Biomarker analysis in stage III–IV (M0) gastric cancer patients who received curative surgery followed by adjuvant 5-fluorouracil and cisplatin chemotherapy: epidermal growth factor receptor (EGFR) associated with favourable survival

Abstract

The aim of this study was to analyse the impact of epidermal growth factor receptor (EGFR), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), aurora kinase (ARK) A/B, and excision repair crosscomplementing gene 1 (ERCC1) on the efficacy of adjuvant chemotherapy with 5-fluorouracil and cisplatin (FP) after curative gastric resection. Normal and cancer tissue were separately obtained from gastrectomy samples of 153 patients with AJCC stage III -IV (M0) who subsequently treated with adjuvant FP chemotherapy. TS, DPD, TP, ERCC1, and ARK proteins were measured by immunohistochemistry (IHC). EGFR expression was investigated using a standardized IHC with the EGFR PharmDx assay. Amplification of EGFR gene was analysed using fluorescent in situ hybridisation (FISH). In multivariate analysis, stage, ratio of positive to removed lymph nodes, and EGFR expression were significant prognostic factors for overall survival. Patients with higher EGFR expression had better overall survival than those with lower expression (relative risk: 0.475 (95% confidence interval, 0.282 -0.791, P ¼ 0.005). Low EGFR expression might be a predictive marker for relapse in curative resected stage III -IV (M0) gastric cancer patients who received adjuvant FP chemotherapy.

Prognostic significance of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase expression in biliary tract cancer patients receiving adjuvant 5-fluorouracil-based chemotherapy

“…However, other studies reported discordant results in gastric cancer patients (14,15). TS expression in stage III-IV gastric cancer patients who received curative surgery followed by adjuvant chemotherapy was not associated with clinical outcomes (14).We also previously demonstrated that TS expression was not correlated with chemotherapeutic response or OS in metastatic gastric cancer patients (15) and that TS expression did not exhibit a statistically significant association with OS. Patients with lower TS expression levels exhibited a trend to correlate with a shorter OS compared to those with higher TS expression levels OS (P=0.222).…”

“…A previous meta-analysis also reported an HR of 1.35 for a high TS expression in 2,610 patients with localized colorectal cancer (13). However, other studies reported discordant results in gastric cancer patients (14,15). TS expression in stage III-IV gastric cancer patients who received curative surgery followed by adjuvant chemotherapy was not associated with clinical outcomes (14).We also previously demonstrated that TS expression was not correlated with chemotherapeutic response or OS in metastatic gastric cancer patients (15) and that TS expression did not exhibit a statistically significant association with OS.…”

“…A recent meta-analysis confirmed a poorer overall survival of patients with enhanced TS activity, compared to those with low TS activity (13). However, conflicting results have been reported regarding TS expression in gastric cancer (14,15).…”

Gene copy number gain of EGFR is a poor prognostic biomarker in gastric cancer: evaluation of 855 patients with bright-field dual in situ hybridization (DISH) method

“…Although the criteria for EGFR amplification are not formally established and a wide range of EGFR/CEN7 ratios (1.7-6.0) were used in previous studies [3,5,22,24,26,29,30], the frequency of EGFR amplification did not vary among these studies, which may be attributed to the fact that the EGFR/CEN7 ratio is [10.0 in most patients with EGFR amplification, and a defined cutoff value would not influence the results (Fig. 2).…”

“…However, the incidence of EGFR overexpression reported in previous studies varies from 2 % to 81 %, probably the result of differences in antibodies, scoring systems, and observers [4,21,[24][25][26][27][28][29][30][31][32]. In contrast, the frequency of EGFR gene amplification in gastric cancers is consistently less variable (2-7 %), although most of these studies lacked a sufficiently large number of patients or a detailed EGFR GCN examination [3,5,22,24,26,29,30]. The correlation between overexpression and EGFR GCN has not been firmly established.…”