Metabolomic and BH3 Profiling of Esophageal Cancers: Identification of Novel Assessment Methods of Treatment Response for Precision Therapy

Background: The number of patients with esophageal cancer keeps rising. For many patients, a combination of surgery, chemotherapy, and radiation is necessary to completely treat the disease. Usually, patients receive chemotherapy and radiation at the same time followed by surgery to remove the part of the esophagus with the tumor (Neoadjuvant chemoradiotherapy (nCRT)). Researchers want to learn how to make this treatment more effective. Objective: To see if biopsies before treatment can show which patients will do the best with a combination of chemotherapy, radiation, and surgery. Eligibility: Adults at least 18 years old with esophageal adenocarcinoma or squamous cell carcinoma who should be treated with chemotherapy, radiation, and surgery. Design: Patients will undergo standard testing that is routine for all patients with this disease. These tests include: Medical history Physical exam with activity and nutritional assessment Standard lab tests Imaging studies including a computerized axial tomography (CAT) scan and positron-emission tomography (PET) scan Breathing test into a machine to measure size and function of lungs. Biopsy for a small sample of tumor is removed by esophagogastroduodenoscopy (EGD): A tube inserted into the mouth under anesthesia Endoscopic ultrasound is performed in some but not all patients. Patients will have nCRT at the clinic or with their local doctor. In 6 -12 weeks after nCRT, patients will undergo surgery with: 1. A robotically-assisted, minimally-invasive esophagectomy 2. Or, a traditional, open approach. After surgery, patients are usually in the hospital for 2 weeks and have a feeding tube for at least 2 weeks and potentially longer until they are eating enough to not lose weight. Patients will return for follow-up visits with labs and CAT scans every 6 months for the first two years then every year afterwards.

Background: * The incidence of esophageal cancer continues to increase with an estimated 16,900 new cases and 15,700 deaths in 2016. Esophageal adenocarcinoma (EAC) is the dominant histology in the United States and accounts for the rising incidence; the incidence of esophageal squamous cell cancer (ESCC) remains stable. * Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy is now a standard approach for locally advanced, operable esophageal cancer. * A survival advantage compared to surgery alone was demonstrated in the phase III Chemo Radiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial. * Patients who experience a pathological complete response (pCR) following neoadjuvant therapy are most likely to have long-term survival. * Presently, accurate assessment of pathologic response requires esophagectomy. Positron-emissions tomography (fludeoxyglucose (FDG-PET)) and endoscopic evaluation with biopsies fail to detect cancer in a significant percentage of patients with residual disease following neoadjuvant therapy. * Currently there are no validated tissue or serologic biomarkers which can be used to guide surgical management of esophageal cancer patients based on response to nCRT. Primary Objective: -To determine whether a metabolomic signature in tumor, blood, or urine or whether BH3 profiling of pre-neoadjuvant tumor biopsies correlates with the outcome of pathological complete response after neoadjuvant chemoradiotherapy for patients with esophageal adenocarcinoma or squamous cell carcinoma. Eligibility: -Patients with locally-advanced, histologically confirmed EAC or ESCC who are candidates for nCRT and esophagectomy. Design: * Patients will receive standard of care nCRT either at the National Cancer Institute (NCI) or at referring institutions. * Specimens of plasma, urine, and esophageal tumor with matched normal esophagus will be obtained before neoadjuvant therapy for metabolomic profiling and BH3 profiling. Blood, urine, normal esophagus, and tumor (if present) will be obtained after neoadjuvant therapy. * Patients will undergo an esophagectomy as a robotically-assisted, minimally-invasive esophagectomy (RAMIE) or a traditional open approach for contraindications to minimally-invasive approaches or based on institutional expertise. * Analysis will be performed to determine if pathological complete response (pCR) after chemoradiotherapy (CRT) correlates with pretreatment metabolomic signatures or BH3 profiling in tumor, blood or urine. * Patients with EAC and ESCC will be evaluated independently. * The accrual ceiling will be set to 120 patients for the entire study - 80 patients for EAC and 40 patients for ESCC to allow for unevaluable patients. The accrual is expected to be completed in 4 years.