Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX‐4 treatment in Asian patients with colorectal carcinoma

Abstract

Glutathione S-transferase P1 (GSTP1) participates in detoxification of potentially genotoxic compounds that may alter the efficacy and toxicity of platinum-based chemotherapy. We analyzed the influence of I105V polymorphism of GSTP1 on clinico-pathological features and outcomes in 166 Chinese patients with metastatic colorectal carcinoma who had been treated with first-line FOLFOX-4. Combined analysis of GSTP1 I105V, ERCC1-118, and XPD-751 polymorphisms was also conducted. The results showed that, in comparison with Caucasian populations, a remarkably lower prevalence of Val105 allele variants was noted (24.7%). Patients with Val105 allele variants had a higher response to FOLFOX-4 (56.1% vs 37.6%, P = 0.04), and a longer progression-free (P < 0.01) as well as overall (P < 0.01) survival. By adjusted analysis, this polymorphism was identified as an independent prognostic factor (P = 0.01). In combined analysis, patients without any risk genotype, including GSTP1-105 Ile/Ile, ERCC1-118 C/T or T/T, and XPD-751 Lys/Gln, had significantly longer progression-free and overall survivals (P < 0.01). In addition, patients with Val105 allele variants had a higher incidence of grade 3/4 cumulative neuropathy after different cycles of treatment. These data suggest that Asian populations have a lower prevalence of I105V polymorphism in GSTP1. I105V polymorphism in GSTP1, by reducing its enzymatic activity and consequential detoxification to oxaliplatin, could be a key determinant for a better outcome, but more neurotoxicity, to FOLFOX-4 treatment. (Cancer Sci 2010; 101: 530-535) C olorectal carcinoma (CRC) is one of the leading causes of cancer-related mortality in Taiwan and its incidence has increased steadily over the past few decades. Oxaliplatin is very effective in treating metastatic CRC patients, (1,2) and improves the disease-free survival of patients with stage II ⁄ III CRC. Neuropathy is the major toxicity of oxaliplatin, and the incidence of oxaliplatin-induced severe neuropathy has varied from 12% to 18%.(3-5) Oxaliplatin-induced neuropathy includes an acute, transient peripheral nerve hyperexcitability,and a chronic, dose-related, peripheral sensory neuropathy with symptoms similar to those caused by cisplatin.(7) Development of chronic neuropathy results in severe disturbance of neurologic functions. Therefore, identification of factors predictive of neurotoxicity to oxaliplatin treatment, including genes involved in the nucleotide excision repair (NER) (8,9) and detoxification pathways, (10) is of extreme interest. Glutathione S-transferases (GST) are a multigene family of enzymes which catalyze the conjugation of glutathione to electrophilic xenobiotics to inactivate them, and thus prevent DNA damage and adduct formation.(11) At least five major classes of the GST superfamily have been identified, (10) among them, the GSTP1, GSTT1, and GSTM1 genotypes have been studies extensively for their influences in the inter-individual variations of outcome to chemotherapeutic agents. (12,13) The isoenzyme GSTP1 is ...

The XPD Lys751Gln Polymorphism has Predictive Value in Colorectal Cancer Patients Receiving Oxaliplatin-Based Chemotherapy: a Systemic Review and Meta-analysis

“…By contrast, one article consisted of two independent studies, and studies included in this article were treated as separate studies (MartinezBalibrea et al, 2008). As a result, a total of 2286 CRC patients were enrolled in the 17 studies included in the pool analysis (Park et al, 2001;Stoehlmacher et al, 2004;Le Morvan et al, 2007;Ruzzo et al, 2007;Martinez-Balibrea et al, 2008;Pare et al, 2008;Lai et al, 2009;Boige et al, 2010;Chen et al, 2010;Etienne-Grimaldi et al, 2010;Farina Sarasqueta et al, 2011;Lamas et al, 2011;Chen et al, 2012;Gan et al, 2012;Li et al, 2012;Kumamoto et al, 2013). The selection procedure is shown in Figure 1, and the key patient characteristics are listed by study in Table 1.…”

“…Several studies have indicated that patients carrying the 751Gln allele tend to have a worse clinical outcome to oxaliplatin-based chemotherapy than those carrying the wild type 751Lys allele (Park et al, 2001;Le Morvan et al, 2007;Pare et al, 2008;Lai et al, 2009;Chen et al, 2010;Leichman et al, 2011). However, the opposite association was identified by two separate studies (Gan et al, 2012;Li et al, 2012), and three studies failed to provide evidence of any correlation (Martinez-Balibrea et al, 2008;Lamas et al, 2011;Kumamoto et al, 2013).…”

Impact of XRCC1, GSTP1, and GSTM1 Polymorphisms on the Survival of Ovarian Carcinoma Patients Treated with Chemotherapy

“…Their success in the treatment of cancer patients is most likely due to inducing DNA adducts, leading to the death of tumour cells [21]. DNA repair and drug metabolism have been reported to worsen the prognosis of patients receiving platinum-based chemotherapy [22,23]. Numerous studies have assessed the roles of gene polymorphisms with regard to the response to treatment and survival of different cancers, including ovarian cancer [24,25,26,27,28,29].…”

Single nucleotide polymorphisms in glutathione S-transferase P1 and M1 genes and overall survival of patients with ovarian serous cystadenocarcinoma treated with chemotherapy

“…However, DNA repair and drug metabolism may hinder the prognosis of patients that are administered platinum-based chemotherapy (22,23).…”