Current Molecular Profiling in Gastric Cancers

Transcript:Johanna C. Bendell, MD: Yelena, I have patients come in, especially young patients who have just been diagnosed with gastric cancer and they’re worried about their children. They ask, “I now have gastric cancer. do I have to worry about my children having gastric cancer?” Are there any hereditary gastric cancer syndromes that are around, and are they prevalent or not?

Yelena Y. Janjigian, MD: That’s a great question, and we do see increasing incidence of gastric cancer in young adults, particularly young males. In fact, based on these data and the fact that the returning veterans and young servicemen actually are developing cancer, there’s a high-risk population. The Department of Defense is now funding some of this research to try to look into both hereditary and exposure predispositions. To highlight the most relevant gastric cancer genetic predispositions, the first that comes to mind that is the best described is probably the hereditary diffuse gastric cancer syndrome. In those patients, the prevalence and the penetrance of the CDH1 gene mutation is high. But that’s a rare syndrome, and it’s a relatively clear picture if someone presents at a young age in their early 30s. So, that may not be your typical patient who’s asking you, “Will my children be affected?”

Those types of patients, their tumors could be related to Lynch syndrome or MSI gastric cancer. The microsatellite-instable tumors are characterized by large mutation burden. However, interestingly, in gastric cancer, most MSI tumors are somatic MSI, so they’re not associated with Lynch syndrome. That being said, if you see a lot of gastric cancer, you will see Lynch-associated gastric cancer, and that should always be on your mind when screening the Lynch patients—sending them for a skin check, urologic check, colonoscopy. You should also consider stomach cancer.

Lastly, one of the very interesting and therapeutically potentially relevant syndromes is this homologous repair deficiency (or the BRCA-like gastric cancers). And being from New York and having a lot of patients of Ashkenazi Jewish descent, I see quite a few patients with BRCA-associated gastric cancer. Those patients have a real therapeutic potential here for platinum stratifications, but also for exploration of PARP inhibitors. So, the field has evolved, and we are certainly interested in the somatic side of the tumor. But the germline data are just as important and need to be considered.

Johanna C. Bendell, MD: You bring up a lot of important points, and we talk so much now about molecular profiling of patients with cancer as well. What are your recommendations? A community oncologist sees a patient who’s—let’s put him in the middle, somewhere like 40 years old—comes in with gastric cancer. So, he’s a little bit on the younger side. If you’re recommending to a community oncologist, what do you do to get baseline no matter what, and then, what’s your wish list?

Yelena Y. Janjigian, MD: I’m glad you asked that question. So, the wish list is now reality. With the pembrolizumab approval in MSI-high patients, across tumor solid tumors, and with HER2 amplification also being the level 1 recommendation in terms of it should be routinely done, the culture in gastric cancer has been to do a stepwise approach to testing. First, you test all the regular H&E (hematoxylin and eosin) and the IHC to make sure it’s adenocarcinoma, then you start with HER2, then you do some other biomarkers, maybe MMR. EBV is an important biomarker. And then, you get to something else and you run out of tissue. In 2017, we really should plan on doing a multiplexed assay. And generally, in these next-generation sequences—which should be considered a standard in these patients—at this point, you can assess HER2 and you can assess MSI in a prospective and standardized manner. And although MSI gastric cancer is rare, it is a real entity, and in metastatic patients, it could have a significant impact on their outcome for treatment.

Johanna C. Bendell, MD: Dr. Shitara, in Japan, do you also check this at baseline, too?

Kohei Shitara, MD: Yes. For metastatic disease, we should check HER2 status because we have trastuzumab as a HER2 agent. And at this time, checkpoint inhibitors have not yet been approved for gastric cancer, but we already start to profile these metastatic patients based on MSI, by immunohistochemistry, and EB virus status. And also, we are doing a profiling study using NGS, which may identify optimal, some druggable, gene alterations.

Johanna C. Bendell, MD: Yes, sounds very consistent. What about Ian and Manish? Same thing?

Ian Chau, MD: Certainly, for us, testing HER2 is standard. I think, increasingly similarly in our institution, we will test for mismatch repair with immunohistochemistry, but I’m not quite sure. So, in the UK, there is actually funding to test all gastric cancer. It is routinely testing all the colorectal cancers, but it is not routinely testing all the gastric cancers. Actually, while we are at it, there’s one extra point about what you talk to your community oncologist about. In fact, there is also an educational role that we have to teach our community gastroenterologists, who often do the diagnostic biopsies. That is to make sure that they take enough of the diagnostic biopsies because we, quite recently, did an audit in our own practice, looking at patients being referred in from our community hospital to our gastroenterologists. How many are they taking? And, actually, apart from the number of biopsies they’re taking, which day of the week that they take the biopsies also matters because it depends on how long they sit in the paraffin and processing. So, for example, Thursday is not a very good day, apparently.

Johanna C. Bendell, MD: Manish, is that the same for you?

Manish A. Shah, MD: I agree with what was said. I think that multiplex sequencing is a very good point, especially with limited tissue related to the difficulty of diagnoses. I think part of it is getting adequate tissue, and it is a difficult disease to diagnose at times as well. You see an ulcer, and you may not be prepared or could get the right biopsies for it, but I think that is part of it. The other part is that with regard to diffuse gastric cancer, we know that those tumors that have some characteristics, they’re unlikely to be HER2-positive and things like that.

And I just want to touch upon what Yelena said earlier about the management of high-risk patients. So, for Lynch syndrome, the screening for other malignancies is very important. But for diffuse gastric cancer, patients who carry a germline mutation should get a prophylactic gastrectomy above the age of 20. And that’s something; the risk of getting stomach cancer is about 1% per year. And so, the recommendations, or the guidelines, are to, in fact, get a prophylactic gastrectomy at some point in your 20s to reduce the risk of getting stomach cancer in the future. So, that’s one thing I want to make sure community oncologists hear as well.

Transcript Edited for Clarity