Updates on Use of Genomic Testing in Patients with High-Risk, Clinically Localized Prostate Cancer - Episode 1

Staging, Grading, and Risk Stratification of Prostate Cancer

Stephen J. Freedland, MD, describes the process of diagnosing, grading, staging, and stratifying risk for patients with prostate cancer and the typical tests he uses in his clinical practice.

Stephen J. Freedland, MD: Hi, I’m Steve Freedland. I’m a urologist at Cedars-Sinai Medical Center [in Los Angeles, California] and the Durham VA [Veterans Affairs] hospital in Durham, North Carolina.

Diagnosing prostate cancer is tricky. There are a lot of tests we use. Typically, patients [with prostate cancer] are referred for an elevated PSA [prostate-specific antigen] from their primary care doctor. Sometimes we’re doing the actual screening, but usually, they come in the door with an elevated PSA, so it’s our job. I always explain to patients that it’s like a smoke signal, and it’s our job to figure out if there’s a fire there. We do a history. Did they have a UTI [urinary tract infection] at that time? We do a rectal exam. One of the first steps I’m going to do is repeat that PSA and make sure it’s real. You’d be surprised how often the PSA is elevated, and we repeat it. It comes down as normal. For those who truly have an elevated PSA, they’re in the group for whom I’m worried about prostate cancer. They’re not the 95-year-old who’s referred on oxygen. The next step for me would be to get an MRI. Based on the MRI and the PSA level, we make a decision collectively whether to proceed to biopsy. If there’s uncertainty in that decision, at least in my practice, that’s where additional biomarkers—urine or blood—can come into play. To a certain degree, when in doubt, biopsy. If we’re not sure, we can keep doing test after test. But eventually, you have to put some needles in there and find out for peace of mind. It all depends on the patient’s mindsets, comorbidities, and life expectancy—a lot of factors go into play there.

On the 1 hand, prostate cancer is 1 disease. On the other hand, 1 thing we want to know with prostate cancer is: how aggressive is the cancer? Do I need to do something? Do I not? The way we do that is a combination of staging and grading it. The grading is relatively straightforward. The pathologist looks at in the microscope and tells us if there’s cancer, yes or no. Second, if there’s cancer, how aggressive does it look under the microscope? Third, how much cancer? Is it 1 tiny bit, or is the whole sample chock-full of cancer?

In terms of the grading, we’ve used a system called the Gleason Grading Score, in which you often see 2 cancers: 1 looking a little more aggressive, 1 a little less aggressive. We graded each of those on a score of 1 to 5, 5 being very aggressive, 4 being pretty aggressive, and 3 not so aggressive. Over time, we’ve gotten away from 1s and 2s. Then we give 1 number to what we see the most of, another number to what we see the second most of. If only you see all 1 type, then it would be like a 3+3 or 4+3. Then we add those 2 together, and we do what we call the Gleason sum. That score realistically ranges from 6 to 10. It’s weird to tell a patient, “You have a 6 of 10, and that’s a great number.” We’ve renumbered it with a grade group that’s 1 to 5. It corresponds to the Gleason scores, 6 being 1.

In terms of staging, the first step is usually the rectal exam. Do I feel a little nodule? Do I feel a big nodule? Do I feel no nodule? That will help me determine the TNM, the tumor stage. In terms of nodes and metastasis—the N and M—for patients with higher-risk disease, we’ll do imaging. Traditionally it’s been a bone scan and a CT scan, so you can look for lymph nodes, liver involvements, and bone involvements. More recently people have been doing PSMA [prostate-specific membrane antigen] imaging to help stage tumors. Its role is still unclear. That’s the future. Are we in the future today? It depends on whom you ask. That’s the standard staging and grading system we use for prostate cancer.

The question is of my patients, how many present with clinically localized, and then how do we further differentiate those patients? They are quite a heterogeneous group of people. The majority present with localized disease. If we include a bit more advanced [disease], but not metastatic, probably 90%, 95% of my patients present with localized disease. It’s often aggressive localized disease. We’re doing a better job at weeding out nonaggressive disease to not even get to the point of biopsy, but the vast majority would be clinically localized disease. If we’re doing PSMA imaging on everybody, that may change the game, but we’re not—at least in my practice—at that stage.

With clinically localized disease, there’s a classic line about the turtles: the tumors are slow growing and will never go anywhere. The rabbits that jump around can eventually spread out. Then there are the birds that, the minute you find them, they’re flying out of the cage and spreading all over the place. This is the classic analogy for prostate cancer and other diseases. We need to be able to differentiate these tumors from the slow-grown, nonaggressive to the really aggressive. The way most of us do it, and the way I do it in my practice, is to use what the NCCN [National Comprehensive Cancer Network], AUA [American Urological Association], and EAU [European Association of Urology] have all adopted: the traditional D’Amico risk scoring system.

It’s low risk, intermediate risk, and high risk. It’s defined based on PSA thresholds. To be low, you have to have a PSA of less than 10 ng/mL, Gleason less than 6, and a clinical T1, which is if I feel nothing on exam or T2A, or I feel a small little nodule on exam. Then we have high risk, which is PSA above 20 ng/mL, Gleason 8, or clinical T3 disease. Everything in the middle is intermediate risk.

We’re now understanding that even within those 3 categories, there are subcategories. We have very low and low risk. We have favorable intermediate and unfavorable intermediate. We have high and we have very high risk. The 1 that makes a difference clinically in terms of how we manage patients is the differentiation between favorable and unfavorable intermediate risk. Low risk is active surveillance regardless. High risk, whether it’s high or very high risk, is going to be treatment. It’s the intermediate risk, and in particular that favorable intermediate risk, where we start to think that active surveillance may still have a role to play. That’s generally how we think about clinically localized prostate cancer.

Transcript edited for clarity.