Predictive value of ERCC1 and RRM1 gene single-nucleotide polymorphisms for first-line platinum- and gemcitabine-based chemotherapy in non-small cell lung cancer patients

Mlak,Radosław; Krawczyk,Paweł; Ramlau,Rodryg; Kalinka-Warzocha,Ewa; Wasylecka-Morawiec,Maja; Wojas-Krawczyk,Kamila; Kucharczyk,Tomasz; Homa,Iwona; Kozioł,Piotr; Ciesielka,Marzanna; Chudziak,Dorota; Milanowski,Janusz

doi:10.3892/or.2013.2696

Predictive value of ERCC1 and RRM1 gene single-nucleotide polymorphisms for first-line platinum- and gemcitabine-based chemotherapy in non-small cell lung cancer patients

Authors:
- Radosław Mlak
- Paweł Krawczyk
- Rodryg Ramlau
- Ewa Kalinka-Warzocha
- Maja Wasylecka-Morawiec
- Kamila Wojas-Krawczyk
- Tomasz Kucharczyk
- Iwona Homa
- Piotr Kozioł
- Marzanna Ciesielka
- Dorota Chudziak
- Janusz Milanowski
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Affiliations: Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-954 Lublin, Poland, Wielkopolska Center of Pulmonology and Thoracosurgery of Eugenia and Janusz Zeyland, 60-569 Poznan, Poland, Regional Centre of Oncology in Lodz, 93-509 Lodz, Poland, Department of Forensic Medicine, Medical University of Lublin, 20-954 Lublin, Poland
Published online on: August 26, 2013 https://doi.org/10.3892/or.2013.2696
Pages: 2385-2398

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Abstract

Platinum-based chemotherapy with third generation drugs (such as gemcitabine) is an efficacious regimen of first-line treatment of patients with advanced, unresectable non-small cell lung cancer (NSCLC), without activating EGFR mutations. Mechanism of action of cytostatics are distortions in the DNA. ERCC1 and RRM1 are key proteins involved in the repair of DNA, thus, they may be responsible for the ineffectiveness of therapy. We investigated whether ERCC1 (19007C>T) and RRM1 (-37C>A) polymorphisms impact response to chemotherapy and survival in 62 patients with NSCLC treated with platinum and gemcitabine. Single nucleotide polymorphisms (SNPs) were assessed using a PCR-RFLP method in DNA isolated from PBLs. There were no statistically significant relationships between ERCC1 genotypes and response to therapy (p=0.581, χ2=1.09) as well as patient overall survival (OS). Carriers of the RRM1 AC genotype showed disease progression significantly more frequently (p=0.019, χ2=5.473) compared to carriers of the AA or CC genotypes. Carriers of the ERCC1/RRM1TT/CC genotype combination showed disease control significantly more frequently (p=0.047, χ2=3.95) compared to carriers of other genotype combinations. Patients with AA or CC genotypes of RRM1 showed significantly higher progression-free survival probability (p=0.0001, HR=0.39, 95% CI, 0.22-0.70) and OS probability (p=0.0104, HR=0.39, 95% CI, 0.18-0.82) compared to those with the AC genotype. In Cox regression model, poor performance status (p=0.0016, HR=4.78, 95% CI, 1.82-12.56), AC genotype of RRM1 gene (p=0.0414, HR=2.47, 95% CI, 1.04-5.87), lack of prior surgical treatment (p=0.0425, HR=4.71, 95% CI, 1.06-20.92) and lack of subsequent lines of treatment (p=0.0127, HR=3.23, 95% CI, 1.29-8.11) were significantly associated with shortening of patient survival. The analysis of RRM1 (-37C>A) more than ERCC1 (19007C>T) polymorphism may be a promising tool in the qualification of NSCLC patients for chemotherapy containing platinum compounds and gemcitabine.

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1	Dela Cruz CS, Tanoue LT and Matthay RA: Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med. 32:605–644. 2011.PubMed/NCBI
2	NSCLC Meta-Analysis Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer. A systemic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol. 26:4617–4625. 2008. View Article : Google Scholar : PubMed/NCBI
3	Simon GR, Ismail-Khan R and Bepler G: Nuclear excision repair-based personalized therapy for non-small cell lung cancer: from hypothesis to reality. Int J Biochem Cell Biol. 39:1318–1328. 2007. View Article : Google Scholar : PubMed/NCBI
4	Jordheim LP, Sève P, Trédan O, et al: The ribonucleotide reductase large subunit (RRM1) as a predictive factor in patients with cancer. Lancet Oncol. 12:693–702. 2011. View Article : Google Scholar : PubMed/NCBI
5	Stewart DJ: Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer. Crit Rev Oncol Hematol. 75:173–234. 2010. View Article : Google Scholar : PubMed/NCBI
6	Bepler G, Sharma S, Gautam A, et al: Tumor genotype, RRM1 expression and outcome of patients with lung cancer. Eur J Cancer. 38(Suppl 7): 82(Abstr 265). 2003.
7	Vilmar A and Sorensen JB: Excision repair cross-complementation group 1 (ERCC1) in platinum-based treatment of non-small cell lung cancer with special emphasis on carboplatin: a review of current literature. Lung Cancer. 64:131–139. 2009. View Article : Google Scholar
8	Olaussen K, Dunant A, Fouret P, et al: DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 335:981–983. 2006.PubMed/NCBI
9	Ceppi P, Volante M, Novello S, et al: ERCC1 and RRM1 gene expression but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol. 17:1818–1825. 2006. View Article : Google Scholar : PubMed/NCBI
10	Paz-Ares L, Souliers D, Melezinek I, et al: Clinical outcome in non-small cell lung cancer patients with EGFR mutation: pooled analysis. J Cell Mol Med. 14:51–69. 2010. View Article : Google Scholar : PubMed/NCBI
11	Mitsudomi T, Morita S, Yatabe Y, et al: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial. Lancet Oncol. 11:121–128. 2010. View Article : Google Scholar
12	Zheng Z, Chen T, Li X, et al: DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med. 356:800–808. 2007. View Article : Google Scholar : PubMed/NCBI
13	Bepler G, Olaussen KA, Vataire AL, et al: ERCC1 and RRM1 in the international adjuvant lung trial by automated quantitative in situ analysis. Am J Pathol. 178:69–78. 2011. View Article : Google Scholar : PubMed/NCBI
14	Cobo M, Isla D, Massuti B, et al: Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. J Clin Oncol. 25:2747–2754. 2007. View Article : Google Scholar : PubMed/NCBI
15	Simon GR, Schell MJ, Begum M, et al: Preliminary indication of survival benefit from ERCC1 and RRM1-tailored chemotherapy in patients with advanced non-small cell lung cancer: evidence from an individual patient analysis. Cancer. 118:2525–2531. 2012.PubMed/NCBI
16	McWhinney SR and McLeod HL: Using germline genotype in cancer pharmacogenetic studies. Pharmacogenomics. 10:489–493. 2009. View Article : Google Scholar : PubMed/NCBI
17	Bepler G, Zheng Z, Gautam A, et al: Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance. Lung Cancer. 47:183–192. 2005. View Article : Google Scholar : PubMed/NCBI
18	Chang PM, Tzeng CH, Chen PM, et al: ERCC1 codon 118 C→T polymorphism associated with ERCC1 expression and outcome of FOLFOX-4 treatment in Asian patients with metastatic colorectal carcinoma. Cancer Sci. 100:278–283. 2009. View Article : Google Scholar
19	Isla D, Sarries C, Rosell R, et al: Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer. Ann Oncol. 15:1194–1203. 2004. View Article : Google Scholar : PubMed/NCBI
20	Tibaldi C, Giovannetti E, Vasile E, et al: Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res. 14:1797–1803. 2008. View Article : Google Scholar : PubMed/NCBI
21	Ryu JS, Hong YC, Han HS, et al: Associated between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy. Lung Cancer. 44:311–316. 2004. View Article : Google Scholar : PubMed/NCBI
22	Su D, Ma S, Liu P, et al: Genetic polymorphisms and treatment response in advanced non-small cell lung cancer. Lung Cancer. 56:281–288. 2007. View Article : Google Scholar : PubMed/NCBI
23	Krawczyk P, Wojas-Krawczyk K, Mlak R, et al: Predictive value of ERCC1 single-nucleotide polymorphism in patients receiving platinum-based chemotherapy for locally-advanced and advanced non-small cell lung cancer: a pilot study. Folia Histochem Cytobiol. 50:80–86. 2012. View Article : Google Scholar
24	Ren S, Zhou S, Wu F, et al: Association between polymorphisms of DNA repair genes and survival of advanced NSCLC patients treated with platinum-based chemotherapy. Lung Cancer. 75:102–109. 2012. View Article : Google Scholar : PubMed/NCBI
25	Kalikaki A, Kanaki M, Vassalou H, et al: DNA repair gene polymorphisms predict favorable clinical outcome in advanced non-small-cell lung cancer. Clin Lung Cancer. 10:118–123. 2009. View Article : Google Scholar : PubMed/NCBI
26	Yu D, Shi J, Sun T, et al: Pharmacogenetic role of ERCC1 genetic variants in treatment response of platinum-based chemotherapy among advanced non-small cell lung cancer patients. Tumour Bio. 33:877–884. 2012. View Article : Google Scholar : PubMed/NCBI
27	Takenaka T, Yano T, Kiyohara C, et al: Effects of excision repair cross-complementation group 1 (ERCC1) single nucleotide polymorphisms on the prognosis of non-small cell lung cancer patients. Lung Cancer. 67:101–107. 2010. View Article : Google Scholar : PubMed/NCBI
28	Ludovini V, Floriani I, Pistola L, et al: 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. J Thorac Oncol. 6:2018–2026. 2011. View Article : Google Scholar
29	Liao WY, Shih JY, Chang GC, et al: Genetic polymorphism of XRCC1 Arg399Gln is associated with survival in non-small-cell lung cancer patients treated with gemcitabine/platinum. J Thorac Oncol. 7:973–981. 2012. View Article : Google Scholar : PubMed/NCBI
30	Feng JF, Wu JZ, Hu SN, et al: Polymorphisms of the ribonucleotide reductase M1 gene and sensitivity to platin-based chemotherapy in non-small cell lung cancer. Lung Cancer. 66:344–349. 2009. View Article : Google Scholar : PubMed/NCBI
31	Song D, Ai-Lin G, Zhi-Hong Ch, et al: RRM1 single nucleotide polymorphism −37C>A correlates with progression-free survival in NSCLC patients after gemcitabine-based chemotherapy. J Hematol Oncol. 3:102010.