Urologists Discuss Their Use of Biomarker Tests in Considering Active Surveillance

Raoul S. Concepcion, MD

Editor-in-Chief of

Urologists in Cancer Care

Director of Clinical Research Urologic Surgeon Urology Associates, PC Nashville, TN

When an otherwise healthy man has a biopsy that is positive for prostate cancer, it’s not unusual for him to be opposed to treatment, telling his urologist that, based on what he’s read, no one dies of the disease.

On the other hand, another man in the same situation is just as likely to insist that his prostate be removed—yesterday, if possible.

Neal Shore, MD, medical director of Carolina Urologic Research Center and a partner with Atlantic Urology Clinics, in South Carolina, has heard these comments from patients time and again, and he knows that they stem from a lack of information.

Luckily, due to a growing understanding of biomarkers for disease severity and progression in prostate cancer, urologists have more opportunities than ever to gather the information their patients need to make informed treatment decisions, Shore and a group of colleagues said during a May peer exchange panel discussion hosted by OncLive TV.

A battery of new tests that recognize biomarkers in urine, blood, or prostate tissue can help urologists determine who needs an initial biopsy; who, after a negative biopsy, needs a rebiopsy; which patients, after a positive biopsy, have a higher risk of progression or mortality; and how individual patients being treated with various therapies are likely to respond, said Raoul S. Concepcion, MD, of Urology Associates in Nashville, Tennessee, and Editor-in-Chief of Urologists in Cancer Care.

These products can help urologists avoid overtreating patients, Shore said, and some, in conjunction with multiparametric MRI, can help avoid unnecessary repeat biopsies and their potential side effects, such as infection, added panelist Philippa Cheetham, MD, of Winthrop Urology and the Department of Urology at Winthrop University Hospital, in New York.

The assays will probably be used most effectively together in panels, “particularly for those people who are at high risk for prostate cancer with strong family histories,” Cheetham said.

“This whole discussion about biomarkers really comes down to this ever-evolving and growing important field of personalized medicine, precision medicine,” Concepcion said. “We have these long discussions with patients about prostate cancer, and we tell them about survival statistics, and we tell them the chances that they have nodal disease vs extracapsular disease. [But] this is all population-based data, so we’re making the assumption that, number 1, every tumor acts the same way, and number 2, everyone’s immune system acts the same way, and it’s really not that way. We know that all Gleason 3+3s, 3+4s don’t behave the same way, and it really comes down to the patient’s own individual tumor.”

Philippa Cheetham, MD

Urologists are already using a number of the tests, and many more are being developed—so many that it may be difficult fordoctors to keep track of them all.

Weighing Active Surveillance Versus Treatment

“Many of these biomarkers are still being used in research settings,” Cheetham said, “and yet we have to be educated to counsel the patients as to whether we think this is a good idea, and understand the sensitivity and specificity of these tests.”In their discussion, the panelists focused on assays that can help urologists determine which patients with prostate cancer can safely stay on active surveillance, and which need treatment.

There are a handful of assays already, or soon to be, available to help make that choice, the speakers said, including:

• Oncotype DX genomic prostate score, which looks at the expression of 17 genes in biopsy tissue
• Prolaris, which looks at cell-cycle progression genes from prostate cancer biopsies to determine the likelihood that a patient will die or experience biochemical recurrence
• ProMark, which measures protein biomarkers from prostate cancer biopsies to help determine the risk that the cancer will become aggressive
• Prostate Health Index, a mathematical formula that combines total PSA, free PSA and [-2] proPSA

“In a lot of our practices we’re trying to increase that patient population that can go on active surveillance, and I think this will be the role for [these assays],” said panelist Kenneth Kernen, MD, a partner with the Michigan Institute of Urology. “Nationally, we’re still way behind, and hopefully, [Oncotype DX] and a test like Prolaris will help stratify those patients who can go on active surveillance successfully.”

Both Shore and Cheetham said they have been turning to Oncotype DX when a patient appears eligible for active surveillance, to check his risk of progression before settling on the strategy—without a repeat biopsy.

“I’m a strong believer in active surveillance, but I’m also looking for reasons to take patients off active surveillance if I feel that it’s not safe for them,” Cheetham said. “If you have a patient whose biopsy shows Gleason 6 prostate cancer and they have a very, very favorable [Oncotype DX] score, in conjunction with a negative MRI with no evidence of capsular involvement, I would be encouraged [to keep them on surveillance]. For patients who have a Gleason 6 on biopsy with a negative MRI and a stable PSA, but their [Oncotype DX] score is very high, then that makes you sit up and think: ‘Does this patient have more aggressive disease?’”

Kenneth Kernen, MD

Shore said that a very low score indicates a patient falls into a very low-risk category by NCCN classification, supporting his maintenance on active surveillance, while a higher score can mean a patient should be upgraded to a higher-risk status, and may benefit from prostatectomy or radiation.

Ultimately, the test answers the question: “What is the risk, if you did a radical prostatectomy on this patient, that he’d have either non-organ confined disease or [dominant pattern 4 histology]?” Shore said.

Reimbursement Issues

“In our retrospective studies and even some prospective studies, about 20% of patients will eventually upgrade [beyond low risk], so why not be able to spare those other 80% surgery or radiation?” Shore asked. “That’s where I’ve used Oncotype DX.”When it comes to incorporating these assays into practice, the main stumbling block won’t be medical, but will involve health-insurance reimbursement, predicted the panelists, who included Oliver Sartor, MD, a professor of Cancer Research at the Tulane School of Medicine, and Michael Williams, MD, of Urology of Virginia.

While the bar for gaining commercial marketing approval is “much, much lower” for such assays than for pharmaceuticals, securing insurance reimbursement for biomarker-based tools may be quite difficult, Concepcion said. The companies that are assigned reimbursement codes by the Centers for Medicare & Medicaid Services (CMS) will be the most likely to receive coverage by insurance plans across the board, the speakers noted.

Oliver Sartor, MD

“I think we’re all familiar with the graveyard of past diagnostics and prognostics that are no longer around because they came out with their validation studies but they didn’t do what are called prospective clinical utility trials, and they never got CMS-approved diagnostic codes for reimbursement, so they’re gone,” Shore said. “Thanks to Dr. Elaine Jeter, who ran the Palmetto Division of CMS and who’s now heading the MolDx program—the Molecular Diagnostics Services program—there’s a very scientific vetting of the different biomarkers that are being asked to receive reimbursement, primarily through CMS, which I think will be the standard for other insurance companies. And one of the biggest things is having what are called subject-matter experts in the field review their validation trials, but also their prospective clinical utility trials. A prospective clinical utility study has to show that our colleagues took the information and really did something with it…that it really changed their behavior. And when you think about it, that’s just good stewardship.”

Shore said he believes the companies that make the newer assays are doing all they have to, scientifically, in order to gain the confidence of CMS and other insurance companies. He noted that his research center has been involved in many of those studies.

“Most of these companies have done fabulous work validating their assays, really great science, and not just once but twice,” he said. “Additionally, they’re all moving forward with multi-institutional prospective trials, demonstrating that it really [sparks] a change in physician behavior, because that’s where we’re going to see benefit to patients and also cost-comparative effectiveness.