The Molecular-Driven Classification of Gastric Cancers

Insights From: Yelena Y. Janjigian, MD, Memorial Sloan Kettering Cancer Center; Alan P. Venook, MD, University of California San Francisco; Zev A. Wainberg, MD, UCLA School of Medicine


Yelena Y. Janjigian, MD: We’ve recognized that gastric cancer is a heterogenous disease and there are unique subsets of tumors based on histology, clinical behavior, and biology. Now that The Cancer Genome Atlas published, we’ve established that molecularly the subtypes are quite distinct. That’s where the field has evolved beyond the WHO classifications, or just histologic classification, to really recognize, on the molecular level, that these tumors are distinct.

And so, we see that esophageal squamous cell cancer and adenocarcinoma of the esophagus are molecularly different and should never be approached in the same clinical trial for the same patient population. In fact, the squamous cell of the esophagus is biologically very similar to very aggressive types of head and neck squamous cell tumors. Within adenocarcinomas, esophageal adenocarcinomas are biologically similar to GE junction tumors. Therefore, these tumors can be used and put together in similar clinical trials if we’re developing molecularly targeted agents.

These tumors tend to be chromosomally unstable and have a lot of amplifications in the receptor tyrosine kinase, such as HER2, EGFR, or MET. There are also p53 mutations, so they tend to be more aggressive and grow and metastasize at an earlier time in the disease. And also, these tumors tend to be non-MSI, although what’s important to note is that we can’t guess based on anatomy if this going to be an MSI tumor or an EBV tumor. Histologic and molecular characterization is quite important.

So, there are chromosomally unstable tumors, and then the 3 other biologic subtypes are genomically stable tumors. Those are the signet ring cell histology, most commonly. Those are the claudin-rearranged tumors, E-cadherinaltered tumors. And we’ll talk about claudin as a possibility for targeted agents in the future.

MSI and EBV subtypes within the TCGA are most provocative and important for targeting with immunotherapy. EBV-positive gastric cancer is rare but very important to study and to diagnose, as 80% of those tumors are PD-L1 positive. And then within MSI, the indication for immunotherapy is quite strong and responses can be quite dramatic. Although these tumors are rare in metastatic patients, they’re important to look for as they will dramatically change the treatment algorithm.

Transcript Edited for Clarity 
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