Molecular Marker Expression Is Highly Heterogeneous in Esophageal Adenocarcinoma and Does Not Predict a Response to Neoadjuvant Therapy

Abstract

A reliable method to identify pathologic complete responders (pCR) or non-responders (NR) to neoadjuvant chemoradiation therapy (NAT) would dramatically improve therapy for esophageal cancer. The purpose of this study is to investigate if a distinct profile of prognostic molecular markers can predict pCR after neoadjuvant therapy. Expression of p53, Her-2/neu, Cox-2, Beta-catenin, E-cadherin, MMP-1, NFkB, and TGF-B was measured by immunohistochemistry in pre-treatment biopsy tissue and graded by an experienced pathologist. A pCR was defined as no evidence of malignancy on final pathology. Molecular profiles comparing responders to non-responders were analyzed using classification and regression tree analysis to investigate response to NAT and overall survival. Nineteen patients were pCRs and 34 were NRs. pCRs were more likely to be alive at follow-up than NRs (p < 0.01). Thirty-seven distinct profiles were identified. Expression of molecular markers was highly heterogeneous between patients and did not correlate with a response to NAT, survival (p = 0.47) or clinical stage (p = 0.39) when evaluated either as individual markers or in combination with other expression patterns. NAT dramatically impacts survival through a mechanism independent of known molecular markers of esophageal cancer, which are expressed in a highly heterogeneous fashion and do not predict response to NAT or survival.

Clinical predictors of pathologically response after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma: long term outcomes of a phase II study

“…But imaging methods such as PET-CT following NCRT for esophageal cancer was also not accurate enough to identify patients with pathological response for clinical application (13). Recently, concerns about molecular markers related to the treatment response have been raised by the clinicians and researchers (14,15). However, the clinical application of the markers is not widely available and their clinical relevance needs to be further validated.…”

P53 and SOX2 Protein Expression Predicts Esophageal Adenocarcinoma in Response to Neoadjuvant Chemoradiotherapy

“…Kitamura et al showed that p53 was significantly associated with increased sensitivity to nCRT, whereas other studies could not confirm this correlation. [44][45][46] The majority of immunohistochemical studies have been performed in patients with ESCC or mixed population of EAC and ESCC patients, therefore to be interpreted with caution. In addition, in contrast to our study, others scored strong nuclear p53 as aberrant only.…”

The role of transforming growth factor β in upper gastrointestinal cancers: A systematic review

“…For example, several studies have indicated that TGF-β expression is correlated with tumor size, lymph node metastasis, clinical stage and shorter survival in gastric cancer [16,17] and esophageal cancer [18,19]. However, other studies did not find this correlation [20,21] and a few studies even reported an inverse correlation [22,23], which could indicate tumor-restricting properties of TGF-β.…”