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

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.

Effect of ERCC1 polymorphism on the response to chemotherapy and clinical outcome of non-small cell lung cancer

“…In addition, studies examining SNPs and clinical outcome of NSCLC showed contradictory data. The ERCC1 protein belongs to the nuclear excision repair complex and is involved in the repair of platinum-based induced interstrand and intrastrand cross-links (Mlak et al, 2013). A previous study indicated that the rs11615 polymorphism is associated with reduced ERCC1 mRNA expression and protein levels, which are associated with reduced repair capacity and survival time (Metzger et al, 2012).…”

“…Excision repair cross-complementation group 1 (ERCC1) is an endonuclease essential in the nucleotide excision repair pathway and plays a role in DNA repair capacity and cancer risk as well as the clinical outcome of cancer (Wang et al, 2005). Recently, several studies suggested that variants in ERCC1 influence the susceptibility to and prognosis of various cancers Mlak et al, 2013;Yang et al, 2013;De Dosso et al, 2013). Few studies have investigated the role of ERCC1 variants in the clinical outcome in NSCLC (Ozdemir et al, 2013;Mlak et al, 2013).…”

“…Recently, several studies suggested that variants in ERCC1 influence the susceptibility to and prognosis of various cancers Mlak et al, 2013;Yang et al, 2013;De Dosso et al, 2013). Few studies have investigated the role of ERCC1 variants in the clinical outcome in NSCLC (Ozdemir et al, 2013;Mlak et al, 2013). In this prospective study, we analyzed the role of 3 common single-nucleotide polymorphisms (SNPs) in ERCC1 for predicting tumor responses and the clinical outcome of 163 NSCLC patients.…”

Study on the ERCC1 gene polymorphism response to chemotherapy and prognosis of gastric cancer

“…ERCC1 is located on chromosome 19q13.32, interacts with other NER proteins, and guides the 5'-incision activity of the NER pathway (Volker et al, 2001). Previous studies reported that the ERCC1 polymorphism is correlated with increased chemotherapeutic sensitivity and may be a prognostic marker for various cancers treated with chemotherapy (Mlak et al, 2013;Moxley et al, 2013;Rumiato et al, 2013). The association between the ERCC1 polymorphism and gastric cancer has been reported in several studies (Huang et al, 2008;Liang et al, 2010;Yin et al, 2011).…”

ERCC1 mRNA expression is associated with the clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy

“…Previous studies have suggested that ERCC1 and RRM1 may play a role in chemosensitivity and the clinical outcomes of NSCLC patients treated with platinum-based chemotherapy (Kotoula et al, 2012;Leng et al, 2012;Pesta et al, 2012;Mlak et al, 2013). However, few studies have investigated the effect of ERCC1 and RRM1 on the clinical outcome of NSCLC or the association between ERCC1 and RRM1 expression and clinical characteristics.…”