Increasingly Sensitive Genetic Testing Advances GI Cancer Diagnosis and Management

John Lindsay Marshall, MD

The field of precision medicine in gastrointestinal (GI) cancer is growing rapidly, and is leading to a future where individualized patient care is the norm, according to John Lindsay Marshall, MD.

“I’m looking forward to the further evolution of precision medicine,” Marshall said in an interview with OncLive®.

In the interview, Marshall outlined key points from a presentation he gave on the evolution of precision medicine in GI cancer during the 4th Annual Precision Medicine Symposium^®. He discussed past, present, and future developments in molecular testing, as well as the unique offerings of tissue and blood tests and the ways in which these precise approaches will ultimately make cancer diagnosis and treatment more efficient and effective going forward.

Marshall is the chief of Hematology and Oncology, a professor of medicine and oncology, and the director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers at Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC.

OncLive^®: What has the evolution of precision medicine in GI cancer looked like?

Marshall: We take precision medicine for granted today, but it wasn’t always that way. We began early on with doing a gene test here, a protein test there. As [our capabilities] evolved over the past 5 to 10 years, we realized that we needed more than 1 test.

Then, we started to learn about [mutations] that only emerged in big tests, like next-generation sequencing, whole genome sequencing, or whole-transcriptome sequencing. The future is looking even more complicated, [as we learn to do] proteome and phosphoproteomic sequencing.

We’ve gone from having 1 single snapshot to a terabyte of data on a given patient. That evolution is probably making us confused right now. However, as we go forward, it’s going to make our jobs much easier.

What testing options are currently available?

Right now, the current standard of care for almost every patient with metastatic disease is broad molecular profiling. There are blood tests and tissue tests, and we need to understand what those different tests tell us and what they don’t tell us.

We know about scans, which scans we’re going to order, [whether they] need contrast, and what we’re going to see or miss with a test. With genetic testing, molecular profiling, and precision medicine, we’re not quite so smart yet. [The tests differ from each other in] what they tell you, what you [can find with them], and what you can’t find with them, depending on their technologies. As the technologies evolve, we need to keep up with them as well.

[There are] key tests that must be done in all GI cancers, and there are select precision medicine tests that you can’t start treating a patient without knowing [the results of]. You can’t just know what’s under the microscope; you need to know what’s in the genes and proteins to test and treat patients.

What are the optimal scenarios in which to use those key tests?

The most basic of our tests is immunohistochemistry, where tissue on a slide is stained, and 48 hours later, you know whether [the mutation is] present. HER2 and PD-L1 are [detected through] immunohistochemistry.

The next level is genetic testing. You can [look at] isolated genes, such as BRAF, and see whether a mutation is there. Most pathology departments have the technology for that. But as [we now] want to know every gene out there, you need a bigger piece of tissue, and you need a lab that can do high-throughput next-generation sequencing.

The evolution after that will be proteome sequencing, where you are going to need a big enough piece of tissue, and the quality of the tissue is going to matter, such as whether it’s been ischemic. We’re going to need to understand that as well.

As far as blood testing goes, there are 2 kinds of tests. One is not tissue enriched, meaning you just look in the blood, you don’t know what you’re going to find, but you look for common cancer genes that might be mutated in the blood. Those are incredibly effective, but some patients aren’t spilling their [mutations] into the blood, and therefore you don’t find anything. They’re non-shedders, as we call them, or the copy number is not high enough to detect [the mutations] in a simple blood test.

The other [type of blood test] is tissue enriched. There, you take a patient’s tumor and sequence it so you know what you’re looking for, and you can go much deeper. Those are the kinds of tests that are being used for minimal residual disease [MRD]. [There’s been] an evolution of blood testing. Both are incredibly valuable blood tests, but they have different places in the clinical scenario.

Liquid biopsy is easier than getting a tissue biopsy; if you had to put a needle in a patient, just a blood sample would be [ideal]. That’s where this science is all going, to where we will be able to answer most of our questions from a simple blood test.

[However, with blood testing, we miss many mutations, and these tests don’t tell us everything.] Today’s standard is still tissue-based testing. But if you can’t get a biopsy sample, if the tissue can’t be analyzed fast enough, or if you know what specific genes you’re looking for, liquid biopsies looking for cancer genes can be effective.

The other [benefit of blood testing] is to look at MRD, to see if there is cancer there. [In this case,] we don’t care much about what genes are involved, [we just want to know]: Is the cancer still there? That’s another kind of liquid biopsy that’s looking for a different answer.

What does the future look like for the precision medicine field?

Precision medicine is not going to go away. It’s going to be increasingly a part of what we do day in and day out. [In the future,] we may do fewer scans and more blood and precision medicine testing. General treatments are going to be fewer and fewer; [instead,] there’s going to be specific treatments for individual patients. We’re not going to have 1-size-fits-all therapies much anymore as the [landscape] gets further divided.

[These advances are] going to make us smarter. We’re going to be more efficient, and [diagnosis and treatment are] ultimately going to be easier. We just need to wait the next few years to let artificial intelligence and gene testing technology come together to make for a better world.