0.026). Severe(grade≥3) diarrhea was more common in WT/M-M/M group (44.4% vs. 17.9% in WT/WT,p = 0.06) as was any grade mucositis (55.6% vs. 9.5% in WT/WT,p = 0.002). On multivariate logistic regression analysis, UGT1A1*6 WT/M-M/M status was the only variable associated with(a/w) occurrence of both mucositis[OR = 10.4] & severe(grade≥3) diarrhea[OR = 4.8]. UGT1A1*28 WT/M-M/M patients had better OS[338 days(95% CI = 190-486) vs. 216 days(95% CI = 136-296) in WT/WT group;p = 0.045]. On multivariate Cox proportional hazards analysis, better OS was independently a/w number of CTx cycles, UGT1A1*28 WT/M-M/M status, maximum % dose of CPT11 delivered & inversely with age. Conclusions: UGT1A1*6 & UGT1A1*28 polymorphisms are a/w increased toxicity & improved OS respectively in North Indian SCLC patients receiving CPT11-CTx.