Katz Explains the Role of Different Stratification Strategies in Prostate Cancer

Aaron E. Katz, MD, FACS

Men with prostate cancer who were defined to have clinically low- to intermediate-risk disease according to the National Comprehensive Cancer Center (NCCN) guidelines were recategorized based on the 17-gene Oncotype DX Genomic Prostate Score, according to a study.

Overall, 62% of patients who were in the low-risk group and 34% in the intermediate-risk group were reclassified with the new genomic scoring system. This demonstrated that some patients with low-risk disease as per the NCCN guidelines may have more aggressive disease, which might require a different treatment approach.

Investigators used the 17-gene reverse transcription polymerase chain reaction (RT-PCR) prostate assay to evaluate the clinical experience of 33,000 patients with clinically low-risk prostate cancer in the United States. Investigators were able to redefine the risk assessment in these patients, which helped for better decision making and disease management.

In an interview with Targeted Oncology, Aaron E. Katz, MD, FACS, professor, Department of Urology, NYU Long Island School of Medicine, chairman, Department of Urology, Winthrop Hospital, NYU Langone Health’s Perlmutter Cancer Center, discussed the findings from a study of the 17-gene Oncotype DX Genomic Prostate Score.

TARGETED ONCOLOGY: What do the NCCN guidelines state about active surveillance for patients with clinically low-risk prostate cancer?

Katz: Currently, the guidelines state that men have either very low or low risk prostate cancer, defined as a prostate-specific antigen (PSA) less than 10 and Gleason score of 6 or 7 with low risk, 3 plus 4 in tumor cores that are typically less than 5, so let’s say 2 to 3 cores with less than 50% of the tumor volume and with MRI showing typically no PI-RADS 4 or 5, these are good candidates for surveillance or active surveillance based upon their life expectancy, which should be taken into consideration.

Now, understandably that many of these patients that are also in the low and even in the low to intermediate risk candidates could also be candidates for definitive therapy, whether that be radiation therapy with external beam conformal or SBRT, which is a new form of radiation that we've been using, or radical prostatectomy, which the majority of patients in this country are undergoing robotically.

To answer your question, the patients that are in the low or intermediate risk category with favorable characteristics, typically longer PSA doubling times slower PSA velocity, and normal imaging on MRI, can be considered suitable candidates for active monitoring or active surveillance. I have a program at NYU that I call active holistic surveillance where we employ dietary strategies in combination with monitoring their PSA, MRI, and a biopsy strategy, if indicated.

TARGETED ONCOLOGY: What methods currently exist for determining which patients fall under the low-risk category?

Katz: It would be the biopsy strategy, so if we have biopsies that don't show a lot of cores that don't show any indicative of a primary pattern, we do biochemical assays, like the PSA, which is very important looking at a PSA that you'd like to be under 10. Now I've personally put patients on active surveillance that have PSA higher than 10 because you also have to stratify by prostate volume. This is where MRI, I think, can be very helpful as well, not only for indicating whether or not there's a certain lesion in the prostate by PI-RADS, but also the volume of the prostate. We can come up with a strategy known as PSA density, so the lower the density, the more likely the patient would do favorably on an active surveillance program.

You also have physical examination, and I think, some institutions are getting away from doing digital rectal exams and I wonder if that's going to happen especially now that we're going to more telemedicine where we can't really examine the patient but just look at an image or look at a number like a PSA on a screen. I personally still feel that a digital rectal examination can be very helpful and making sure that there's no new change in a nodule or a hardness or a firmness, which would make me concerned that there may be disease outside the prostate and make that patient not the [ideal] candidate for active surveillance.

TARGETED ONCOLOGY: Can you provide some background on this assay in terms of its clinical validity?

Katz: The genomic assay Oncotype DX is the genomic prostate score, and the genomic prostate score has been validated by a number of institutions and as part of the NCCN guidelines now to help physicians and patients stratify as to who should or should not be on an active surveillance program. The way that it was developed was to look at a number of different genes that are expressed in the prostate, 17 genes. Some of these genes are regulated by hormones. Some of them are proliferating genes.

The nice thing about this assay is it goes through a number of different genes, number different categories of genes, and within each category, there are 2 to 4 genes within that category. The idea behind this, which is rather amazing, is that rather than looking under the microscope and seeing the cellular architecture and describing what's classically been used for many years now is the Gleason grading system. It gives us an added feature, an additional layer, by looking and isolating just the cancer cells and extracting the DNA, then doing what's called an RT-PCR reverse transcriptase polymerase chain reaction to look at the expression of specific genes that are turned on in these cells, and you can come up with a new score, a genomic prostate score, that can give us individualized specific expression within those cancer cells to determine whether or not they are more aggressive or less aggressive than what we have thought by looking at the classic Gleason grade under the microscope. So, it appears, and this is not only true for prostate but probably true for breast and colon as well, that not all of these cancers that we think are the same category act the same way.

Now we have a way of extracting the DNA and looking at the aggressiveness of the cells, and yes, it's been validated by a number of well-known neurological academic institutions, Cleveland Clinic, University of California Santa Francisco, and Johns Hopkins, as well have all done great studies validating this by looking at men that were undergoing radical prostatectomy, so they are correlating the genomic score to the final pathological grade and pathological stage of the cancer at the time of radical prostatectomy to validate it, which it was. I routinely have been using this in my patients that come to me that are considering active surveillance.

TARGETED ONCOLOGY: What is the rationale for the active surveillance study? What were the findings?

Katz: This was a study looking at the 17-gene RT-PCR assay the genomic score essay looking at the clinical experience in 33,000 patients with clinically low risk prostate cancer in the United States. What we were able to do was to redefine the risk assessment in these patients.

What we showed was that in men that were in the low and intermediate risk groups that they were recategorized based upon the new genomic score as the low risk patients who are stratified or reclassified, and that’s 62%. The intermediate risk patients were re-categorized in 34%, so it's very interesting to understand that some of these patients that we consider low risk may actually a harbor some more aggressive disease and may require some definitive treatment.

We have found in our studies, and if you look at some of the studies that have been done long-term on practicing surveillance, a significant number of them will progress and will require definitive treatment. So what we're able to do now is identify these patients much earlier with this study and reclassify them as we have done so this is a clear validation of the test, this 17-gene RT PCR assay. It's an important study. I think it will change the management. It will help, as I initially started to tell you, and change the management and help both physicians and patients make a more educated decision about their treatment decision.

TARGETED ONCOLOGY: What are the key takeaways from this study?

Katz: I think the point that you want to take home is that we've relied on certain risk categories for men, based upon their Gleason, their PSA, the number of cores they have, their rectal examination. We're now moving into a new direction, into the into a new future of a new era, if you will, of molecular staging or molecular stratification. I think it's an exciting era and 1 that will continue to be expanded in its use in oncology. I think it probably will expand toward breast, ovarian, and colon cancers, as well as maybe some other cancers like leukemia or lymphoma, but it is an interesting time.

I was happy to see that we were able to do this study and look at it very carefully and critically, so I'm excited about it and am feeling encouraged that we are really a bit because you have to understand that the men that come to the office, they're very anxious They've been told they have cancer. If we can find that the cancer truly is an indolent cancer, it's non-aggressive cancer that you can wait maybe 2 years, maybe 5, maybe 15 or 20 or forever in your life and don't have to undergo surgery or radiation, and I've seen that in my practice, for sure, then that's a big deal for a lot of men. Despite advances in radiation and surgery, we've made great strides with robotic surgery and stereotactic body radiotherapy, but they're not 100% curative, and they can be associated with toxicity for men, such as urinary and sexual toxicity, acutely and also chronically, so we have to be very mindful as well about the quality of life.

_Reference

_{Bennett J, Aboushwareb T, Lau N, Stoppler M, Katz A. The 17-gene RT-PCR prostate assay: clinical experience in 33,000 patients with clinically low-risk prostate cancer. J Urol. 2020:203(suppl 4):MP23-07. doi: 10.1097/JU.0000000000000856.07}