Zachary Klaassen: Hello, and thank you for joining us today for this NCCN Clinical Practice Guidelines in Oncology brought to you by Uro Today. We are looking at prostate cancer version 2.2021, and specifically the risk stratification for clinically localized disease. My name is Zach Klassen, I'm an Assistant Professor in the Division of Urology at the Medical College of Georgia. And with me is Christopher Wallis, who's an Assistant Professor in the Division of Urology at the University of Toronto.

Today, we're going to specifically focus on Risk Stratification for prostate cancer, the utilization of Nomograms, as well as the utilization of Tumor Multigene Molecular Testing. So first to discuss risk stratification. When looking for the ultimate treatment of prostate cancer, this requires an assessment of risk for each patient. And this leads to several questions that may arise, including how likely is a given cancer to be confined to the prostate or spread to regional lymph nodes. How likely is the cancer to progress or metastasize after treatment? And finally, how likely is adjuvant or salvage radiation to control cancer following radical prostatectomy?

When looking at localized prostate cancer, this is best characterized by several variables, including a digital rectal exam and radiographical determination of the clinical T stage, as well as Gleason score and the extensive cancer in the biopsy specimen, as well as serum PSA level. This is an overview of the NCCN and Guideline Risk Stratification. And we can see here on the left is the risk groups, including very low, low, intermediate, high, and very high. And for today's purpose of discussion, we'll be focusing on essentially the clinical and pathological features.

So just to highlight these briefly for a very low NCCN risk, they'd have to have all of the following, including T1C disease, grade group one, PSA less than 10, fewer than three biopsy fragments or cores positive with less than 50% in each core and a PSA density of less than 0.15. For patients with NCCN and low-risk disease, they can have all of the following, but does not qualify for very low risk, including having T1 to T2A, grade group one or PSA less than 10.

For intermediate risk, we'll focus on this a little bit more in subsequent slides, but just a brief overview that says all the following, including no high risk features, no very high risk group features, as one or more of the following intermediate factors, including T2B to T2C, grade group two or three, or PSA of 10 to 20. In terms of high risk disease, these patients are categorized as high risk if they have exactly one of the following features including T3A or grade group four or five, or PSA greater than 20. And finally those with very high risk features has at least one of the following, including T3B to T4 disease, primary Gleason pattern five, two or three high-risk features are greater than four cores with grade group four or five disease.

In 2014, the International Society of Urologic Pathology had a consensus conference and changed the grading of prostate cancer. And this was held in 2014, looking at a new grading system, including several grade groups, which we'll discuss here. The first is grade group one, which includes Gleason score of less than or equal to six and has only individual discreet well formed glands. Grade group two include a Gleason score of 3+4=7, with predominantly well-formed glands with a lesser component of poorly formed or fused or cribriform glands. Grade group three encompasses Gleason score of 4+3=7, with predominantly poorly formed fused cribriform glands with a lesser component of well-formed glands and in patients with greater than 95% poorly formed fused or cribriform glands at the time of radical prostatectomy. The component of less than 5% well-formed glands was not factored into the grade. Looking at grade group four, this includes Gleason score of 4+4=8, 3+5=8, or 5+3=8.

This also includes only poor formed fused cribriform glands or predominantly well-formed glands and lesser component lacking glands or predominantly lacking glands and a lesser component of well-formed glands. And finally, grade group five includes Gleason score of 9 to 10 disease with a lack of gland formation or with necrosis, +/- poorly formed fuse cribriform glands. And again, in patients with greater than 95% poorly formed fused or cribriform glands at the time of radical prostatectomy, the component of less than 5% of well-formed glands is not factored into the grading.

There's been several studies looking at validating the ISUP Grade Groups, and this is one of the larger ones published in European Urology in 2016, by the Epstein Group. This was a sample size of 20,845 men undergoing radical prostatectomy as well, as well as 5,501 men undergoing radiotherapy. The primary outcome for this study was biochemical recurrence. We look here on the left. We can see that the grade group one class is green. The group two is orange. The group three is dark blue. The group four is red and the group five is purple. And when we look at recurrence free progression following radical prostatectomy stratified by prostatectomy grade, we see it early and even splitting of the curves suggesting that the grade group does in fact have a good delineation for probability of recurrence free progression among men undergoing radical prostatectomy.

When we look at the right, using the same color scheme as the prostatectomy group, this is for patients undergoing radiation, that were stratified by pre-radiation therapy biopsy grade. We do see a splitting of the curves, not quite as clean as the prostatectomy group, but a general delineation between grade group 1, 2, 3, 4, and 5.

So based on this, the NCCN Panel accepts the new Grade Group System to inform better treatment discussions compared to those using Gleason score. However, there is heterogeneity that exists within each group. Example one includes at intermediate risk patients by clinical stage, so these are patients with T2B or T2C. These patients have a lower risk of recurrence than men categorized according to Gleason score. In this case, Gleason score of 7 or PSA level 10 to 20. The second example is a high risk by clinical stage, which is T3A, has a lower risk of recurrence than men categorized according to Gleason score 8 to 10 or PSA level greater than 20. The panel does also note that there's heterogeneity in the low risk groups based on PSA level and percent positive cores. And based on several studies, the NCCN guidelines have separated intermediate risk into favorable and unfavorable stratification.

So as you recall, we talked about the overview of the NCCN risk groups. This is a more detailed look at the intermediate group. As I mentioned, intermediate has all of the following features listed in this part of the table right here, but then they delineate this by favorable and unfavorable. So favorable intermediate risk has all of the following, including one intermediate risk factor, grade group one or two, and less than 50% biopsy cores positive. The unfavorable intermediate risk has one or more of the following, including two or three intermediate risk factors. Grade group three and greater than 50% biopsy cores positive. I'll now turn it over to Chris who will discuss the Nomograms utilized in patient workup.

Christopher Wallis: Thanks Zach. So as Zach alluded to, there can be significant heterogeneity among the risk categories as a result of differences in the prognostic ability of the various characteristics, including stage and grade. And so these can be accommodated just having the grades for these Nomograms. And Nomograms by definition are predictive instruments using a variety of data to predict outcomes. And this can be done more accurately for an individual patient through the use of a nomogram than simply the risk categories as they're able to combine relevant prognostic variables.

And so historically speaking, the Partin Tables where the first to achieve widespread use for counseling men, and particularly with respect to pre-surgical counseling and this comprises PSA, Gleason score, clinical stage and provides a prediction of the likelihood of a variety of pathologic findings, including organ confined disease, extra prostatic extension, seminal vesicle involvement and lymph node involvement. Nomograms however, can be used for many reasons apart from simply preoperative planning. And so following initial diagnosis, they can be used to guide decision-making regarding the appropriateness of active surveillance, whether surgery is an appropriate treatment option among patients opting for surgery, particular nuances of surgical approach, including nerve sparing or the role of pelvic lymphadenectomy, as well as in the provision of radiotherapy, whether brachytherapy or external beam.

However, we can also use Nomograms later in the disease trajectory. And we can use postoperative characteristics following radical prostatectomy to predict biochemical progression free survival, to assess the potential efficacy of adjuvant or salvage radiotherapy. However, Nomograms to date have not been able to reliably predict metastasis or cancer specific death.

So the NCCN Guidelines Panel recommends the use of NCCN risk groups to begin the discussion of treatment options for patients with localized prostate cancer. And that Nomograms may be used to provide a more nuanced, additional individualized information.

Now, I'm going to turn to the use of Tumor Multigene Molecular Testing, which may build on the clinical data that is utilized in Nomograms. So these molecular assays have been developed in an effort to improve decision-making, particularly in the context of men considering active surveillance for versus active treatment and those considering adjuvant treatment for recurrence and the rationale for molecular assays is that there's residual heterogeneity among groups to find based on clinical characteristics, whether they're in risk groups or Nomograms, and these molecular assays, if they're able to provide accurate and reproducible information, may reduce the uncertainty about risk of progression.

And so this is a study from the music collaborative, looking at a variety of tissue-based molecular assays in nearly 4,000 men. And among patients with favorable risk of prostate cancer, rates of active surveillance were about 45% of men who had genetic testing that was above the threshold. About 76% in those who results were below the threshold. And as we might expect in an unselected group who did not receive genetic testing, results were somewhat intermediate, although lower than the average of the two.

Now when we look at a different context for the use of genetic testing this time following radical prostatectomy, the use of the Decipher Test can change management recommendations in nearly 40% of patients. When we look at clinical benefit of changing these recommendations, it not only changes our recommended treatment approach, but may actually translate to clinical outcomes. And so for those who have high risk characteristics of going to the Decipher Assay, PSA recurrence rates were substantially reduced with the use of adjuvant radiotherapy. However, no difference was shown for men with lower intermediate risk based on their Decipher Assay. And so this may allow us to more appropriately provision the use of adjuvant radiotherapy.

As you can see on the right of the screen, the accumulative incidents of recurrence was lower for those who followed the recommendation, than those who did not. As a result, the NCCN Panel recommends the use of the Decipher molecular assay, patients have adverse pathological findings at the time of radical prostatectomy to inform adjuvant therapies.

This slide taken from the NCCN Guideline outlines the variety of tests that may be used, notably a Decipher Oncotype DX, Prostate Polaris, and ProMark commercialized and relatively readily available. Each of these looks at a slightly different platform and different outcomes. Although in many cases, they can provide a similar information in the same clinical setting.

So to summarize, the risk stratification in patients with prostate cancer, the NCCN Panel is recommending that men with low or favorable intermediate risk disease and life expectancy, may benefit from the use of molecular testing with Decipher Oncotype DX, Prostate Polaris, or ProMark from their initial risk stratification should decide between active surveillance or active curative intent treatments. For patients with unfavorable intermediate or high-risk disease and a life expectancy greater than 10 years, Decipher and Polaris may still have a role. And for patients who've already undergone radical prostatectomy and have adverse features identified, the Decipher assay may be useful in informing adjuvant therapy.

I would like to thank you for taking the time to join us for this discussion as the NCCN And Clinical Practice Guidelines in Oncology, and hope you'll join us for future discussions. Thanks again.