Current status of predictive biomarkers for neoadjuvant therapy in esophageal cancer

Abstract

Neoadjuvant therapy has been proven to be extremely valuable and is widely used for advanced esophageal cancer. However, a significant proportion of treated patients (60%-70%) does not respond well to neoadjuvant treatments and develop severe adverse effects. Therefore, predictive markers for individualization of multimodality treatments are urgently needed in esophageal cancer. Recently, molecular biomarkers that predict the response to neoadjuvant therapy have been explored in multimodal approaches in esophageal cancer and successful examples of biomarker identification have been reported. In this review, promising candidates for predictive molecular biomarkers developed by using multiple molecular approaches are reviewed. Moreover, treatment strategies based on the status of predicted biomarkers are discussed, while considering the international differences in the clinical background. However, in the absence of adequate treatment options related to the results of the biomarker test, the usefulness of these diagnostic tools is limited and new effective therapies for biomarker-identified nonresponders to cancer treatment should be concurrent with the progress of predictive technologies. Further improvement in the prognosis of esophageal cancer patients can be achieved through the introduction of novel therapeutic approaches in clinical practice.

Keywords: Esophageal cancer, Neoadjuvant therapy, Response prediction, Molecular biomarker, Chemoradiation

Core tip: To achieve individualization of neoadjuvant therapy for locally advanced esophageal cancers, predictive biomarkers are urgently needed. Biomarker development using multimodal approaches, including gene expression profiling, single nucleotide polymorphisms, microRNAs, proteomics, immunohistochemistry, serum biomarkers and conventional blood tests, seem promising. Independent validation studies will establish novel prognostic modalities based on molecular biomarkers. Progress of predictive modalities and further studies on the molecular background of patients with a poor prognosis will facilitate the development of new effective therapies for patients resistant to the present neoadjuvant therapy. Prognostic stratification of patients will promote efforts toward novel therapeutic strategies.

INTRODUCTION

Esophageal cancer is the fifth most common cause of cancer-related death for men and the eighth for women worldwide[1]. Despite the use of modern surgical techniques in combination with radio- and chemotherapy, early recurrence is common and the overall 5-year survival rate remains below 40%[2]. Consequently, there is a great interest in multimodal approaches to the treatment of esophageal cancer and neoadjuvant chemotherapy, alone or in combination with chemoradiotherapy (CRT), is becoming the standard approach of care in locally advanced esophageal cancers. Randomized trials of different neoadjuvant therapy protocols have been conducted in patients with locally advanced cancers. Meta-analyses of those randomized trials have revealed only modest survival advantages, except in the case of patients who achieved a complete histopathological response and seemed to highly benefit from a neoadjuvant regimen[3-9]. However, a significant proportion (60%-70%) of treated patients did not respond well to these treatments and experienced severe adverse effects[8,10]. In addition, nonresponsive patients may lose the option of surgical resection after ineffective chemotherapy[11] and the prognosis of nonresponders has been found to be inferior to that for patients treated by surgery alone[12]. While there is an obvious correlation between the response and prognosis, the response to chemotherapy or radiotherapy is variable, even when patients are at the same clinical stage. Thus, an accurate risk stratification of cancer patients for therapy is of paramount importance for avoiding potential morbidity due to ineffective treatment and prevention of further disease progression. With this background, identification of predictive markers would allow accurate risk stratification and individualization of multimodality treatment for patients with locally advanced esophageal cancer[13].

In recent years, molecular biomarkers that can predict the response to neoadjuvant therapy in esophageal cancer have been investigated by using multidimensional approaches. Global expression transcriptomics and proteomics studies allow for simultaneous screening of several thousand molecules and knowledge-based methodologies such as immunohistochemistry are focused on a specific molecule or pathway. These approaches are based on their own unique principles and the performance of predictive molecular biomarkers developed by using each approach seems to be equally promising. Here, we have reviewed the current status of molecular biomarkers predictive for response to neoadjuvant therapy in esophageal cancer. We have focused on predictive markers that can be used to analyze pretreatment samples such as diagnostic biopsies or serum specimens obtained before neoadjuvant treatment. These biomarkers will help avoid unnecessarily invasive treatments. We have summarized promising candidates for predictive molecular biomarkers in esophageal cancer according to the type of development modality.

MOLECULAR BIOMARKERS FOR RESPONSE PREDICTION