Single nucleotide polypmorphisms in ERCC1 are associated with disease progression, and survival in patients with advanced stage ovarian and primary peritoneal carcinoma; A Gynecologic Oncology Group Study

Abstract

Objective

This study evaluated common polymorphisms in excision repair cross-complementation group 1 (ERCC1) involved in repair of platinum-induced DNA damage in advanced-stage, epithelial ovarian/peritoneal/tubal cancer (EOC/PPC/FTC) patients treated with intravenous carboplatin- and paclitaxel-based chemotherapy.

Methods

Pyrosequencing was performed to examine single nucleotide polymorphisms (SNPs) in codon 118 and C8092A in ERCC1 in leukocyte DNA from the Gynecologic Oncology Group phase III protocol, GOG-182. Kaplan–Meier method and adjusted Cox regression modeling were used to examine associations between ERCC1 polymorphisms and progression-free survival (PFS) and overall survival (OS).

Results

The genotype distribution at codon 118 (n = 278) in ERCC1 for CC, CT, and TT was 23%, 45% and 32%, and the median OS was 32, 47 and 43 months, respectively. Patients with the CT + TT versus CC genotype in codon 118 in ERCC1 were at a reduced risk of death (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.49–0.95, p = 0.025). The genotype distribution for C8092A in ERCC1 (N = 280) was 50%, 42% and 8%, and the median OS was 45, 40 or 30 months for CC, CA and AA, respectively. Women with the CA + AA versus CC genotype in C8092A in ERCC1 had a trend suggesting an increased risk of death (HR = 1.29, 95% CI = 0.97–1.72, p = 0.077).

Conclusions

The polymorphism in codon 118 in the DNA repair gene ERCC1 was an independent predictor for better survival in EOC/PPC/FTC patients treated with intravenous carboplatin- and paclitaxel-based chemotherapy. The relationship between the C8092A polymorphisms in ERCC1 and survival was modest with an effect size that was not always statistically significant.

Introduction

The treatment of advanced stage epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC) consists of a combination of cytoreductive surgery followed by platinum + taxane-based chemotherapy [1], [2]. Despite the use of aggressive surgery and combination chemotherapy, ovarian cancer remains the most lethal gynecologic cancer with an estimated 21,880 new cases resulting in 13,850 deaths in 2010 in the United States (US) [3]. The majority of patients respond well to primary therapy with 60–80% of patients achieving clinical remission. However, approximately 15% of patients will have platinum-refractory disease and experience progression on primary therapy. An additional 30% will recur within 6 months of completing treatment, and will generally have platinum resistant disease. Eventually, the majority of patients with advanced stage EOC or PPC will develop recurrent disease that is platinum resistant, limiting the success of subsequent cytotoxic chemotherapy.

There are numerous mechanisms for platinum resistance that have been described, including defects in the DNA repair pathways such as DNA mismatch repair, base excision repair (BER), and nucleotide excision repair (NER) [4], [5]. Excision repair cross-complementation group 1 (ERCC1)–xeroderma pigmentosum group F (XPF) heterodimers are the only DNA repair proteins essential for both the NER and DNA interstrand crosslink repair (ICL-R) pathways. Not surprisingly, ERCC1–XPF heterodimers are absolutely required for the repair of all types of platinum-induced DNA damage including intrastrand cross-links that produce local kinks and unwinding of duplex DNA as well as interstrand cross-links that impede DNA replication and transcription. The exonuclease activity associated with the ERCC1–XPF heterodimer is responsible for the 5′ incision and cleavage of damaged DNA during the repair process [5]. Defects in ERCC1 are associated with a DNA repair deficiency, and cells without functional ERCC1 protein are not able to repair platinum-induced DNA adducts [6], [7], [8]. Additionally, it has been shown that increased ERCC1 expression in ovarian cancer cell lines is associated with the development of platinum resistance [9], [10]. Studies evaluating ERCC1 expression in relationship to patient survival have shown a correlation between increased expression with decreased survival in lung, colon, pancreatic, gastric, bladder, and esophageal cancers [11], [12], [13], [14], [15], [16], [17], [18].

Genetic alterations in the ERCC1 gene, especially variants that may be linked to transcript expression or stability have potential clinical utility as prognostic factors, marker of response to chemotherapy, and/or predictive markers for guiding treatment selection. A number of studies have examined the association between expression [19], [20], [21], [22], [23] or single nucleotide polymorphisms [20], [24], [25], [26], [27], [28] in ERCC1 and clinical outcomes including response to platinum-based therapy, progression-free survival (PFS) and overall survival (OS) in patients with EOC. Among these studies, polymorphisms in ERCC1 have been shown to be associated either with risk of platinum-resistance [24], worse PFS and OS [25], [26], [27], similar PFS [25], [26], [27], [28], or similar OS [20], [24], [25], [26], [27]. Weberpals et al. provided evidence that patients with low levels of mRNA expression of tumoral ERCC1 had improved OS [22]. In contrast to expression studies of ERCC1 in pre-treatment archival tumor, Darcy et al. showed the mRNA expression of ERCC1 in post-treatment leukocytes was not associated with either PFS or OS [29].

The purpose of the current study was to evaluate the affect of two common polymorphisms in the ERCC1 gene, on PFS and/or OS in women with stages III–IV EOC, PPC or FTC treated in the US with carboplatin + paclitaxel-based combination chemotherapy. Polymorphisms in codon 118 and C8092A in ERCC1 were evaluated in leukocyte DNA from women enrolled in the multi-institutional, phase III trial conducted by the Gynecologic Oncology Group, GOG 182. The addition of gemcitabine, pegylated liposomal doxorubicin or topotecan to carboplatin + paclitaxel either as a sequential doublet or triplet did not result in significant improvements in OS compared with the carboplatin + paclitaxel control arm [30].