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Promise and Progress - Transforming Prostate Cancer

Transforming Prostate Cancer
Issue No. 2013

Transforming Prostate Cancer

By: Valerie Matthews Mehl
Date: January 3, 2013


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(Left to right: Schaeffer, Partin, and Carter

Prostate cancer is an iconoclast among cancers.  It is at odds with what experts know to be the optimal approach for most cancers: Find it early and treat it early. Prostate cancer is different.  It may be one of the few cancers humans can live with.  It is most often slow growing, and even late-stage cancers can many times be held in check for years. On the other hand, it is a cancer that kills many men. It is the second leading cause of cancer death for men.  The challenge, then, is deciphering the “good” prostate cancer from the “bad.”  As a result, it is a model for personalized cancer medicine as Johns Hopkins urologists and cancer scientists and clinicians lead the way, using the most advanced science and technology to redefine for the world who to screen, who to treat, and who to safely leave alone.

Where We Came From, Where We Are Going 

The innovation that sets the Johns Hopkins prostate cancer program apart can be traced, in part, to the inventive thinking of Patrick Walsh and Donald Coffey.  They set the standard—challenging clinicians and investigators to think beyond the status quo; beyond what is adequate to what is extraordinary. Walsh developed an anatomical, nerve-sparing approach to surgery that, for the first time, cut out and cured prostate cancer without causing devastating side effects for men.  Patients the world over traveled to Johns Hopkins to have Walsh’s surgery, and urologists-in-training sought to come to Johns Hopkins to learn the pioneering technique.  Today, remains the most common surgery performed at Johns Hopkins. 

Forward thinking, Walsh compiled an extensive database of thousands of patients and followed them for 30 years. What he and others learned from these men became the laboratory fodder for the bespectacled inquisitor Donald Coffey who began exploring the basic biology of prostate cancer and provided some of the first insights to the subtle and unique variations of cancer DNA.   Like Walsh, he shared what he learned. One of Johns Hopkins School of Medicine’s first triple professors was the consummate teacher, inspiring generations of researchers to not only look for answers but to ask questions that had never before been asked. 

Those who studied under Walsh and Coffey became leaders in prostate cancer treatment and research at Johns Hopkins and around the world.  Walsh, a clinician, and Coffey, a basic scientist embodied the bench-to-bedside collaborations that are the hallmark of Johns Hopkins medicine and provided strong roots for a prostate cancer program. 

This is, in many ways, the golden age.  Generations of clinicians and investigators provide incredible depth to the prostate cancer program much like grandparents do for a family.  Today, under the leadership of Kimmel Cancer Center Director William Nelson, Brady Urological Institute Director Alan Partin, and Radiation Oncology and Molecular Radiation Sciences Director Theodore DeWeese, Johns Hopkins experts, from a wide range of disciplines, are on the forefront poised to transform how prostate cancer is detected, diagnosed, and treated. 

First Do No Harm

The purpose of early detection is to catch a cancer early so that it can be removed or destroyed before it causes harm.  It makes sense for most cancers.  The problem with detecting prostate cancer early, however, is that the diagnostic procedures and treatments can sometimes, particularly in older men, cause more harm than the disease itself. 

PSA (Prostate Specific Antigen), the test that makes the early detection of prostate cancer possible, is at the center of the dilemma.  Recently, the United States Preventive Task Force recommended against routine PSA testing for early detection claiming the harms outweighed the benefits. Their announcement gained widespread attention, but the truth is, experts at Johns Hopkins had been evaluating the test and changing prostate cancer screening and treatment long before the U.S. Preventive Task Force weighed in.

“We’ve know for a long time that there is a lot of harm that can potentially come with PSA testing,” says, urologist H. Ballentine Carter who has studied and evaluated the test in large populations of men for more than 20 years.  Carter and other Johns Hopkins prostate cancer experts say that PSA is not inherently a bad test as it has been characterized in recent headlines.  The problem, they say, is not so much with the PSA test, but instead how the test is used.

Before the Prostate Specific Antigen test, or PSA as it is now commonly known, hit the market in the late 1980s, prostate cancer was essentially an untreatable disease.  There was no method for finding the cancer, and men went to the doctor only after they began experiencing symptoms, such as trouble urinating or blood in their urine. By that time, the cancer was already well advanced, and it could not be cured.  Surgery was used primarily to relieve symptoms, such as bladder obstructions caused by tumors, and it often left men incontinent and impotent.  For a man with prostate cancer, it seemed that if the cancer did not claim his life, it certainly would claim his quality of life.

It is no surprise, then, that when a test was developed that could detect the cancer early, before there were any symptoms, it was going to be used.  Imagine, Carter says, if such a test existed for pancreas or lung cancer.  Overdetection or not, people would be standing in line to get the test.

With no science to guide when prostate cancer screening should begin and how often it should be done, however, the nation, overzealously embarked on a practice of overscreening, overdetecting, and overtreating the cancer with free screenings and “awareness” campaigns that helped fuel the trend.

The result was a dramatic increase in prostate cancer incidence, and most experts agreed that many of the cancers detected would have never caused any harm. Doctors were finding a lot of prostate cancers, but many of them, Johns Hopkins scientists found, would never be a problem.  “Now,” Carter says, “we must move to a more measured approach.”

He and other Johns Hopkins prostate cancer experts are putting medical science back in the equation and using sound research to determine how best to screen for prostate cancer and how to tease out the prostate cancers that are likely to kill from those less aggressive forms that may not require treatment.

Personalized Cancer Screening

The numbers are staggering.  Each year 20 million men get screened with PSA.  Many of them undergo unnecessary biopsies, suffer complications such as infection and bleeding, and still others have surgery, radiation treatment, hormonal therapies, and drug treatments that have unpleasant side effects.  Out of all of these men, less than one-third of 1 percent will die from the disease.  “It’s clear that for many men, the benefits may be small and the harms significant,” says health policy expert and Maryland Cigarette Restitution Fund supported investigator Craig Pollack.  The challenge is figuring out from among the masses, which men will benefit from screening and which ones will not. 

Confusion abounds, says Pollack.  Ask patients why they get screened, and they say it is because their doctor recommended it.  Ask doctors why they recommend screening, and they say their patients expect it.  While Pollack finds that most primary care providers he has surveyed recognize the issues surrounding routine PSA screening, they are unsure about how to explain it to their patients.  

 “There are clearly some misperceptions,” Pollack says, “and since the majority of screening occurs in the community, we need to provide them with a decision-making tool that can help them improve their practice.” 

Such a tool, a novel computer-based system, which can be integrated with patients’ electronic medical records, was developed by Carter, Pollack, cancer prevention and control expert Elizabeth Platz, and other Johns Hopkins cancer and public health experts. It will be piloted in Johns Hopkins Community Physicians offices throughout Maryland.  They hope it will help primary care providers discuss prostate cancer screening with their patients and direct PSA to men who will benefit and away from those who will not. 

The decision-making tool takes into account age and personal medical history, along with previous PSA test results and serves as an interactive guide for physicians to use when talking to patients about prostate cancer screening.  Pollack and his colleagues found that while most physicians said they took age and life expectancy into account when deciding to order PSA screening, many also said they had a hard time estimating life expectancy in their patients and welcomed help in this area.

Screening is not one size fits all, says Carter. While Pollack acknowledges that making the shift from a population approach, in which everyone is screened, to an individualized approach, directed to only those who good research tells us will benefit, can be challenging.  Men who are not recommended for screening, particularly if they have been screened in the past, may be concerned, and doctors may worry they could miss a cancer. However, Pollack says there is conclusive evidence that annual screening is not necessary for everyone.  “An individualized approach just makes sense,” he says.  “Our goal is to demonstrate that a personalized approach results in better care and fewer complications at a lower cost, and that is good for everyone,” says Pollack. “  

If a man aged 40 to 75 comes in for an appointment, rather than routinely offering screening, doctors will instead be prompted to discuss the potential benefits and risk of PSA with him. The tool includes talking points to help guide doctors to speak to their patients about the potential risks and benefits of PSA screening. Doctors will also be prompted to explain the potential harms and benefits of treatment. 

“The goal is to reduce screening, and ultimately treatment, in people we know, with certainty, will not benefit, and increase it among people who will,” Carter says.  Men have grown to expect PSA screening to be part of their annual physical.  This tool helps address misperceptions about screening and facilitates discussions that will help doctors and patients make more informed decisions. Carter has conducted large population studies involving thousands of men, and the data overwhelmingly show that men over age 75 are more likely to die with prostate cancer than of it, particularly if they have other more pressing health problems.  As a result, these men will not benefit from PSA, and Carter says doctors should explain that to them.  Kimmel Cancer Center director and prostate cancer expert William Nelson frames it this way, “I tell men who are over 75 and considering routine screening, ‘You don’t need it.  You’ve won.  Prostate cancer is not going to be a problem for you.’” 

If the doctor and patient determine screening would be beneficial, the tool also provides recommendations for when and how often to rescreen.

With all of the confusion, clinician Michael Carducci wants to be sure that men who have prostate cancer understand that the PSA controversy only involves screening. PSA, he says, remains a vital tool in monitoring men who have already been diagnosed and in determining if there is a medical problem in men who are experiencing symptoms.  “If you are a guy who is up five times a night going to the bathroom, you have blood in your urine, or erectile dysfunction.  This is no longer screening.  This is diagnosis,” says Carducci.  “It is important that men understand the difference.”

To Treat or Not to Treat

Some of the greatest potential of personalized medicine is in using our new knowledge about the biology of cancer to get the right treatments to the right patients. Sometimes the right treatment may be no treatment.  

One important way to reduce harm to men is to individualize the management of prostate cancer. PSA alone is not responsible for the adverse affects men have suffered; it has been what doctors have done with PSA—mainly overtreating the disease.  When a man is diagnosed with cancer, Carter says, it is important for him to know that invasive treatments are not the only option.

Treatments for prostate cancer can include the surgical removal of the prostate, radiation, hormonal therapies, and chemotherapy.  Each of these has the potential to cause serious problems, such as erectile dysfunction, impotence, and urinary incontinence or bowel damage. For many men, treatment is clearly the best option, and our prostate cancer clinicians are among the best in the world. Johns Hopkins clinicians have pioneered surgical, radiation, and drug remedies for the disease, but they have also been on the forefront of a nontreatment approach.  It is called active surveillance—active being the key word.

Carter, although one of the world’s leading prostate cancer surgeons, believes that putting the scalpel aside is sometimes the best tactic for men who are diagnosed with a low-grade form of the disease.  The approach has been the focus of research in the Brady Urological Institute at Johns Hopkins since 1995.  Data gleaned from several large studies unequivocally showed that many men with low-grade disease would never be harmed by their cancer but could be, and all too often are, harmed by treatment. “The majority of men diagnosed with prostate cancer each year are over 65 and have a low risk of dying of their disease if treatment is deferred,” says Carter.  “Yet, more than 90 percent of these men, including 80 percent who are over age 75, are likely to choose some form of treatment.  Active surveillance addresses excessive treatment of milder stages of prostate cancer, especially in seniors.” 

About 40 percent of men are diagnosed with low-risk disease, and for a significant number of them, active surveillance offers a way to very carefully monitor their cancer and give them the option to delay treatment as long as it does not progress.  Many of these men will never require treatment, but if they do, careful surveillance allows the growing cancer to be spotted and treated while it is still curable. A National Cancer Institute (NCI) model that uses computer simulation to determine patient outcomes evaluated all of Carter’s active surveillance data and compared it to data from men who would have qualified for active surveillance but chose surgery.  In a worst-case scenario, the NCI model found that over a 15-year period, men who chose active surveillance stood to gain an average of seven additional years of not being treated, and at the most, risked losing three months of life.

Pennsylvania businessman Alex Cameron was one of the first participants in active surveillance.  Cameron was in his late 50s in 1999 when he was diagnosed with prostate cancer and began exploring options including hormone therapy, brachytherapy, and surgery.  In his research, he also learned of Carter’s active surveillance approach and scheduled an appointment.  He admits that with a wife, three daughters, and eight grandchildren to live for, the idea of leaving the cancer alone was somewhat troubling to him and his loved ones.  Cameron’s prostate cancer fit the parameters for active surveillance.  He had a low Gleason score and his cancer was very slow growing.  “Active surveillance sounded like a win-win good thing,” says Cameron.  He says regular biopsies done under local anesthesia to monitor his cancer were a minor inconvenience in exchange for his ongoing and treatment-free health.  He said he was also comforted by the knowledge that five of the world’s best prostate cancer pathologists were reviewing his biopsy samples.  Today, at age 71, Cameron remains active and healthy and confident that he made the right decision.  “For any guy in my situation,” he says, “active surveillance is the way to go.”

Cameron is among the more than 1,000 men who have participated in active surveillance since Johns Hopkins began offering it 16 years ago, and there are currently about 600 men enrolled. The average participant is 67 or older.  This option, Carter says, is for men who are likely to live out their natural lives without being harmed by prostate cancer.  In other words, prostate cancer is not going to kill them.  The men have a PSA test and rectal exam every six months as well as an annual biopsy to carefully monitor their cancer. More recently, Carter has added MRI (magnetic resonance imaging) to surveillance.  “We know that there is potential to underestimate the extent of disease in some men, and MRI helps us make sure we haven’t missed anything,” says Carter.  “A recent study showed that when MRI found there was no cancer there, there was really no cancer there.”

For many years, Johns Hopkins was the only cancer center to offer active surveillance.  This is, in part, because medical reimbursement is a fee-for-service system that favors procedures.  Johns Hopkins urologists, arguably the best trained in the world, were the only ones willing to explore the possibility of a better option for some patients.   

Endorsement of active surveillance by the Prostate Cancer Foundation and heightened concerns about overtreatment stemming from the U.S. Preventive Task Force’s recommendation, is now bringing this “no-treatment” treatment new consideration.

The Prostate Cancer Foundation is working to provide patients more assurance and has established the National Proactive Surveillance Network, a Web-based system (NPSN.net) that provides education about active surveillance and helps patients find participating doctors. Soon, patients and physicians will be able to securely access the system to enter, review, and track their own data.  Men participating in active surveillance would be able to enter all of their PSA data and track their personal results to see where they fall in respect to other participants.

Molecular Reassurance 

Still, Many men, upon learning they have prostate cancer, are uncomfortable leaving the cancer untreated. “They need stronger, quantifiable reassurance that their cancer won’t hurt them, and we don’t have the ability to give them that right now,” says prostate cancer researcher Srinivasan Yegnasubramanian.  He believes if physicians were able to remove any doubt, it might change minds and significantly improve outcomes for men. He is working to create an accurate test that could be applied to blood or urine and provide clear biological evidence to distinguish aggressive prostate cancers from the slow-growing type, which could be left alone.

A Gleason score is an excellent barometer of aggressiveness, but it is only as good as the sample, he says.  In men who have a prostatectomy, it is very telling because pathologists have the entire prostate to examine.  When a tumor is sampled through a biopsy, though technology has greatly improved, it is still possible to miss critical areas of a tumor that could be the key to distinguishing harmless cancers from dangerous ones.  Removing this uncertainty is at the core of Yegnasubramanian’s research.

His test is based on chemical alterations to specific regions of genes.  They occur without mutating DNA but can have the same effect as mutations and silence the function of important tumor suppressor genes.  These changes, known as epigenetic alterations, are a signature for cancer and when they are seen or begin to increase, they can alert doctors to a growing cancer.   Moreover, they are very common in prostate cancer.  “Epigenetic alterations can occur more frequently and consistently than mutations in prostate cancer,” says Yegnasubramanian.

Not only do these alterations serve as signatures for cancer, they are also potential therapeutic targets.  Unlike mutations, in epigenetic alterations, affected genes are not missing.  Instead, they are silenced by changes in the chemical environment, so researchers have the opportunity to use drugs to revert genes back to normal function.  Epigenetic signatures could be used to distinguish indolent prostate cancers from aggressive ones, monitor cancers for progression and recurrence, and to determine whether treatments are working.

In recent years, the pace of these discoveries has greatly accelerated because of a new technology known as next generation sequencing. This powerful technology has the ability to rapidly and simultaneously sequence millions to billions of DNA molecules.  As a result, cancer research that used to take decades can now be completed in weeks. Yegnasubramanian is the director of the Kimmel Cancer Center’s Next Generation Sequencing Center, located in the David H. Koch Cancer Research Building. 

He and his team are using this technology, in conjunction with new techniques they have developed, to profile prostate cancers and identify a panel of epigenetic markers unique to prostate cancers with high Gleason scores and another to characterize cancers with low Gleason scores.  Once they identify the specific markers that brand both aggressive cancers and slow growing ones, they can adapt the technology to find them in blood and urine.

“If there is a question we can ask where genomic information can help inform who should get a particular treatment and who should be monitored, I think we can go after it,” says Yegnasubramanian.  “The prostate cancer program has one of the best teams on earth to define and tackle these questions.”  Though many centers are thinking about these problems, Yegnasubramanian says Johns Hopkins is uniquely positioned because of its strength in translational medicine to make progress.  “We have equal strength in the clinic and the laboratory,” he says.  “This is a major asset that is rarely found in other centers doing genome research.  Some have the research component but do not have the clinical strength we have here.  Having both, allows us to make the critical connection between what we find in the laboratory and what will truly benefit patients.”

 

Yegnasubramanian also is collaborating with Kenneth Kinzler, one of the world’s leading cancer genetics experts, Stephen Baylin, a foremost epigenetics expert, and veteran prostate cancer investigators Michael Carducci and Mario Eisenberger to better understand how differences in the prostate cancer genome and epigenome have an impact on treatment outcomes. His research will help physicians make the right treatment decisions for each individual prostate cancer patient.

 

In prostate cancer that recurs and spreads after treatment, the first line of approach is hormone (androgen) suppression therapy—in essence cutting off the supply of hormones that are believed to be fueling the cancer.  At this stage, most men will survive about four years.  However, our investigators have found that there are extremes in patient survival that could provide important new clues about the disease.  Some men progress rapidly and may die within the first year of their recurrence, but others appear to be cured by the hormone suppression therapy, living for years without any sign of cancer recurrence. Yegnasubramanian and team believe the reasons for these differences are hidden within the genome and epigenome of prostate cancer, and they are hoping to use the power of next generation sequencing to uncover the biological differences. 

What is different about the cancer DNA of long-term survivors versus those men who have a very rapid progression? The answer would allow clinicians to direct more intensive therapies to men whose cancer DNA predestines them to be less responsive to standard treatments and give less therapy, or stop treatment altogether, in men whose cancer DNA points to long-term remission.  What they learn about the extremes of treatment responses should also help all men with prostate cancer by shedding new light on other mechanisms that could be targeted in treatment.  What the investigators uncover about the genetic and epigenetic basis of extremes of therapeutic response in prostate cancer will likely reveal similar information about other cancers.

Proving a Negative

There is the old adage, “You can’t prove a negative.” This dilemma is at the core of creating better screening and diagnostic tests for prostate cancer that limit the need for invasive procedures. How do we use scientific discoveries to prove the absence of cancer with the same certainty as we prove the existence of cancer?

Despite its problems, Brady Urological Institute Director Alan Partin and other prostate cancer experts say PSA is an invaluable tool in helping monitor men who have already been diagnosed and, even with its limitations, remains useful in the diagnosis of prostate cancer.  With a little help, Partin says it could be even better. 

Throughout his career, Partin collected blood, urine and serum samples from his patients and created the world’s largest prostate biorepository.  It greatly advanced the understanding of prostate cancer and has been critical in his work to develop biomarker tests that could augment PSA. The tests, he says, could help diagnose prostate cancer without exposing men to repeated biopsies.  PSA detects cancer but it also detects a lot of other things.  “We need a test that when it’s negative, we know the patient is OK.  When it’s positive, we want to be confident that it’s truly positive.  We don’t want to continue doing four biopsies to find the one cancer we’re looking for,” says Partin, who is the David Hall McConnell Professor of Urology. 

A positive PSA means only that a man could have prostate cancer.  Currently, the only way to know for sure is to biopsy the cancer, a process in which a needle is guided by ultrasound, and more recently MRI and other imaging technologies, through the rectum into the tumor.  While Johns Hopkins cancer researchers and engineers have led the way in developing new technologies that make prostate tumor biopsies [For Web exclusives and IPAD version, link to Song/Stoinavici story on robot-assisted biopsies from “Engineering Cures” issue.”] remarkably precise and safe, many men still undergo repeat biopsies to confirm or disprove a cancer.  Each biopsy carries a risk of bleeding and infection.  Partin believes a new urine test based on a genetic discovery by Brady Institute laboratory scientist William Isaacs may help dispel some of the uncertainty and alleviate the need for multiple biopsies.

Unlike PSA, this new gene-based urine test, called PCA3, only detects prostate cancer, but it too has its limitations.  While PCA3 outshines PSA in terms of its specificity to prostate cancer, it is not as sensitive, so it has the potential to miss cancers.  PSA, on the other hand, is very sensitive—quite good at picking up abnormalities in the prostate—including (but not limited to) cancer. Combined, the two tests compensate for the other’s shortcomings and, as a result, have the potential to very accurately detect cancer.  If a man has an elevated PSA, but a biopsy did not reveal cancer, Partin says the PCA3 test could potentially serve as the final word.  “If a PCA3 is negative, you can trust that the patient probably does not have prostate cancer.  If it is positive, then he probably does,” Partin explains.  “It adds another piece of information to help us better and more safely diagnose prostate cancer.”

Partin also is working on a test called AccuPSA to monitor prostate cancer patients following surgery for what is referred to as biochemical recurrence.  The test uses new nanotechnology approaches to measure PSA values 1,000 times lower than a standard PSA test.  A rising PSA without any visual tumors is considered a biochemical recurrence, and warns clinicians that prostate cancer cells may remain in the prostate and increases the likelihood that the cancer will ultimately return and spread.   

Partin and team studied blood samples from 31 men who had undetectable PSA, using the standard test, for five years after prostatectomy. On

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