In a whole-genome sequencing study of 129 esophageal adenocarcinoma (EAC) samples, researchers detected three subtypes that correspond to three potential ways to treat the disease with existing drugs.
“This work gives us a new, simple way to stratify patients for clinical trials according to their dominant genetic signature for this very difficult-to-treat disease,” said Rebecca Fitzgerald, M.D., professor of cancer prevention at the University of Cambridge in the UK. Nearly half of those cancers now have actionable mutations, she said.
The subtypes correspond to faults in DNA repair pathways, more DNA mistakes and more immune cells in tumors, and patterns showing evidence of the cell aging process (Nat. Genet. 2016; doi:10.1038/ng.3659). Faults in DNA repair pathways may now be tested with poly(ADP–ribose) polymerase (PARP) inhibitors. PARP is a family of proteins involved in DNA repair and apoptosis. PARP inhibitors are now used to treat breast, ovarian, and prostate cancers. The second subtype can be treated with immunotherapy drugs, and the third subtype might respond to drugs that target cell surface proteins that induce cell division.
“Until recently, treatment[s] of esophageal adenocarcinoma have been one-size-fits-all regimens of chemotherapy, radiation, and surgery, which have not been very successful,” said Adam Bass, M.D., of the division of molecular and cellular oncology at Boston’s Dana–Farber Cancer Institute. “We are now able to move to a model of more personalized, combination therapies,” he said.
“This work gives us a new, simple way to stratify patients for clinical trials according to their dominant genetic signature for this very difficult-to-treat disease.”
EAC is the seventh-leading cause of cancer death in the United States, with about 18,000 new cases and 15,000 deaths per year, and has been rising steeply over the past four decades. Researchers believe that gastrointestinal reflux disease (GERD), in which stomach acids chronically back up through the esophagus, and Barrett esophagus (BE)—GERD-induced inflammation and precancerous changes—and obesity are contributing to the steep increase of cases in the West.
The overall 5-year survival rate for EAC ranges from 5% to 30%, depending on the stage in which the cancer is discovered. Survival rates have not improved much in decades. A study in Scientific Reports shows that surgery with radiotherapy in metastatic disease produced a 17.5% overall survival rate in comparison with 8.4% with surgery, 4.5% with radiation, and 3.4% with no local treatment (doi:10.1038/srep28280). “These results are not very different from the previous CROSS study, which are pretty depressing,” Fitzgerald said (Lancet Oncol. 2015; doi:10.1016/S1470-2045(15)00040-6). Until now, early detection rates have been low, but Fitzgerald and others hope that will change with new genomics-related discoveries.
Rates of EAC that originate at or near the junction of the stomach have increased steeply, said Timothy Wang, M.D., Dorothy L. and Daniel H. Silberberg Professor of Medicine at New York’s Columbia University College of Physicians and Surgeons. Researchers have observed that changes the esophagus undergoes as it morphs into BE render that part of the esophagus, in cellular terms, more like the stomach. Cells in the esophagus are replaced with cells that resemble the stomach lining. Patients with BE have columnar epithelial cells, similar to those normally present in the stomach and intestines, in the surface linings of their lower esophagus, which normally contain only squamous cells. Wang, Bass, Fitzgerald, and others are using genomics to understand why and how those changes occur to better treat EAC and BE and to understand why some cases of EAC seem to skip the BE phase and become cancerous directly, Wang said.
“My hypothesis is that the cell of origin of both BE and cancer [is] the same, and likely involves stem cells,” Wang said. A BE translational research network, BETRnet, in which Wang is involved, focuses on the early biological events that drive the development of EAC and the relatively low rate of progression from BE to EAC.
Many recent genomics studies such as Fitzgerald’s have found EAC to have an unstable genome, many genetic derangements, and a variety of mutations. Within those discoveries lie new opportunities. In 2013, Bass and collaborators identified an unexpected pattern of mutations: a switch of one of the “letters” of DNA for another, called a transversion, which they believe could result from acid reflux exposure (Nat. Genet. 2013; doi:10.1038/ng.2591). Those accounted for about 30% of the mutations they found.
The team also discovered two genes, ELMO1 and DOCK2, which in unison activate RAC1, a gene that affects cell invasion. Those genes may be responsible for tumor spread earlier in carcinogenesis than in other cancer types, Bass said. “Unlike many other cancers, there seems to be no strong oncogene driving this disease,” Fitzgerald said. At least one mutation seems to be present in 25% of chromatin-remodeling genes such as ARID1A and SMARCA4, Fitzgerald said.
Bass later published research showing that the immune checkpoint protein PD-L2 is expressed in BE and EAC but not in non–Barrett esophagus esophagitis (Cancer Immunol. Res. 2015; doi:10.1158/2326-6066.CIR-15-0046). The research of Fitzgerald, Bass, and others underscores the potential for PD-1 inhibition and other immunotherapy approaches, given the many mutations in that cancer. Treating patients whose tumors have DNA repair flaws could be another worthwhile path, Fitzgerald said.
The question of which patients are most likely to progress from GERD to cancer, and from BE to cancer, occupies scientists. Because research indicates that only a few mutations are necessary to change BE into cancer, and that no additional driver mutations are necessary for progression, epigenetic changes could push the transition. Genomewide studies indicate that loss of methylation is the major change in the transition to EAC. Many researchers believe that epigenetic-targeting drugs could be tested to prevent progression. Using hypermethylation as a biomarker for monitoring may be possible.
Recent work from Cancer Research UK indicates that infrared light may detect early signs of EAC in BE patients when a dye is applied to tissue samples (J. Biomed. Opt. 2016; 21: 084001 doi:10.1117/1.JBO.21.8.084001). The dye adheres to healthy esophageal cells, but not to precancerous ones.
Over the past few years, Fitzgerald has developed an alternative procedure to endoscopy by which to identify which patients with BE are high- and low-risk. The Cytosponge is a small mesh sponge on a string within a soluble gelatin capsule that can be administered orally to collect esophageal cells for analysis.
In a new study, her team gave 468 patients with BE the Cytosponge before endoscopy, which with additional lab tests detected low-risk patients. She used three protein biomarkers; two methylation markers, MYOD1 and RUNX3; glandular atypia; and TP53 mutation status (Lancet Gastroenterol. Hepatol. 2016; doi:10.1016/S2468-1253(16)30118-2). Together with patients’ age and obesity status, she developed a mathematical model to classify risk status.
Several trials under way are testing immunotherapies in esophageal cancers. With the Fitzgerald and other new studies, more evidence now exists that sequencing patients’ tumors to stratify them for trials may lead to better survival rates and quality of life.
