Sequencing Decisions in Gastroesophageal Cancers - Episode 3

Biology and Location of Gastroesophageal Cancers

Transcript:Johanna C. Bendell, MD: We have the Cancer Genome Atlas. Yelena, can you tell us a little bit more about what that’s about and how do we apply that?

Yelena Y. Janjigian, MD: So, the Cancer Genome Atlas is an effort through the NCI to develop a roadmap, or an atlas, of different solid tumors. There’s an effort to do this in esophageal and gastric cancer. The gastric cancer paper was published first, and recently, we published the joint squamous cell esophageal adenocarcinoma, but also incorporating the gastric cancer data into it. So, the first iteration of this analysis demonstrated that within gastric cancer, or gastric adenocarcinoma, there are 4 different molecular subtypes, and these are pristine, relatively early stage tumors that have not been exposed to chemotherapy or radiation and really are not exactly translatable to the metastatic patients who you see in your clinic. These are earlier stage tumors. And what we saw was that among the 4 different subtypes, MSI (or microsatellite unstable) tumors and EBV (or Epstein-Barr—related) tumors were the most PD-L1–positive and likely susceptible to immune checkpoint inhibitors. In that cohort of patients, however, the incidence of those tumors were likely overestimated as there continued to be a relatively favorable prognosis in early stage cancers. And so, in that sense, those data are put in quotation marks because for your metastatic patient, it may not be as commonly seen.

For the most common tumors that we see in the United States and in the West, going back to Ian’s comment that it is very complicated, it’s not just about the type of surgery you do or the tumor location, it’s also about the molecular characteristics of the tumor. And so, in the United States, we tend to have more aneuploid or chromosomally unstable tumors. They’re p53-mutant, they’re aggressive, and I’ve had patients who are undergoing “screening” for endoscopies, just had a normal endoscopy, and a year later, they already have a T3N1 tumor. And it’s because within 6 to 8 months, the tumor grew quickly. And generally those tumors are associated with chemotherapy or resistance and aggressive tumor biology. In the H. pylori or the endemic type of gastric cancer, generally those are distal tumors that are less aneuploid-driven and could be potentially less complicated to target.

To Manish’s point, the signet ring cell (or the diffuse gastric cancer) is a completely different entity. It’s very difficult to pick up sometimes on endoscopies. They tend to grow on top of things and into forming a mass, so this is linitis plastica approach. And genomically, they’re very quiet, at least on the DNA level. There may be claudin inhibitors as one mechanism of treatment, targeting the RhoA pathway, although that’s a big question mark. They’re a big challenge. Within esophagus cancer, one thing we know is that squamous cell tumors are a completely different entity and, actually, phenotypically and genomically are more similar to the badly behaving head and neck cancers. We could target the esophageal adenocarcinomas in the GE junction, adenocarcinomas, together.

Johanna C. Bendell, MD: And speaking of the GE junction, Ian, you were talking about educating your gastroenterologists. Certainly, with this new emergence of GE junctional cancers being so prominent, what are we telling our gastroenterologists in terms of helping us classify these different tumors?

Ian Chau, MD: We hope that on the stand-up reporting of endoscopy, they would tell us where the junction is, endoscopically. Although, I do actually see some not-inconsistencies. But between the imaging of what radiologists call the tumor that is at the junction versus what the gastroenterologist says that that is—whether the tumor is at a junction, whether it extends proximally or distally—there can be some differences. But, certainly, I think nowadays—especially when we plan for multimodality treatment for localized disease with the surgeons, and chemotherapy, and radiotherapy—it is very important for our gastroenterologists to accurately document for us the location of the junction, the location of the tumor relative to the junction.

Johanna C. Bendell, MD: And this is the Siewert classification, right?

Ian Chau, MD: Yes.

Johanna C. Bendell, MD: And we’re seeing this more and more in clinical trials that they actually want to know if it is the top, middle, or bottom of the GE junction that might give us a little bit of a difference.

Transcript Edited for Clarity