Dr. Oliver Sartor, one of the leading researchers in advanced prostate cancer today, has the following to say about this month’s conversations.
Three of the biggest areas in prostate cancer right now are: 1) the use of the checkpoint inhibitor PD-1 to treat men with mismatch DNA repair defects, 2) the use of either PARP inhibitors or platinums to treat mismatch DNA repair defects, and 3) better imaging techniques.
Within the next year or two, we’ll be able to define a subset of patients who will benefit from the PD-1 inhibitors that Dr. Charles Drake discusses in his conversation on immunology. I anticipate that PD-1 inhibitors may be meaningful for around 10% of men.
The FDA recently approved Keytruda (pembrolizumab) for those with mismatch DNA repair mutations, which applies to a subset of prostate cancer patients. This story will be meaningful to watch as testing for these mutations becomes more prevalent.
As Dr. Daniel Petrylak alludes to, there are now a variety of rapidly moving clinical trials looking at the combination of three DNA repair defects—BRCA1, BRCA2, and ATM. Data to support the use of PARP inhibitors in men with this combination of repair defects is rapidly evolving. This practice remains unproven in prostate cancer, though, despite promising preliminary data published by Dr. Joaquin de Mateo in the New England Journal of Medicine in 2016. [See Prostatepedia June 2016 for a conversation with Dr. Mateo about his work.]
But I do want to make sure that Prostatepedia readers are aware that if you have metastatic prostate cancer and a DNA repair defect—like BRCA1, BRCA2, and ATM—there is some reasonable preliminary data to support using carboplatin. We have a manuscript at press right now that shows that if you have an inherited BRCA2 mutation, there is better activity if a carboplatin plus a taxane are administered as opposed to just giving you a taxane alone. Thus carboplatin appears to be an option for men with certain DNA repair alterations.
Advances in imaging are also discussed in several of the conversations that follow. PSMA imaging is moving quickly. Axumin (fluciclovine F18) is the new imaging technique on the block with FDA approval. I think that in using these newer imaging techniques we will be able to define oligometastatic disease groups more and more efficiently. The consequences will be less therapy that just sets patients up to fail and, hopefully, more therapy that, if targeted to those lesions, will have a meaningful effect.
Stay tuned: the prostate cancer field is evolving really fast right now. I believe some men with advanced disease will potentially have molecularly targeted therapies available to them within the next several years.
Dr. Jeffrey Swensen is the Associate Director of Molecular Genetics at Caris Life Sciences in Phoenix, Arizona.
Prostatepedia spoke with him recently about prostate cancer screening for men with BRCA2 mutations. (See Prostatepedia March 2017 for a discussion with Dr. Swensen about molecular profiling for prostate cancer.)
Should a man with a BRCA2 inherited mutation be screened earlier for prostate cancer?
Dr. Swensen: Carrying a pathogenic BRCA2 mutation increases the risk for prostate cancer, and that cancer is more likely to be aggressive and earlier onset. There are recommendations that suggest male BRCA2 carriers should be screened more aggressively for prostate cancer. Male BRCA2 and, to a lesser extent, BRCA1 mutation carriers are also at increased risk for other cancers, including male breast cancer and pancreatic cancer. Screening male BRCA2 mutation carriers for breast
cancer is generally recommended; screening for pancreatic cancer is generally not unless there is a family history of that cancer.
Would it make sense to offer prostate cancer screening to male children of a prostate cancer patient earlier?
Dr. Swensen: No. A man with a BRCA2 mutation tends to get prostate cancer at an earlier age than the standard person in the population. But it’s generally not really early onset.
A female with a BRCA1 or BRCA2 mutation is at higher risk for breast and ovarian cancer and the onset can be at a considerably younger age. However, screening is typically not performed on these women until they’re adults.
Male BRCA2 mutation carriers are at increased risk for cancers, but the risk is not the same magnitude as the risk for the women. The lifetime risk has been estimated to be around 20% for prostate cancer in a male BRCA2 mutation carrier; a female carrier of a BRCA2 or BRCA1 mutation has a lifetime risk of breast cancer that may be up to 80%.
A female BRCA1 or BRCA2 mutation carrier will be counseled and followed extensively. After they reach a certain age and have had children, they can have their breasts and ovaries removed to significantly reduce their risk. That is what Angelina Jolie did.
Are there any other mutations that are significant for prostate cancer?
Dr. Swensen: There is a mutation in another gene that has been shown to be a risk factor for prostate cancer: G84E in the HOXB13 gene.
This mutation is carried by about 0.5% of individuals of European ancestry. It is not a high-risk mutation. Male carriers have a two to threefold increased risk of prostate cancer. The mutation is not known to be therapeutically significant.
Is that mutation associated with an increased risk of getting prostate cancer or of getting aggressive prostate cancer?
Dr. Swensen: That has still not been clearly defined.
Does it make sense to offer prostate cancer screening earlier to men with the G84E germline mutation in HOXB13?
Dr. Swensen: It is one of many genetic factors that will influence an individual’s risk of cancer. At this time, though, screening is not warranted.
Ms. Merel Grey Nissenberg, a California attorney specializing in medical malpractice cases, is the President of both the American- based National Alliance of State Prostate Cancer Coalitions (NASPCC) and the California Prostate Cancer Coalition (CPCC).
Prostatepedia spoke with her about the recent proposed changes to the US Preventive Services Task Force (USPSTF) recommendations on screening.
How did you become involved in prostate cancer advocacy?
Ms. Merel Grey Nissenberg: I’m a trial attorney. I handle medical malpractice cases.
Obviously, I don’t have a prostate. I don’t have anybody in my family who passed away from prostate cancer, but I’m very interested in prostate cancer and in cancer advocacy.
In my law practice, I’ve handled a lot of prostate cancer cases with inexcusably late diagnoses. Just shabby care. A lot of those clients have passed away because of that.
In 1994, I handled a case that had a surgical oncologist as one of our experts. He recommended that I start working on the California Division of the American Cancer Society’s Prostate Cancer Task Force, which I did.
I then went on to co-chair the task force. In 1997, there was a California-wide American Cancer Society meeting on prostate cancer. We thought it would be great to have a statewide California coalition for prostate cancer. Everybody said we couldn’t do it because California is too big. We heard that challenge. The California Prostate Cancer Coalition is now 20 years old!
Was this the first American statewide prostate cancer coalition?
Ms. Nissenberg: At that time, Pennsylvania had a coalition and Massachusetts had a fledgling coalition. A few other states were just starting coalitions.
In 2001, I went to a meeting with 20 state leaders in Washington, DC, at the former National Prostate Cancer Coalition (NPCC.) NPCC is now ZERO. We wanted to see how the states could help their organization—and how NPCC could help the states with their missions.
At that meeting, I met a lot of people from other state coalitions. I said I’d like to set up coalitions in all 50 states. Jan Marfyak, a prostate cancer survivor who was co-chair of the Pennsylvania coalition at the time, thought that was a great idea. Together, we started raising money to set up state coalitions.
In 2004, we decided to set up a national alliance, an umbrella organization, which would allow states to network with each other and to share best practices. This is now the thirteenth year of the National Alliance of State Prostate Cancer Coalitions.
Our original goal was to make prostate cancer a national healthcare priority by becoming a collaborative force that developed and mentored state prostate cancer coalitions.
In 2014, we added two core priorities: awareness and education, and public policy advocacy. To address awareness and education, we created a guide on prostate cancer screening aimed at patients and primary care physicians alike.
How have the United States government’s recommendations on prostate cancer screening changed?
Ms. Nissenberg: When I first got involved with prostate cancer advocacy, the recommendation was inconclusive whether you should screen or not. In fact, in our work, we use the word “testing” because the term “screening” is so controversial.
In 2012, which was the most recent USPSTF Recommendation, the US Preventive Services Task Force announced a straight across-the-board D recommendation: do not screen. Most physicians saw the “D” at the top of the page and never read beyond that.
But then we went back and looked. In the middle of the middle sections of the recommendations, in the Clinical Consideration section and in the Reply to Public Comments section, the Task Force clearly says that if a man wants to have an informed discussion about prostate cancer, his physician must—this is mandatory language—have that discussion with him. It is then the patient’s decision based on his own values and preferences whether or not to get tested. It was buried in the guidelines, but it’s there.
I know a lot of men have since gone for their regular physicals and have not been offered PSA testing, even though they’re getting blood drawn for other things. The issue of prostate cancer screening is not brought up. They’re not even offered digital rectal exams (DRE).
There was a huge outcry after the 2012 Guidelines became final; they did not take into account your family history, if you’re African-American, or if you have been exposed to Agent Orange or any other type of banned chemicals. (Agent Orange is a huge risk factor for Vietnam veterans.)
The 2012 recommendation scared men away from asking for testing. Later the California Prostate Cancer Coalition and the American Cancer Society worked together briefly to get some language into the ACS guidelines that we could both live with. We did not like the way ACS used the phrase potential benefits and harms instead of potential benefits and potential harms. (The word “potential” only referred to the benefits, not the harms.) It made the benefits only potential, but the harms certain.
Precision in language is important…
Ms. Nissenberg: Exactly. But the USPSTF proposed changes to the guidelines in April of this year; it would still be a D recommendation for men 70 and over (with no regard to life expectancy), but a C for men 55 to 69. They’re recommending that a man speak with his physician and that the physician offer the man an informed discussion about prostate cancer testing.
Based on the 2012 guidelines, physicians didn’t have to bring up testing at all. They were completely relieved of the responsibility of bringing up prostate cancer testing. Physicians felt that legally they didn’t have to discuss testing with men.
An informed discussion is not the physician telling you why you don’t want to be tested. Your physician is supposed to discuss the risks of being diagnosed with a cancer that doesn’t need treatment. He or she should also discuss the benefits: if you have an aggressive disease, early detection is critical.
Men need to know that this is their decision to make, based on their preferences and values. It’s not for someone else to say that you don’t need to know about this.
I’ve dealt with cases in my law practice in which the doctors actually note in medical records that the patient wants a PSA. “Patient is worried about prostate cancer.” And still some doctors have refused to test. Some of those patients are dead now. People tend to trust whatever the physician says.
It’s that old hierarchal relationship people have had with their doctors.
Ms. Nissenberg: Right. They just tend to think he or she has this superior experience, training, and expertise, so if the physician says don’t worry, the patients won’t worry.
But, as I said, physicians haven’t even been bringing testing up and have felt legally justified in not doing so.
The way I see it is that you have to educate, not just the primary care doctors, but also men—prospective patients—so they know to ask about prostate cancer screening. You can’t ask for an informed discussion about something you don’t know exists. We need to educate both groups.
So from the D recommendation of 2012, the proposed guidelines now say that physicians should discuss the potential benefits and risks associated with screening with men 55 to 69.
But the NASPCC and the CPCC have problems with the new proposed guidelines. First, why start at age 55? We advocate that a man get a baseline PSA in his early 40s. This gives a risk assessment; you can then personalize follow-up.
If you’re at low risk based on your PSA reading, you don’t have to come back for retesting for another five years. (No one is suggesting that men get yearly PSA tests.)
If you’re at intermediate risk, you get retested every one to two years, depending on your other risk factors.
Men at high risk would obviously need immediate follow-up.
Even the Task Force itself acknowledges in the Frequently Asked Questions section of the new proposed draft guidelines that sometimes you don’t see a benefit to screening for over 10 years. Sometimes 10- 15 years. If you wait to get baseline tests until men are 55, you lose an opportunity to prevent some of them from developing metastatic disease.
Another change in the recommendations is that the Task Force now discusses active surveillance. The guidelines say that there are men who will choose active surveillance, so those men will not be overtreated by definition. But the guidelines did not also acknowledge the fact that we now have urine, blood, and tissue markers that can help determine whether or not a man is at risk for aggressive disease. Why worry about overtreatment if a man is diagnosed, but not acknowledge the availability of biomarkers to select those at high risk for clinically significant prostate cancer?
Lastly, NASPCC and CPCC believe that Vietnam veterans and others exposed to Agent Orange should be included in the Task Force definition of a high-risk group (that currently includes African-American men and men with a family history of prostate cancer).
We do applaud that the Task Force is now finally openly talking about informed decision-making.
It’s important to remember that not everyone who is tested will be overtreated. (I don’t believe there as such a thing as overdiagnosis.) Diagnosis is just information.
You can choose not to be treated once you have the information.
Ms. Nissenberg: Exactly. You wouldn’t tell a woman, “You don’t really want to know if you have breast cancer, dear.”
After a certain age, women get mammograms yearly.
Ms. Nissenberg: Exactly. Physicians take that choice away from men.
We distribute our decision-making guide to physicians as well as patients so that they know which questions the patient is going to ask. (Men aren’t going to be coming in with 500 pieces of paper from the Internet.)
In the guide, we talk about things like baseline PSA, the importance of family history, ethnicity, and exposure to Agent Orange. Questions like: If I have a biopsy and it reveals cancer do I necessarily have to have treatment? What is active surveillance?
Good, basic questions and answers.
Why are they revising the guidelines now? Because of the outcry in the prostate cancer community? Or is this just part of the normal cycle of revision?
Ms. Nissenberg: It is part of the normal cycle of revision. The outcry probably helped precipitate it, but this is just their normal timeframe.
What do you feel are the greater implications of the guideline changes?
Ms. Nissenberg: The implications are that more men will hopefully be tested. More men will have that conversation and make their own informed decision about whether they want to be tested or not.
The changes to the guidelines will raise awareness at the very least.
The changes are a good start, but we’ve got to go further.
David Crawford is the distinguished Professor of Surgery, Urology, and Radiation Oncology, and head of the Section of Urologic Oncology at the University of Colorado Anschutz Medical Campus as well as the driving force behind PCMarkers.
Prostatepedia spoke with him about how practitioners can fine-tune prostate cancer screening.
Why did you become a doctor?
Dr. E. David Crawford: I got my interest in medicine from my family. They had a nursing home. I worked there when I was in high school and college, so I was around patients and doctors. I saw the compassion the doctors had and really liked it. I got to know a few of them.
Even though that was only a snapshot, I thought medicine would be a good thing to do. Then I got a job during college doing evaluations of people before surgery. That was how I got interested in urology.
My interest in prostate cancer began when I was at the University of California, Los Angeles, as a Fellow. I was dumbfounded that most of the patients we saw with prostate cancer were advanced and incurable.
I had an opportunity to work with Schering Corp. I did a study and got one of their drugs called Eulexin (flutamide) approved.
A man named Perry Lieber from Las Vegas came to see me. The only way he could get Eulexin (flutamide) was on my Phase III trial. He was a spokesman for Howard Hughes. He wanted to get the word out about early detection for prostate cancer. We started some of the early screening back in the 1980s in Las Vegas and in Colorado. Unfortunately, he died of prostate cancer.
This was in 1988. We didn’t know what we were doing. We had PSA; we were testing and biopsying a lot of people. At first, that was good because we found a lot of aggressive prostate cancers.
Once we filtered through those, though, we were biopsying people at lower and lower PSAs and finding prostate cancers that didn’t need to be found. There was a lot of overdiagnosis and overtreatment.
That went on for a while. Then the US Preventive Services Task Force said they think screening does work, but that it does more harm than good, so they couldn’t recommend it. (They have more recently changed their recommendations.)
That put the brakes on things, but I think it was needed. When we do too many biopsies and rebiopsies and overtreat people, we have no way to restratify them.
I think the way forward is pretty simple. It involves prostate cancer markers: blood, urine, and tissue-based markers.
But first consider who orders PSA tests in the United States: family practice doctors order 92% of PSA tests. We have to educate these family practice doctors.
I did a study a few years ago that looked at the PSA cutoff of 1.5 ng/ ml. What if you find prostate cancer in that zone of 1.5 to 4? We found that 70% of men who had their PSA analyzed had a level of less than 1.5 ng/ml and, therefore, could come back in 5 years for another one.
That’s an easy message: a PSA above 1.5 to 4 ng/ml is a danger zone. Prostate cancer marker tests come into play in men with PSAs in that gray zone of 1.5 to 4 ng/ml.
Everyone is talking about informed decision-making with these tests before a PSA is performed, but this is not going to happen. Family practice doctors have more significant things to talk about with their patients: obesity, hypertension, or diabetes. They don’t get informed decision to check your cholesterol, your blood pressure, or your weight. They get informed decision after the fact.
I think you should do the same thing with PSA. Doctors should order the PSA tests in the right group of people. If the PSA is less than 1.5, no discussion is needed. Tell the man to come back in five years.
If his PSA is greater than 1.5, we need the next layer of testing and discussion. The goal right now is simple.
PSA is a frontline test to help identify people at risk for having prostate cancer. PSA doesn’t tell us what kind of risk. It doesn’t tell us if the man has low- grade or high-grade prostate cancer. That is where some of these new tests come in. PSA screening by itself, without any further testing, is gone. PSA is just the first test.
If a doctor were considering doing a biopsy and worried about prostate cancer, the next step would be genomic testing.
What sorts of genomic testing would be appropriate in this setting?
Dr. Crawford: The tests fall into three buckets: blood-based, urine-based, and tissue-based.
The ones I’m working on now are either blood- or urine-based tests. The prostate health index (PHI) is a formula that looks at several forms of PSA to come up with the relative risk of having prostate cancer. Phi is FDA-approved in the US for use in men with a PSA above 4: it gives their relative risk of having prostate cancer.
There are two issues with PHI. First, in Europe, the PSA cutoff is 2. In the United States, the PSA cutoff is 4. But we still have a lot of prostate cancer in men with a PSA between 1.5 and 4. We published a paper that showed a 10-13% higher risk in men with a PSA between 1.5 and 4.
Second, we need more data on PHI levels and high-grade cancers. We’ve done some studies that show that there seems to be a good correlation between high PHI levels and high-grade cancers.
The other test is 4Kscore, which looks at the four prostate-specific kallikreins in the blood: Total PSA, Free PSA, Intact PSA, and Human Kallikrein 2 (hK2). The company adds their secret sauce and gives your relative risk of having high-grade prostate cancer.
If your 4Kscore is less than 7%, you don’t worry. Above 7%, you do. Still, some people have high-grade cancer when their 4Kscore is below that—you have to account for other risk factors—but it’s another good blood test. It’s easy to do. The cost is down to less than $700 now. They’re trying to get Medicare coverage.
Another test is the urine-based test SelectMDx. This test is done after a digital rectal exam. It is based on two genes that are overexpressed in high-grade prostate cancer. You measure the messenger RNA in urine.
What I like about SelectMDx is that if the test comes back negative, it has a 99% negative predictive value that you don’t have a high-grade cancer like a Gleason grade 8, 9, or 10 and a 98% chance you don’t have a Gleason 7 or above cancer.
If the SelectMDx comes back negative, it makes you feel really good. If it comes back positive, it gives you a relative risk of low-grade and high-grade cancers. The aim is to find the higher- grade cancers.
Right now, I think one of the more promising genomic tests is the SelectMDx.
Why so much of a push to develop these molecular markers?
Dr. Crawford: It’s time. This is the era of personalized medicine. This is a way of addressing the issue of overdiagnosis and overtreatment.
There are approximately 1.4 million prostate biopsies done in the United States every year, but we only diagnose a couple hundred thousand people with prostate cancer. Many get rebiopsied and rebiopsied and rebiopsied.
If your biopsy is positive and you’ve picked up a low-grade cancer, you might then choose a molecular marker to determine your cancer’s aggressiveness. These are the tissue-based genomic tests, such as Oncotype DX, Prolaris, and Decipher.
Another is called ConfirmMDx. This is a tissue-based test that looks for genetic changes called methylation genes around the cancer. (These are areas of cancerization.)
If the biopsy is negative and we order ConfirmMDx on the tissue and that test comes back as positive, it means we’ve widened the target area: we may have missed something and need to go back and look again with another biopsy.
Are prostate cancer markers covered by insurance?
Dr. Crawford: Only PHI and PCA3 have been approved. (PCA3 has pretty much gone by the wayside, though, after the introduction of SelectMDx.)
It happens this way: the company does some clinical trials, they bill insurance, and then they submit to Medicare. They get local coverage determination in which the test will be covered for a period of time while they continue to investigate.
The companies who make these markers are not big companies with deep pockets. They have a limited budget.
If we wait for an endpoint of death on some of these studies, none of us will be around to see the results. We need to think about other endpoints. We are looking at these other endpoints.
I’m excited about all this. I think we’ve got a way forward now. Most family practitioners believe that screening does do some good, but they know that it also does some harm. Now that we’ve got the tools to deal with screening, let’s deal with it. Patients believe in screening. We don’t want to go back to where we were with metastatic disease being the norm.
Do you think the former recommendation against screening ended up having a positive impact? That it forced the prostate cancer community to reevaluate the issue of overtreatment?
Dr. Crawford: A lot of people don’t think that, but I do. There was a lot of overdiagnosis and overtreatment.
Sometimes when you tell a man he has cancer, he wants it taken care of yesterday. Many don’t understand that some prostate cancers are like skin cancers. You don’t cut off your arm because you have a small basal cell cancer on your wrist. It’s the same way with prostate cancer. There are low-grade, nonthreatening Gleason 6 cancers.
Are these prostate cancer markers now widely accepted among family practitioners?
Dr. Crawford: No. Family practice doctors don’t know much about these markers at all. Urologists don’t either. This is the beginning of a long educational process. It’ll take patients asking about the tests. Often, patients drive change: that’s just the way things happen.
Many of our readers are influential in their communities. What would you say to those men about getting the word out about prostate cancer markers?
Dr. Crawford: There are a lot of hereditary and germline mutations being put forth in prostate cancer: as many as 5% up to 20% of prostate cancer patients will have some of these mutations.
One of my recommendations is that if you have germline mutations of prostate cancer like BRCA2 (and others) your family members should get tested.
The PSA cutoff of 1.5 falls in very nicely with this. If your PSA is 1.5 or above, get the tests we discussed— like the SelectMDx or the 4K.
What about repeating these tests? If a man consistently has a high PSA, would it make sense to keep repeating these tests?
Dr. Crawford: He should be referred to a urologist.
Are these tests at all useful in men on active surveillance or with low-grade cancers?
Dr. Crawford: Thirty percent of patients fail active surveillance. When these men eventually have surgery, sometimes they have adverse pathology. Why did that happen? It happened because when we did the biopsy, we missed the bad cancer—the Gleason 7s, 8s, 9s, and 10s. Some of these tissue markers, like Prolaris and Oncotype DX, can help in that scenario.
Part of the follow-up for men on active surveillance is a repeat biopsy. I haven’t met a lot of men who like to have biopsies every year, but they do it.
After a while, doing repeat biopsies and monitoring gets to be more expensive than treatment. A urine test like SelectMDx or 4K can help you determine who needs to be rebiopsied.
What I’m looking at now is whether or not doing the SelectMDx every other year can eliminate the need for biopsies. And I’m finding the answer is yes.
Dr. Preston Sprenkle: My father was a physician. I liked the idea of helping people and doing something that was both intellectually challenging, yet also socially and intellectually rewarding.
I wasn’t sure, though, so after college I worked in consulting for a little while also volunteering in an ER and in some free clinics. I really valued those experiences with patients and the one- on-one interactions. I recognized how much good you can do and how much you can help someone by just listening and being attentive to their needs and concerns. Those experiences solidified my desire to go into medicine.
When I started medical school, I quickly realized that I really enjoyed anatomy and surgery. Urology is a fantastic specialty because you come in contact with a wide variety of patients—from children to very old patients, men and women. Even though most people think urology just centers on men, we actually take care of a lot of women too.
Urology involves a lot of surgeries that can be complicated and take a lot of time and energy, but there is also a lot of one-on-one patient-based care dealing with very personal things like sexual function or urinary function. Urology is somewhat unique among surgical specialties in that we not only operate on patients, but very often follow them for many years, allowing for long-term relationships with our patients.
I then became interested in cancer care. The current challenge is to improve the way we take care of cancer patients. Cancer is scary. Fortunately, in many cases it is very treatable and even curable. But hearing the C-word can be terrifying. Most people shut down and don’t really hear much after learning they’ve been diagnosed, so it can be a little longer process to help them understand that there are opportunities for cure.
What is the thinking behind the clinical trial you’re running?
Dr. Sprenkle: We opened this trial to better understand the relationship between the BRCA2 mutation, or BRCA2 deletion, in men and the incidence of prostate cancer.
There have been several studies showing that men with prostate cancer who have a BRCA2 mutation have a more aggressive prostate cancer more likely to have lymph node positivity.
What we have not been able to identify is where that starts. These men were arguably diagnosed with prostate cancer because they had an elevated PSA. Is their risk higher because they were diagnosed later in the course of their prostate cancer, or is their risk higher because the BRCA2 deletion causes them to have higher-grade prostate cancer?
When we started this trial, there was no information and no long- term prospective studies. (I believe there recently has been a trial that suggests that on a stage-for-stage basis it actually may not be much worse to have BRCA2, but that was not around when we started this trial.)
We are trying to understand the incidence of prostate cancer in this population of men with the BRCA2 mutation. This is, in part, a registry for all men who have a known BRCA2 mutation. We offer them prostate cancer screening with standard techniques: PSA blood tests, DRE, etc. But we also offer an MRI and MR-targeted biopsy to evaluate if there are any radiologic characteristics that could be used.
If 28-30% of men in a general population have prostate cancer with a PSA cut-off of 4, is that the same for men with a BRCA2 mutation? Or should we be screening men with this mutation earlier? Or biopsying them with a lower PSA? Do men with this mutation have a 30% rate of prostate cancer with a PSA of 2?
There is a famous trial called the Prostate Cancer Prevention Trial that used a medication to shrink the prostate. During the trial, they biopsied men if they had an elevated PSA and then at the end of that trial. Even men who didn’t get treatment were biopsied at the end, independent of what their PSA was. The trial gave a tremendous amount of information about what the likelihood is of developing prostate cancer when your PSA is as low as 1. Based on the results of this trial, we know that approximately 8% of men with a PSA of 1 or less have prostate cancer on a random biopsy—even though we typically don’t biopsy those men.
This current trial is an opportunity for us to gain information about how—or if—the incidence of prostate cancer is different in a population of men with a BRCA2 mutation.
Are you just looking for men without prostate cancer with the BRCA2 mutation?
Dr. Sprenkle: Yes. Any man who has at least a 10-year life expectancy qualifies to be screened.
Dr. June Chan is a Professor in the Departments of Epidemiology and Biostatistics and Urology at the University of California, San Francisco.
Her research focuses on how diet, exercise, and lifestyle factors contribute to prostate cancer aggressiveness, progression, and death.
Prostatepedia spoke with her about the impact of diet and lifestyle on prostate cancer.
What do we currently know about the relationship between diet, lifestyle, and prostate cancer?
Dr. Chan: We have observed that there are some relationships between diet and exercise and the risk of clinically relevant prostate cancer. As our studies evolved—and the field evolved alongside the development of PSA screening in the United States—it became important to define and focus on clinically relevant prostate cancer as an outcome.
Back in the early to mid-1990s when some of our first studies came out, we were just looking at specific dietary factors and the risk of overall development of prostate cancer. With PSA screening came the understanding that there are indolent tumors and overdiagnosis; we needed to adjust to that in the field.
Part of my work as a postdoctoral fellow was to collect detailed data in large cohort studies so we could classify men in a more clinically meaningful way. We collected details on stage, grade, and subsequent PSA values so that we could try to distinguish more indolent tumors from more aggressive tumors.
Once we started to do that, it became more interesting because we really started to refine our questioning. The question isn’t just, “Is vegetable intake associated with overall risk?” The question becomes: “Is vegetable intake associated with the risk of having bad prostate cancer? A cancer that will do harm.” As studies have matured, we’ve focused on the risk of developing metastases and prostate cancer-specific mortality.
The field had to change as we started to understand the biology of prostate cancer better. Some of that early observational data that came from us looking at total prostate cancer risk needed to be looked at again. That is the stage we’re in now. We look at those questions differently now that we have more clinically relevant outcomes with more time.
What do we know about the impact diet and lifestyle have on the risk of developing prostate cancer? What do we know about the impact diet and lifestyle have on progression? About the risk of developing aggressive versus low-risk disease?
Dr. Chan: I’ll focus on what we know about clinically relevant cancer or, at least, some of the findings that have persisted over time.
The first thing, which is not discussed as much, is that smoking is potentially related to the risk of fatal prostate cancer. Some of the earliest data come from autopsy studies. They looked at people who had not necessarily been diagnosed with prostate cancer but had died for some other reason. They were able to correlate smoking history with a worse-looking grade and worse- looking features of prostate cancer.
Dr. Stacy Kenfield published a paper looking at the risk of fatal prostate cancer and smoking history. Her work showed that smoking has a broad effect —not just on respiratory cancers. Smoking elevates your risk of other cancers as well.
Some of our work indicates that exercise may be important for deterring the risk of having recurrent or fatal prostate cancer. The story started with two reports that we put out in 2011. Dr. Kenfield led one team and Dr. Erin Van Blarigan led the other. (I was mentoring both researchers.) We had the opportunity to ask about exercise and prostate cancer survivorship in two distinct populations. The results were somewhat complementary.
In one study, it appeared that vigorous physical activity was associated with a benefit or reduction in the risk of metastatic fatal prostate cancer among men diagnosed with localized disease.
The other study had a shorter follow-up, so we weren’t able to look at metastasis and death, but we did look at a combined outcome of recurrence, metastasis, and death —or the initiation of secondary treatment after primary therapy in prostate cancer survivors.
While there was a trend toward a benefit for physical activity, what was particularly interesting was that we saw a benefit from brisk walking versus slower walking pace. It suggested that there was something specific about aerobic exercise, or cardiopulmonary exercise, that offered a benefit. We’ve been pursuing that in other studies.
What do you mean by benefit?
Dr. Chan: In one study, there was a reduced risk of prostate cancer recurrence. In the other study, there was a reduced risk of prostate cancer death.
Per-Anders Abrahamsson is the Chair of the Department of Urology at Skåne University Hospital at Lund University in Sweden and the Secretary General of the European Association of Urology (EAU).
Prostatepedia spoke with him about European urology and lessons learned from the randomized European screening trial.
How does the European approach to prostate cancer differ from approaches in other parts of the world? Or is there even a specifically European approach?
Dr. Abrahamsson: Yes, absolutely. In Europe in the 1990s, we were very conservative, with few exceptions. We didn’t really introduce early detection or screening programs whatsoever. In 1991, when I was working in the United States, the American Congress, American Cancer Society, and American Urologic Association all launched screening programs for prostate cancer.
At that time, Bob Dole was a Republican in Congress. He underwent surgery for prostate cancer. All of a sudden, you found advertisements in all the American airports for early detection (screening) of prostate cancer.
That was totally different from what we experienced in Europe at that time. We were a little bit more strict and conservative.
On the other hand, we knew for sure that we had a very high mortality rate for prostate cancer, especially in Scandinavia and Sweden, where I come from. In fact, we had the highest mortality rate in the world at that time.
Of course, we started to wonder what could we do about it.
That is why Sweden and Finland joined the European Randomized Screening Trial in the early 1990s.
How important are international collaborations for prostate cancer research?
Dr. Abrahamsson: Extremely important. I realized that when I was doing my PhD thesis in the 1980s, but even more so when I ended up in Rochester. As I said earlier, in Rochester, I had the opportunity to recruit good researchers from all over the world and to interact and collaborate with a number of leading centers in the United States and Canada. That sort of international collaboration was critical and crucial—and is even more important now in 2017.
You cannot do it alone. Collaboration is the key, especially if you look at patient-oriented research, what we call clinical research. You need increasing numbers of patient cohorts to study and follow over time in order to find out whether or not, for instance, screening can make a difference in terms of reducing mortality. Also to evaluate new treatment options, not only in surgery or radiation, but also for drugs and gene therapy coming out of vaccines, etc.
In July, Prostatepedia is talking about advances in urology, radiation therapy, oncology and immunotherapy for prostate cancer.
Dr. Jeffrey Swensen is the Associate Director of Molecular Genetics at Caris Life Sciences in Phoenix, Arizona.
Ms. Merel Grey Nissenberg: I’m a trial attorney. I handle medical malpractice cases.
Dr. June Chan is a Professor in the Departments of Epidemiology and Biostatistics and Urology at the University of California, San Francisco.
Per-Anders Abrahamsson is the Chair of the Department of Urology at Skåne University Hospital
at Lund University in Sweden and the Secretary General of the European Association of Urology (EAU).
Prostatepedia 