Assessment of Nucleotide Excision Repair XPD Polymorphisms in the Peripheral Blood of Gemcitabine/Cisplatin–Treated Advanced Non–Small-Cell Lung Cancer Patients

Camps, Carlos; Sarries, Carmen; Roig, Bárbara; Sánchez, José Javier; Queralt, Cristina; Sancho, Eva; Martı́nez, Natividad; Tarón, Miguel; Rosell, Rafael

doi:10.3816/clc.2003.n.004

Cited by 47 publications

(25 citation statements)

References 14 publications

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“…Other studies in lung cancer patients yielded inconsistent results and showed no significant association between clinical outcome and the C/C genotype in codon 118 of ERCC1 (18,19) and with polymorphisms at codons 312 and 751 in XPD (11,12,19,20). Therefore, the use of genotypic analysis of nucleotide excision repair genes as a predictor of clinical outcome to platinum-based treatments is still controversial and further studies are warranted.…”

Section: Lung Cancer Is the Leading Cause Of Cancer-related Deaths Inmentioning

confidence: 96%

Correlation of CDA, ERCC1, and XPD Polymorphisms with Response and Survival in Gemcitabine/Cisplatin–Treated Advanced Non–Small Cell Lung Cancer Patients

Tibaldi

Giovannetti

Vasile

et al. 2008

Clinical Cancer Research

194

128

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Purpose: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in non^small cell lung cancer (NSCLC). Polymorphisms at the xeroderma pigmentosum group D (XPD), excision repair cross-complementing 1 (ERCC1), and cytidine deaminase (CDA) genes have been associated with alterations in enzymatic activity and may change sensitivity to the widely used cisplatin-gemcitabine regimen. Gln polymorphisms and response, clinical benefit, toxicity, time to progression (TTP), and overall survival (OS) was estimated using Pearson's m 2 tests, the Kaplan-Meier method, the log-rank test, and the Cox proportional hazards model. Results: The CDA Lys 27 Lys polymorphism significantly correlated with better clinical benefit (P = 0.04) and grade z3 neutropenia and thrombocytopenia, as well as with longer TTP and OS (P = 0.006 and P = 0.002, respectively), whereas no significant associations were found among ERCC1 and XPD polymorphisms and both response and clinical outcome. Finally, the enzymatic activity assay showed a significant lower mean in subjects harboring the CDA Lys 27 Lys polymorphism. Conclusions: Our data suggested the role of CDA Lys 27 Lys polymorphism as a possible predictive marker of activity, toxicity,TTP, and OS in advanced NSCLC patients treated with cisplatin and gemcitabine. These results may be explained by the lower enzymatic activity associated with the Lys 27 Lys CDA and offer a potential new tool for treatment optimization. Lung cancer is the leading cause of cancer-related deaths inWestern countries. Non -small cell lung cancer (NSCLC) accounts for >85% of primary lung cancers and approximately two thirds of NSCLC patients are diagnosed at an advanced stage (1).Pooled data from older randomized trials of cisplatin-based chemotherapy versus best supportive care showed that cisplatin-based chemotherapy was associated with a modest improvement in overall survival (OS; ref. 2). In more recent randomized trials, new cytotoxic drugs such as paclitaxel, docetaxel, vinorelbine, or gemcitabine in combination with a platinum compound have shown an absolute 15% to 20% improvement of survival in favor of chemotherapy versus best supportive care. In particular, the 1-year survival rate for best supportive care was 11% to 17% versus 30% to 35% for chemotherapy, which prolonged median survival by 3 to 4 months (3). However, none of the last-generation doublets was shown to be superior to the others and they all seemed to have reached the therapeutic plateau, with objective response rates of 30% to 40%, median survival time of 8 to 10 months, and 1-year survival rate of 30% to 40% (4). Indeed, a four-arm randomized phase III trial showed no substantial differences in response rate, time to progression (TTP), and OS among paclitaxel (24-hour infusion) -cisplatin, docetaxel-cisplatin, paclitaxel-carboplatin, and gemcitabine-cisplatin combination (4). Therefore, the cisplatin-gemcitabine combination is one of the standard regimens for the treatment of ...

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Section: Lung Cancer Is the Leading Cause Of Cancer-related Deaths Inmentioning

confidence: 96%

Correlation of CDA, ERCC1, and XPD Polymorphisms with Response and Survival in Gemcitabine/Cisplatin–Treated Advanced Non–Small Cell Lung Cancer Patients

Tibaldi

Giovannetti

Vasile

et al. 2008

Clinical Cancer Research

194

128

View full text Add to dashboard Cite

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“…The XPD Lys751Lys genotype, which is related to suboptimal DRC, was observed to be associated with longer median survival in CRC patients treated with oxaliplatin/FU . In another study, a trend toward better response was observed in non-small-cell lung cancer patients with XPD Asp312Asn SNP, although the correlation did not reach statistical significance (Camps et al, 2003).…”

Section: Pharmacogeneticsmentioning

confidence: 99%

Genetic susceptibility to tobacco-related cancer

et al. 2004

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Although cigarette smoking is the dominant risk factor for several epithelial cancers, only a small fraction of individuals with tobacco exposure develop cancer. The underlying hypothesis is that genetic factors may render certain smokers more susceptible to cancer than others. Genetic alterations in critical regulatory pathways may predispose cells to carcinogenesis. These pathways include regulation of xenobiotic metabolism; control of genomic stability, including DNA repair mechanisms, cell-cycle checkpoints, apoptosis and telomere length; and control of microenvironmental factors, such as matrix metalloproteinases, inflammation and growth factors. In addition, epigenetic events, such as promoter hypermethylation and loss of imprinting, are also involved in carcinogenesis. In this review, we will summarize recent advances in genetic susceptibility to tobacco-related cancer. Emphasizing on risk assessment, we will describe how genetic variations in the above-mentioned genetic pathways modify the tobacco-related cancer risk. In addition, we will discuss how genetic variations may assist in predicting clinical outcome, such as the natural history of cancer and treatment response. The measurements of genetic susceptibility by both genotypic and phenotypic assays are covered in the text. Finally, we present a number of current concerns that need to be addressed as the exciting field of molecular cancer epidemiology advances rapidly.

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“…Association between tumor expression level of SLC29A1 [Kim, 1999;Myers et al, 2006], ERCC1 [Bepler et al, 2006], and DCK Shi et al, 2004] and clinical outcomes in patients treated with gemcitabine has been reported. Genetic variations in CDA [Gilbert et al, 2006;Sugiyama et al, 2007;Yonemori et al, 2005], DCTD [Gilbert et al, 2006], ERCC2 (XPD) [Camps et al, 2003;Petty et al, 2007], and XRCC3 [de las Penas et al, 2006] genes were implicated to have association or trend with response, toxicity, or survival in gemcitabine-treated patients. SNPs in RECQL, RAD54L, XRCC1, and ATM were investigated in patients treated with gemcitabine and were found to have significant effects on overall survival [Li et al, 2006].…”

Section: Introductionmentioning

confidence: 99%

Discovery of genetic profiles impacting response to chemotherapy: application to gemcitabine

et al. 2008

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For the Focus Section on PharmacogeneticsChemotherapy is a major treatment modality for individuals affected by cancer. Currently, a number of genomebased technologies are being adopted to identify genes associated with drug response; however, large-scale genetic association applications are still limited. Here we describe a novel strategy based on the genetic and drug response data of the NCI60 cell lines to discover potential candidate genetic variants associated with variable response to chemotherapy. As an example we have applied this strategy to discover single genetic markers and haplotypes from candidate genes previously implicated in the pharmacobiology of gemcitabine. Single-marker association analyses have implicated the association of four SNPs within the gene loci of CDC5L, EPC2, POLS, and PARP1. We have also investigated the combined effect of SNPs using haplotype-based analysis. Accordingly, we have shown modest association of haplotypes in six genes, whereas the most significant associations included a haplotype of the POLS gene. The hypothesis-generating tool presented in this study can be applied to drugs profiled in the NCI60 cell line screen and provides an effective means for the identification of genes associated with drug response. The results obtained using this novel methodology can be used to better design the clinical trials for effective study of the chemotherapeutic agents and thus provide a basis for individualized chemotherapy. Hum Mutat 29(4), [461][462][463][464][465][466][467] 2008.

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Assessment of Nucleotide Excision Repair XPD Polymorphisms in the Peripheral Blood of Gemcitabine/Cisplatin–Treated Advanced Non–Small-Cell Lung Cancer Patients

Cited by 47 publications

References 14 publications

Correlation of CDA, ERCC1, and XPD Polymorphisms with Response and Survival in Gemcitabine/Cisplatin–Treated Advanced Non–Small Cell Lung Cancer Patients

Correlation of CDA, ERCC1, and XPD Polymorphisms with Response and Survival in Gemcitabine/Cisplatin–Treated Advanced Non–Small Cell Lung Cancer Patients

Genetic susceptibility to tobacco-related cancer

Discovery of genetic profiles impacting response to chemotherapy: application to gemcitabine

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