Dr. Dan George, Duke Health, on Phenotypic Precision Medicine in Prostate Cancer

By Robert Dillard - Last Updated: September 17, 2021

GU Oncology Now recently spoke with Daniel George, MD, a medical oncologist at Duke Cancer Center who specializes in genitourinary cancers. Dr. George discussed novel therapies that are shaping the way advanced prostate cancer is treated, specifically, phenotypic precision medicine.

GU Oncology Now: Can you provide us with some background on yourself?

Dr. Dan George: Yeah, sure. I’m a medical oncologist at Duke University. I’ve been here 18 years from professor of medicine and surgery and I really co-lead our Center for Prostate & Urologic Cancers in the Duke Cancer Institute. And my background has been in drug development and in biomarkers for GU cancers. But more recently, I focused on some of the real-world applications for all these advances that we’ve had in GU cancers, in particular, prostate and kidney cancer.

Can you discuss some novel therapies that are changing the treatment paradigm in prostate cancer?

Prostate cancer has completely changed in the last 10 years. If you look at the therapies that we use, 90% of the treatments for advanced prostate cancer are new in the last 10 years. And I suspect in the next five years, we’re going to see another handful or more therapies come on into this field. And as it gets more crowded with therapies and as we turn over into more effective therapies, what comes from that is more precision, more understanding of the disease biology, and specifically how to target it. And I think that’s what you’re seeing in sort of this next generation of therapies that have come through, in particular, we look at over the last few years some of the therapies that are really predicated on genetic alterations in the tumor or in the host, or therapies that are really focused on a certain clinical phenotype that we might see by either patterns or spread or biologic features of those metastases. And I think that’s really adding to the effectiveness of this next generation of therapies.

Are there any challenges using phenotypic precision medicine? 

Rob, this is a relatively new term to the field and I want to just take a moment to describe it because when I talk about a phenotype, most people think about things like eye color or hair color as a phenotype. It doesn’t change the function of the hair or the function of the eye, but it does change how it appears outwardly. And when I think about phenotypes in prostate cancer, it’s a little bit more complicated to them because these are phenotypes that actually do have prognostic and biologic implications regarding the disease. And it’s not simply a black and white yes or no description, some of these phenotypes are mixed. So when we think about something that is say an imaging phenotype, patients that have a certain uptake on a PET scan, whether that be FDG or PSMA or what have you. We can visualize and see the tumor directly, number one, but number two, we can see tumors that have high avidity for that marker, medium, or low.

And then we can see even within a certain patient, an intratumoral variation between sites of disease, high uptake, medium uptake, or no uptake. And so, phenotypes are really giving us a whole body look, it’s an outward appearance. It’s something that is expressed on typically the surface of cells or within cells, but they’re not necessarily at the genetic molecular level, it’s a little bit above that. And it really gives us a opportunity, especially with imaging, to look at the sum of all of those features in the patient. And that’s so important with advanced disease, that’s where we see greater and greater heterogeneity, not just within the population, but within each individual patient.

How do you think phenotypic precision medicine will shape the future of advanced prostate cancer?

So when I think of advanced prostate cancer now, I’m not thinking about this as one disease and that’s different from how we thought about it. Just a few years ago, we would call this hormone refractory or castration-resistant prostate cancer and metastatic, nonmetastatic, but that was the only terminology that we used. And the fact is that this is not a monolithic disease, as I mentioned. There’s a spectrum of this biology across the population and even within individual patients, particularly as that tumor burden increases. And so now I think we’re going to start thinking about PSMA avid tumors, FDG avid tumors, maybe there’ll be neuroendocrine imaging or neuroendocrine features that we begin to look at and think of this. We already think about BRCA2 positive tumors and we may think about loss of PTEN tumors or other genetic alterations.

And I think we’re going to overlay some of our genetic subtypes with our phenotypic subtypes. And I think when we do that, then we’re going to get even more kind of, we call it precision, but it’s really kind of enrichment strategies for the therapeutic approaches. And those therapeutic approaches now are going to get moved into these patients earlier and earlier as we begin to look at how to layer or combine those with other settings like ADT, but then maybe also with that next generation or engine receptor pathway inhibitors, or thinking about kind of layering with chemotherapy or even other investigational or newly emerging therapies like PARP inhibitors or immunotherapy. So I think it’s an exciting time in the field, but it’s going to create change and I think as oncologists we’ve had to embrace change in the way we practice. I think change is going to become the norm now and just understanding kind of how the iterations of treatment sequence need to keep evolving and personalizing towards whatever profile we’re seeing in patients is going to be important and there’s going to be more profiles to come.

Any closing thoughts?

Yeah, let me just say that this is a time of change in prostate cancer, not just in the way we treat this disease, but the way that we kind of work up and evaluate this disease longitudinal. And as we’ve sort of begun to sort of become systematic in our approach to genetic profiling, I think we’re going to have to become systematic in our approach to imaging in this disease. And that change is hard because it’s going to create a different workflow, it’s going to create communication interaction with our payers and more explanation to our patients. But I think it’s going to create also greater effectiveness and benefits to our patients. And I think at the end of the day that’s what we’ve got to embrace, but recognize this isn’t simply a time of another therapy now, this is a time of really another paradigm or approach to how we really characterize this disease going forward.

And that to me is super exciting, but it’s more work. So I appreciate everybody out there taking care of advanced prostate cancer patients. If we can help as a community, academics like myself, more than happy to. I think we’re in this together and I hope together we really advance this field. Thank you.

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