Understanding the Underlying Mechanisms of Gastric and Esophageal Cancer

Adam Bass, MD

Adam Bass, MD

Understanding how gastric and esophageal cancers are triggered and their genetic makeup is vital to developing and testing new therapies, according to Adam Bass, MD.

In an interview withTargeted Oncology, Bass, Assistant Professor of Medicine, Harvard Medical School, Physician/Scientist, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, discusses subclasses of gastric and esophageal cancer, mechanisms by which cancers are activated within a patient from dormancy, and the potential for uncovering an optimal treatment.

TARGETED ONCOLOGY:Can you tell us about your recent work examining the subclasses of both gastric and esophageal cancer?

Bass:I recently presented some of the work we've done, and are continuing to do, which is trying to look at the different molecular and genetic subclasses of esophageal and gastric cancer. I think it's fair to say that over time, even though we've recognized that there's some inherent heterogeneity in gastric and esophageal cancer, a lot of our therapies, especially our systemic therapies for metastatic disease, have taken a one-size-fits-all approach.

Some of the work we've done in collaboration with others has been to look across these cancers with different genomic technologies to understand the different types of cancers in the different subclasses that are present. Even beyond the different subclasses, we have to think about what some of the real salient features of these different tumors are and which particular oncogenes that might be turned on could give you some guidance as to optimal targets for new therapies.

TARGETED ONCOLOGY:What are the molecular differences that lead you to believe that they should be treated differently?

Bass:What we have found is that there are different classes of gastric and esophageal cancer, especially different classes of gastric cancer in which the fundamental ways these cancers get started are quite different. For example, there are some cancers that have underlying them a defect in their ability to repair DNA, and this results in lots and lots of DNA mutations. These are cancers that are called microsatellite unstable. We've seen that there are some intriguing targets that are sometimes mutated in these cancers, and sometimes we see that these cancers often have higher expression of some of the markers that may suggest benefit to new immunotherapies. We've already seen that colon cancers with microsatellite instability (MSI) also tend to do well with immunotherapy.

By contrast, there are other gastric cancers that initiate in part because they are infected with the Epstein-Barr Virus, the same virus that causes mono and the same virus that's implicated in a number of head and neck cancers. These cancers with MSI have high expression, in some cases extremely high expression, in some of the markers that could indicate partial response to immunotherapy.

There are other cancers whose foundation is a different type of genomic instability than you see in MSI. MSI tumors have lots of point mutations, but there are other classes of gastric cancers that have really abrupt and marked chromosomal aberrations where you get this mixing and matching of different pieces of chromosome and many, many copies of certain cancer-promoting genes. In those, there are a number of different genes that get overexpressed and amplified that are often targeted by either existing or emerging inhibitors.

As you see, there are different classes of cancers in which the underlying mechanism of how these tumors emerge is different, and in that setting there may be, with our thinking, different ways to develop therapies. Maybe even looking at existing therapy in light of these changes might help us understand where existing therapy may be more or less effective.

TARGETED ONCOLOGY:Is there a possibility of finding the “optimal” treatment?

Bass:It's fair to say that most cancer therapy in general has been developed around the question of finding optimal treatments for different anatomical classes of cancer. We ask what the best chemotherapy for colon cancer is, and that might be different than what we think is the best for non-small cell lung cancer. Once you look more at the cancers, you realize that there are distinct subtypes. For example, in breast cancer we now recognize that the way to treat a ER-positive and a triple negative or a HER2-positive are quite different because of the underlying biology and the underlying vulnerabilities.