What is Phenotypic Precision Medicine and its Role in GU Oncology? - Part 1

In part one of this two-part interview, Evan Ya-Wen Yu, MD, Professor, Clinical Research Division, Fred Hutch Cancer Consortium, discusses what precision medicine is, how patients were treated before precision medicine, and biological markers in urologic oncology.

He is interviewed by Daniel Tennenbaum, MD, urology resident at Maimonides Medical Center in Brooklyn, NY.

Dr. Daniel Tennenbaum:

Hello. Thank you for joining us. I’m here today with Dr. Evan Yu, a medical oncologist who treats patients with prostate, bladder, and testicular cancer at the Fred Hutch Cancer Consortium in Seattle, Washington. Having completed his medical school training at the University of Washington, Dr. Yu then completed his medical training at Harvard’s Brigham and Women’s Hospital, and then pursued an oncology fellowship at the Dana Farber Cancer Institute also under the Harvard umbrella.

Dr. Yu has a background in basic science as a researcher, where he studies the biological mechanisms of drug sensitivity and treatment resistance. His overall goal is to discover novel biomarkers that can help guide treatment and aid in the development of novel treatments for cancer. Today, Dr. Yu is joining me to help us better understand precision medicine and its role in GU oncology. Dr. Yu, thank you very much for coming today.

Dr. Evan Ya-Wen Yu:

Well, thanks for having me here today. It’s always a pleasure.

Dr. Tennenbaum:

So how would you describe what precision medicine is?

Dr. Yu:

The magical question. I think all oncologists and all patients love the idea of precision medicine. I think loosely the way to think about precision medicine is that you’re treating a specific subset of patients who have some sort of specific characteristic in their tumor that predisposes them to response to a specific therapy. I think that’s really important to consider because there’s a lot of forms of precision medicine.

Most classically, we’ve thought about forms with a biomarker, a blood-based biomarker, a gene alteration that we see in the tumor. I think that’s how most people think of precision medicine. And in this day and age, we’re starting to develop more and more treatments that can target specific gene defects or defects in specific cancer cell pathways. Big picture, that’s how I think of precision medicine. Happy to dive more into details.

Dr. Tennenbaum:

All right. We certainly will. Prior to the developments of precision medicine, how would you describe the way treatment was offered to patients before the development of this?

Dr. Yu:

I think if you think about how cancer patients are treated, most everything we do is derived from clinical research, clinical trials. So that’s why I always find it very important to counsel my patients on the ideas that there are a lot of things we don’t understand, we don’t know, and what we do know, the only reason we know it is that patients enrolled on clinical trials and established that literature and that data that serves as our foundation of knowledge that we use to treat cancer patients today.

However, in the past, we didn’t understand cancer biology as well. And for that reason, we would take patients in certain clinical disease states with certain diseases and characteristics, clinical characteristics who had fit into a more homogenous disease state.

Let’s say they’d received one prior line of therapy, and this was a second line therapy. And all those patients would be enrolled onto a trial with a new therapeutic tested against maybe some standard of care, and what would emerge would be you’d see some patients would respond well and others wouldn’t. And you’d just hope that the drug was efficacious enough and the cancer biology was amenable enough to respond to that therapy and enough patients responded.

Now, I’m sure for almost every treatment, there are predisposing biologic factors, most of which we don’t quite understand yet, but we’re starting to get in that era now where we can pick out those biologic factors and directly target them. So in the past, it was just try all and see what ends up happening. “Is drug X better than previous standard of care or not?” We didn’t try to select patients based on biological characteristics, because we didn’t know any better.

Dr. Tennenbaum:

Can you speak more to the biological markers that you were referring to? Are these just simple blood tests? What else is involved?

Dr. Yu:

So it totally depends. I mean, I think when you think about precision medicine, most people refer now in this day and age to things you might find in the tumor. So for instance, nowadays we have the ability to do panel sequencing, to look at certain genetic defects in the tumor. And when you find that there are certain genes that we know that we have drugs that are available for that might be able to target those defects or those pathways, downstream signaling pathways in the cancer cells, and that’s what most people think of precision medicine.

I think it’s a lot broader than that. That’s where the field has gone and there are examples of that within GU cancers that I could certainly talk about, but yeah, I mean I think most of it is people think precision medicine is test the tumor. What sort of genetic defects are there? And do I have a drug to go after that? That’s the 30,000 foot view.

Dr. Tennenbaum:

Sure. And how do we see that within the world of urologic oncology?

Dr. Yu:

So I’ll give you a few different examples. In prostate cancer, recently we’ve found that maybe about a quarter of men have some sort of DNA repair gene defects in their tumors. About half of those alterations, men with those alterations inherited those, what we call germline, and about half of them are they’re called somatic where they just develop spontaneously over time.

Regardless, we found that certain classes of drugs like PARP inhibitors seem to work well for that. And the way to think about it is that this repair pathway through these genes like BRCA1, BRCA2, PA2b, these are just a few genes to name are part of humongous recombination repair. Okay? And that’s an important DNA repair mechanism. So if a cancer cell gets damaged in their DNA, they have to repair their DNA. Otherwise, if enough damage accumulates, they’re going to have to die. It’s called apoptosis and they selectively die that way.

A cancer cell has to protect itself as well, and if you have one of those predisposing genetic defects, that might have helped led to that cancer, but that’s also a weakness in the cancer that we can target because they can’t repair DNA as well via that homologous recombination repair pathway. Now PARP, as I mentioned, as we have PARP inhibitors, PARP facilitates single strand break repair. That’s another type of DNA repair pathway.

So the whole idea is you take somebody with a cancer that’s already has some DNA repair problems, and now you hit it again with a drug that inhibits another DNA repair pathway and that causes a selective death in those cancer cells. So that’s called synthetic lethality in the laboratory and use of PARP inhibition is just one way of showing it in the clinic. So that’s one example.

Dr. Tennenbaum:

Well, I think that’s a great example. Are there similar or same philosophy I should say to cancers outside of prostate cancer?

Dr. Yu:

Yeah. So I’ll talk about bladder cancer. In bladder cancer, patients with metastatic disease, it’s been found that FGFR or fibroblast growth factor receptors, that these may be drivers of the disease and in metastatic disease, it tends to be FGFR3 mutations, or you can have these kind of fusion proteins between FGFR2 and three. That’s a little less common, but it can happen.

There’s a drug out there now called erdafitinib that’s a small molecule inhibitor of FGFR. That has been shown in patients that have received prior platinum therapy to have really quite robust response rates. They received an accelerated approval and there are ongoing randomized phase street trials ongoing to see if it’s positive in those studies compared against a reasonable standard of care that they might then get… FDA might grant them a full approval. So that’s an example in bladder cancer.

Dr. Tennenbaum:

Then I may as well ask about kidney cancer. I understand that kidney cancer is relatively chemo resistant and radiotherapy resistant. It sounds like kidney cancer would be a good forum for precision medicine to help treat the cancer.

Dr. Yu:

Yeah. I think there are a lot of opportunities upcoming. There’s a more and more understanding of the biology there. One class of drugs that traditionally we started off using in kidney cancers are the antiangiogenic agents. I think there might be opportunities as we understand those biologic pathways better to refine that, but not quite as prime time yet in kidney cancer as may as in some other cancers, but certainly opportunity there.

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