Association of Pretherapeutic Expression of Chemotherapy-Related Genes with Response to Neoadjuvant Chemotherapy in Barrett Carcinoma

Abstract

Purpose: We analyzed pretherapeutic gene expression patterns of patients with locally advanced adenocarcinomas of the esophagus with regard to response to neoadjuvant chemotherapy. Experimental Design: Pretherapeutic, paraffin-embedded, formalin-fixed endoscopic esophageal tumor biopsies of 38 patients with locally advanced esophageal adenocarcinomas (Barrett adenocarcinoma) were included. All patients underwent two cycles of cisplatin and 5-fluorouracil (5-FU) therapy with or without additional paclitaxel followed by abdominothoracal esophagectomy. RNA expression levels of 5-FU metabolism-associated genes thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, MAP7, and ELF3, of platinum-and taxane-related genes caldesmon, ERCC1, ERCC4, HER-2/neu, and GADD45, and of multidrug resistance gene MRP1 were determined using real-time reverse transcriptase-PCR. Expression levels were correlated with response to chemotherapy, histopathologically assessed in surgically resected specimens. Results: Responding patients showed significantly higher pretherapeutic expression levels of MTHFR (P = 0.012), caldesmon (P = 0.016), and MRP1 (P = 0.007). In addition, patients with high pretherapeutic MTHFR and MRP1 levels had a survival benefit after surgery (P = 0.013 and P = 0.015, respectively). Additionally, investigation of intratumoral heterogeneity of gene expression of relevant genes (MTHFR, caldesmon, HER-2/neu, ERCC4, and MRP1), verified in nine untreated Barrett adenocarcinomas by examination of five distinct tumor areas, revealed no significant heterogeneity in gene expression indicating that expression profiles obtained from biopsy material may yield a representative genetic expression profile of total tumor tissue. Conclusions: Our results indicate that determination of mRNA levels of few genes may be useful for the prediction of the success of neoadjuvant chemotherapy in individual cancer patients with locally advanced Barrett adenocarcinoma.

Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

“…Nevertheless, the majority of cases were contained in both tissue microarrays so that correlation between immunohistochemistry, bright field double in situ hybridisation and fluorescence in situ hybridisation could be performed in approximately 100 cases. Discrepancies between the various in situ hybridisation methods and immunohistochemistry in our study may not only be caused by methodical or technical differences or the 'grey zone' of low-level gains 12 but also represent the phenomenon of intratumoral heterogeneity of ErbB2 expression in gastro-oesophageal adenocarcinomas, [23][24][25][26] because the cores of the donor blocks were obtained from slightly different tumour areas. Therefore, a heterogeneous distribution of ErbB2-positive cell clones may also be responsible for those divergent findings.…”

Gene expression alterations in formalin-fixed, paraffin-embedded Barrett esophagus and esophageal adenocarcinoma tissues.

“…DPYD expression has been reported in EAC and correlated with chemoresponse. 33,34 Differential expression of ADH7 [alcohol dehydrogenase 7 (class IV, mu or sigma subunit] was previously identified by a microarray and SAGE (serial analysis of gene expression) study. 35 We confirm here the significant progressive reduction in retinoic acid receptor gamma (RARG) expression 11,31 and highly altered expression of other retinoic acid and retinoid X receptors have been reported.…”

The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

“…In retrospective studies, elevated ERCC1 expression has correlated with platinum resistance in patients with colorectal, 15 gastric, 16 esophageal, 6,17 head and neck, 18 and NSCLC. [19][20][21] Ovarian tumors from patients clinically resistant to platinum compounds have been shown to have elevated levels of ERCC1.…”