Efficacy of Gemcitabine in Patients with Non–Small Cell Lung Cancer According to Promoter Polymorphisms of the Ribonucleotide Reductase M1 Gene

Abstract

Purpose: High ribonucleotide reductase M1 (RRM1) expression in resected lung cancers has been associated with better clinical outcomes. However, gemcitabine-treated patients with high tumoral RRM1 expression generally evidence poor prognoses due to the decreased efficacy of gemcitabine therapy. This study was designed in accordance with the hypothesis that polymorphisms (-37 and -524) of the RRM1 promoter gene sequence, which regulate RRM1expression, could influence the efficacy and prognosis of lung cancer patients treated with gemcitabine-based chemotherapy. Experimental Design: A retrospective dataset of 97 patients with advanced non^small cell lung cancer treated with gemcitabine regimens as a first-line treatment was studied in this work. The allelotyping of RRM1 promoter polymorphisms was conducted via real-time PCR using genomic DNA obtained from peripheral WBC. Results: The RRM1 promoter allelotype was RR37CC-R524TT in 58 patients, RR37AC-RR524CT in 29 patients, and other allelotypes in 10 patients. The response rate for gemcitabinecontaining chemotherapy was 49.5 %. The response rate was significantly higher in the RR37AC-RR524CT group (65.5%) compared with the group containing other allelotypes (42.6%; P = 0.039). Overall survival and progression-free survival did not differ significantly by allelotype. Conclusions: We detected significant differences in response rates to gemcitabine-based chemotherapy according to the allelotypes of the RRM1 promoter sequence, which could be determined using the germline DNA. Further functional and clinical studies will be required before this can be used as a predictive marker.

In Situ Protein Expression of RRM1, ERCC1, and BRCA1 in Metastatic Breast Cancer Patients Treated with Gemcitabine-Based Chemotherapy

“…A decrease in the level of the equilibrationsensitive nucleoside transporter of gemcitabine and the genotype of RRM1 gene promoter polymorphisms may also play a role in gemcitabine resistance [33,34].…”

Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer

“…19,27,29 No significant associations were detected for both RRM1 G2464A and A2455G polymorphisms and RRM1 gene expression. These results are in agreement with a previous study showing no significant association between mRNA levels of wild-type and polymorphic types in RRM1 G2464A alone (P ¼ 0.301), or a combination of several types of RRM1, including RRM1 A2455G, in 62 human cancer cell lines were used, including six lung cancer cell lines.…”

“…Indeed, the RRM1 promoter allelotypes RR37CC-RR524TT were associated with overall and disease-free survival in resected NSCLC patients, but no correlation was found with tumor RRM1 expression. 26,27 Similarly, no significant association was detected between RRM1 mRNA expression and the RRM1 G2464A SNP, which is apparently associated with chemosensitivity to gemcitabine in 62 cancer cell lines. 28 This SNP, together with the A2455G polymorphism was associated with clinical outcome after gemcitabine treatment in breast cancer patients, but no analyses on RRM1 expression levels in tissues were conducted in this study.…”

One Step Closer to the Target: Intracellular Pharmacokinetics of Gemcitabine

“…There are two relatively common polymorphism in the European population c.2223A>G and 2464G>A with minor allele frequencies of 0.5 and 0.16 respectively. The 2464G>A has been shown to be associated with GEM sensitivity in vitro (Kwon et al, 2006)and haplotype is associated with response (but not survival) in patients with NSCLC treated with GEM (Kim et al, 2008). A small study suggested a relationship between -37C>A and progression free survival (PFS) (S. Dong et al, 2010).…”