Anson: When a patient has a 3+3 Gleason grade on their biopsy, about 25% of the time, you will actually find higher-grade disease if that man chooses to go to surgery later on. And there's again, the 25% likelihood of missing higher grade disease on biopsy.

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Joel: I'm happy to tell you that Anson, who is a medical science liaison from Genomic Health has agreed to return and tell us about another very important genetic test that has been developed by Genomic Health. This test is for men diagnosed with both low and intermediate-risk prostate cancer, the test is called the Oncotype DX Genomic Prostate Score Test. 

Welcome back, Anson, and thank you so much for being willing to come back and do another podcast with us. I guess the best place would be to-- as far as discussing this test, is to understand where the test fits in, who it's good for, or basically, what is low and intermediate risk of prostate cancer.

Anson: Sure, and thanks for having me back, Joel. Low-risk prostate cancer is typically found on a PSA blood test. That's the first indication that the prostate cancer might be present. 

What ends up happening is that the physician will follow up with a biopsy of the prostate to determine the presence or absence of the cancer. That could be graded and then put into different risk buckets, so there's a very low risk, low risk, intermediate risk and high risk. Specifically, low-risk cancer is typically a small tumor, it's contained within the prostate. 

What we know from our studies over the decades is that it's probably very slow growing and won't become life-threatening. The formal diagnosis that groups like the National Comprehensive Cancer Network, or NCCN for short, for low-risk prostate cancer is stage T1c or T2a. 

So it's either detected by PSA or it's confined to one side of the prostate as detected by a digital rectal examination. The PSA level is less than 10 nanograms and the Gleason score, which is a grade of how bad the cancer looks like, is 3+3 or none as Gleason grade six or great group one. 

So, there's different terminologies for that, but basically, it's probably the most indolent or slowest growing form of prostate cancer that we classify. 

The intermediate-risk group, when we do the Oncotype test, is specifically for favorable intermediate prostate cancer and that's patients with low volume 3+4 disease. So that means the patient has a little bit of a dominant pattern three and a little bit of pattern four cancer. This is also called grade group two disease. Favorable intermediate risk, again, is typically a low volume 3+4 cancer.

Joel: If a man is diagnosed with either low risk or favorable intermediate-risk prostate cancer, what are their treatment options?

Anson: There's three major options that you can choose at this point once you're actually diagnosed. There's surgery, there's radiation and then there's active surveillance. 

For surgery, that's actually the physical removal of the prostate gland and the intent behind that is to remove the gland and thereby remove the cancer that's contained within the gland, removing it from the body. At that point, you're typically considered to be "cured". 

There's also radiation which is, rather than physically removing the prostate, you will actually irradiate the prostate and the intent there is to actually kill cancer cells within the prostate. 

The third option is actually called active surveillance. So rather than attempt to destroy the cancer either by physically removing it or radiating it, we're actually consciously choosing to do disease monitoring. 

Specifically, this is a very thoughtful decision that both the patient-physician make to delay immediate treatment. So immediate treatment like surgery or radiation, and instead, you'll actually check on the status of the prostate cancer routinely. It could be every 12 months, it could be every 18 months. 

These checks usually occur with a combination of the PSA testing, as well as repeat MRI imaging and biopsy. As long as the disease is "stable" so there's no rises in PSA, you don't see anything unusual on MRI and the Gleason grade remain the same on repeat biopsy, the disease is considered it to be stable and you actually don't do anything more. 

Once a physician sees progressions or higher PSA or perhaps a higher Gleason grade that will motivate or trigger a physician to make another decision which is to potentially take that patient to immediate surgery or immediate radiation.

I think surgery and radiation together as the decision to act right now, both options work really well. Patients risk of death and metastasis for prostate cancer after immediate treatment like surgery radiation can be as low as 1 to 5% in 10 years. 

While they may no longer have to worry about the cancer after those treatments, the big downside is that there's long lasting side effects that come with surgery and radiation that can actually significantly affect your quality of life. On the other hand, with active surveillance, the decision is to intentionally delay immediate therapy until you actually need it. A lot of the times, you can actually have the prostate cancer remain in place and it won't actually harm the patient. 

Oftentimes, men will actually die of other causes, it could be a heart disease, or stroke, or accident and have prostate cancer and never actually know about it. 

So prostate cancer, in general, can be a very slow moving disease that you actually don't need to treat. This is good because it actually preserves a higher quality of life for the man and that could last many, many years routinely meet men who have been on active surveillance for 10 or more years. That means 10 years with their prostate intact and not having to deal with the side effects from surgery and radiation. 

Of course, the downside to that is people do get anxious and physicians also worry about whether or not they selected of like person to be on active surveillance because there's always a potential for missing your opportunity to cure the patient of the disease rather than just simply monitoring it.

Joel: You give us a lot of really good information. If you do have one of the more aggressive treatments; surgery or radiation, as you indicated, you're going  affect the quality of life, but you're also going to hopefully not have to deal with prostate cancer going forward.

 I think that's really important for people to remember. So, it's basically quality of life versus not having to deal with the cancer again. That's kind of the conundrum, we have Gleason grades where the cancer gets rated, we look at the PSA number and, probably, the PSA doubling time which is the time it takes a PSA number to double in size or go from two to four to eight to sixteen. We look at where the cancer is and how much cancer is found on the biopsy. So, we have all this information that we can use to make a decision, where does the Oncotype DX Genomic Prostate Score Test fit into the decision making process?

Anson: This is a great question. What we know is that a lot of the tools that we currently have at our disposal. they are good but they're not great. So far as the Gleason score has been around for 40 years, and it will be around for likely another 40 years, it's a really useful assessment of the patient's aggressiveness for their prostate cancer but what we know is that when you do a biopsy of the prostate gland, you're only sampling about 1% of the total volume. So, there's a consistent worry and it's potentially missing higher-grade disease. 

When you look at large studies of 8000 men or more, when a patient has a 3+3 Gleason grade on their biopsy, about 25% of the time, you will actually find higher-grade disease if that man chooses to go to surgery later on. So, there's again, the 25% likelihood of missing higher gradedisease on biopsy. 

So there's a limitation that what you're seeing on the biopsy is not necessarily representative of the disease in the prostate. What the Genomic Prostate Score does is cover the gap and actually look for the likelihood that the cancer is actually being much more aggressive than you think based on traditional measures. It's the same concept of judging a book by its cover versus actually reading the book. 

With the traditional measures of Gleason score and PSA and other modalities, your kind of getting a general assessment of how they look, but the Genomic Prostate Score is actually reading out the genetic signature of the prostate cancer itself. That actually gives you a lot more insight into what the future behavior that prostate cancer is going to be in the future.

Joel: When this test was validated? What were the criteria? How do we know that it's a test that's going to give information that's going to either prevent someone from developing metastatic prostate cancer or being overtreated?

Anson: The original validation of the test was actually really cleverly designed. We know that a prostate cancer is actually a multifocal disease which means that there could be different spots of cancer throughout the prostate gland itself. What I have mentioned earlier, if you take a biopsy needle and sample one part of the prostate, you can, in theory, be missing the actual high-grade speck of cancer, maybe close by the needle, but wasn't actually touched by the biopsy needle. What we did was develop a Genomic score that was predictive of what the biology of the tumor is, regardless of what pattern you hit. 

So, you can hit the lower grade pattern or the higher grade pattern, and you'll still get an accurate insight into the biology of the tumor. 

What we did to actually validate the test was we took a cohort of men from UCSF, these are all men that were diagnosed with cancer and then subsequently tend to radical prostatectomy within six months. 

What we did was blind ourselves to the actual outcome of the radical prostatectomy in terms of what disease the patient really had and we tested the patient's biopsies. Patients with high GPS scores, so the score is from 0 to 100; For the ones that had higher scores, it was sure enough had more often than not, had really bad disease on the radical prostatectomy. Whereas the patients with low scores actually had low-grade or indolent disease. 

So, that was a validation of our tests being able to predict, just using biopsy tissue alone, what was going to be in the actual rest of the gland. That was the original validation. 

We actually have newer data and actual active surveillance cohorts where men were put on active surveillance based on the GPS result, and we follow those men for several years about two or three years. The preliminary data shows that GPS is still predictive of bad disease should that man be taken to delayed surgery. This is the first of its kind data and it really shows that the GPS result was really good at identifying patients that had low-grade disease that you can just put on active surveillance versus men that you should probably take immediate therapy.

Joel: Would it be correct to sum this up that the men who may actually get the most benefit from this test are men who are newly diagnosed, are men who were told that their Gleason score is 3+3 or 3+4, just to confirm that there isn't some tissues that had been missed by the actual biopsy itself?

Anson: Correct. That's the target population where physicians could go either way where you can put them on actor surveillance or taking them to immediate surgery. Right now, they are really lacking the tools at least before the GPS test became available, they really didn't have a good way of sorting patients from one bucket into the other. The GPS tests can give you a higher level of confidence that should that patient have a low score, you can reasonably and very confidently put them on active surveillance and should that patient have a high score. You can constantly take that patient to surgery and know that that was the best bet for that patient.

Joel: So that's for newly diagnosed. Now, if you have a man who's on active surveillance, and they go off a year after being on active surveillance and they have another biopsy, would it make sense for the test to be repeated on that new biopsy?

Anson: It's actually at the discretion of the physician. A lot of our data sets are men that are newly diagnosed with prostate cancer. So that's what we're technically validated for. So, it's at the discretion of the physician if they want to submit a sample of a biopsy that was taken because the patient is already on active surveillance and this is a surveillance biopsy. 

Technical answer, you should only submit if you're newly diagnosed. However, there is research being done on patients that are undergoing active surveillance and those surveillance biopsies are sent to us, so the data should be forthcoming.

Joel: Where are we with insurance coverage for this test?

Anson: The test has been out on the market at least since 2013. So, Medicare does cover it and a lot of large players also cover the cost of the test. For the smaller payers that don't necessarily cover the cost of the test, the good thing is that the company is very patient focus. We want to be sure that patients have access to this test, so we have a very good financial assistance program. Patients are welcome to call in and contact the company, discuss that in our billing group can go into more details about that.

Joel: Given what we said about someone having a retest on a new biopsy, I'm assuming that currently Medicare and Medicaid will not pay for that retest.

Anson: To my knowledge, I don't believe they will pay for the second test. The way we validated the result was to make the decision, go or no go for surgery or radiation versus after surveillance.

Joel: If I were to call you up, and I've been on active surveillance for a year and a half or two years, and I wanted a delayed test, is that something that would make sense even though I've been on active surveillance for a year or so already?

Anson: Potentially, yes. What we have done in practice is that you can submit a sample that's up to three years old. Interestingly enough, we developed our test on samples that are over 20 years old. So, in terms of integrity and whether or not the result is accurate, there's no real concern about that because we're using tissue blocks that are over 20 years old. 

In terms of utility, there is some utility in deciding whether to continue on active surveillance but again, that's really up to the physician to do.

Joel: I don't have my biopsy. I got a report that said I have Gleason 3+3, how do I go about getting the tests done?

Anson: All of the tissue that's taken out especially for cancer workups are stored at hospital pathology labs and they typically have a retention plan for up to 10 years, I believe in California is the minimum is 10 year retention time. So, all these samples are going to be stored for quite a bit of time. It's at the physician discussion should they want to order the test, they will submit an order form to our company either via fax or through our online portal. At that point, our company will reach out to the pathology lab. 

This is an established process and all the pathology labs across the US are familiar with us (Genomic Health). So, they'll know how to send the tissue block to us that's stored in a small piece of wax. 

They'll overnight mail that to us, we will take a small section of that tumor sample, run it through our lab testing and then returned the remnant sample to the hospital for storage again. The process itself is pretty straightforward and it's all done basically behind the scenes between our lab and the hospital once the physician was with us.

Joel: How long does the process usually take?

Anson: Typically said that it takes about 10 to 14 days for the patient to get a result after we received the sample. But to be honest, our lab is really good at what it does and we can turn around samples in about seven calendar days from the day we get it.

Joel: How would these test results delivered to the patient?

Anson: It'll always go from our lab to the physician’s portal or fax to the physician's office, then the physician will communicate the results to the patient. When it's about a two-page report with the genomic prostate score that value from 0 to 100 on the first page, as well as some additional data points, like the percent risk of adverse pathology. Adverse pathology being what's the likelihood of me having high risk or non-organ confined disease and my prostate right now.

Joel: For a man believes that he could benefit from the Oncotype DX Genomic Prostate Cancer Score test, how would they go about arranging for it?

Anson: The test always needs to be ordered by the physician's office. Reach out to your urologist and occasionally, your radiation oncologist will also order the test. Once they submit the test order will be able to retrieve the specimen and take care of the actual testing process itself. So, ultimately it ends up becoming a discussion between the patient and your urologist or physician to get the test ordered.

Joel: Is there anything else that we should talk about in reference to the tests that we have missed?

Anson: I think one of the really important things to highlight is that there was a large study published about three years ago called, PROTECT. This is really why active surveillance became a very viable alternative. They looked at is men with prostate cancer, and they were put into three separate groups. One group was given surgery, one group received radiation, the other group received active surveillance protocol where they were just monitored for their diseases as I have mentioned. When you look at the ten year outcomes data, the outcomes were identical in terms of overall survival for all three groups. 

So, you can literally do intense immediate therapy, which is a radiation or surgery, or simply do after surveillance and all those men have identical outcomes. The limitation to this data is that when you look at metastasis free survival, so how long did a man live without developing aggressive metastatic cancer, there was actually a separation and curves where the patients who received radiation and surgery did better by a slight margin, but slight but significant margin than the active surveillance patients. 

What this tells us is two things. One is that there is a certain level of equivalence between the three different therapeutic options which makes active surveillance very viable. 

But then also because there was an increased rate of metastasis for patients with active surveillance, we have to be very careful and judicious about who we select for active surveillance. I would argue that the genomic process score is a very important tool and that selection process to actually have an understanding which person is going to be the patient with indolent, slow growing prostate cancer and which one has a [inaudible] and actually has an aggressive prostate cancer that should be taken straight to immediate therapy.

Joel: Men, as they're making a decision whether to do surgery, radiation or active surveillance, if they can get more information that's based on real science as this test is-- they're going to be more comfortable in making decisions. I believe they will also make better decisions by to see those men who could benefit from it, avoid being overtreated and use the alternative active surveillance and preserve their quality of life which also is important with treatment aspects of prostate cancer. 

Thank you again for joining us the second time. It's really generous of you to give your time to us. We appreciate it. If we have any other questions, I will send them on to you. 

This has been Joel Nowak from Cancer ABCs along with Mr. Anson Tharayanil from the Genomic Health and we've been talking about how to make a better decision on considering active surveillance, as opposed to a more aggressive treatment for newly diagnosed prostate cancer, specifically for prostate cancer that based on the traditional measures, have been called low-risk intermediate or favorable intermediate prostate cancer. Thank you so much for joining us and until our next podcast.

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