Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
Department of Biotechnology, Thapar University, Patiala, Punjab, India.
Oncologist. 2021 Aug;26(8):701-713. doi: 10.1002/onco.13757. Epub 2021 Apr 12.
Irinotecan (CPT11) is an important drug for small cell lung cancer (SCLC) chemotherapy (CTx). UDP-glucuronosyltransferase 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.
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 UGT1A17, UGT1A16, and UGT1A127 and by PCR-DNA sequencing for UGT1A128. Patients were classified as homozygous wild-type (WT/WT), heterozygous mutant (WT/M), or homozygous mutant (M/M) for each polymorphism assessed.
Of 140 patients enrolled, no mutant alleles were found for UGT1A127 or UGT1A17. Frequency of UGT1A16 polymorphisms (n = 111) was 89.2% for WT/WT, 8.1% for WT/M, and 2.7% for M/M. For UGT1A128 (n = 102), this was 41.2% for WT/WT, 43.1% for WT/M, and 15.7% for M/M. UGT1A16 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 UGT1A16 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, UGT1A16 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). UGT1A128 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.
UGT1A16 and UGT1A128 polymorphisms were associated with increased gastrointestinal toxicity and improved OS, respectively, in North Indian patients with SCLC receiving CPT11-CTx.
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 UGT1A16 polymorphisms was found to be 10.8% UGT1A16 and 58.8% UGT1A128 homo/heterozygous mutant, respectively. UGT1A16 homo/heterozygous mutant status was associated with severe diarrhea and mucositis. UGT1A1*28 homo/heterozygous mutant status was independently associated with improved overall survival.
伊立替康（CPT11）是小细胞肺癌（SCLC）化疗（CTx）的重要药物。UDP-葡萄糖醛酸基转移酶 1A1（UGT1A1）多态性可影响 CPT11 相关毒性。本研究旨在评估 SCLC 患者在接受 CPT11-CTx 治疗时 UGT1A1 多态性的流行情况及其与临床结局的关系。
在印度北部的一家转诊中心，对 140 例未经治疗的 SCLC 患者进行 CPT11-铂类双联化疗。评估的临床结局包括血液学和胃肠道毒性（不良事件通用术语标准，版本 3.0）、缓解率（RECIST）和总生存期（OS）。所有入组患者在 CPT11-CTx 治疗前采集外周血，提取基因组 DNA。采用聚合酶链反应（PCR）-限制性片段长度多态性检测 UGT1A17、UGT1A16 和 UGT1A127，PCR-测序检测 UGT1A128。根据每种检测到的多态性，将患者分为 UGT1A17 或 UGT1A16 野生型纯合子（WT/WT）、杂合突变型（WT/M）或突变型纯合子（M/M）。
在 140 例患者中，未发现 UGT1A127 或 UGT1A17 的突变等位基因。UGT1A16 多态性（n = 111）的频率为 WT/WT 89.2%、WT/M 8.1%和 M/M 2.7%。UGT1A128（n = 102）为 WT/WT 41.2%、WT/M 43.1%和 M/M 15.7%。与 WT/WT 相比，UGT1A16 WT/WT 患者更能耐受 >95%预测 CPT11 剂量（59.6% vs. WT/M-M/M 联合组的 25.0%；p =.026）。UGT1A16 WT/M-M/M 组也更常发生严重（≥3 级）腹泻（41.7% vs. WT/WT 的 17.2%；p =.044）和黏膜炎（41.7% vs. WT/WT 的 8.1%；p =.005）。多变量逻辑回归分析显示，UGT1A16 WT/M-M/M 状态是与发生黏膜炎（优势比[OR]，10.4）和严重腹泻（OR，4.8）相关的唯一变量。UGT1A128 WT/M-M/M 患者的 OS 更好（320 天[95%置信区间，203-437]vs. WT/WT 组的 216 天[95%置信区间，140-292]；p =.047）。多变量 Cox 比例风险分析显示，UGT1A1*28 WT/M-M/M 状态与更好的 OS 独立相关（风险比，0.35），而客观影像学反应缺失、中重度吸烟和年龄增长与更差的 OS 相关。
在接受 CPT11-CTx 的印度北部 SCLC 患者中，UGT1A16 和 UGT1A128 多态性与胃肠道毒性增加和 OS 改善相关。
UGT1A1 基因多态性已知可影响伊立替康相关毒性。在这项对接受一线伊立替康-铂类化疗的小细胞肺癌患者进行的前瞻性队列研究中，发现 UGT1A16 多态性的流行率分别为 10.8%和 58.8%，UGT1A128 分别为 UGT1A16 和 UGT1A128 杂合/纯合突变。UGT1A16 杂合/纯合突变状态与严重腹泻和黏膜炎相关。UGT1A128 杂合/纯合突变状态与改善的总生存期独立相关。
