Dana-Farber / Brigham and Women's Cancer Center

Esophageal and Gastric Cancer Specialists Develop New Therapeutic Approaches and Assessments for Treatment Response and Prognosis

Drs. Zinner, Mamon and Enzinger

In the Center for Esophageal and Gastric Cancers, part of the Center for Gastrointestinal Oncology at Dana-Farber/Brigham and Women’s Cancer Center, a multidisciplinary team of experts is developing new therapeutic approaches to improve care for patients with esophageal and gastric cancers. Additionally, groundbreaking fundamental research into the genetics and biology of esophageal and gastric cancers is being performed to pave the way for future advances in the care of these diseases.

“Much of our current efforts combine clinical research and correlative science to better understand how patients are responding to therapies at a molecular level and identify new pathways for targeted treatments in esophageal and gastric cancers,” said Peter C. Enzinger, MD, Director of the Center for Esophageal and Gastric Cancers.

View Video: Dr. Enzinger discusses targeted therapies for esophageal and gastric (stomach) cancers.

Establishing the Role of Angiogenesis Inhibitors

Medical oncologists in the Center have made important discoveries that are laying the groundwork for the study of new therapies. Charles S. Fuchs, MD, MPH, Director of the Center for Gastrointestinal Oncology, recently led an international Phase III trial of ramucirumab, a monoclonal antibody VEGFR- 2 antagonist, in patients with advanced gastric or gastroesophageal junction (GE) adenocarcinoma (Lancet. 2013 Oct 1. pii: S0140-6736(13)61719-5. doi: 10.1016/S0140-6736(13) 61719-5). The study demonstrated that ramucirumab had a survival benefit (see Figure 1) for these patients, making it the first effective biological treatment to be given as a single drug when patients progress following first-line chemotherapy.

Center specialists are currently leading two promising trials of angiogenesis inhibitors in patients with advanced gastric or GE adenocarcinoma. As part of these studies, endoscopic biopsies of tumors, performed by Center gastroenterologist Kunal Jajoo, MD, are taken before and after treatment to assess molecular response to therapy.

  Figure 1
Treatment with ramucirumab significantly improved overall survival compared with placebo.Median overall survival was 5.2 months in patients receiving ramucirumab and 3.8 months in those receiving placebo. Estimated rates of six month overall survival were 41.8 percent in the ramucirumab group and 31.6 percent in the placebo group. Rates at 12 months were 17.6 percent versus 11.8 percent.
  • CAPOX, Bevacizumab and Trastuzumab for Patients with HER2-Positive Metastatic Esophagogastric Cancer – This Phase II clinical trial is designed to determine the safety and effectiveness of a combination of chemotherapy, capecitabine and oxaliplatin, plus the antibodies bevacizumab and trastuzumab. Using biopsies from patients on therapy will enable researchers to investigate the effects of therapy on the ERBB2 Pathway, including theRAS-MAPK and PI3K signaling pathway components.
  • FOLFOX +/- Ziv-Aflibercept for Esophageal and Gastric Cancer – This Phase II clinical trial is testing the safety and effectiveness of the investigational drug Ziv-aflibercept in combination with mFOLFOX6 (Fluorouracil, Leucovorin, and Oxaliplatin) compared to mFOLFOX6 alone. Biopsies in this study are evaluating various markers for response to anti-angiogenesis agents. For more information regarding these trials, please contact Eileen Regan, RN, OCN, at (617) 632-3898 or [email protected]

Additional studies include:

  • RTOG 1010 is a Phase III study comparing standard preoperative chemoradiation to preoperative chemoradiation with trastuzumab in patients with esophageal cancer. Please contact site Principal Investigator Harvey J. Mamon, MD, PhD, at (617) 525-7358 or [email protected] for more information.

Surgical Advances

Led by Scott J. Swanson, MD, Director, Minimally Invasive Thoracic Surgery, Dana-Farber/Brigham and Women’s Cancer Center, thoracic surgeons in the Center perform among the highest number of resections for esophageal cancer in the nation. Most of these procedures are completed using complex minimally invasive approaches, including minimally invasive esophagectomy (MIE), offering patients a
much faster rate of recovery with less pain and long-term complications, including lower rates of pneumonia.

With significant experience in the use of innovative MIE approaches, surgeons in the Center maintain a very low mortality rate for MIE. Minimally invasive approaches also are used to address gastric cancers with esophageal involvement. In these cases, thoracic surgeons collaborate with gastrointestinal
surgeons in the operating room to surgically treat these patients.



Figure 2

In gastric cancers, surgical oncologist Jiping Wang, MD, PhD, and his team have developed a novel system to improve the accuracy of staging and assessment of prognosis in patients who have undergone surgical resection for gastric cancer. The new staging system modifies the traditional approach for assessing the tumor status of lymph nodes obtained at time of surgery (see Figure 2). A retrospective analysis of more than 18,000 gastric cancer patients showed that this new model more accurately predicted survival (Ann Surg. 2012 Mar;255(3):478-85.). New risk models, such as this one, will help Center specialists to more effectively identify patients who should receive additional therapy following gastric cancer resection.

Dr. Wang also has taken a leadership role in offering educational resources for surgical techniques in gastrectomy. As part of this effort, he is coordinating an upcoming online video forum through the Society for Surgery of the Alimentary Tract and has delineated the anatomic standard for D2 lymph node dissection in the upcoming issue of Annals of Surgery. Gastrointestinal surgeons in the Center have increasingly performed D2 lymphadenectomy in patients with gastric cancer. In 2012, the percentage of patients in the Center with 16 or more lymph nodes resected and examined was 78 percent, compared with less than 30 percent in 2000 (see Figure 3).

Figure 3

Identifying Key Genetic Alterations

Adam Bass, MD, a medical oncologist in the Center for Gastrointestinal Oncology, directs a laboratory studying gastric and esophageal cancers. Much of Dr. Bass’ work has focused on the use of new state-of-the-art technologies to understand the specific genetic mutations that cause these cancers. Building on these genetic discoveries, his laboratory is striving to define optimal approaches to use emerging targeted therapies to treat gastric and esophageal cancers.

Through the National Institutes of Health (NIH) The Cancer Genome Atlas (TCGA) program, Dr. Bass is co-chairing the largest ever project to map the genomic changes in stomach and esophageal cancers. A comprehensive genomic analysis of nearly 300 gastric cancers, performed by TCGA researchers, is expected to be published in early 2014.

Significant findings from Dr. Bass’ research include:

  • Published the largest ever genomic sequencing project in esophageal adenocarcinoma (EAC), identifying both a novel genetic mutation signature in these cancers and potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis. (Nat Genet. 2013 May;45(5):478-86);
  • Genomic comparison across gastrointestinal adenocarcinomas of the esophagus, colon, and stomach defined genomic features common and distinct to various gut-derived adenocarcinomas, potentially informing novel opportunities for targeted therapeutic interventions. (Cancer Res. 2012 Sep 1;72(17):4383-93);
  • Team identified SOX2 as a lineage-survival oncogene in esophageal squamous cell carcinoma. (Nat Genet. 2009 Nov;41(11):1238-42.).

“The foundation for much of our current work is based on the observations we have made during our study of the cancer genome,” said Dr. Bass. “We are now applying these findings to our investigation of targeted treatments for particular subgroups of esophageal and gastric cancer.”

As part of this effort, Dr. Bass is collaborating with the leaders of Profile, one of the nation’s most comprehensive personalized medicine initiatives in cancer. Profile utilizes next-generation sequencing to analyze the entire genetic code of 305 cancer-related genes in the DNA sample.

Every Dana-Farber/Brigham and Women’s Cancer Center patient is offered the opportunity to participate in the study. Profile aims to identify targeted therapies that are most likely to be effective in individual patients. The databases of tumor genetic profiling data derived from a very large number of patients, and linked to clinical information, make Profile a powerful tool for discovery and supports proposals for new research studies and clinical trials.

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