Association of Cytidine Deaminase and Xeroderma Pigmentosum Group D Polymorphisms with Response, Toxicity, and Survival in Cisplatin/Gemcitabine-Treated Advanced Non-small Cell Lung Cancer Patients

Ludovini, Vienna; Floriani, Irene; Pistola, Lorenza; Minotti, Vincenzo; Meacci, M.; Chiari, Rita; Garavaglia, Daniela; Tofanetti, Francesca Romana; Flacco, Antonella; Siggillino, Annamaria; Baldelli, Elisa; Tonato, Maurizio; Crinò, Lucio

doi:10.1097/jto.0b013e3182307e1f

Cited by 53 publications

(44 citation statements)

References 29 publications

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“…Severe GCB toxicity in NSCLC patients was reported in cases with heterozygous c.437CT variant and, to a lesser degree, in those with homozygous c.435TT variant (25,26). Interestingly, the latter was also found to be related to better response to GCB treatment, owing to reduced serum CDA concentration and higher exposure to active GCB metabolites (27,28).…”

Section: Discussionmentioning

confidence: 93%

“…Data on the relationship between CDA polymorphisms and GCB toxicity are inconsistent (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Severe GCB toxicity in NSCLC patients was reported in cases with heterozygous c.437CT variant and, to a lesser degree, in those with homozygous c.435TT variant (25,26).…”

Section: Discussionmentioning

confidence: 99%

“…Data regarding toxicity related to CDA polymorphisms are inconsistent (16)(17)(18). Nevertheless, several studies demonstrated that single nucleotide polymorphism (SNP) of CDA c.79 A>C, c.208 G>A and c.435C>T, with resulting decreased serum CDA concentration, may lead to severe toxicity induced by GCB (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

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Severe acute toxicity following gemcitabine administration: A report of four cases with cytidine deaminase polymorphisms evaluation

et al. 2017

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Abstract. Gemcitabine (GCB) is a pyrimidine antimetabolite widely used in various solid tumors as a single agent or as a component of multidrug regimens. In the majority of patients, GCB is well tolerated, however life-threatening complications occasionally occur. The current report presents four cases of severe acute toxicity, which included two that were fatal, following administration of GCB alone or in combination with cisplatin. Of the four cases, in one, a Naranjo Adverse Drug Reaction Probability Score was definite, in two, probable and in one possible. To determine the potential causes of these toxicities, polymorphic variants of cytidine deaminase, the primary enzyme involved in the hepatic metabolism of GCB, were assessed. The homogeneous c.435TT variant was detected in one patient and a heterozygotic c.435CT variant in two, one of whom additionally harbored a heterozygotic c.79AC variant. IntroductionGemcitabine (GCB) is an anticancer agent widely used alone or in combination with other cytotoxics in the treatment of various malignancies including non-small cell lung cancer (NSCLC), pancreatic, bladder, breast, ovarian, prostate cancer, and cholangiocarcinoma (1). GCB toxicity is generally mild, transitory and rarely dose limiting. Most common side effects include laboratory alterations, such as myelosupression, transaminase elevation, mild proteinuria and hematuria, whereas symptomatic toxicities are usually well controlled and not life threatening (2-4). Factors increasing GCB toxicity include its combination with platinum derivatives or taxanes, liver and kidney diseases, and alcohol abuse (5-10). There are no evidence-based and generally accepted recommendations for dose modifications of GCB, and clinical decisions are typically made based on empirical grounds.The main enzyme involved in hepatic metabolism of GCB is cytidine deaminase (CDA), encoded by the CDA gene located in locus 1p36. 2-35 (11-15). Data regarding toxicity related to CDA polymorphisms are inconsistent (16)(17)(18). Nevertheless, several studies demonstrated that single nucleotide polymorphism (SNP) of CDA c.79 A>C, c.208 G>A and c.435C>T, with resulting decreased serum CDA concentration, may lead to severe toxicity induced by GCB (18-31).We describe here severe toxicity in four patients treated with GCB used alone or in combination with cisplatin. For each case, the probability of adverse drug reaction probability was assessed using the Naranjo scale described in the study by Naranjo et al (32). In the search of potential toxicity causes, we performed in all cases evaluation of CDA polymorphisms. Case 1.A 67-year-old-woman was diagnosed with poorly differentiated tubule-solid gallbladder adenocarcinoma invading the liver and spreading to the greater omentum. The patient reported recurrent pain in the upper abdomen, but was otherwise in a fairly good condition [World Health Organization Performance Status (WHO PS) 2], with body mass index of 18.6 and no apparent active inflammatory symptoms. Serum alanine transaminase (ALT) and a...

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Severe acute toxicity following gemcitabine administration: A report of four cases with cytidine deaminase polymorphisms evaluation

et al. 2017

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“…in practical terms, this translates to lower risk for treatment failures and for development of resistance to various anticancer agents in cancer cells with low repair capacity. it has already been shown for different types of tumours (hematological as well as solid) that carriership of allelic forms of DnA polymorphisms associated with lower capacity for DNA repair (specifically XPD polymorphisms in exon 10 and exon 23, as well as polymorphisms in several genes participating in repair by BeR and recombination) may predict higher rates of response to treatment and better outcomes in terms of progression-free survival (37,40,56). interestingly, there are exceptions to this, as it has been shown that the presence of the Gln allele of the lys751Gln polymorphism of the XPD gene may actually be associated with reduced survival in patients treated with combined platinum/5-fluorouracil regimens for advanced colorectal cancer (52).…”

Section: Using Information About Individual Repair Capacity For Desigmentioning

confidence: 99%

“…carriership of polymorphisms in the XPD, ERCC1 and XRCC1 genes conferring lower capacity for DnA repair has been shown to be associated with higher risk for acute and late toxicity in 'standard' chemotherapy or radiotherapy regimens (40,59). What is more, polymorphic variants of genes which are not known to be associated with substantial decrease in the capacity for DnA repair may apparently also modify the risk for toxicity following anticancer therapy, as the R allele of the P72R polymorphism has been found to be more frequent in vascular skin lesions following radiotherapy for breast cancer than the P allele (61).…”

Section: Using Information About Individual Repair Capacity For Desigmentioning

confidence: 99%

War without Weapons—Constitution of Healthy and Pathological Phenotypes Associated with Polymorphisms in Genes Involved in the Maintenance of Genome Integrity

Oluwaseun

Khalil

2012

Biotechnology & Biotechnological Equipment

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Evaluation of Prediction of Polymorphisms of DNA Repair Genes on the Efficacy of Platinum‐Based Chemotherapy in Patients With Non‐Small Cell Lung Cancer: A Network Meta‐Analysis

Liu

et al. 2017

J of Cellular Biochemistry

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This network meta-analysis (NMA) was conducted to compare the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC). These included ERCC1 (rs11615, rs3212986, rs3212948), XRCC1 (rs25487, rs25489, rs1799782), XPD (rs13181, rs1799793), XPG (rs1047768, rs17655), XPA (rs1800975), XRCC3 (rs861539), APE1 (rs3136820), and RRM1 (rs1042858). The PubMed and Cochrane library databases were reviewed from their inception to February 2017 and studies which met our inclusion criteria were included in our investigation. This network meta-analysis combines direct and indirect evidence to assess the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC. We evaluated the predictive value through the use of the odd ratios (OR) and drawing surface under the cumulative ranking curves (SUCRA). A total of 26 eligible cohort studies were enrolled in this NMA. The pairwise meta-analysis indicated that in terms of overall response ratio (ORR), ERCC1 (rs11615), XRCC1 (rs25487, rs1799782), and XPD (rs13181) polymorphisms are associated with the efficacy of platinum-based chemotherapy in NSCLC. The result of this NMA suggests that there is no significant difference in predictive value of 8 DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC patients. The rank of SUCRA values of the 14 SNPs in the eight DNA repair genes were: XPD (rs1799793)→ERCC1 (rs3212986)→XPA(rs1800975)→ERCC1(rs3212948)→XRCC1(rs25487)→XRCC3(rs861539)→APE1(rs3136820)→ERCC1(rs11615)→XRCC1(rs1799782)→RRM1(rs1042858)→XPD(rs13181)→XPG (rs1047768)→XPG(rs17655)→XRCC1(rs25489). ERCC1(rs11615), XRCC1(rs25487, rs1799782) and XPD(rs13181) polymorphisms were better predictors in evaluating the efficacy of platinum-based chemotherapy in NSCLC patients. J. Cell. Biochem. 118: 4782-4791, 2017. © 2017 Wiley Periodicals, Inc.

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Association of Cytidine Deaminase and Xeroderma Pigmentosum Group D Polymorphisms with Response, Toxicity, and Survival in Cisplatin/Gemcitabine-Treated Advanced Non-small Cell Lung Cancer Patients

Abstract: Our data suggest polymorphic variations of drug metabolic gene were associated with response and toxicity of cisplatin/gemcitabine-based therapy and progression-free survival of patients with advanced NSCLC.

Cited by 53 publications

References 29 publications

Severe acute toxicity following gemcitabine administration: A report of four cases with cytidine deaminase polymorphisms evaluation

Severe acute toxicity following gemcitabine administration: A report of four cases with cytidine deaminase polymorphisms evaluation

War without Weapons—Constitution of Healthy and Pathological Phenotypes Associated with Polymorphisms in Genes Involved in the Maintenance of Genome Integrity

Evaluation of Prediction of Polymorphisms of DNA Repair Genes on the Efficacy of Platinum‐Based Chemotherapy in Patients With Non‐Small Cell Lung Cancer: A Network Meta‐Analysis

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