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The Evolving Treatment Landscape in Gastric/GEJ 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
Published: Thursday, Feb 08, 2018



Transcript: 

Yelena Y. Janjigian, MD: The field of gastric cancer, and the personalized therapy for gastric cancer, evolves. We know that immune checkpoint inhibitors are an important strategy in a subset of patients, and that strategy will likely, with time, move on to earlier lines of therapy: to first-line, second-line, or even perioperative settings. But this is a small subset of the population that truly dramatically benefits, and with time we will develop biomarkers to better stratify these patients.

We already know that MSI and EBV-positive gastric cancer responds to these agents. And for those patients, earlier lines of therapy will probably be important. Ideally, repeated biopsies and biomarkers are important to help us stratify and characterize these patients for targeted agents, such as the HER2, MSI, and PD-L1 biomarkers that are all validated biomarkers now in gastric cancer. So, we have 3 tissue biomarkers that are important: HER2, PD-L1, and MSI.

Repeated tumor biopsies have been shown to be important in HER2-positive tumors to assess for loss of HER2 and a rise of secondary alterations. But understandably, these biopsies can be difficult to obtain, they give you somewhat of a static nature of the tumor with 1 time point and 1 tumor location, and they can be difficult to interpret. What the field is moving toward are liquid biopsies, where we can detect a tumor shedding into the circulating tumor DNA and pick these minute fragments of DNA out and do a next-generation sequencing of them, a tumor assessment for HER2, MSI, and so on.

This is a field that’s rapidly evolving, but our data suggest that up to 70% of metastatic disease sheds quite a bit of DNA into the bloodstream. So, it would be important to test this further in a randomized or prospective fashion, but we know that this is an important strategy and an important tool in the future of drug development for gastric cancer.

Alan P. Venook, MD: It’s a really interesting question to start thinking about, where will we be in 5 years with the checkpoint inhibitors? Because where we were 5 years ago, they weren’t on our radar. They’ve taken us by storm, and we’ve all seen patients have dramatic results. Having said that, I don’t know how far along we’re going to go before we realize maybe it’s not a free lunch.

In particular, there’s a huge effort to put it early in treatment as well as in the adjuvant setting. With treatments that so reliably cause autoimmune disease or that can cause complications, I worry about the long-term consequences. I don’t really know where they’ll fit. What I worry about is that we will move them quickly into many settings, but we may wind up moving them out of settings down the road. I hope not, but I believe that the enthusiasm may get us using the drugs too often and too early. If we can use them early, it would be fabulous in that it’s obviously where we’d like to go. But I’m pessimistic, because if the immune system were meant to be unchecked, then doing so with the checkpoint inhibitors could cause lots of problems.

Zev A. Wainberg, MD: Gastric and GE junction cancers are quite heterogeneous, which means both the cancer’s behavior is heterogeneous and the way oncologists treat it is heterogeneous. There is often a different treatment approach in the United States versus Europe versus Asia. In Asia, where gastric cancer is one of the most common malignancies and everybody has a lot of experience with it, it is typically treated with a very aggressive surgical approach. They have aggressive screening programs there. So, they encounter a very different kind of disease than we do in the United States and western Europe. In the United States and western Europe, there’s a little more of GE junction cancer. We will typically, in the United States, treat a lot of patients with radiation, which is much less common in Europe as a way of managing this cancer.

We do see some management differences there. In the United States, in particular, many of the studies with GEJ have involved neoadjuvant chemoradiation approaches or even adjuvant chemoradiation approaches, which are not routinely done in Europe to the same extent. Beyond that, the chemotherapy regimens are very similar now. I would say there is a tendency in the United States to use FOLFOX, which is more of a standard chemotherapy regimen in the United States as opposed to 5FU and cisplatin, or capecitabine and cisplatin, which is a little more common in Europe. But besides that, the chemotherapy regimens are very similar. Anthracyclines were much more common in Europe than they have been in the United States, but those have become much less used based on the recent data. So, there are some nuanced differences, certainly, between the United States and Europe, but overall, the management is quite similar in many respects.

Transcript Edited for Clarity 
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Transcript: 

Yelena Y. Janjigian, MD: The field of gastric cancer, and the personalized therapy for gastric cancer, evolves. We know that immune checkpoint inhibitors are an important strategy in a subset of patients, and that strategy will likely, with time, move on to earlier lines of therapy: to first-line, second-line, or even perioperative settings. But this is a small subset of the population that truly dramatically benefits, and with time we will develop biomarkers to better stratify these patients.

We already know that MSI and EBV-positive gastric cancer responds to these agents. And for those patients, earlier lines of therapy will probably be important. Ideally, repeated biopsies and biomarkers are important to help us stratify and characterize these patients for targeted agents, such as the HER2, MSI, and PD-L1 biomarkers that are all validated biomarkers now in gastric cancer. So, we have 3 tissue biomarkers that are important: HER2, PD-L1, and MSI.

Repeated tumor biopsies have been shown to be important in HER2-positive tumors to assess for loss of HER2 and a rise of secondary alterations. But understandably, these biopsies can be difficult to obtain, they give you somewhat of a static nature of the tumor with 1 time point and 1 tumor location, and they can be difficult to interpret. What the field is moving toward are liquid biopsies, where we can detect a tumor shedding into the circulating tumor DNA and pick these minute fragments of DNA out and do a next-generation sequencing of them, a tumor assessment for HER2, MSI, and so on.

This is a field that’s rapidly evolving, but our data suggest that up to 70% of metastatic disease sheds quite a bit of DNA into the bloodstream. So, it would be important to test this further in a randomized or prospective fashion, but we know that this is an important strategy and an important tool in the future of drug development for gastric cancer.

Alan P. Venook, MD: It’s a really interesting question to start thinking about, where will we be in 5 years with the checkpoint inhibitors? Because where we were 5 years ago, they weren’t on our radar. They’ve taken us by storm, and we’ve all seen patients have dramatic results. Having said that, I don’t know how far along we’re going to go before we realize maybe it’s not a free lunch.

In particular, there’s a huge effort to put it early in treatment as well as in the adjuvant setting. With treatments that so reliably cause autoimmune disease or that can cause complications, I worry about the long-term consequences. I don’t really know where they’ll fit. What I worry about is that we will move them quickly into many settings, but we may wind up moving them out of settings down the road. I hope not, but I believe that the enthusiasm may get us using the drugs too often and too early. If we can use them early, it would be fabulous in that it’s obviously where we’d like to go. But I’m pessimistic, because if the immune system were meant to be unchecked, then doing so with the checkpoint inhibitors could cause lots of problems.

Zev A. Wainberg, MD: Gastric and GE junction cancers are quite heterogeneous, which means both the cancer’s behavior is heterogeneous and the way oncologists treat it is heterogeneous. There is often a different treatment approach in the United States versus Europe versus Asia. In Asia, where gastric cancer is one of the most common malignancies and everybody has a lot of experience with it, it is typically treated with a very aggressive surgical approach. They have aggressive screening programs there. So, they encounter a very different kind of disease than we do in the United States and western Europe. In the United States and western Europe, there’s a little more of GE junction cancer. We will typically, in the United States, treat a lot of patients with radiation, which is much less common in Europe as a way of managing this cancer.

We do see some management differences there. In the United States, in particular, many of the studies with GEJ have involved neoadjuvant chemoradiation approaches or even adjuvant chemoradiation approaches, which are not routinely done in Europe to the same extent. Beyond that, the chemotherapy regimens are very similar now. I would say there is a tendency in the United States to use FOLFOX, which is more of a standard chemotherapy regimen in the United States as opposed to 5FU and cisplatin, or capecitabine and cisplatin, which is a little more common in Europe. But besides that, the chemotherapy regimens are very similar. Anthracyclines were much more common in Europe than they have been in the United States, but those have become much less used based on the recent data. So, there are some nuanced differences, certainly, between the United States and Europe, but overall, the management is quite similar in many respects.

Transcript Edited for Clarity 
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