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Precision Medicine Meets Prostate Cancer

Illustration by Patric Sandri

Precision Medicine Meets Prostate Cancer

Doctors at Johns Hopkins are using high-tech tools to better tailor treatment to each individual — avoiding surgery for slow-growing tumors and using targeted medicines for those with aggressive cancer.

Gerard Brown was shocked when his Johns Hopkins urologist, Alan Partin, called him at work with news that he had prostate cancer. He was 58 years old and felt perfectly healthy. Over the years, he knew that elevated levels of prostate-specific antigen (PSA) had been found in his bloodwork, indicating he was at risk for cancer, but numerous biopsies taken by his local doctor in northern New Jersey and at Johns Hopkins’ Brady Urological Institute (where he had turned for a second opinion) had all come back negative.

Brown’s positive biopsy scored a 6 on the Gleason scale — a grading system used to determine the likelihood of a person’s prostate cancer spreading — meaning his cancer posed the lowest possible risk. When he shared the results with his home doctor, he was encouraged to play it safe and have his prostate removed. Urologist Patrick Walsh at Johns Hopkins suggested a different approach: monitoring his cancer through the Brady Institute’s Active Surveillance Program. Brown had a difficult decision to make.

Building Confidence in ‘Active Surveillance’

Taking a “wait and see” approach can be nerve-wracking when it comes to cancer. The thought of killer cells multiplying inside one’s own body will spark anxiety, if not outright dread, in even the most stoic of patients. The longer a man lives, the harder it is to avoid a cancer diagnosis, especially when it comes to prostate cancer, which has been found in up to 80 percent of 80-year-old men during autopsies.

Removing the prostate can be a tempting solution to prevent this common cancer from spreading to other parts of the body, but the surgery carries risks of urinary incontinence, erectile dysfunction and sterility, not to mention the financial and emotional burden of such a procedure. “A prostatectomy may cure cancer anxiety, but oftentimes it’s unnecessary and won’t increase a person’s odds of living longer,” says urologist Christian Pavlovich, director of Johns Hopkins’ Precision Medicine Center of Excellence for Prostate Cancer and the Active Surveillance Program.

Today, medical experts in the United States advise most men with low-risk prostate cancer — which accounts for roughly half of new, early-stage diagnoses — to monitor its growth using what’s called active surveillance. Rather than pursuing immediate treatment, these patients are asked to come in for periodic exams, biopsies and testing. Over 2,000 men have been enrolled in Johns Hopkins’ Active Surveillance Program at the Brady Urological Institute since it began in 1995, making it one of the oldest and largest surveillance programs in the world. Of those patients, fewer than 1 percent have died from prostate cancer after 15 years of monitoring. Despite these numbers, the majority of low-risk patients in the U.S. choose surgical removal or radiation of the prostate instead of active surveillance.

At Johns Hopkins, researchers have been working to reduce the rate of overtreatment by using the power of precision medicine to alleviate men’s fears. By gathering and analyzing data from thousands of similar patients, Johns Hopkins’ Precision Medicine Center of Excellence for Prostate Cancer has been developing cutting-edge statistical tools that can better predict the odds of a person’s cancer becoming more aggressive. Showing patients their personalized data over time and how it compares to their peers is giving many men the peace of mind to continue with active surveillance rather than choose more aggressive treatments.

Since 2016, Johns Hopkins’ Active Surveillance team has been fine-tuning a software algorithm it developed to help prostate cancer patients understand their surveillance risk and enable their physicians to better monitor their condition. Dubbed the Active Care tool, the platform translates decades of patient data from the Active Surveillance Program to predict the trajectory of each patient’s cancer. Used with all 800 patients currently enrolled in the program, Active Care allows doctors to see the odds of a man’s cancer acquiring metastatic potential based on what happened to other men of the same age who had similar biopsy results and PSA scores.

For example, Active Care may tell a patient that, out of 100 similar men who chose to have their prostates removed, only one person was found to have Gleason Grade Group 4 or 5 cancer cells, which are the most dangerous. The software has a graphic interface that makes it easy for patients to see and understand these personalized risks as well as how their cancer has changed — or not changed — over time. Staff members are constantly uploading patient data, which are used to update the Active Care model every week.

“Patients appreciate the personalized touch. They like to be able to look at their own progress and, usually, their odds are pretty good,” says Pavlovich.

Pavlovich is currently working with biostatistics colleague Aki Nishimura and Ph.D. candidate Zitong Wang to integrate MRI data into the Active Care model, which was designed before MRI became a standard part of prostate cancer surveillance. He hopes that by entering the results of patients’ scans, the tool will become even more accurate at predicting the best course of action for patients.

“Patients seeing the data tend to be less excited about doing surgery,” explains Pavlovich, who is also a surgeon on the Sidney Kimmel Comprehensive Cancer Center’s multidisciplinary prostate cancer team. “We all used to be pretty fired up, with an understandable desire to cure, but, as surgeons, we’ve learned to hold our peace with men who are not at significant risk.”

In 2018, Johns Hopkins researchers collaborated with other medical centers on a study to determine whether providing individualized health predictions, like those generated by the Active Care tool, alleviates prostate cancer-related anxiety and improves risk understanding for men in active surveillance programs. Their findings, published in the journal Urology, indicated that patients felt an increase in perceived cancer control after visiting their doctors, but for men who viewed their data and statistics on Active Care, the increase was twice as high.

“I’m confident that if [my cancer] does change, this program will find it in plenty of time to do something about it,” says Charlie Cronheim, who has been enrolled in Johns Hopkins’ Active Surveillance Program for nearly 15 years. “It’s been a very satisfying process because I don’t worry day to day.”

The Promise of Precision Medicine

The United States spent $4.1 trillion, or $12,530 per capita, on health care in 2020. It is the most expensive health care system in the world, but according to the Bloomberg Global Health Index, the country ranks 35th in overall health.

“Estimates show about 40% of health care cost waste is from doing things that don’t add value,” says biostatistician Scott Zeger, who helped create the Active Care tool and co-directs Johns Hopkins’ inHealth program. “The foundational idea behind inHealth is to capture that waste and reinvest it to improve health.”

Johns Hopkins launched inHealth, short for “intelligent health care,” as a universitywide collaboration to use medical data more intelligently to improve health outcomes. Such efforts have become more broadly known in the medical industry as “precision” or “personalized” medicine. By providing more personalized information, the hope is that inHealth will convince more providers and patients to forgo treatments — such as a $40,000 prostatectomy — for individuals who are unlikely to benefit. In this way, the program aims to not only make patients healthier but also lower health care costs while helping people avoid possible complications from medical procedures that don’t add significant value.

Over the last six years, inHealth has designated 26 precision medicine “centers of excellence” across Johns Hopkins Medicine to tackle a range of diseases, including multiple sclerosis, pancreatic cancer, lung cancer, asthma, myositis, scleroderma, Alzheimer’s and bipolar disorder. Each center has — or is in the process of creating — its own statistical models and software interfaces, which use homogeneous patient data that are relevant to each illness. The very first center to launch was the Precision Medicine Center of Excellence for Prostate Cancer, thanks in large part to retired urologist H. Ballentine Carter.

Recognized internationally as a leader in prostate cancer research, Carter founded Johns Hopkins’ Active Surveillance Program and generated an impressive database of prostate cancer patients, which proved instrumental in creating the center’s first predictive models. “His insights and genius drove the creation of the center,” says Zeger.

In 1995, when Carter began the surveillance program, taking the “wait and see” approach was a controversial idea. “There was substantial resistance to monitoring men with a diagnosis of prostate cancer, regardless of grade,” he recalled, in a 2019 interview. “Our goal was to demonstrate the safety of this approach for carefully selected men. We now know that, for these men, the risk of death from prostate cancer … is 26-fold lower than the risk of death from other causes over 15 years.”

Tailoring Treatment in Aggressive Cases

Unfortunately, many men don’t qualify for active surveillance because their cancer is deemed too aggressive. When these higher-risk cases are first diagnosed, doctors usually find a tumor that’s confined to the prostate and treat it with surgery or radiation. At Johns Hopkins, if the disease is more widespread, a medical oncologist will evaluate the best course of action using state-of-the-art precision medicine tools developed here, explains oncologist Cathy Handy Marshall.

One of the first things Marshall looks for is whether her patient has a genetic mutation that could affect how their cancer responds to different therapies. At least half a dozen genes can carry inherited mutations that increase a person’s chances of developing prostate cancer, including ATM, CHEK2 and BRCA genes, the latter of which are typically associated with breast cancer. When functioning normally, these genes aid in cell replication and help stop tumor growth. But when they carry a mutation, the odds of developing cancer increase.

Marshall has been working to create a clinical genomic database to better understand how to treat individuals with these mutations — individuals who make up about 25 percent of her patients. Her team has been collecting men’s clinical and genomic information and then working with pathologists, bioinformatics experts and the team that oversees Johns Hopkins’ Epic medical record system — which can tailor data to meet the needs of researchers — to find treatment solutions.

“What makes Johns Hopkins special is the breadth of people working on this problem. There are medical oncologists, like me, who work with people across all different departments, including nonphysicians and Ph.D. scientists,” says Marshall, who is also part of the Kimmel Cancer Center’s prostate cancer team. “This genetics work was first started at Johns Hopkins in Brady Urology. What we’re doing now is really building on decades of Johns Hopkins research.”

Over the last 10 years, Johns Hopkins’ prostate researchers have contributed to a number of notable genetic advances. In 2012, they were the first to identify a rare, inherited mutation in the HOXB13 gene that makes men 10 to 20 times more likely to develop prostate cancer, a finding published in The New England Journal of Medicine. Two years later, Brady urologists contributed biological samples and data from 800 African American patients to a global study that identified 23 new genetic variants that increase the risk of prostate cancer. In recent years, Brady has been spearheading efforts to map the genes linked to prostate cancer to improve detection and treatment of the disease.

By looking at patterns in patient data, Marshall’s research has helped identify drugs that are more likely to work for certain people. For example, drugs known as PARP inhibitors were recently FDA-approved to treat metastatic prostate cancer in men with genetic mutations, but Marshall authored one of the first studies showing that patients with ATM mutations have tumors that don’t respond well to PARP inhibitors, which she published in European Urology in 2019. She also discovered that patients with BRCA2 mutations respond better to PARP inhibitors than those with BRCA1 mutations, a finding published in JCO Precision Oncology last year.

Since the 1940s, one of the only options for treating metastatic prostate cancer has been hormone therapy, administered through chemical or surgical castration. Prostate cancer cells depend on hormones, such as testosterone and dihydrotestosterone, to thrive. Removing the testicles or placing patients on hormone therapy drugs deprives the cancer cells of this fuel by cutting off hormone production — but the side effects can be severe. Most men with advanced prostate cancer don’t feel sick, but when they start hormone therapy, they often experience fatigue, impotence, loss of muscle mass, weight gain, increased belly fat, osteoporosis and even increased cardiovascular risks.

Hormone therapy is still routinely used today, but Johns Hopkins doctors are prescribing it in conjunction with other therapies that are tailored to each patient’s personalized medical data, rather than taking a one-size-fits-all approach. Depending on a person’s genetics, age and other medical factors, patients may be treated with hormone therapy and a combination of radiation, immunotherapy, chemotherapy or targeted drugs, like PARP inhibitors.

“Using precision medicine and targeted medicine gives us different pathways to attack cancer. It allows us to better select patients so we’re not exposing everyone to medicines they wouldn’t necessarily get a benefit from, and we’re expanding the type of tools we’re using to attack prostate cancer,” says Marshall. “We’re moving away from only thinking about hormone therapy and instead exploring other ways we can target the cancer to kill it.”

If a patient walks into Johns Hopkins for prostate cancer treatment, regardless of whether their disease is low-risk or advanced, chances are good that they will be treated with a precision medicine strategy, either by using a statistical tool like Active Care or through some form of genomic testing.

“In five years, we hope everything at Johns Hopkins will use the inHealth approach — not just in a precision medicine center. It should be the way we do business everywhere,” says Antony Rosen, vice dean for research at the school of medicine and co-director of inHealth.

Laying Groundwork for the Future

After Gerard Brown’s Johns Hopkins biopsy showed he had prostate cancer, he went on a fact-finding mission to decide the best course of action for treatment. During that period in early 2004, his wife, Carole, was frightened by his diagnosis and urged him to follow his local doctor’s advice and get the prostatectomy. But the side effects gave him pause. After conducting his own research and speaking with other prostate cancer survivors in a local support group — one of whom had been treated at Johns Hopkins by Carter — he became convinced that active surveillance was the path for him.

“My local doctor said to me, ‘You’ve got to choose, either us or Johns Hopkins.’ So I left, and I never went back,” says Brown, who has remained in Johns Hopkins’ Active Surveillance Program for almost 18 years, despite the seven-hour round-trip drive for appointments.

For the first 12 years, he visited every six months to receive annual biopsies, PSA tests and physical exams. Today, the data from those visits are being used in predictive models to help other patients decide if they should choose prostate surgery or active surveillance. It’s information that Brown and his doctors didn’t have when he was diagnosed nearly two decades ago.

Years of promising biopsy results — and, later, statistical data generated by the Active Care tool — alleviated the fears he and Carole once felt. “When Dr. Carter was showing me all the statistics, I felt very secure in what I decided to do,” he says. “I don’t worry at all today.”

Brown and his wife are now retired and living in Intercourse, Pennsylvania. At 76, he no longer needs to come to Johns Hopkins for annual biopsies because the odds of his cancer metastasizing before he dies from natural causes is so low. “Every year, the likelihood of me dying of prostate cancer becomes less and less. I’m more likely to slip on a banana peel,” he jokes.

It may take another 20 years to prove that the precision medicine work being done at Johns Hopkins is helping prostate cancer patients live longer, healthier lives, estimates Pavlovich.

Many men live with prostate cancer for decades, and longitudinal studies can’t be rushed.

In the meantime, more than 40 Johns Hopkins researchers are working to find precision medicine solutions to better treat prostate cancer today. In one study, scientists are performing genomic analyses on patients’ biopsies to better quantify their cancer risk and need for routine biopsies. “In five years, we may be able to tell patients who have high PSA levels and a low genetic risk that they don’t need a biopsy,” says Pavlovich.

With an estimated $2.5 billion spent on prostate biopsies in the U.S. annually, such advances could provide significant savings, in addition to sparing patients the inconvenience and discomfort of going under the needle.

Johns Hopkins researchers also hope to show that using Active Care could help doctors avoid unnecessary surgery in cases where men have indolent (slow-growing) tumors. But the tool needs more refinement and real-world use before clinical trials can begin. The Precision Medical Center of Excellence for Prostate Cancer has partnered with outside institutions in the U.S., Italy and northern Europe to validate their model and calibrate it to perform across a large number of patients, thereby laying the groundwork for future trials to begin.

“This is a journey, and it’s a hard journey. We’re still in an experimental phase,” says Zeger. “What we’ve hit upon, in my opinion, is the right way to treat patients. What we need is for the system to embrace it and say: This is the future.”
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