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Objective
Neoadjuvant chemoradiation (NCRT) has become standard in the treatment of locally advanced esophageal cancer with survival correlated to degree of pathologic response. The activation of the PI3K/Akt/mTOR pathway plays an important role in tumorigenesis and resistance to anticancer drugs. The aim of this study was to elucidate the role of the Akt/mTOR pathway in chemoresistance and the prognosis of patients with esophageal adenocarcinoma cell carcinoma (AC) who received NCRT.
Methods
After IRB approval, a prospective trial was instituted in which patients with locally advance esophageal requiring NCRT were consented for endoscopic biopsies of normal and tumor tissue prior to instituting therapy. The tissues underwent gene expression profiling using the Affymetrix 133 Plus 2.0 Gene chip. SAM method was used to analyze significant differentially expression of AKT within normal and tumor tissue. Expression was then correlated to degree of pathologic response. All patients were treated with NCRT followed by esophagectomy. Pathologic complete response (pCR) was defined as no residual tumor, partial pathologic response (pPR) as a 50% reduction in tumor size or nodal down-staging, and non-response (pNR) as no difference between pre-operative and post-operative stage based upon endoscopic ultrasound.
Results
Nineteen patients with adenocarcinoma had biopsies of normal and tumor tissue that were subsequently analyzed via microarray. Comparisons of expressions between normal and tumor revealed consistently significant overexpression of AKT in tumor tissues p=0.007. We identified 10 patients exhibiting pathologic complete response, 6 partial pathologic response, and 3 non-responders. When comparing the expression of AKT between normal and tumor tissue in those ultimately designated as pCR, there persisted a significant over-expression of AKT in the tumor tissues p=01. However in analyzing the degree of expression between pathologic response to NCRT we consistently demonstrated a linear correlation between the expression of AKT and degree of pathologic response. Partial and non pathologic responders consistently had higher expressions of AKT compared to pCR with the non-responders consistently illustrating the highest expression of AKT.
Conclusions
AKT is overexpressed in patients with adenocarcinoma of the esophagus. Moreover, pathologic response to neoadjuvant chemoradiation may be correlated with degree of AKT expression. Additional data is needed to clarify this relationship further and potentially add targeted therapies to the neoadjuvant regimen.