What is Phenotypic Precision Medicine and its Role in GU Oncology? - Part 2

In part two of this exclusive interview, Evan Ya-Wen Yu, MD, Professor, Clinical Research Division, Fred Hutch Cancer Consortium, talks about the differences between phenotypic and genotypic precision medicine, the challenges in implementing precision medicine, which patients can benefit from this type of treatment, and the future of precision medicine.

Dr. Yu is a medical oncologist who treats patients with prostate, bladder, and testicular cancer at the Fred Hutch Cancer Consortium in Seattle, Washington. The interview is conducted by Daniel Tennenbaum, MD, urology resident at Maimonides Medical Center in Brooklyn, NY.

Dr. Daniel Tennenbaum:

In preparing for this interview, I saw some literature describing phenotypic and also genotypic precision medicine. How do those two entities differ and what are the advantages or disadvantages of each?

Dr. Evan Ya-Wen Yu:

I think that’s a good question. I think that now, more and more people are taking a bigger, broader view towards precision medicine than what I initially described. And I’m one of those individuals. What I described is you sequence the tumor, you find some sort of gene mutation or deletion or something like that, and you’re targeting it with a specific drug, but those are, I would say genetic characteristics, things that are happening at the DNA level. That is easy, because the name genotypic precision medicine right there describes it.

If we think a little broader about precision medicine, there are newer drugs, newer approaches, and I think about phenotypical precision medicine to not necessarily be what’s going on in the genes, but be what’s going on downstream in terms of characteristics of the tumor, expression of the tumor?

So for instance, if a tumor expresses certain proteins, overexpresses that, doesn’t necessarily have to be a mutation in the tumor that’s causing that in the genes of the tumor. There can just be high levels of expression in the tumor of that protein, and we have more and more drugs now where we can target towards a specific protein expression on a tumor and maybe even deposit either chemotherapy or radiation type therapy or something specifically to the tumor cells, sparing the patient of excess toxicity because maybe there’s differential expression, higher expression of a protein in the tumor than there are in normal cells. I think of that as more phenotypical precision medicine, because that is some sort of expressed characteristic in the tumor. And I think that’s what most people are using it to describe.

I’ll give you an example. In prostate cancer recently we’ve started using more and more PSMA pet scans. And PSMA is prostate-specific membrane antigen, which is a protein that can be highly expressed in prostate cancer. There’s not necessarily a gene mutation there, but it’s something that the cancer expresses and we can find it with PET imaging and identify it and it helps predict for patients who might respond to treatments, that target PSMA. The first one that’s gotten FDA approved recently is called 177lutetium-PSMA-617, was the original name for it, and that compound basically is a small molecule that finds PSMA and it’s attached to lutetium, which is a beta-emitting radiopharmaceutical and it gets directly brought to the tumor.

So again, not targeting a gene mutation, but targeting an overexpression of a protein on the tumor that brings a treatment directly to it. And there are other drugs in development that might be bispecific antibodies or antibody drug conjugates that are doing the same type of thing, finding an expression of the tumor, targeting it and depositing the therapy directly there like a smart bomb. So that’s precision. It’s just not genotypic precision medicine. I think of that as phenotypical precision medicine.

Dr. Tennenbaum:

It sounds similar to how thyroid cancer has been treated.

Dr. Yu:

Right, exactly. Except for the difference here is this is targeting an expression of a protein on the cancer cell that is differential between other normal cells.

Dr. Tennenbaum:

Exactly. Moving to a bit of a different subject, what has been the biggest challenge in implementing precision medicine into the medical community at large and in more specific terms, in your practice in particular?

Dr. Yu:

I’m fortunate I’m in a big academic center. We’re pretty flush with resources in the fact that when there’s something new and exciting, scientifically, biologically, clinically, we’re on it and we find a way to make it happen. But I realize that not every center is ready to go as soon as a new drug comes out. And when that comes out, especially if there’s testing precision medicine, whether it’s doing gene sequencing or immunohistochemistry or a PET scan, not everybody may have that capability to do that right off the bat. Third-party payers may not be ready to cover it right off the bat and they may push back on that.

And you can see where I’m going with this is just that it takes some enormous resources to do the paperwork necessary to order the tests, to deal with the denials and to come back and spend time and do peer-to-peer with the medical directors for the third-party payers.

So this is a challenge that I think is reasonably unique to oncology and the fact that this is one of the fastest moving fields. There are other fields that are moving this fast, but we’re clearly one of the fastest moving fields, fastest changing fields, coupled with the fact that our new treatments are pretty expensive. This creates a lot of roadblocks down the road. So of course, education needs to happen.

The public and physicians in the community need to learn about this, but I think in this field, most people are eager to learn, out there learning quickly, and sometimes when things don’t uptake as quickly, one of the biggest challenges is having the resources to get over all those hurdles, to get the testing, to then access the drug. If the patient’s copay is huge, to then try to find resources for copay assistance for the patients. So I would say the biggest challenge to implementing precision medicine are just the logistics and the pragmatic considerations. Still the right thing to do though.

Dr. Tennenbaum:

Without question. Unfortunately, that’s a big problem that we, as a community still need to address. Focusing on the patients, however, are there any particular clinical factors within a patient’s presentation or a patient’s history that makes a patient more or less appropriate for precision medicine?

Dr. Yu:

I mean, it depends on the situation. I’ll say that there are certain situations where maybe what you might find is you might find a higher hit rate. You’re looking for a specific genetic defect or over expression of a tumor, so there might be clinical factors like patients who are in this specific disease state, patients who have received a certain type of therapy. And I think one example is I talked about the DNA repair gene alterations, when I quoted around a quarter of patients, that literature is from patients who have metastatic castration resistant prostate cancer.

Now, a lot of those are things that happen early on. They might be germline or they might be somatic events that occurred very, very early on and you could have found it earlier, but now what you’re dealing with is you’re dealing with a more advanced patient population, and those genotypic or phenotypical precision medicine type of drivers are probably often drivers that point towards more aggressive disease. So you’re going to end up with more patients in that disease state.

So there are clinical factors or disease states where you might say, “I’m going to have a higher hit rate of testing positive if I catch somebody in that disease state.” So for prostate cancer, if you’re looking for DNA repair, gene alterations and localized disease, let’s say high-risk localized disease, depends on which study you look at, it might be in the six to 8% range or something like that.

That’s a lot lower than a quarter of patients. And it’s just because those patients that have those alterations are much more apt to develop metastatic disease. But if you’re looking for greater success rate in finding those patients and treating those patients, there may be clinical characteristics or clinical disease states that have higher percentages.

Dr. Tennenbaum:

To follow up on your answer, is there a clinical utility in using precision medicine in that prostate cancer patient who has localized disease?

Dr. Yu:

Well, there are certainly a lot of trials happening. It’s not clear just yet that we can direct therapy. There are some markers, mostly cell cycle gene markers panels that might give us good prognostic in indicators, telling us how, if the patient is more likely to relapse or develop a lethal disease down the road than those who aren’t. And that might help affect treatment a little bit.

But I think most of us, when we think about precision medicine, we want to strive for the highest bar, which is a predictive marker. A predictive marker means if you have this marker, this predicts not just for better or worse outcome, but this predicts for response to specific therapy, A, B, or C. So not quite yet for localized disease, but there are certainly studies underway and I think that I’d be surprised if in the future, we don’t start to see these things imported earlier and earlier to patients who have tumors that express certain characteristics.

Dr. Tennenbaum:

So Dr. Yu, you actually walked into my final question. Speaking about the future of precision medicine, what does precision medicine look like five years from now or 10 years from now?

Dr. Yu:

Oh, I think we’re just doing more and more of it. I think we have even broader definitions of precision medicine because there’s all different ways to do it. It’s not just a gene mutation or a gene amplification or a protein over expression on a tumor or a finding on a PET scan. Maybe there are specific morphologic characteristics even that we’re finding that we can go after when you look at the tumor under the microscope.

There’s a lot of other pathways that haven’t fully, fully been explored. Can we be developing biomarkers that are easier to do, that are more cost effective? I think that’s going to happen down the road. I think we’re going to be doing a lot more panel testing for people, and it’s going to become more mainstream and more affordable down the road to do that. We’ll understand the biology a lot better. We’ll have more targets to go after.

And what comes with that? Our development of more drugs that work against those targets. So I fully expect that five to 10 years down the road, we’re going to be only seeing more and more precision medicine implicated not only in prostate cancer, but in other GU cancers and in other cancers in general across the entire spectrum. So for sure. Or with clinical research, that’s ongoing, with basic science research that’s ongoing.

We’re bringing things from the laboratory to the clinic directly to patients and I just think that we’re only going to see more and more of this refinement and that’s only good for our patients with hopefully more efficacy and less toxicity.

Dr. Tennenbaum:

I think we can all appreciate that that is the shared goal. Dr. Yu, thank you very much for your time.

Dr. Yu:

Thanks for having me here. It’s always a pleasure.

Watch part one of this discussion to learn more about phenotypic precision medicine.