Esophageal Cancer -- Two Separate Diseases

Veronica Hackethal, MD

January 23, 2017

Findings from a new study by the Cancer Genome Atlas Research Network suggest that esophageal squamous cell carcinoma and esophageal adenocarcinoma may be separate diseases.

The results could contribute to the development of new targeted therapies based on cancer type, say researchers in an article published online January 12 in Nature.

"We showed very clearly how strongly esophageal adenocarcinoma and squamous cell cancer are different from each other. The molecular features of esophageal squamous cancer were similar to head and neck cancer, and esophageal adenocarcinoma was molecularly more like gastric cancer," corresponding author Adam Bass, MD, of the Dana Farber Cancer Institute, Boston, Massachusetts, told Medscape Medical News.

The results contribute to an active discussion about the best ways to categorize esophageal cancer, he explained. According to histologic classification, esophageal cancer is differentiated as squamous cell carcinoma (found mainly in the upper and mid esophagus) and adenocarcinoma (found mostly in the lower esophagus). Debate has focused on where to draw the line: Are esophageal adenocarcinomas more like gastric tumors, or should they be classified as esophageal tumors?

"Now we may be able to shift to a model where gastroesophageal adenocarcinoma is a class of cancer that's really separate from esophageal squamous cancer," Dr Bass said.

In the study, researchers carried out a comprehensive analysis of 164 esophageal tumors, 359 gastric adenocarcinomas, and 36 adenocarcinomas found at the gastroesophageal junction. Tumors came from individuals in Western and Asian countries. The researchers performed whole-exome sequencing, single-nucleotide polymorphism array profiling, DNA methylation profiling, and mRNA and microRNA sequencing.

The analysis identified three molecular subtypes of esophageal squamous cell carcinoma (n = 90). One of these subtypes had gene expression similar to a subtype of squamous cell carcinoma of the lung, as well as squamous cell cancer of the head and neck. However, none of these subtypes were linked to human papillomavirus, which has been associated with squamous cell carcinoma of the head and neck.

Esophageal adenocarcinomas showed a strong resemblance to a chromosomally unstable variant of gastric cancer. Seventy-one of 72 esophageal adenocarcinomas fell into this subtype, suggesting that these cancers could be a single disease.

The results are important in terms of deciding which patients to include in clinical trials for these types of cancers. Until now, the organ of origin has been the dominant deciding factor, Dr Bass explained.

"I'm hopeful that we could jointly evaluate patients whose biology is overwhelmingly similar. That may increase the patient population, make it easier to build and accrue trials, and speed trial and drug development," he said.

Evaluation of somatic genome alterations showed frequent changes in cell cycle regulators, with different patterns of cell cycle dysregulation for esophageal squamous cell carcinomas compared to esophageal adenocarcinoma.

Nineteen percent of esophageal squamous cell carcinomas had amplification of the receptor tyrosine kinase EGFR, pointing to EGFR as a target using CDK4/6 inhibitors. Cyclin D1 was also commonly amplified in these cancers.

"We saw lots of alterations in the cell cycle regulation, pointing to the potential for bringing in emerging cell cycle inhibitors to treat these tumors. We're also seeing the potential to include PI3 kinase inhibitors, probably not as monotherapy but as part of therapy," Dr Bass said.

In contrast, esophageal adenocarcinomas showed a broader range of potentially oncogenic amplifications, with frequent changes in receptor tyrosine kinases and downstream signaling mediators. The most common amplification in esophageal adenocarincomas was ERBB2, which was altered in 32% of esophageal adenocarcinomas but in only 3% of esophageal squamous cell carcinomas.

The results suggest that more patients with esophageal adenocarcinoma may benefit from the HER2 antibody trastuzumab (Herceptin, Roche/Genentech). Although trastuzumab is often used off label in esophageal adenocarcinoma, it has only received approval from the US Food and Drug Administration for treatment of gastric and gastroesophageal junction cancer.

Frequent genomic amplifications in esophageal squamous cell carcinoma also included CCND1, SOX2, and TP63. In esophageal adenocarcinomas, frequent genomic amplifications also included ERBB2, VEGFA, GATA4, and GATA6.

"The data are pointing to a lot of different potential targets. The question is really about how to develop the right combinations and in which systems to test them to find the most efficacious therapies," Dr Bass emphasized.

The authors have disclosed no relevant financial relationships.

Nature. Published online January 12, 2017. Full text


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