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Abstract
Aims: Neoadjuvant treatment strategies have been developed to improve the survival of patients with locally advanced esophageal cancer. Since patients with major histopathological response are the ones who mainly benefit from this therapy, we are looking for causes of nonresponse. The multidrug resistance protein ABCB1 belongs to the ATP-binding cassette superfamily of membrane transporters. By exporting positively charged drugs it plays a role in the acquisition of resistance in anticancer therapy. We examined the ABCB1 gene polymorphism C3435T to predict response and prognosis to neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil and 36 Gy) in locally advanced esophageal cancer patients. Materials & methods: A total of 262 patients (216 male; 46 female; median age: 62 years) with locally advanced esophageal cancer (squamous cell cancer: n = 116, adenocarcinoma: n = 146) were included in this study. All patients received a neoadjuvant radiochemotherapy (36.0 Gy, 5-fluorouracil, cisplatin) followed by surgery. Histomorphologic regression was classified according to the Cologne Regression Grade with major response being classifed as having less than 10% vital tumor cells (n = 107) and minor response when 10% or more vital tumor cells (n = 155) were detected in the surgical specimen. Genomic DNA was extracted from paraffin-embedded tissues of all study patients. Allelic genotyping was performed for ABCB1 rs1045642 by real-time PCR using two allele-specific TaqMan® probes in competition. Allelic genotyping was correlated with therapy response and prognosis. Results: Allelic discrimination revealed a TT genotype in 27%, a CC in 19% and a CT genotype in 54% of the study patients. This SNP was not predictive for response of the primary tumor to neoadjuvant radiochemotherapy. The ABCB1 genotype CC was associated with lymph node formation (p = 0.012) and distant metastases (p = 0.019). Patients with a TT genotype exhibited a significantly less positive lymph node status (ypN1 35%) after chemoradiation compared with patients with a CC (ypN1 = 60%) or CT (ypN1 = 46%) genotype. Moreover, patients bearing the TT genotype exhibited no distant metastasis, while five patients with a CC and two patients with CT genotype had distant metastases. In Kaplan-Meier curves, adenocarcinoma patients with a CC genotype showed a worse survival rate than patients with TT or CT (p = 0.048). Conclusion: Our data supports the impact of ABCB1 on effectiveness of esophageal cancer treatment. SNPs of ABCB1 could be helpful in predicting lymph node regression in the multimodality treatment of locally advanced esophageal cancer.
Original submitted 20th August 2010; Revision submitted 22nd October 2010.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.