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The association between COX-2 polymorphisms and hematologic toxicity in patients with advanced non-small-cell lung cancer treated with platinum-based chemotherapy.

ABSTRACT: BACKGROUND AND OBJECTIVE: Overexpression of COX-2 is proved to contribute to tumor promotion and carcinogenesis through stimulating cell proliferation, inhibiting apoptosis and enhancing the invasiveness of cancer cells. Apoptosis-related molecules are potential predictive markers for survival and toxicity in platinum treatment. This study aimed at investigating the association between COX-2 polymorphisms and the occurrence of grade 3 or 4 toxicity in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. MATERIALS AND METHODS: Two hundred and twelve patients with inoperable stage IIIB-IV NSCLC received first-line chemotherapy between 2007 and 2009 were recruited in this study. Four functional COX-2 polymorphisms were genotyped by PCR-based restriction fragment length polymorphism (RFLP) methods. RESULTS: The incidence of grade 3 or 4 hematologic toxicity was significantly higher in G allele carriers of the COX-2 rs689466 (-1195G/A) polymorphism compared with wild-type homozygotes AA (P value?=?0.008; odds ratio, 2.47; 95% confidence internal, 1.26-4.84) and the significance still existed after the Bonferroni correction. Statistically significant difference was also found in grade 3 or 4 leukopenia (P value?=?0.010; OR?=?2.82; 95%CI?=?1.28-6.20). No other significant association was observed between genotype and toxicity in the study. The haplotype analysis showed that the haplotype AGG was associated with a reduced risk of grade 3 or 4 hematologic and leukopenia toxicity (P value?=?0.009; OR?=?0.59; 95%CI?=?0.39-0.88 and P value?=?0.025; OR?=?0.61; 95%CI?=?0.39-0.94, respectively) while the haplotype GGG was associated with an increased risk of grade 3 or 4 hematologic and leukopenia toxicity (P value?=?0.009; OR?=?1.71; 95%CI?=?1.14-2.56 and P value?=?0.025; OR?=?1.65; 95%CI ?=?1.06-2.57, respectively). CONCLUSION: This investigation for the first time suggested that polymorphism in COX-2 rs689466 may be a potent bio-marker in predicting severe hematologic toxicity in NSCLC patients after platinum-based chemotherapy.

SUBMITTER: Zhou F

PROVIDER: S-EPMC3631232 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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The association between COX-2 polymorphisms and hematologic toxicity in patients with advanced non-small-cell lung cancer treated with platinum-based chemotherapy.

Zhou Fei F Gao Guanghui G Ren Shengxiang S Li Xuefei X He Yayi Y Zhou Caicun C

PloS one 20130419 4

<h4>Background and objective</h4>Overexpression of COX-2 is proved to contribute to tumor promotion and carcinogenesis through stimulating cell proliferation, inhibiting apoptosis and enhancing the invasiveness of cancer cells. Apoptosis-related molecules are potential predictive markers for survival and toxicity in platinum treatment. This study aimed at investigating the association between COX-2 polymorphisms and the occurrence of grade 3 or 4 toxicity in advanced non-small cell lung cancer p ...[more]

PMID: 23620771

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Project description:BackgroundIrinotecan (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.MethodsAn 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.ResultsOf 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.ConclusionUGT1A1*6 and UGT1A1*28 polymorphisms were associated with increased gastrointestinal toxicity and improved OS, respectively, in North Indian patients with SCLC receiving CPT11-CTx.Implications for practiceUGT1A1 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, respectively. UGT1A1*6 homo/heterozygous mutant status was associated with severe diarrhea and mucositis. UGT1A1*28 homo/heterozygous mutant status was independently associated with improved overall survival.

Dataset Information

The association between COX-2 polymorphisms and hematologic toxicity in patients with advanced non-small-cell lung cancer treated with platinum-based chemotherapy.

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The association between COX-2 polymorphisms and hematologic toxicity in patients with advanced non-small-cell lung cancer treated with platinum-based chemotherapy.

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