ERCC1 predicting chemoradiation resistance and poor outcome in oesophageal cancer

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Abstract

We assessed whether expression of excision repair cross-complementation group 1 (ERCC1) and/or thymidylate synthase (TS) can predict clinical outcome after preoperative chemoradiotherapy (CRT) in patients with localised oesophageal cancer. Paraffin-embedded pretreatment tumour specimens collected by endoscopic biopsy from patients treated with preoperative CRT (5-fluorouracil/cisplatin or capecitabine/cisplatin plus radiation) were analysed by immunohistochemical assay. Between March 1993 and June 2005, 129 patients were treated with preoperative CRT followed by surgery; of these, 108 biopsy specimens were available for analysis, and 40% and 35% were positive for ERCC1 and TS, respectively. Patients with ERCC1-negative (p < 0.001) or TS-negative (p = 0.04) tumours were significantly more likely to achieve pathologic major response. In multivariate analysis, ERCC1 was the only independent variable predicting pathologic response (p < 0.001). Patients with ERCC1-negative tumours showed tendencies toward prolonged overall survival (p = 0.10) and event free survival (p = 0.08). Prospective studies are required to determine the benefit of preoperative CRT in ERCC1-negative tumours.

Introduction

Oesophageal cancer is the eighth most common cancer worldwide, with 462,000 new cases per year, as well as being the sixth most common cause of cancer mortality. Its prognosis is poor, with a 5-year survival rate of less than 10%.1 A multimodal approach has been used to improve patient outcomes, with concurrent chemoradiotherapy (CRT) followed by oesophagectomy being the standard treatment option.2, 3, 4, 5

We have performed several prospective studies testing the effectiveness of preoperative CRT in patients with operable oesophageal cancer with squamous cell histology.4, 6, 7 We found that pathologic major response was an independent prognostic factor.6 However, the major obstacle to improved outcome in operable oesophageal cancer is the inability to predict response to CRT. If one could predict the response of CRT, treatment could be tailored to chemoradiation or immediate surgery and the survival of patients with operable oesophageal cancer could therefore be improved. In this point of view, it is necessary to investigate the surrogate biomarkers predicting pathologic response to CRT. Although the prognostic effect of biomarkers has been evaluated in operable oesophageal cancer, most of these studies involved relatively small, heterogeneous groups of patients beyond clinical trials. Moreover, there have been few investigations of biomarkers that can predict pathologic response in the preoperative CRT setting.

The nucleotide excision pathway is one of the most important pathways guarding the integrity of the genome, removing a wide variety of DNA lesions including interstrand cross-links caused by cisplatin or radiation.8, 9 The enzyme, excision repair cross-complementation group 1 (ERCC1), plays a rate-limiting role in the nucleotide excision repair pathway.10, 11 In contrast, thymidylate synthase (TS) is the rate-limiting enzyme involved in DNA synthesis,12 and competitive inhibition of its activity appears to be the major mechanism for the antitumour effect of fluoropyrimidines.13 The expression of ERCC1 and/or TS has been associated with clinical outcome in patients with various malignancies.14, 15, 16

We therefore assessed whether expression of ERCC1 and/or TS can predict clinical outcome, such as pathologic response to CRT and survival, in patients with locally advanced oesophageal cancer.

Section snippets

Patient selection and evaluation

Beginning in March 1993, we conducted three prospective clinical trials in 268 patients, aged 18 to 75 years, with locally advanced but resectable, histologically established oesophageal cancer.4, 6, 7 The eligibility criteria for all three trials were identical. Of the 268 patients, 129 underwent preoperative CRT and oesophagectomy. For ERCC1 and TS analysis, each case was required to meet the following criteria: 1) pretreatment pathology available for analysis, 2) completion of the prescribed

Patient characteristics

Of 116 samples tested, 108 were assessable for both TS and ERCC1 expression. The 108 patients (93 men, 15 women) had a median age of 63 years (range, 43 to 73 years). Histologically, all primary tumours were squamous cell carcinomas. Most tumours originated from the middle and lower oesophagus. Patient baseline demographic and clinical characteristics are shown in Table 1.

Association of biological marker expression with patient and tumour characteristics

The median scores (proportion stained × staining intensity) of ERCC1 and TS were 4 and 3, respectively. Based on this,

Discussion

Despite efforts to identify factors predicting pathologic responses to preoperative CRT in patients with locally advanced oesophageal cancer, no suitable markers have been identified to date. In considering the mechanism of CRT, we hypothesised that ERCC1 and TS expression may be associated with response, and we therefore assayed whether the expression levels of TS and ERCC1 could act as biomarkers to predict clinical outcome in these patients. We found that lower ERCC1 expression (ERCC1  4) was

Conflict of interest statement

None declared.

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