Association of pretherapeutic expression of chemotherapy-related genes with response to neoadjuvant chemotherapy in Barrett carcinoma.
OBJECTIVE
We analyzed pretherapeutic gene expression patterns of patients with locally advanced adenocarcinomas of the esophagus with regard to response to neoadjuvant chemotherapy.


METHODS
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.
Langer
Rupert
R
Institute of Pathology and Medical Statistics, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
Specht
Katja
K
Becker
Karen
K
Ewald
Philipp
P
Bekesch
Melitta
M
Sarbia
Mario
M
Busch
Raymonde
R
Feith
Marcus
M
Stein
Hubert J
HJ
Siewert
Jörg-Rüdiger
JR
Höfler
Heinz
H
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D002148:Calmodulin-Binding Proteins / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016629:Esophagectomy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
D002148:Calmodulin-Binding Proteins; D002945:Cisplatin; D004268:DNA-Binding Proteins; D005472:Fluorouracil; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C095888:xeroderma pigmentosum group F protein; C421109:multidrug resistance-associated protein 1