GU Oncology Now recently sat down with Dr. Daniel Spratt, Chair of the Department of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University, and an expert in prostate cancer, to discuss phenotypic precision medicine in advanced prostate cancer. See what Dr. Spratt had to say.
GU Oncology Now: Can you provide us with some background on yourself?
Dr. Daniel Spratt: I’m the current chair of radiation oncology here at Case Western and UH Seidman Cancer Center, and I’m a prostate cancer specialist, specifically in radiation oncology as well as a research interest in translational medicine, including both prognostic and predictive biomarkers and lead a large research team focused on trying to improve outcomes for men with prostate cancer.
How big an impact has precision medicine had on the field of prostate oncology?
Precision medicine, people like to sometimes differentiate it from personalized versus precision medicine. And they sound very similar, but technically they are different terms. Personalized medicine is what we’ve done for decades in prostate cancer, trying to give the right treatment to the right patient based upon the stage of their disease, their PSA, their Gleason score. Precision medicine is taking that to the next level, and it’s trying to say is there some type of characteristic, that could be molecular, it could be genetic, it could be imaging, that really guides us to the therapy that’s going to best benefit a patient or give us maximal information on their prognosis?
It hasn’t been really until the past couple years that prostate cancer finally has really had precision medicine tools, especially in advanced prostate cancer, and so we’re really entering a new era, both from precision imaging as well as precision genetic markers, often obtained from a biopsy or a blood sample. We finally have multiple therapies, some that are FDA approved, including PARP inhibitors that are guided towards men who have certain DNA repair alterations, as well as soon to be a whole new frontier of therapies based upon the expression of PSMA, a protein that’s found mostly on prostate cancer cells, that we have imaging tools and other tools to measure. So, I think it’s a very exciting time, really the past year or two, for prostate cancer.
What makes the use of genotypic biomarkers a challenge in advanced prostate cancer?
Genotypic biomarkers really is the assessment of genetic material. When you think about that, the most common way this is done is through a biopsy. Any type of biopsy is invasive, especially in prostate cancer. The most common metastatic site is bone, and bone biopsies have many challenges. They often it’s only about 70% plus or minus, even in expert hands, accurate, the diagnostic yield, and so it sometimes can be challenging to obtain that tissue because you need that tissue to run it under genetic analysis, genetic sequencing.
So that’s sort of, I guess, challenge number one. But challenge number two is that often men with advanced prostate cancer have dozens, sometimes hundreds of different tumors in their body, some in organs, like the lung or the liver, some in bone, some in lymph nodes, some in the prostate itself. And it’s been shown that although there’s similarities across the different tumors within a given patient, there is heterogeneity, and so it’s not feasible to sample all of those spots in the body to determine what is the composite genetic make-up really of that cancer.
I would say something else that comes into play is although genotype we sort of think of as this gold standard, right? If you have a mutation in a specific gene, it should mean black and white that you’re going to benefit from this drug or not benefit. But in reality, even the best precision medicine tool based on a genotype, such as a DNA repair defect such as having BRCA1 or BRCA2 alterations, the majority of patients do not benefit or have a response or improved outcome from giving a PARP inhibitor. So, even if you have what we think is this genotypic alteration, it’s still we’re missing a component of which patients benefit and not. I would say that there’s definitely strengths to it, but there’s a lot of obstacles and limitations we still face that we’re working on.
What are the advantages of using phenotypic biomarkers in advanced prostate cancer?
Sort of a new category that I think is catching on, some people use the term phenotype. Instead of saying here’s the exact DNA sequence for this patient, a phenotype is really the culmination of a lot of different things. It could be based upon environment, your hormone levels, your genotype that gives a specific phenotype.
And probably the prime example of that right now is the use of PSMA, which stands for prostate-specific membrane antigen. We’re able to assess PSMA expression in many ways. You can do it by more classical genotype method where you obtain tissue and you see the expression levels or the protein levels.
But what we’re able to do now, with great technology that’s been FDA approved now across the United States just recently, is we can get PET imaging, positron emission tomography, of the whole body to assess the burden of prostate cancer in a patient. It provides, it overcomes, I guess, many of those limitations in sort of having to biopsy one tumor in that you can totally noninvasively assess an entire patient’s body relatively quickly, painlessly, and you can assess all of the tumors in the body that at least express in this case PSMA. And so, you can really sort of start to understand differences in the phenotype and its interplay with biology across the whole patient’s burden of disease, and it really is I think a potential game changer.
How will phenotypic precision medicine shape the future of prostate oncology care?
In prostate cancer, I really see that with now the approval of PSMA PET imaging, I think this is going to become, even though we have lots to learn still about it, it’s going to become the standard of care imaging for patients from localized and eventually through advanced prostate cancer. I think that’s because it’s a better imaging tool in the sense that it’s more sensitive, meaning that it can detect more areas of cancer, allow us to be better at what’s called risk stratification, or providing prognosis, how aggressive is this cancer for a patient, as well as very importantly, which we’ve lacked these tools, it now provides therapeutic options.
Because not only if you see these cancer cells can we target them with, let’s say, stereotactic external radiation therapy, but there’s now numerous types of PSMA-directed therapies, one that a study was just reported on and published with Lutetium PSMA, a radioactive molecule linked to protein, basically a molecule that targets those cancer cells showing improved survival in these patients. And there’s numerous other drugs in the pipeline that are being developed and studied to help target those cells.
And so you now finally have a companion, we’ll call it diagnostic tool, total body imaging, very easy to do, and you’ve got therapies that can be directed at it, and you can assess the response with the imaging. And it’s just, we’ve never really had these tools, so I think over the next 12 months in prostate cancer, I think you’re going to see a radical change in the way patients are staged, imaged, prognoses provided, and the therapies that are going to be FDA approved as well as the therapies that are being designed and developed.
No, I think that a very important point that I think sometimes we miss in prostate cancer when we talk about PSMA expression, PSMA imaging, is we think of it just as another imaging tool. But it’s so much more than that, because when we think about other cancers that we have precision medicine tools for, like breast cancer, where almost every woman who gets diagnosed with breast cancer, they do an estrogen receptor basically test of their tumor to see if they have ER positivity expression at various levels. And they do that because not only does having ER-positive breast cancer, is it a favorable prognosis that provides prognostic information, it also helps personalize how they’re treated and there are specific drugs for those women who they benefit from.
We’ve never had that in prostate cancer, and so PSMA is not simply an imaging tool. There are numerous studies showing that having PSMA expression, the intensity or the amount of expression is prognostic, the number of metastases is prognostic, so it provides valuable information, and now it actually is predictive. We actually, patients who have that expression are more likely to benefit from PSMA-targeted therapies. And so, I think that we really need to start interpreting this tool as a true sort of game changer rather than just a fancy imaging agent, and I think our patients are going to reap the rewards from it.