ExosomeDx: Rethinking Prostate Cancer Screening in the Era of Precision Medicine

[Dr. Jose Silva]:
Today we're going to talk about prostate cancer screening and genomic testing. Can you walk us through your path in terms of prostate cancer screening? I know that there's been changes in the guidelines over the years. Can you walk us through since your early days in residency up to this point?

[Dr. David Albala]:
Sure. Thanks for, again, having me, Dr. Jose Silva. Prostate cancer is really an interesting disease state to study. Over the years we've learned so much and things have changed dramatically. When I first started my training, people would come in with advanced prostate cancer. That's right when PSA was being brought into the marketplace and the United States FDA approved it for prostate cancer screening back in the 1980s. We used this blood test, it was a simple blood test, relatively inexpensive, that could be done on everybody that walked through the door, and we started to diagnose more and more men with prostate cancer.

What was really interesting is that as PSA testing became more popular, we actually started to see you know more patients getting treated, and the disease, the number of patients that were dying was starting to drop off. You might say that PSA was a great test, it still is a great test that's used, and really is the first test that we use to screen patients for prostate cancer. Over time, what we started to see is that as we understood prostate cancer more, there's a group of patients that have prostate cancer that may be indolent. The disease grows very, very slowly.

These patients you know were diagnosed with prostate cancer and perhaps some of them didn't even need to be treated. We saw this mortality starting to decrease, but we also saw that we were starting to perhaps over-treat a number of patients. You weigh both sides of the penny if you will, the advantage of diagnosing men with prostate cancer, but also treating patients perhaps didn't need to get treated for prostate cancer. That continued on in the early 2000. Then the United States Preventative Task Force in 2012 really came out with a controversial decision.

That decision was that PSA testing may not have any value. They looked at some studies and this task force essentially recommended against PSA testing. As urologists, we diagnose prostate cancer two ways, one with a digital rectal exam, secondly with a PSA test. You might say, jeez, the digital rectal exam should help us identify these patients, but if I lined 100 men up with prostate cancer and did a digital rectal exam, I would detect prostate cancer in less than 50 of those individuals. Our finger is not a great screening test, but when you combine it with the blood test, you actually then are able to make the diagnosis and make recommendations of biopsy.

The PSA test doesn't diagnose prostate cancer. It's used to give us information on if a patient has an abnormal finding or the PSA is elevated, then we would recommend patients undergo biopsies. Now a biopsy of the prostate typically has traditionally been putting a small probe, an ultrasound probe in the rectum, taking some pictures of the prostate, and then randomly biopsying different areas within the prostate. It's a random biopsy. Then over the years, we then have started to use different tools, and in particular, MRI has come into the forefront in which we can get a lot of good clinical information from an MRI.

It's much more sensitive in picking up these cancers that may be more aggressive. Using MRI techniques or an MRI fusion biopsy, we can actually target an abnormal area within the prostate. Once the task force came out with this recommendation, all of a sudden we started to see our prostate cancer death rates start to increase because we were detecting less cancers. The real goal of PSA was to identify these individuals at an earlier stage and such that we could recommend different treatments. The United States Task Force then re-looked at this data, went from a D rating, which essentially says do not do the test, to a C rating.

That brought into the era of what we call shared decision-making. When a physician meets with a patient, you sit down and talk about risk factors. With prostate cancer there's a variety of risk factors. Age is one risk factor. Race. If you're African American, you have a much higher incidence of prostate cancer. Family history. If your brother or your father, you have a two to threefold increase risk of prostate cancer. Genetic markers. BRCA testing, BRCA1 and BRCA2. If you have these types of mutations, you do have potentially a higher risk of prostate cancer.

Other clinical factors. Diet has been studied, chemical exposure has been studied, maybe less so than you know age, race, or family history, or genetic mutations. Combining all this data, what we want to try to do today in 2013 is identify those patients that have risk factors, do appropriate biopsies, not do biopsies that aren't appropriate in individuals. The PSA test has evolved. We used to use a cutoff of 4. If you had a PSA less than 4 when I trained, the likelihood of prostate cancer was low. If it was above 4, the increased risk of prostate cancer existed.

We then used markers like PSA density, comparing it to the volume of the prostate, the PSA reading. We then developed what we call age-specific PSA ranges. An individual that, say, 40 years old, his PSA, a normal PSA should be 2.5 or less. If you compare that to a 75-year-old man, his normal PSA is up to 6.5. The one shoe doesn't fit every single patient. Over the years, we've learned a significant amount of information about PSA, but we've also learned that it's not the ideal test. It's not a cancer-specific test. We have to combine clinical data. Then, recently, we started to see the use of biomarkers come into helping us identify patients that are these higher-risk patient populations. We can use a variety of biomarkers, not only in the blood, but in the urine, to try to identify patients that have a high risk of prostate cancer. There's been this tremendous evolution. When I first finished my residency, if you were 40 years old and you had a family history of prostate cancer, or you were African American, that's when you got a PSA and a digital rectal exam. Then if you were 45, any individual Caucasian, no family history, those are when men got screened.

Over the years, what we've seen is perhaps we've over-screened patients, and trying to identify patients with prostate cancer. The United States Preventative Task Force made urologists look and say, maybe we should re-look at our guidelines. I think today, the current guidelines are such that if you're 40 to 45 and you have a family history, or you're African American, that's reasonable. Then, for all others, patients starting at age 55 is when these individuals should get screened for prostate cancer. Again, it's a shared decision. You come in, you get examined by your physician, and you have a discussion about this.

You make a shared decision. Then the first test that needs to be done, and our guidelines suggest this, is a routine PSA test. Once you get a PSA test, if it's elevated, you can repeat it to make sure that it's a valid test. If it is elevated, then there are a number of options. You can go right to biopsy if you want. You can do a biomarker test, a urine-based test, or a blood test, to try to pare down, maybe there's a group of these patients that have slightly elevated PSAs that you don't need to do biopsies in, that these patients don't have any risk. Then you can also integrate MRIs in that discussion as well.

[Dr. Jose Silva]:
Dave, in terms of the screening, what have you seen in your community after the message from the task force? Did you see that then primary care physicians stopped doing it?

[Dr. David Albala]:
Yes, primary care physicians in 2012, all of a sudden, stopped doing any PSA testing. Not only did they stop the PSA testing, but they also stopped doing the digital rectal exams. Now you're essentially dismantling the only effective way of identifying prostate cancer. Right after the task force made those recommendations, if you look back at the data and the mortality rates, you start to see a spike. What happens is you do PSA testing and all of a sudden the mortality drops. You stop the PSA testing, and then all of a sudden the mortality starts to increase.

There clearly is a direct relationship. There's been numerous papers published. That's why I think the United States Task Force went back and said, maybe you should discuss this with your physician. Many urologists feel that the backbone of prostate cancer is PSA and testing, and doing this testing, and we feel it should be done in appropriate patients. We also feel we should do biopsies in appropriate patients, because there is a risk with a biopsy.

Infection, bleeding, those are the biggest risk with biopsies. If we can identify those high-risk patients, perhaps we can defer biopsies in patients even if the PSA is slightly elevated. Remember one other thing that you don't have to have an elevated PSA to have prostate cancer. We see patients that have normal PSAs but are diagnosed with prostate cancer. The test is not perfect in identifying cancers in patients, and when you combine it with other things, digital rectal exam, biomarkers, MRI, you increase that sensitivity.

[Dr. Jose Silva]:
Dave, so in your practice, what are you doing? Let's say that patient has an elevated PSA, 60-year-old PSA 5. What will be your next step?

[Dr. David Albala]:
Obviously I'll have him come in. I'll do a digital rectal examination. If the PSA all of a sudden jumped up, I might repeat the PSA to see if it's really just a spurious value. For example, men with prostatitis can have really high PSAs. I want to make sure that man doesn't have prostatitis. Usually when I do a rectal exam, I can feel a boggy or soft prostate that would suggest prostatitis.

Then here's where the fork in the road is. Should I do a biomarker or should I do an MRI to try to help me identify men at higher risk? Again, it's dealer's choice on how you want to do this. I actually think the biomarkers are really a nice way to go personally. In my practice I like to use a biomarker. There's a blood biomarker, for example, like the 4K or the Prostate Health Index. There's a number of commercially available blood tests that you can use for-- for example, the 4K looks at four isoenzymes of prostate cancer, four subtypes of BPH. When we look at those isoenzymes, you'll get a score, and if it's elevated, those patients have a higher risk of prostate cancer. The hot area right now is using exosomes, which are these tiny little extracellular vesicles that are released in prostate cancer patients.

What we can do is collect these exosomes in individuals and then analyze them, and if you have a preponderance or a surplus of these small little RNA, DNA, protein particles, you may have a higher risk of prostate cancer. Now, the urine biomarker area's really expanded. There's a number of commercially available tests. They typically are used in patients that have PSAs between 2 and 10. The FDA guidelines have put in place men typically over 50 or older that have PSAs between 2 and 10. In your individual that's 60 years old, comes in with tha, elevated PSA, after I do my exam, and obviously if I feel an abnormality of the prostate, I may go right to an MRI.

Given that in most of these patients, the prostate feels completely normal, I like using a urine biomarker. I've used blood biomarkers, I've used urine biomarkers. I like using the ExosomeDx test personally. I think it's a simple test to do. There is a test called SelectMDx, which is a similar test that these tests are different in some respects that the Select test uses clinical information. You might say, jeez, is there a family history of prostate cancer? Have you had a prior biopsy? So on and so forth. The Exosome test actually does not. There's a difference in how the markers, you know, are utilized, number one.

Number two, to obtain a SelectMDx test, you have to do a digital rectal examination. The reason for that is you're trying to release from the prostate, this marker that's tested in that SelectMDx test. What's different about the Exosome test is you don't have to do a digital rectal examination. I think that's a little nicer for the patient. When COVID hit and we weren't seeing these patients in the office, the company pivoted to doing this home collection kit. I could do a tele visit, just like we're sitting here talking today through a video. If I say, jeez, [Dr. Jose Silva]:, you have an elevated PSA of 5, you're over 50 years old.

You weren't coming into the office for a digital rectal exam, but I could send the whole kit to you and we could then do this Exosome test by just peeing in a special apparatus, sending the specimen off to Boston to be analyzed. Then that would essentially be a risk evaluation tool that I could say, your Exosome test came back at 25, which is above the cutoff of 15.6. The negative predictive value and the sensitivity are quite high, above 15.6, and you're a young guy, I want to do a biopsy on you. Whereas if it came back below 15.6, I would say the likelihood of you having prostate cancer is extremely low, and I don't think we need to do a biopsy.

What's nice is the Exosome test has been validated. There's been two large clinical trials. One was in JAMA Oncology in 2016. The other one was in European Urology. Over 1,000 patients were used in the validation study. Essentially what these studies showed is if I do this, I can reduce the number of biopsies I do in individuals by 27%. Think about that. If you have an elevated PSA and we do this test, 30% or a third of 100 patients may not need to get a biopsy done, and I'll be confident that they don't have prostate cancer, high-grade prostate cancer.

When we think about prostate cancer, in the past we've thought about prostate cancer as a single entity. In other words, if you had prostate cancer, it was bad and we needed to treat you. We now look at it a little bit differently. We know that people can have low-grade prostate cancer, live a perfectly normal life, and not have to get treated at all. It's really interesting. I was a professor at Duke for 11 years, and I essentially built my career on doing robotic prostatectomies. I've done over 2,200 robotic prostatectomies in my career. When I was at Duke, my active surveillance rates or patients that would come in with low-grade disease, was about 17%.

The likelihood, if you had prostate cancer and came and saw me back in 2005, I would say you got a Gleason 6 tumor, we need to take your prostate out, and you would be operated on by me. That would be a good thing because you'd do pretty well, but it may not be the right thing. Now, I look at my active surveillance rates and they're 45%. The likelihood, if you came in with a Gleason 6, average tumor, not a lot of disease, I'm going to tell you what we're going to do is more likely than not just follow you. You may exist and go on for your whole lifetime without any kind of treatment.

I tell patients, if you go on an active surveillance protocol, a third of patients eventually in their prostate cancer journey are going to get treated with either surgery or radiation, or focal therapy. There's so many different options today. Two-thirds of patients, 66 out of 100 are going to be able to go their whole life without any kind of treatment for their prostate cancer.

[Dr. Jose Silva]:
If you're following that one-third, where you come by a couple of years without any treatment or without risk of metastatic disease, I guess it's a win for the patient because you don't have to live with these possible side effects of either radiation or surgery.

[Dr. David Albala]:
No question. There are side effects with those. Getting back to the biopsies, here's a test that reduces almost a third of patients from getting an unnecessary biopsy. I've done a lot of biopsies in my career. I've been practicing for 30, almost 34 years now. I remember when I first started doing prostate biopsies, I started my career out at Loyola University in Chicago. We'd stick an ultrasound probe in. We wouldn't use any anesthetic, and we'd do these biopsies. It was cruel punishment to these men. They would be jumping off the table.

Over the years, we've been a little kinder. We now use lidocaine to do a prostate block, but it's still uncomfortable. There's no question. If you can avoid that number of biopsies, and here we have a test that does that, and it's a simple test. When I look at new tests, there are five things to me that make a difference between how to understand, should I use this test or not? I look at the efficacy of the test. Does the test perform in a way I want it to perform? In other words, if I do an Exosome test, is it efficacious to the patient? One could argue, yes.

It reduces the number of unnecessary biopsies. What are the side effects? There's not a lot of side effects from collecting a urine test. There are side effects if you do a prostate biopsy. Infection, bleeding are the biggest things, and patients have died in the past from prostate biopsies. That risk is really low. That risk still exists. What's the ease of doing the procedure or biopsy, or whatever test you're doing? A urine-based test where a patient can do it in his home, pretty nice to do. It's simple. He just pees in a little cup, and you're done.