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

Background: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in non-small cell lung cancer (NSCLC). Genetic variations in drug metabolism may affect the clinical response, toxicity, and prognosis of NSCLC patients treated with cisplatin/gemcitabine-based therapy. Patients and Methods: We evaluated seven single-nucleotide polymorphisms of six genes CDA Lys27Gln (A/C); CDA C435T; ERCC1 C118T; XRCC3 Thr241Met (C/T); XPD Lys751Gln (A/C); P53 Arg72Pro (G/C), and RRM1 C524T in 192 chemotherapy-naive patients with advanced NSCLC treated with cisplatin/gemcitabine-based regimen by TaqMan probe-based assays with 7300 Real-Time PCR System, using genomic DNA extracted from blood samples. Results: The CDA 435 T/T genotype was significantly associated with better response (p = 0.03). The CDA 435 C/T genotype was associated with a significantly increased risk of nonhematological toxicity of grade ≥3 (p = 0.02) after adjusting for performance status, age, and type of treatment regimen. In the multivariate Cox model, the XPD 751 C/C genotype was a significant prognostic factor of longer progression-free survival (p = 0.006). Conclusion: 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.

[1]  E. Giovannetti,et al.  Correlation of CDA, ERCC1, and XPD Polymorphisms with Response and Survival in Gemcitabine/Cisplatin–Treated Advanced Non–Small Cell Lung Cancer Patients , 2008, Clinical Cancer Research.

[2]  H. Ueno,et al.  Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  M. Taron,et al.  Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[4]  R. Weinshilboum,et al.  Gemcitabine Pharmacogenomics: Cytidine Deaminase and Deoxycytidylate Deaminase Gene Resequencing and Functional Genomics , 2006, Clinical Cancer Research.

[5]  R. Ferrell,et al.  Identification of functional single nucleotide polymorphism haplotypes in the cytidine deaminase promoter , 2006, Human Genetics.

[6]  B. Giraudeau,et al.  ERCC1 Codon 118 Polymorphism Is a Predictive Factor for the Tumor Response to Oxaliplatin/5-Fluorouracil Combination Chemotherapy in Patients with Advanced Colorectal Cancer , 2005, Clinical Cancer Research.

[7]  K. Sabapathy,et al.  Evaluation of the Combined Effect of p53 Codon 72 Polymorphism and Hotspot Mutations in Response to Anticancer Drugs , 2005, Clinical Cancer Research.

[8]  H. Ueno,et al.  Severe Drug Toxicity Associated with a Single-Nucleotide Polymorphism of the Cytidine Deaminase Gene in a Japanese Cancer Patient Treated with Gemcitabine plus Cisplatin , 2005, Clinical Cancer Research.

[9]  G. Bepler,et al.  Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance. , 2005, Lung cancer.

[10]  H. Dienemann,et al.  Specific combinations of DNA repair gene variants and increased risk for non-small cell lung cancer. , 2004, Carcinogenesis.

[11]  M. Taron,et al.  Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[12]  D. Neuberg,et al.  Excision Repair Cross-Complementation Group 1 Polymorphism Predicts Overall Survival in Advanced Non-Small Cell Lung Cancer Patients Treated With Platinum-Based Chemotherapy , 2004, Clinical Cancer Research.

[13]  D. Neuberg,et al.  XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  Youngchul Kim,et al.  Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy. , 2004, Lung cancer.

[15]  T. Crook,et al.  Polymorphism in wild-type p53 modulates response to chemotherapy in vitro and in vivo , 2004, Oncogene.

[16]  D. Goldstein,et al.  Pharmacogenetics goes genomic (vol 4, pg 937, 2003) , 2004 .

[17]  David B. Goldstein,et al.  Pharmacogenetics goes genomic , 2003, Nature Reviews Genetics.

[18]  T. Eisen,et al.  TP53 polymorphisms and lung cancer risk: a systematic review and meta-analysis. , 2003, Mutagenesis.

[19]  S. Groshen,et al.  ERCC1 gene polymorphism as a predictor for clinical outcome in advanced colorectal cancer patients treated with platinum-based chemotherapy. , 2003, Clinical advances in hematology & oncology : H&O.

[20]  K. Ota,et al.  A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity. , 2003, Pharmacogenetics.

[21]  R. Rosell,et al.  Assessment of nucleotide excision repair XPD polymorphisms in the peripheral blood of gemcitabine/cisplatin-treated advanced non-small-cell lung cancer patients. , 2003, Clinical lung cancer.

[22]  A. Duncan,et al.  Regulation of cisplatin resistance and homologous recombinational repair by the TFIIH subunit XPD. , 2002, Cancer research.

[23]  K. Hemminki,et al.  The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk. , 2002, Carcinogenesis.

[24]  Hongbing Shen,et al.  Modulation of repair of ultraviolet damage in the host-cell reactivation assay by polymorphic XPC and XPD/ERCC2 genotypes. , 2002, Carcinogenesis.

[25]  S. Groshen,et al.  A Xeroderma pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer. , 2001, Cancer research.

[26]  E. Bowman,et al.  Functional significance of XPD polymorphic variants: attenuated apoptosis in human lymphoblastoid cells with the XPD 312 Asp/Asp genotype. , 2001, Cancer research.

[27]  P Vineis,et al.  XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. , 2001, Carcinogenesis.

[28]  C I Amos,et al.  Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. , 2001, Cancer research.

[29]  M. Christian,et al.  [New guidelines to evaluate the response to treatment in solid tumors]. , 2000, Bulletin du cancer.

[30]  J. Yu,et al.  Comparison of two human ovarian carcinoma cell lines (A2780/CP70 and MCAS) that are equally resistant to platinum, but differ at codon 118 of the ERCC1 gene. , 2000, International journal of oncology.

[31]  M. van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors , 2000, Journal of the National Cancer Institute.

[32]  G. Peters,et al.  Decreased resistance to gemcitabine (2',2'-difluorodeoxycitidine) of cytosine arabinoside-resistant myeloblastic murine and rat leukemia cell lines: role of altered activity and substrate specificity of deoxycytidine kinase. , 1999, Biochemical pharmacology.

[33]  S. Seeber,et al.  Recombinant gene products of two natural variants of the human cytidine deaminase gene confer different deamination rates of cytarabine in vitro. , 1998, Experimental hematology.

[34]  R. Momparler,et al.  Drug resistance to 5-aza-2′-deoxycytidine, 2′,2′-difluorodeoxycytidine, and cytosine arabinoside conferred by retroviral-mediated transfer of human cytidine deaminase cDNA into murine cells , 1998, Cancer Chemotherapy and Pharmacology.

[35]  C. A. Blau,et al.  Forced expression of cytidine deaminase confers resistance to cytosine arabinoside and gemcitabine. , 1996, Experimental hematology.

[36]  H. Pinedo,et al.  Regulation of phosphorylation of deoxycytidine and 2',2'-difluorodeoxycytidine (gemcitabine); effects of cytidine 5'-triphosphate and uridine 5'-triphosphate in relation to chemosensitivity for 2',2'-difluorodeoxycytidine. , 1996, Biochemical pharmacology.

[37]  A. Sancar.  DNA repair in humans. , 1995, Annual review of genetics.