Polymorphisms in TS, MTHFR and ERCC1 genes as predictive markers in first-line platinum and pemetrexed therapy in NSCLC patients

Krawczyk, Paweł; Kucharczyk, Tomasz; Kowalski, Dariusz M.; Powrózek, Tomasz; Ramlau, Rodryg; Kalinka, Ewa; Winiarczyk, Kinga; Knetki-Wróblewska, Magdalena; Wojas‐Krawczyk, Kamila; Kałakucka, Katarzyna; Dyszkiewicz, Wojciech; Krzakowski, Maciej; Milanowski, Janusz

doi:10.1007/s00432-014-1756-6

Cited by 25 publications

(23 citation statements)

References 29 publications

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“…(2014)Asian (China)235180/5558 (29–84)IIIA-IVDDP+TAX/DOC/GEMOR, OSPCR-CTTP XRCC1 rs25487 103 Zhou, M. (2014)Asian (China)9356/3761.5 (NR)IIIB-IVDDP+GEMORPCR-RFLP XPD rs13181 rs1799793, CDA rs2072671 104 Zhao, X. (2014)Asian (China)192132/6060.8 (26–79)IIIA-IVPlatinum-basedOR, OSMALDI-TOF-MS ERCC1 rs3212986 rs11615 rs2298881 105 Lv, H. (2014)Asian (China)9154/3759 (34–80)IIIB-IVDDP+TAX/GEM/NVPORTaqMan-MGB GSTP1 rs1695 106 Krawczyk, P. (2014)Caucasian (Poland)11559/5661 (NR)II-IVDDP/CBP+PEMOSHRM, PCR-RFLP ERCC1 rs11615 107 Sullivan, I. (2014)Caucasian (Spain)161125/3663.7 (36–85)IIIA-IVDDP/CBP-basedOR, OSDynamic array chips ERCC1 rs3212986 rs11615, XPD rs13181 rs1799793, XPG rs1047768 rs17655, XRCC1 rs25487 rs1799782, rs25489, XPA rs1800975 108 Dong, C M. (2014)Asian (China)9238/5457 (40–6)IIIB-IVPlatinum-basedORPCR-RFLP MTHFR rs1801133 109 Liu, D. (2014)Asian (China)378297/8162.4 (36–78)I-IVDDP+GEM/DOC/NVP/TAXOR, OSPCR-RFLP XPG rs1047768 rs17655 XRCC1 rs25487 rs1799782 110 Kou, G. (2014)Asian (China)5014/3656 (45–78)IIIB-IVDDP+NVPORPCR-RFLP ERCC1 rs3212986 111 Kalikaki, A.…”

Section: Resultsmentioning

confidence: 99%

Genetic Polymorphisms and Platinum-based Chemotherapy Treatment Outcomes in Patients with Non-Small Cell Lung Cancer: A Genetic Epidemiology Study Based Meta-analysis

Tan

Qiu

Zhu

et al. 2017

Sci Rep

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Data regarding genetic polymorphisms and platinum-based chemotherapy (PBC) treatment outcomes in patients with NSCLC are published at a growing pace, but the results are inconsistent. This meta-analysis integrated eligible candidate genes to better evaluate the pharmacogenetics of PBC in NSCLC patients. Relevant studies were retrieved from PubMed, Chinese National Knowledge Infrastructure and WANFANG databases. A total of 111 articles comprising 18,196 subjects were included for this study. The associations of genetic polymorphisms with treatment outcomes of PBC including overall response rate (ORR), overall survival (OS) and progression-free survival (PFS) were determined by analyzing the relative risk (RR), hazard ration (HR), corresponding 95% confidence interval (CI). Eleven polymorphisms in 9 genes, including ERCC1 rs11615 (OS), rs3212986 (ORR), XPA rs1800975 (ORR), XPD rs1052555 (OS, PFS), rs13181 (OS, PFS), XPG rs2296147 (OS), XRCC1 rs1799782 (ORR), XRCC3 rs861539 (ORR), GSTP1 rs1695 (ORR), MTHFR rs1801133 (ORR) and MDR1 rs1045642 (ORR), were found significantly associated with PBC treatment outcomes. These variants were mainly involved in DNA repair (EXCC1, XPA, XPD, XPG, XRCC1 and XRCC3), drug influx and efflux (MDR1), metabolism and detoxification (GSTP1) and DNA synthesis (MTHFR), and might be considered as potential prognostic biomarkers for assessing objective response and progression risk in NSCLC patients receiving platinum-based regimens.

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Section: Resultsmentioning

confidence: 99%

Genetic Polymorphisms and Platinum-based Chemotherapy Treatment Outcomes in Patients with Non-Small Cell Lung Cancer: A Genetic Epidemiology Study Based Meta-analysis

Tan

Qiu

Zhu

et al. 2017

Sci Rep

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“…This among other polymorphisms has been suggested as molecular predictive markers by some publications in both SCLC and NSCLC [32,33]; but the results are not encouraging enough to promote these tests in the regular practice.…”

Section: Pemetrexedmentioning

confidence: 89%

Pharmacogenomics in the Treatment of Lung Cancer: an Update

et al. 2015

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Significant advances have been made in the analysis of the human genome in the first decades of the 21st century and understanding of tumor biology has matured greatly. The identification of tumor-associated mutations and the pathways involved has led to the development of targeted anticancer therapies. However, the challenge now in using chemotherapy to treat nonsmall-cell lung cancer is to identify more molecular markers predictive of drug sensitivity and determine the optimal drug sequences in order to tailor treatment to each patient. This approach could permit selection of patients who could benefit most from a specific type of chemotherapy by matching their tumor and individual genetic profile. Nevertheless, this potential has been limited so far by reliance on the single biomarker approach, though this is now on the way to being overcome through whole genome studies.

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“…While several studies have shown that an increased number of 28-bp variable number tandem repeat (VNTR) sequences in the 5′-UTR of the TYMS gene (i.e. the 3R/3R genotype) and/or a 6-bp insertion/deletion polymorphism in the 3′-UTR of TYMS may influence outcomes with pemetrexed, 10,11,13,15 others have demonstrated opposite results or no association at all. 12-14 Similarly, two prior studies concluded that NSCLC patients who were homozygous for a substitution of thymine for cytosine in nucleotide 677 of the MTHFR gene (i.e.…”

Section: Discussionmentioning

confidence: 99%

Pretreatment Red Blood Cell Total Folate Concentration Is Associated With Response to Pemetrexed in Stage IV Nonsquamous Non–Small-cell Lung Cancer

Bagley

Vitale

Zhang

et al. 2017

Clinical Lung Cancer

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Objectives Pemetrexed inhibits folate-dependent enzymes involved in pyrimidine and purine synthesis. Prior studies of genetic variation in these enzymes as predictors of pemetrexed efficacy have yielded inconsistent results. We investigated whether red blood cell (RBC) total folate, a phenotypic rather than genotypic marker of cellular folate status, was associated with response to pemetrexed-based chemotherapy in advanced non-squamous non-small-cell lung cancer (NSCLC). Materials and methods We conducted a prospective cohort study of patients with stage IV non-squamous NSCLC receiving first-line chemotherapy containing pemetrexed. Pretreatment RBC total folate was quantified using liquid chromatography/mass spectrometry. We then compared objective response rate (ORR) between patients with RBC total folate concentrations above and below an optimal cut-off value determined from the receiver operating characteristic (ROC) curve. A logistic regression model was used to adjust for age, sex, and use of bevacizumab. Results The ORR was 62% (32 of 52 patients). ROC analysis was used to establish that a RBC total folate cutoff value of 364.6 nM optimally discriminated between pemetrexed responders and non-responders. Patients with RBC total folate below 364.5 nM had an ORR of 27%, compared to 71% in patients with RBC total folate above this value (p=0.01). This difference persisted after adjusting for age, sex, and use of bevacizumab (OR 0.07, 95% CI 0.01 - 0.57, p=0.01). Conclusions Low pretreatment RBC total folate is associated with inferior response to pemetrexed-based chemotherapy in stage IV non-squamous NSCLC. Larger, multicenter studies are needed to validate RBC total folate as a predictive marker of pemetrexed response.

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Polymorphisms in TS, MTHFR and ERCC1 genes as predictive markers in first-line platinum and pemetrexed therapy in NSCLC patients

Cited by 25 publications

References 29 publications

Genetic Polymorphisms and Platinum-based Chemotherapy Treatment Outcomes in Patients with Non-Small Cell Lung Cancer: A Genetic Epidemiology Study Based Meta-analysis

Genetic Polymorphisms and Platinum-based Chemotherapy Treatment Outcomes in Patients with Non-Small Cell Lung Cancer: A Genetic Epidemiology Study Based Meta-analysis

Pharmacogenomics in the Treatment of Lung Cancer: an Update

Pretreatment Red Blood Cell Total Folate Concentration Is Associated With Response to Pemetrexed in Stage IV Nonsquamous Non–Small-cell Lung Cancer

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