Genetic polymorphisms of GSTP1 and XRCC1: prediction of clinical outcome of platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC) patients

F Zhou,H Lv,T Jiang,R Yao,J Liang,Z Yu

doi:10.4414/smw.2011.13275

Abstract

Platinum agents cause DNA cross-linking and oxidative damage. Genetic polymorphisms of GSTP1 and XRCC1 involved in glutathione metabolic and DNA repair pathways may explain inter individual differences in chemosensitivity and clinical outcome in NSCLC patients treated with platinum-based regimens. We used DNA sequencing methods to evaluate genetic polymorphisms of the GSTP1A313G and XRCC1G28152A in 111 patients with stage IV NSCLC treated with platinum-based chemotherapy. Clinical response was evaluated according to RECIST criteria after 2-3 cycles of chemotherapy and time to progression (TTP) was calculated from the time of initial treatment to disease progression. GSTP1A313G and XRCC1G28152A polymorphisms, both alone and in combination, were significantly associated with response to treatment and clinical outcome (p <0.05) in NSCLC patients treated with platinum-based chemotherapy. These polymorphisms independently predicted clinical outcome even after taking into account age, gender, tumour histology, tumour differentiation and chemotherapy regimens. Genetic polymorphisms of GSTP1 and XRCC1 may be important predictive factors in platinum-treated patients with advanced NSCLC. Assessment of genetic variations of GSTP1 and XRCC1 could facilitate therapeutic decisions for individualised therapy in advanced NSCLC.

Highlights

Lung cancer is one of the most prevalent cancers worldwide, and it has become the leading death cause in cities in China [1]
Genetic polymorphisms of Glutathione S-transferase P1 (GSTP1) and X-ray cross-complementing group 1 (XRCC1) involved in glutathione metabolic and DNA repair pathways may explain inter individual differences in chemosensitivity and clinical outcome in non-small cell lung cancer (NSCLC) patients treated with platinum-based regimens
We used DNA sequencing methods to evaluate genetic polymorphisms of the GSTP1A313G and XRCC1G28152A in 111 patients with stage IV NSCLC treated with platinum-based chemotherapy

Summary

Introduction

Lung cancer is one of the most prevalent cancers worldwide, and it has become the leading death cause in cities in China [1]. Platinum-based doublets are used as standard first line chemotherapy in NSCLC patients, with an objective response rate of about 40%, a median survival time of 8–10 months and a one-year survival rate of 30–40% [3, 4]. Platinum agents remain the most commonly used chemotherapeutic agents in advanced NSCLC patients and are known to act through the formation of bulky intra- and interstrand DNA adducts that inhibit DNA synthesis and transcription. Proposed mechanisms of resistance to platinum agents have been attributed to inactivation of platinum compounds through the glutathione metabolic pathway and increased tolerance to DNA damage as a consequence of enhanced DNA repair capacity. Glutathione S-transferase P1 (GSTP1) is a subclass of GSTs that directly participates in the detoxification of platinum compounds and is an important mediator of both intrinsic and acquired resistance to platinum [6]. Previous studies have shown that expression level and the polymorphic A313G of GSTP1 are linked to the sens-

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