Why did I say that no PSA number above 1, by itself, is a guarantee that you don’t have cancer?  Why do we say this in our book?

Because that’s what H. Ballentine (Bal) Carter, M.D., the great Johns Hopkins urologist and scientist, discovered.  In fact, he says:  “There is no PSA value below which you can guarantee someone they don’t have prostate cancer,” and no value that automatically means it’s cancer.  “There are men with PSAs of 20 who don’t have prostate cancer, and men with 0.5 to 1 who can have very serious prostate cancer.”

So, basically:  Your PSA number, by itself, means Jack.  What happens to it over time means everything.

This is called PSA velocity.  It is a concept pioneered in the 1990s by Carter, working with Patrick Walsh, M.D., my co-author on many books and publications, and it’s a very effective way to detect prostate cancer.  I recently interviewed Carter, who retired this summer after 32 years at The Brady Urological Institute at Johns Hopkins, for Discovery, a magazine published by the Brady.  He devoted his career to making sense of PSA, and what he has accomplished is incredible.  Among many findings, Carter also came up with median PSA numbers based on age, which we will discuss in a minute.

It’s a shame that many doctors, including even some urologists, don’t seem to grasp these simple and very effective ideas, and instead focus on the PSA number itself – an idea that was outdated 20 years ago.

I say this because I don’t know how many times I have talked to men who say:

“My doctor says I don’t need to worry about screening for prostate cancer until I’m in my 50s, and even then, it’s not really that big a deal.”

And, “My doctor says my PSA number is low, so everything’s fine, I don’t need to worry about it.”

This makes me very frustrated.  I’ve written about the travesty that happened in prostate cancer screening here, so we won’t go into that now.

Let’s get back to Bal Carter and PSA, and let’s time-travel, very briefly, to the late 1980s, when widespread screening for prostate cancer did not exist.  The discovery of PSA (prostate-specific antigen, an enzyme made by the prostate) had just made it possible, for the first time, to learn about prostate cancer from a blood test – but nobody knew what to do with PSA, or how to use it along with the rectal exam and the new use of transrectal ultrasound-guided biopsy in diagnosing prostate cancer early.

“There was controversy about even using PSA,” Carter recalls.   “There were voices saying, ‘Beware, we’re going to uncover a lot of cancers that never should have come to light.’”  And that was true.  So then came controversy over the PSA threshold:  what was the magic number that would indicate the need for a prostate biopsy?  “In retrospect, that was probably the wrong thing to be asking,” Carter says.  “There was just not a good understanding then of PSA as a continuum.”

Carter pioneered the concept of PSA velocity – the rate at which PSA rises over time.  “But that’s never been tested as a screening tool.  I honestly believe if we had not focused on a single, absolute threshold, and instead had focused on changes in PSA to alert us that someone has an aggressive cancer, in the long run we may have identified more individuals with the cancers that need to be treated, and eliminated more who don’t need to be treated.  But that will require a carefully done, prospective trial.”

Carter started looking at this years ago, in studies that would lay the foundation for PSA screening and also for safe, vigilant active surveillance as a mainstream treatment for low-risk prostate cancer.  How that came about, he says, “was really the brilliance of Pat Walsh.  When I first joined the faculty, he came to me and said, ‘What do you think would happen if we looked at changes in PSA?’  I said, ‘I think they’ll probably rise faster in people who have prostate cancer.  How can we study that?’  And he said, ‘Have you ever heard of the Baltimore Longitudinal Study of Aging (BLSA)?’”  The BLSA was conceived in 1958, when gerontologists at the Baltimore City Hospitals were trying to find a better way to study aging.  At that time, and even today, scientists would compare men and women who were in their twenties to people who were decades older.  But these scientists had a better idea:  to revisit the same person every two years, with a history and physical and blood samples that were stored.  This made it possible to look at men who had prostate disease, benign enlargement, or localized or metastatic prostate cancer – and then work backward, describing the changes in PSA, over the previous 20 to 30 years.

“I had never heard of it,” Carter continues.  “He said, ‘I know they have a large frozen serum bank, and we might be able to use some of that to look at the question: do PSA levels rise faster in men who have aggressive disease vs. men who don’t have prostate cancer?’  Sure enough, that’s the way it turned out.”

Carter’s work, Walsh says, “has changed the way prostate cancer is treated today around the world.”  Although Carter is a fine surgeon, “he has done his best not to operate on men who don’t need it.  He was a voice of reason at a time when the diagnosis and treatment of the disease underwent revolutionary changes.  With the introduction of widespread PSA testing in 1990, the diagnosis of prostate cancer reached epidemic acceleration and led to abuses fed by the greed of many fellow urologists.  Those are tough words, but there is no other way to explain it.  Bal emphasized the harm of overdiagnosis and overtreatment, proposed solutions based on improved screening practices, and developed guidelines for identifying men who should not be treated.  He began by learning about PSA.”

Using blood samples that had been collected for decades by the BLSA, Carter described how age and prostate disease influenced PSA.  “Based on his unique observations, he proposed new ways to interpret PSA levels, and specified intervals for testing that were the most informative,” says Walsh.  As Chairman of the AUA’s Guidelines Panel, Carter developed recommendations for how all urologists should screen for prostate cancer.

A Prostate Barometer

We discuss PSA in detail in chapter 4 of our book, but briefly:  PSA should never be considered a one-shot, cut-and-dried reading.  Instead, it’s like having a prostate barometer, so your doctor doesn’t have to wait for the PSA level to reach a magic number before acting.  With PSA velocity, what matters is a significant change over time, and for this to be accurate, you need to have multiple PSA measurements taken in the same laboratory, because PSA measurements can vary slightly from lab to lab.

The level of change depends on your PSA number.  For men with a PSA greater than 4, an average, consistent increase of more than 0.75 ng/ml over the course of three tests is considered significant.  Let’s say that over 18 months, your PSA went up from 4.0 to 4.6 to 5.8.  Clearly, something’s going on here.

But what if your PSA is less than 4?  Walsh says:  “Because we now realize that men with PSA levels as low as 1.0 may have cancer,” guidelines have been established for PSA velocity in these men, too:  In these men, work by Carter and colleagues suggests, any consistent increase in PSA is alarming, even an increase as small as 0.35 ng/m. a year.  They also found that many years before a man’s prostate cancer was diagnosed, when his total PSA levels (as opposed to more complex PSA readings, such as a free PSA test) were still low, a PSA velocity of greater than 0.35 ng/ml a year predicted who would later die from prostate cancer.  If you have a PSA between 1 and 4 and it is consistently rising faster than about 0.4 ng/ml a year, you should get a biopsy.

What Should My PSA Be for My Age?

Be aware:  15 percent of men with a PSA level lower than 4 have prostate cancer, and 15 percent of these men with cancer have high-grade cancer, the aggressive kind that needs to be treated.  That’s why we say in the book:  “There is no safe, absolute cutoff above a PSA level of 1.0 at which a man can rest assured that he is not at risk of harboring a high-grade cancer.  Thus, what probably is going to matter the most in the future is your PSA history.”  Get that baseline PSA level in your early 40s, or at age 40 if you have a family history of prostate cancer, of cancer in general, or if you are African American.

Then, depending on the baseline level – whether you are above or below the 50th percentile for your age – take a repeat PSA test every two to five years.  If you are in your 40s and your PSA level is greater than 0.6 ng/ml, or if you are in your 50s and your PSA is greater than 0.7, you should have your PSA measured at least every two years.  If your PSA is below this percentile, you may be able to wait as long as five years for the next test.  These are Carter’s numbers.  In another study, of a larger group of men, urologists Stacy Loeb of New York University and William Catalona of Northwestern University found the comparable numbers to be 0.7 for men in their 40s and 0.9 for men in their 50s.  

So, if you’re 50 and you have a PSA of 2.5, for example, and your doctor says it’s low, that doctor is wrong.  It’s actually high for 50.  It could be prostatitis, or benign prostatic enlargement (BPH).  But it could also be cancer, and you need to get it checked out.  A good next step would be to check the free PSA, with a test such as the Prostate Health Index (PSA has various forms in the blood, and these “second-tier” PSA tests can help tell whether it’s more likely to be higher because of BPH or cancer.)   The higher the free PSA, the higher the likelihood that you are free of cancer, as Carter says.  The numbers from studies vary, but one free PSA cutoff is 25 percent.  If your free PSA is higher than that, your PSA is more likely to be elevated because of BPH than it is of cancer.  If your free PSA is lower than 25, you are more likely to have cancer.

So, basically, to sum up:  You can’t just look at a PSA number and know very much at all.  It’s like looking at a Most Wanted photo and saying, “That guy looks guilty,” or “He has kind eyes!  He’s probably been framed! He’s no criminal.”  No self-respecting detective would ever try to get a warrant based on appearance.  You investigate first.  This is why you study PSA, watch what it does, and if it’s going up, check the free PSA, with a “second-tier” PSA test such as the Prostate Health Index (PHI); you also may need a biopsy.  Don’t just give it a free pass after one test because “the number’s low.”

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. You should start at age 40.  Many doctors don’t do this, so it’s up to you to ask for it.

©Janet Farrar Worthington

 

 


Why do I write so much about prostate cancer?  Because I can’t get away from it.  And now prostate cancer, never very far away, has hit close to home.  Again.

Before I tell you my story, please study this picture.  This is a picture of a miracle.  It’s not a pincushion.  It’s an MRI of a prostate, and the needle biopsy that used this MRI image to find its target – the spot of cancer in what’s ordinarily the most difficult-to-reach, out-of-the-way spot possible.  Those green needles aren’t all in there at the same time; this just shows where the needles went.  Two of them went directly into that spot of cancer.  Believe me when I tell you – as four of the most respected urologists in the U.S. have told me – this cancer would have been missed with the traditional transrectal biopsy, which uses ultrasound.  More about this in a minute.  The cancer is aggressive – Gleason 9.  But it is very small.  It is curable, the urologists all believe.  I believe it, too.

That’s my husband’s prostate.  At this very moment, we are scheduling surgery to get it taken out.

I feel like I’ve been in training for this moment for 28 years. 

That’s when prostate cancer made its first unwelcome entrance into my life – when my father-in-law, Tom, died of it at age 53.  My husband, Mark, was a medical Chief Resident at Johns Hopkins at the time, and all he could do for his dad was make sure his terrible pain was controlled.  Tom never had a chance; he had gone to see the doctor for back pain.  That turned out to be prostate cancer, which had already invaded his spine.  Tom never had a PSA screening test; nobody did back then.  That would change in a couple of years.

I worked at Hopkins, too, as the editor of the medical alumni magazine.   When Tom had been diagnosed, his doctor told him, “Don’t worry about it.  Prostate cancer is an old man’s disease – the kind you can live with for years.”  Tom died within months of his diagnosis.  I wanted to know how a 53-year-old man could die of an old man’s disease, so I decided to do a story about prostate cancer.  I set up an interview with Patrick Walsh, the head of urology at Hopkins, and we wrote a story that would change my life forever.  That sounds kind of melodramatic, but it’s true.  I have been writing about prostate cancer ever since.

Back then, I had no idea that Pat Walsh was the surgeon who invented the nerve-sparing radical prostatectomy, and that he had developed the best prostate cancer research and treatment program in the world at that time.  I wrote about Tom’s battle with cancer, and Walsh’s operation, and the research that was happening at Hopkins.  In those pre-internet days, we were inundated with requests for reprints.  Some 3,000 reprints later, we decided to write our first book.

That book was called, The Prostate: A Guide for Men and the Women Who Love Them.  We wrote it for women as well as men, because in Walsh’s experience, it was the women who got their men – fathers, husbands, brothers, sons – to the doctor.   I found this to be true:  as we were writing it, in 1992, I told both my parents that my dad should go to the doctor and get his prostate checked, and he should get this new thing called a PSA blood test.  My mom made him go and keep going every year.  He hated it, especially the rectal exam, but he went.

In 1997, when Dad was 63, his doctor felt something suspicious on his prostate – a rough patch.  “Probably prostatic calculi” (the prostate’s version of tiny gallstones), he said, but he ordered a biopsy, done by Dad’s local urologist in South Carolina.  A pathologist found prostate cancer.  My parents called me.  I called Pat Walsh about 30 seconds later.  We sent the slides to Hopkins for a second opinion, and they were read by a world-renowned urologic pathologist, Jonathan Epstein.   Two months later, Pat Walsh took out my dad’s prostate, and saved his life.  Dad had initially been diagnosed with Gleason 6 (3 + 3) disease, but – like many men – he actually turned out to have some slightly higher-grade cancer, and his pathologic stage was Gleason 3 + 4.

Note:  My dad never read my book.  My mom did, and on the eight-hour drive up I-95 to Baltimore for the surgery, she read aloud passages of the book she had highlighted.

A few years later, Mark’s grandfather, Charles, died at age 85 of complications from radiation therapy for – you guessed it, prostate cancer.  Radiation was not nearly as precise back then as it is now, and there were a lot of complications, particularly in the rectum.  Frankly, I don’t think he even needed to be treated; at his age, with heart problems, he could have done watchful waiting – the precursor to active surveillance back in the day.

A few months after that, my beloved grandfather, whom we all called Pop, died.  Of a heart attack after being put on a great big dose of estrogen – another treatment they didn’t have the hang of back then – for prostate cancer.  Like Mark’s grandfather, Pop was in his eighties, had no symptoms, and probably didn’t even need to be treated.  We know so much more now.

Patrick Walsh and I kept writing books on prostate cancer, and our first book morphed into a more cancer-focused book, Dr. Patrick Walsh’s Guide to Surviving Prostate Cancer.  Over the years, the news got better and better – particularly the chapters on advanced and metastatic prostate cancer.  When we first started, the news there was bleak.  Now, in large part due to research funded by the Prostate Cancer Foundation (PCF), for which I am proud to work as a science writer, there is more hope for treating advanced prostate cancer than ever before.  But, as my dad’s case has shown, there’s a lot to be said for early diagnosis and treatment.  Ideally, Walsh and I wrote, prostate cancer will be a blip on the radar screen – it’s caught early, it’s treated, and then it’s gone, and you get on with your life.  Many men with low-grade disease may never need treatment; they can be safely monitored for years.

When Mark reached age 40, I made sure he got his PSA tested every year.  His PSA was very low (less than 1, and then right around 1) when he was in his forties and early fifties.  Because of his family history, I told him and his doctor about getting a genetic test (which I have written about) to screen for 16 mutated genes known to be linked to aggressive cancer.  Mark took the test, and thank God, it was negative.  His PSA went up to 2, so his doctor ordered another test three months later.  It was 3.  We took another test; also 3.  I had suggested to Mark and his doctor that he get the prostate health index (PHI) test, which looks at different types of PSA.  Mark’s free PSA had dropped from 25 down to 18 – not encouraging.  As we said in our book:  free PSA of 25 and above is more likely to be free of cancer.

I called Pat Walsh.  He told Mark to come to Hopkins.

We live in a small town in Arizona.  Our internist said, “at least get the biopsy done here.”

I said these words:  “Absolutely not.  You need an MRI.”

I knew this for several reasons:  I had written about it from interviews with respected urologists including Bal Carter, of Hopkins; Stacy Loeb, of New York University; and Edward (Ted) Schaeffer, of Northwestern.  And I had interviewed Rob Gray – a young guy with a young family, whose battle-scarred prostate had endured multiple ultrasound-guided biopsies, all negative, but whose PSA had continued to go up.  His doctors told him not to worry about it; Rob worried.  He would still be worrying today, except he had a fusion MRI, which combines several different ways of looking at the prostate.  Because of all his other biopsies, his prostate had developed scar tissue that masked the cancer.  The MRI found it.

That stayed with me.  Then, just weeks ago, I interviewed Hopkins urologist Michael Gorin about two things in particular.  One is multi-parametric (mp) MRI, which is similar to fusion MRI, but it’s what they call it at Hopkins.  Gorin has developed software that allows him to take the findings of mpMRI and use them as a road map to guide the biopsy.

The other thing Gorin is doing is getting to the prostate by a different approach: through the perineum.   The perineum is the area between the scrotum and the rectum.

The traditional transrectal ultrasound (TRUS) biopsy, as its name suggests, reaches the prostate through the rectum.  There are a lot of problems with the TRUS biopsy.  Because it goes through the rectum, there is a risk of infection.  There is no risk of infection from the perineum; in fact, they don’t even give antibiotics for this approach.  And, most worrisome about the transrectal approach:  it’s hard to cover the entire prostate.  This is a problem especially for African American men, who tend to develop prostate cancer in the anterior region of the prostate.  Basically, as Ted Schaeffer, an excellent surgeon and coauthor of the book, explained, if you think of a prostate as a house, the transrectal biopsy comes in from the basement.  It’s pretty good at reaching the main floor, but not that great at reaching the attic.  It’s a South to North approach.

The transperineal approach goes from West to East, and instead of a house, Mike Gorin uses the analogy of a car:  the needle comes in from the headlights to the tail lights, but it can go lower, from the front tires to the back tires, or higher, from the front windshield to the rear windshield.

Now, combine this approach with MRI, and it’s a whole new world for diagnosis.

Compared to MRI, TRUS is blind.  It’s lame.  There, I said it.  Imagine you’re playing paintball at night, and you’re trying to hit a target.  You do the best you can, but you miss a lot.   Then the other team comes in and cleans your clock – because these guys have night-vision goggles.  They can actually see what they’re trying to hit.   MRI gives the urologist night-vision goggles.

When Mark got his MRI, it showed a 6 mm lesion – a spot the size of a smallish pearl on a necklace.  There was a 70-percent chance that this would be cancer.  Gorin took that MRI and used it to guide the biopsy.  Out of 15 cores taken throughout the prostate, he took two samples from inside this spot; he had a target to hit, and he nailed it.  He is my hero.

I’m telling you this because I have learned some things that I want you to know.  In fact, like the Ancient Mariner in the very old poem by Samuel Coleridge, I feel compelled to tell you this, and I hope you will feel bound to listen.  And I hope to God that someone else will be helped by what I’ve learned, including:

Every patient needs a treatment warrior.  An advocate.  Mark is an incredibly smart doctor, but he was just as stunned at having a possible diagnosis of cancer as any other patient.  His internist wanted him to go to the local urologist for a biopsy.  Our small town is not up on all the latest technology.  We don’t have an MRI for prostate biopsies.  They don’t do the transperineal approach. Again, I am certain that if Mark had gotten the traditional TRUS biopsy, this would not have been found.  The lesion on his prostate was in the anterior region – hard to reach, especially if the doctor can’t see and doesn’t have an MRI-revealed target to try to hit.  But Mark would have done as his doctor suggested, because he was stunned and he didn’t know as much as I happen to know about prostate biopsies, because his area of expertise is digestive diseases, not prostate cancer.

The difference between ultrasound and MRI is night and day.  It’s life-changing, and life-saving.

There is no safe PSA number above 1, as Bal Carter has said for years, and as we say in Chapter 4 of our book.  My dad’s PSA was very low:  only 1.2.  And yet, he had Gleason 3 + 4 disease.  Mark’s PSA is only 3.  Please understand this point.  This may be the most important of all.  I have talked to so many men over the last nearly three decades.  So many men who were wrongly assured by their doctor – because their doctors did not know better– that “Your PSA is going up, but it’s still pretty low.  Don’t worry about it.”  If your PSA is going up, worry about it.  It may not be cancer, but you have to check.  If your doctor sees one PSA reading and judges the number by itself, that doctor is not giving you the best advice. 

            You must look at PSA velocity:  the rate of rise of PSA over time.  I will be covering this in more detail in the next post.

And finally – again, because I have written about this disease for nearly 30 years, and talked to so many men with every stage of prostate cancer – the doctors who urge men not to get tested, who tell them not to worry about it, who say there’s no benefit to getting screened for prostate cancer, that the risk of complications from biopsy are too great, that too many men are overtreated, are just plain wrong.

As urologist Stacy Loeb told me:  “A diagnosis of prostate cancer doesn’t mean you need to get treated.”  But you should be the one to make that decision; don’t let cancer make it for you.  Not all men need treatment.  Because of Mark’s family history and his Gleason score, even though the one spot of cancer is very small, we will be getting treatment.  Surgery.  I say we, because it’s both of us.  We’re a team.

Mark is worried about the main complications of surgery – temporary urinary incontinence and the risk of erectile dysfunction (ED).  Of course he is; nobody wants these complications.

I’m not.  There is a huge difference between dealing with the side effects of treatment for localized disease – cancer that is confined within the prostate, cancer that can be cured with surgery or radiation – and the side effects of treatment for advanced disease, treatment that begins with shutting down the male hormones.

The complications from surgery can be treated, and as Pat Walsh says, “Where there’s a will, there’s a way.”

“But what about incontinence?”  I don’t care.  I know that it’s almost always temporary, and if not, biofeedback is wonderful, and he can start doing the Kegel exercises now.  Absolute worst-case scenario, there’s surgery to get an artificial urinary sphincter.  We’ll deal with it.   It will be okay.

“But what about ED?”  I don’t care.  We’ll deal with it.  There are many treatments, starting with drugs.  Worst-case scenario, there’s surgery:  a prosthesic implant.  I don’t think this will happen; the cancer is nowhere near the neurovascular bundles, the nerves responsible for erection (discovered by Pat Walsh, who developed the “nerve-sparing” radical prostatectomy).  I think he will be just fine.

What matters is him being there for me, our son in high school, our son who just graduated college, and our daughter and son-in-law, who are about to have their first baby.  That’s all I care about.  Mark not being there is unthinkable.  Right now, the score in our family is prostate cancer 3 (Tom, Charles, and Pop), our family (my dad, who is about to celebrate his 84th birthday) 1.

I don’t want prostate cancer to win against our family ever again. 

When Pat Walsh called with the biopsy report, it took a second to shift from “Oh, my God,” to “Let’s roll.”  We had been praying for low-grade cancer, Gleason 3 + 3, but this high-grade; it is aggressive.  So we are now dealing with high-risk cancer.  But it is small-volume, thank God!  Because it was detected early.

“Thank God,” Walsh agreed.  “We could not have found it any earlier,” and without MRI, it wouldn’t have been found at all.  “These are the lesions we consistently missed” with TRUS biopsy.  He explained that where Mark’s tumor is, in the posterior apex of the prostate, is like the nose cone of an airplane.  It’s behind the urethra; almost impossible to reach through the rectum – but Gorin reached it through the perineum.  One more thing, Walsh said:  “It was found with a new machine that Mike Gorin has had only for a week.  This was truly a targeted MRI.”  Thank God!  Now let’s roll.

Note: This MRI is shown with Mark’s permission.  He, too, has made it his mission to help men get screened for prostate cancer, and if they have a rising PSA, to get it checked out.

Update: Apparently, the strength of the magnet in the MRI matters a lot.  The stronger the magnet, the stronger the image.  The prostate MRI magnet used for Mark is 3 Tesla.

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

©Janet Farrar Worthington

 

 

 

 

This is part of On the Horizon:  a series written with the sole purpose of sharing hope:  showing you some of the new treatments that are being developed to fight cancer that has defied everything else.  Because I write for the Prostate Cancer Foundation’s website, I get to interview scientists developing highly promising treatments that aren’t widely available yet, but they’re in the works.  Salma Kaochar, of Baylor College of Medicine, is one of these scientists.

How do you stop a runaway train?  Take a few seconds and think about it; feel free to draw from any runaway-themed movies you might have seen.

Well, you could go after the track: rip it up: a train can’t go very far without a track.  Get rid of its fuel:  this was an idea in “Air Force One,” where Harrison Ford dumped jet fuel in mid-air.  Slow it down:  in “Unstoppable,” Denzel Washington and Chris Pine tried to halt a runaway by pulling it from behind with another engine. This didn’t work for very long; next, they tried to engage the brakes – first on the individual cars, and then on the main engine.  Blow it up: If you didn’t really care about innocent bystanders or collateral damage, you could just take a rocket-powered grenade or heat-seeking missile and try to destroy the runaway engine… if you happened to have such a weapon, if you knew how to use it – and if, of course, this weapon actually works like you hope it will.

Metastatic prostate cancer is like a runaway train. Every day, scientists are getting closer to stopping it, with a drug or treatment that targets one of cancer’s weak spots.  Cut off its fuel:  That’s the reason for ADT (androgen deprivation therapy), shutting down testosterone and other androgens (male hormones) that drive the cancer; and also for androgen receptor-blockers, drugs like abiraterone and enzalutamide.  Hinder its ability to grow:  that’s the purpose of chemotherapy, and of drugs that target angiogenesis – like the tracks for the train, there are pathways cancer needs before it can get rolling.  But these types of drugs often don’t work for long.

Wouldn’t it be nice to target several of these ideas at once?  Not an either-or situation, but a “this mechanism and this one, too, and also this one.” 

That has been the dream.  What could be even better?  A drug that would not mess with the male hormones; something that would enable men to keep their testosterone and prevent the side effects of ADT.

We may have found one.  It’s preliminary, and probably two years away from clinical trials, but Salma Kaochar, Ph.D., Nicholas Mitsiades, M.D., Ph.D., and colleagues at Baylor College of Medicine seem to have found a promising new strategy that rips up the track, and dumps the jet fuel, and turns on the brakes – and causes, at least in mice, no collateral damage. 

It shortstops prostate cancer at the protein level and at the same time, turns up the immune system – in a way unlike any form of immunotherapy currently available– and doesn’t affect testosterone at all.

“We are developing a first-in-field approach to target the previously undruggable family of cancer-promoting genes for the treatment of both androgen receptor-dependent and androgen receptor-independent castrate-resistant prostate cancer (CRPC),” says Kaochar.  She presented her findings at the 2018 Scientific Retreat of the Prostate Cancer Foundation.

What is this secret weapon, and how does it work?  If we continue with our movie analogies – and pardon me for doing so, but otherwise this stuff is hard to explain – then it’s like that scene in “Raiders of the Lost Ark,” where Indiana Jones, faced with a fearsome, sword-wielding assailant, pulls out a pistol and shoots him.  He doesn’t try to out-fence a master swordsman.   He changes the game.

Kaochar and colleagues have found a potential game-changer, a target that no one has ever tried in cancer before: p160 SRCs, or “steroid receptor coactivators.”  These are “master regulators of transcription factor (key proteins) activity necessary for cancer cell proliferation, survival, metabolism, cell motility, invasion and metastasis,” she explains.  “In prostate cancer, they are required for the function of the androgen receptor and its variants.”

Transcription factors are proteins that act as a key to turn on a gene – just like a key in the ignition of a car.  Except here, if you have more keys, you can make the engine go faster.   “In CRPC, there is frequent overactivation of p160 SRCs,” Kaochar continues. “This results in increased androgen receptor activity, faster growth of the prostate cancer cell (more powerful and determined cancer cells), resistance to therapy, and bad outcomes.  Increased levels of these SRCs are associated with very poor prognosis.  SRCs are also important for the energy homeostasis (energy balance) in prostate cancer.”

The most deadly prostate cancers are addicted to SRCs.  They’re like crack for cancer. 

But guess what?  “SRCs can be reprogrammed.  They can be suppressed.”  And this can happen in localized tumors as well as in metastatic cancer.  Theoretically, there is no point in cancer at which this couldn’t start to work.  “Our goal is to find something to hit cancer at that late stage, where there’s absolutely no other treatment, where it’s all over, everywhere.”

In mice, Kaochar and colleagues are using “pulses” of treatment, not one continuous treatment.  Each pulse shuts down all the machinery cancer needs to grow, and also energizes the body’s immune system to fight the cancer.

Overactivation of SRCs appears to be extremely common in prostate cancer, and in other forms of cancer, as well.  So far, in laboratory tests using various types of aggressive, hormone- and chemotherapy-resistant prostate cancer cells (because men with prostate cancer don’t all have the same genetic mutations), 100 percent of prostate cancer cell lines tested in a dish have tested positive (see below) as being driven by SRC.

“These p160 SRC molecules are important in many cancers,” Kaochar says, “including uveal melanoma,” a particularly nasty form of melanoma that attacks the eye. “Uveal melanoma is a hormone-independent cancer, and it is heavily addicted to these molecules.”  Not only is uveal melanoma deadly; it is an “orphan disease,” rare, and lacking big financial support for research.  Kaochar’s research, funded by the Prostate Cancer Foundation, may lead to the first effective treatment for this disease, too.

*      *    *

 

Could Controlling Metastatic Cancer Really Be Just a Matter of Tweaking?

If you’re a certain age – old enough to remember life before digital TVs – you probably know a lot about the fine art of tweaking.  If your picture was fuzzy, there were lots of ways to fiddle with the TV to try to fine-tune it.  There was the antenna, of course; actually, there were two, one up on the roof, and the rabbit ears on the TV set itself.  Then there were the knobs:  color, contrast, brightness, horizontal and vertical control.  It took a lot of trial and error, but tweaking was the key to a better picture.

Could controlling cancer be anywhere near that simple?  Well, in practice, it’s a heck of a lot more difficult, but the idea may be that simple:  tweaking the cancer cells, and also fine-tuning the normal cells.

Salma Kaochar and colleagues at Baylor are really developing several things at once: One is a sophisticated test to see if a man’s prostate cancer – and, quite possibly, anyone’s melanoma, breast cancer, pancreatic cancer, glioblastoma, ovarian cancer, etc. – is controlled by SRCs, which do various biological things, ranging from housekeeping chores like DNA repair, to controlling the metabolism, to controlling various proteins and driving cancer cell growth.  She is working on a simple test that works like a stoplight:  green means positive, yellow means maybe, and red means no. But the thing is, cancer might test red today, but as it continues to mutate and become more dangerous, it might test green in a few months. 

So far, 100 percent of the various prostate cancer and other cancer cell lines Kaochar has tested – in RNA sequencing and tests of more than 1,000 different genes – have come back green.  “More than 92 percent of the genome is coded by SRCs,” says Kaochar. “In prostate cancer and breast cancer, we have seen the same thing, and we believe it’s true in multiple different cancers.”

In cancer cells in a dish, “SRC 160 looks like a real vulnerability,” says Kaochar.  Jonathan Simons, M.D., medical oncologist and molecular biologist, and CEO of the Prostate Cancer Foundation, which has funded this work, describes it as “hitting the carotid artery.  If it works, it would be a stopper.”

But, “the more we learn, the more complicated the story gets,” Kaochar cautions.  “It’s exciting to have something that does so many things and has so much promise.  But at the same time, we have to carefully examine everything, and make sure there is no toxic effect.  That’s the spectrum where we’re really focused right now.”

Because this is first-in-field – a whole new class of drug – it will require a lot more testing before it can be tried in humans. Starting with cell cultures, then mice, then rats, then larger mammals.  “We just don’t know what their off-tumor effect,” on normal cells that are just minding their own business, “would be.”

Kaochar’s idea is that this drug would tweak the body: turn down SRC function in cancer – slowing down cancer cell growth, and also shutting down the cancer’s drive to metastasize – but also turn up the immune system at the same time, so the body can fight off the cancer.

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

 

I’ve said it before, because this is what some of the finest researchers in prostate cancer have told me:  The goal for aggressive prostate cancer is to find out which genes are involved and treat with gene-specific medicine — ideally, even preventing the need for androgen deprivation therapy (ADT).  We’re not there yet, but some men are blazing the trail for the future.  Chris Seelye is one of them.  He just happens to have a mutation in a particular gene, BRCA2, that just happens to respond particularly well to platinum-based chemotherapy: a drug called carboplatin, given in combination with another chemotherapy drug, docetaxel.  Chris is an exceptional responder to this treatment.

The very best part of my work, including the writing I do for the Prostate Cancer Foundation, is getting to talk to men like Chris:  men who are beating the odds dramatically.  Men who weren’t expected to make it, who are, in fact, thriving because of treatments that didn’t exist a few years ago.

Not very long ago, the future looked pretty bleak for Chris.  At just 62, this professional photographer from Washington State thought he had maybe a year to live.   “I was facing a terminal illness and was reaching the time where I had to start making decisions,” he says.  Decisions like, “Do I continue pursuing my love of photography, or is it time to start selling equipment and cutting back and sitting on the couch dreaming of the days when I could do those things?”

Then Chris, a U.S. Navy Veteran who served in the Vietnam era, joined a clinical study.  His oncologist, Bruce Montgomery, M.D., is leading it at the Veterans Affairs (VA) Puget Sound Health Care System as part of a new partnership  between the VA and the Prostate Cancer Foundation.  Montgomery, who is also on the faculty at the University of Washington School of Medicine, Fred Hutchinson Cancer Center, and the Seattle Cancer Care Alliance, thought Chris might do well in this study because of the genetic makeup of his metastatic cancer.

He did not anticipate that Chris would go into complete remission,  because he had “metastatic, castrate-resistant prostate cancer,” Montgomery says, “the kind that kills men.  As part of the VA-PCF collaboration, we did deep (genetic) sequencing of his cancer and we found that he has a mutation in his BRCA2 gene.  Because we knew he had this, we got him in this study.  His PSA has gone from over 200 to 1.  The scans he had initially, which showed metastatic disease, are now essentially normal.  He’s had a complete radiographic response.”  In other words, scans are not able to find cancer in Chris Seelye.

What Helped Chris?  A Chemo Combo

Men in this study receive carboplatin (not a standard drug in the treatment of prostate cancer) along with docetaxel.  Small data sets from Montgomery’s group and others predicted an 80-percent likelihood of response to this treatment if a patient has a tumor with BRCA2, and those responses are likely to be “exceptional” – significant and long-lasting. On the other hand, the expected response to docetaxel alone (the standard chemotherapy Chris would otherwise have received) is 25 percent or less.

Exceptional responses are what ongologists wish for desperately but, too often, do not see in men with metastatic prostate cancer. “It’s hard to actually put into words, to be honest with you,” says Montgomery.  “We all, every day, hope for a miracle.  And this is as close to a miracle as we get right now.”

PCF funding helped develop gene-targeted therapy– a whole new way to approach cancer. Recent research, also funded by PCF, found that people with many different kinds of cancer share mutations in genes like BRCA1 and BRCA2, which are often linked to breast and ovarian cancer. This means that a drug that helps a woman with breast cancer who has a defective BRCA gene will also help a man with prostate cancer who has the same bad gene.  It’s treating the gene, not just treating the specific organ that has cancer.

Not Going to Let Myself Get Depressed.”

 Chris joined the Navy when he turned 18, did a four-year hitch at the Naval Air Station in Alameda, California, was honorably discharged as a 3rd-class Petty Officer, went to school on the GI Bill to “learn about things I didn’t know,” and has spent his career doing mainly industrial, technical, and nature photography, plus professional printing and publishing.  “I learned of my prostate cancer in 2014,” he says, “after a year of working with my primary caregiver to diagnose a set of (urinary) symptoms.”  When he finally took a PSA test, it was “through the roof,” and a biopsy diagnosed high-grade cancer.

Although some men might go through “a period of denial, saying ‘why me,’ I never really had that,” Chris says.  “I knew that keeping a good attitude was paramount to successful treatment, so I refused to let myself get depressed, and even to this day, I have not gone down that road.  I just couldn’t get myself to make it worse.”  It helped him, Chris adds, early on when a doctor explained, “We’re not treating your cancer, we’re not curing your cancer.  We are managing.  That was very helpful in terms of my acceptance, not getting this false hope of, ‘maybe I’m the one, the first person to ever beat a terminal cancer.’”

And yet, here he is, the exceptional responder.  Chris is still getting used to the term.

At first, “my expectations were that realistically, this is my best last chance.  I was either going to be dead within a year or this was going to present a better alternative.  So far, the results have been pretty stellar.”  But Chris is cautious when he talks about the future. “I would phrase it that I have optimism, as opposed to hope.  I know that still, we’re not talking about cure, we’re talking about management – but I’m optimistic.  I had an expected expiration date.  Now, with participating in this study, that’s taken away.  I don’t see an expiration date any more– or if there is one, it’s years out, as opposed to months out.”

Although he’s not ready to call this combination therapy a life-saver, “it certainly is a life-extender.  I’m highly optimistic that this quite likely is going to keep me going long enough for the next round of treatments that are in the research phase now.”  One day, he believes, his doctors won’t be talking about a terminal illness anymore, but a chronic one.  “I’ll take chronic over terminal any day.”

If you have just been diagnosed with, or are battling prostate cancer, Chris has this advice for you:  “Don’t just hope, but know that new treatments are coming online practically as we speak.  Newly diagnosed patients actually have better treatment options than I had just three years ago.”  And if you have not been diagnosed with prostate cancer but are having urinary symptoms:  “Get the PSA test.  I was 59 when I was diagnosed.  Had a PSA been done when I was 55, maybe the outcome might have been different early on.”

And, if you can, participate in a clinical trial:   “It’s a life changer.  With this study, new questions are being asked and investigated. It happens that I have this specific genetic defect.  This alliance between the VA and the PCF looking at exactly that question has allowed me to participate in a study and my prognosis is very different than it was. I would strongly encourage the VA to participate in every cancer study that they can get their hands on, particularly as we’re moving away from  management to actual treatments” for metastatic cancer.  “I happen to be one of the very early patients who actually has optimism that in my course of treatment, we’re going to actually achieve the transition from terminal illness to chronic illness.”

For now, as for selling his beloved photography equipment: “That’s off the table!  I’m looking forward to the winter of (photographing) migratory birding season; that’s going to start up in less than a month. I’m ready to go and I’m ready to keep going.”

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

I’ve had a lot of requests to print a talk I recently gave. Here it is. — Janet

Recently, I took part in a large, two-day community cancer seminar in Prescott, Arizona, presented by Prescott United Methodist Church.   Many people have asked for copies of my talk, so here it is.  Readers of this blog will find some of this material familiar, but I’ve collected it all into one place.  I would call it “Prostate Cancer in a Nutshell,” but that doesn’t sound very good… I’m sharing it with you now because I want you to know that there really is hope.

I’m not a doctor.  But I have been writing about the very latest in prostate cancer research and treatment for more than 25 years. What I hope to do today is give you kind of a “state of the union” talk on the latest advances. Some of these are not yet available, but they are coming. Everything I have to talk about is very hopeful.

I started writing about prostate cancer when my father-in-law died of it at age 53.  I was the editor of the Johns Hopkins medical magazine at the time, and so I arranged to interview Patrick Walsh, Director of the Brady Urological Institute at Hopkins.  I had no idea that he was the surgeon who invented the nerve-sparing radical prostatectomy, the operation to remove the prostate but preserve continence and potency. We wrote an article about prostate cancer in 1993, it got 3,000 requests for reprints, and when my daughter, Blair, was born, I left Hopkins and Pat Walsh and I wrote our first book.  We’re now on our sixth book.  At that time, PSA, prostate-specific antigen, was new, and although there was a PSA blood test, nobody knew what to do with the results.  I made my dad start getting the PSA test, and my mom and I made him start getting his prostate checked.  He did not appreciate it, especially the rectal exam.  But he did it, and in 1997 was diagnosed with prostate cancer, even though his PSA was very low – 1.2.  Patrick Walsh took out his prostate.  He had no complications from the operation, and his PSA remains undetectable today.  That was 21 years ago, and he just happens to be visiting today.  Dad, hold up your hand. (VJ readers, my dad got a big round of applause here!)


SCREENING

I’m starting with screening, because it just makes me mad.  Screening is the best thing you can do to avoid dying of prostate cancer.  But ever since 2012, millions of American men haven’t been screened for prostate cancer because their doctor said they didn’t need it, because that’s what the U.S. government told them.  And yet: About one out of seven American men – about 160,000 this year alone – will be diagnosed with prostate cancer at some point in his life.  Not all prostate cancer needs to be treated; many men with low-risk cancer can safely do Active Surveillance.  But many men do need treatment.

American men need a baseline PSA test and rectal exam to check for prostate cancer in their forties, and then they need follow-up screening at regular intervals.  Men who are at higher risk – men with a family history of prostate cancer and other cancer, and African American men – need to start screening earlier, ideally at age 40.

In 2012, the government – the Congressionally funded Band of Geniuses known as the U.S. Preventive Services Task Force, USPSTF for short –recommended against routine screening for “men of average risk” for prostate cancer.  There was not a single urologist on this panel, by the way. The USPSTF placed fear of overtreatment over the value of detecting curable disease.

Many urologists and oncologists believe the USPSTF made some bad assumptions. One is that many men are treated overzealously; that men who have slow-growing disease are subjected to surgery or radiation and suffer side effects from treatment they didn’t need. And it is absolutely true that, back in the 1990s when scientists were just beginning to figure out PSA, many men were treated who probably didn’t need it.

But that’s not the case today.

The other bad assumption was that all men are the same.  They’re not.  Some men are a lot more likely to develop the kind of prostate cancer that really needs to be treated.  These include men with a family history of prostate cancer and men of African descent.  Also, we now know that just having a history of cancer in your family – even if it’s not prostate cancer – raises your risk of getting prostate cancer.  Also, all men of average risk are not alike:  men who smoke cigarettes, for example, are at higher risk; so are men who are obese. We’ll get to that.

This summer, my boss at the PCF, medical oncologist and molecular biologist Jonathan Simons, sent me an article in the World Journal of Urology.  The senior author was Jim Hu, urologist and urologic oncologist at Weill Cornell Medicine.

The title: “Unintended Consequences of Decreased PSA-based Prostate Cancer Screening.” The article begins: “In May 2012, the USPSTF issued a grade D recommendation against PSA-based prostate cancer screening,” which is why so many family doctors stopped screening men for prostate cancer.

So, how is that working out for us?

To find out, Hu and colleagues looked at nearly 20,000 men at nine high-volume referral centers in the U.S. from 2008 to 2016.  They broke these men into two groups– from 2008-2012, and 2012-2016.  Before and after the Band of Geniuses.  From 2012-2016, they found fewer men were diagnosed with low-grade cancer, the kind that is easiest to kill.  Unfortunately, what this really shows is that these cancers were not caughtwhen they were low-grade.  They also found across the board that high-grade cancers increased by 24 percent.

Between 2008 and 2012, 6.2 percent of men had a biochemical recurrence, a return of PSA after treatment, which is not supposed to happen.  Between 2012-2016, that number had nearly tripled to 17.5 percent. All centers experienced consistent decreases of low-grade disease and absolute increases in intermediate and high-risk cancer.

The new guidelines give a grade of C, which is not exactly encouraging but is better than a D, to prostate cancer screening in men aged 55 to 69.  This is still not good enough.    

If you want to know the value of PSA screening, ask the 45-year-old guy diagnosed with metastatic prostate cancer who’s just starting ADT, androgen deprivation therapy, the suppression of male hormones including testosterone.  Oh, wait – 45-year-old men aren’t even mentioned in these guidelines.  Some men are diagnosed with prostate cancer in their early forties, and a few are diagnosed in their late thirties.  For many men, age 55 is too late to start screeningAnd 69 is too early to quit.  

Pat Walsh and other Hopkins scientists recently reported that even using age 75 as a blanket cutoff for PSA screening is missing some significant prostate cancer. Men diagnosed at 75 or older account for 48 percent of metastatic cancers and 53 percent of prostate cancer deaths.  So basically, if you’re in good health and are 75 and over and you don’t want to die of prostate cancer, you should keep getting screened.

Also: many men don’t know their family history.  You may be at higher risk and not know it.

Do you need screening for prostate cancer?  Well, Do you want to know, or not?  If you do, ask your doctor to start checking you for prostate cancer, with a PSA blood test and a physical exam.  If you don’t, then don’t.

But remember: If you are diagnosed with prostate cancer, that doesn’t necessarily mean that you need treatment.  You may be that guy who can safely live his life with a little bit of cancer that will never spread beyond his prostate.

If you are diagnosed with cancer that needs to be treated:  Prostate cancer that’s localized, confined to the prostate, can be cured with surgery or radiation; however, both treatments have a risk of side effects, including erectile dysfunction (ED) and, with surgery, the risk of incontinence. With an experienced surgeon at a high-volume center, the risk of complications is much lower.  These side effects are often temporary, and they can be treated.  With ED, where there’s a will, there’s a way:  in other words, if you want to have your sex life back, there are treatments that will restore it.  And don’t let anyone tell you that men who get radiation instead of surgery dodge the ED bullet.  They don’t. But again, there are good treatments, and I have specifics in the book and on my website.

Incontinence is usually temporary after surgery, and gets better as your muscles get stronger.  If it persists, there are treatments for this, as well.  

Maybe you’re thinking, “The treatment is not worth it. I don’t want the side effects. I’ll take my chances and just deal with cancer if I have to.”  If it turns out that you do have it, and that the cancer has spread outside the prostate, it may not only be very difficult to cure:  In this case, side effects aren’t just a “maybe.”  You will definitelyhave side effects from ADT– androgen deprivation therapy, the shutting down of male hormones including testosterone.  These can include impotence, breast swelling, weight gain, bone density changes, a higher risk of metabolic syndrome, diabetes, heart attack, stroke, or cognitive changes.   Note: These side effects can and should be fought with diet and exercise, and many men do very well on ADT for decades. But catching the disease early and treating it while it’s confined to the prostate, is better.

 

DIAGNOSIS 

Very briefly:  The whole point of getting regular PSA tests is to watch what the number does.  It should not be going up.  If it is, you should have a prostate biopsy.

Biopsies are not infallible.  Even with 12 or 14 cores of tissue (it used to be 6), cancer can still be missed.  Why?  Prostate cancer is multifocal– that means, there’s not one obvious tumor that sticks up like a marbleand screams, “Here I am, I’m cancer!”  The average prostate that has cancer in it has seven individual spots of cancer– and if you think of the prostate as a strawberry, these spots of cancer are like the little black seeds on it.  Just little dots.  They’re easy to miss.  African American menhave an even tougher situation; their prostate cancer tends to develop in an out-of-the-way place at the apex of the prostate – the attic, instead of the basement, where the needle comes in, so it’s harder to reach.

Several new forms of MRI can help target a biopsy and detect cancer.  I recently wrote about a man named Rob who was a human pincushion; he had endured five prostate biopsies, some saturation biopsies – all inconclusive.  But his PSA kept rising.  In fact, he had developed scar tissuein his prostate that masked the presence of cancer.  But a fusion biopsy, guided by MRI and ultrasound, found cancer.  Robhad his prostate out, the cancer turned out to be intermediate grade; it was confined within the prostate, and he’s fine now.  Rob is just 49 years old.

MRI is even more effective when combined with PHI – the Prostate Health Index.  This is a “second-line” blood test that combines three molecular forms of PSA into a single score.  There are other “second-line” biomarker tests, and more on the horizon, including tests for circulating tumor cells in the blood, urine tests, and molecular and genetic tests of biopsy sample tissue. One of these, developed by Hopkins pathologist Angelo De Marzo, is called the PTEN IHC test.  IHC is immunohistochemistry, and it involves using antibodies to stain cells.  PTEN is a “tumor suppressor” gene; it puts the brakes on cancer.  But cancer doesn’t like brakes, so in about half of all lethal prostate tumors, PTEN is knocked out. The loss of PTEN is a powerful predictor of aggressive cancer.  This test is not widely available yet.

Second opinion on pathology:

Another thing you can do is get a second opinion on your biopsy slides.  You can send your biopsy tissue to an experienced tertiary-level hospital to have a urologic pathologist take a look at it.  At Hopkins, world-class pathologist Jon Epstein and colleagues do second opinions on 15,000 cases a year, sent from all over the world.  They can also do IHC and other tests.

 WHAT CAUSES PROSTATE CANCER? 

Chronic Inflammation.  One cause of chronic inflammation is charred meat.

When meat is cooked at a high temperature – when a steak, burger, hot dog, or even a piece of cooked fish gets those grill marks that most of us really like to see – it produces a bad ingredient called PhIP.   PhIP is a “pro-carcinogen,” a chemical that turns into something that can attack and mutate your DNA.  PhIP is known to cause prostate and other cancers in rats.  However, when scientists feed rats tomatoes and broccoli along with PhIP, the rats live longer and have fewer prostate and other cancers than the rats that ate the PhIP alone.  Vegetables help counteract PhIP.  In the entire world, those least likely to get prostate cancer are men in rural Asia, who eat the traditional anti-inflammatory diet – low in meat, high in fruits and vegetables, with hardly any processed carbs.  No soda, lots of green tea.  No fries, lots of rice.  No burgers, lots of vegetables.  However,when those same men with their low risk come to America, over time, their risk goes up to the level of an American man’s. You are what you eat.

Good news: Men of any age can benefit from eating anti-inflammatory foods.

The opposite is also true: Obesity and one of its consequences, diabetes, make these flames of inflammation burn even higher.   This may be one reason why ruralAsian men are less likely to get prostate cancer: they have a lower body mass index, BMI, which means less stress on their cells.  If you are overweight or borderline diabetic, you turn on more insulin to try to control your blood sugar.  Insulin secretes molecules called cytokines, which can encourage inflammation.  This can put added stress on the body and perhaps tip the balance toward cancer.

The prostate is particularly vulnerable to inflammation because it’s just chock full of inflammatory cells called prostaglandins. So the prostate is already a tinderbox.

Bad genes:  We’ll cover this more in a minute, but the good news even with bad genes is that they are not automatically your destiny: we know this from studies of identical twins.  There are many cases where one twin gets cancer, and one does not.  Their genes are the same, so it must be something in their diet or lifestyle, too.

High blood sugar: Men who have diabetes are not more likely to getprostate cancer, but they are three times more likely to die of it if they do get it. Nondiabetic men who have high blood sugar have almost a five-times greater risk of dying from prostate cancer.  If you are pre-diabetic or diabetic, you can lower your risk of lethal prostate cancer by getting your blood sugar under control, improving your diet, and exercising.

Smoking:  Men who smoke, even if they don’t have a diagnosis of prostate cancer, are more likely to die of prostate cancer in the future.  Men who have been treated for prostate cancer who keep smokingare more than twice as likely to die of it, too, because cancer is more likely to recur.  The good news: Recent smoking matters more than if you smoked 30 years ago.  Your risk of dying of prostate cancer starts going down the day you stop smoking!  In 10 years, it’s the same as if you had never smoked!  Quitting now can make a big difference.  If you smoke, you should quit, and if you have prostate cancer, you should definitelyquit. There is no point in the spectrum of prostate cancer where quitting smoking is not helpful.

No drug protects against prostate cancer as much as having a healthy weight and being physically active. 

Lose that gut. Like smoking, obesity is linked to more aggressive disease and death from prostate cancer.  For men who have prostate cancer, being obese and continuing to gain weight is associated with higher disease recurrence and death. Among 2,500 men with localized prostate cancer in the Physicians’ Health Study, a one-unit increase in body mass before cancer diagnosis was associated with a 10-percent increase in a man’s risk of dying of prostate cancer.  A five unit increase raised the risk of dying of prostate cancer by 20 percent.

If you’re a young man, losing weight might stop prostate cancer from developing.  If a tumor is already there, but very small and not detectable, losing weight may delay the growth of cancer.  If you have a diagnosis of cancer, losing weight can slow cancer or help prevent it from spreading.  “It’s never too late to lose weight.”

Drink coffee.  Coffee is good!  Regular or decaf!  Let’s look at this study from Italy, published in the International Journal of Cancer:  In the Moli-sani Project, investigators looked at coffee consumption in nearly 7,000 men, age 50 and up in rural Italy.  They followed them, on average, at least four years, and during this time 100 of these men were diagnosed with prostate cancer.  It turns out that the more coffee the men drank every day, the less likely they were to develop prostate cancer.  Men who drank more than three cups a day had the lowest risk of getting prostate cancer.

Note:  these men took their coffee black, or maybe with a bit of milk.  In other words, they didn’t have five shots of whipped cream, etc. Also, their coffee was unfiltered– not brewed or instant.

A Harvard study published in the Journal of the National Cancer Institutefound that coffee was associated with a lower risk of gettingprostate cancer, andof developing aggressive, potentially lethalcancer.  Men who drank one to three cups a day, regular or decaf, had a 29-percent lower risk, and the risk went down as the coffee drinking went up.  Men who drank at least six cups a day had a 60-percent lower risk.  Amazingly, the heavy coffee drinkers also tended to be smokers – so coffee seems to have helped counteract cigarettes.

In other studies, coffee has been linked to a lower risk of developing Type 2 diabetes; liver cancer, endometrial cancer, postmenopausal cancer and colorectal cancer.

Coffee has powerful antioxidant effects.  Coffee is the number one source of antioxidants in the diet of the American man. This is sad.

Coffee is also anti-inflammatory.  Many studies have shown that heavy coffee drinkers have lower levels of circulating inflammatory markers in their blood.

Coffee has helpful effects on insulin and glucose metabolism.

Coffee cuts lipids, the body’s fatty acids.  It reduces fasting cholesterol and triglycerides.

Coffee helps the gut’s microbiome.  It increases diversity in the microbiome, the eight pounds of bacteria living happily in your gut.  Bad gut flora may promote inflammation, and vice versa.

Exercise:  Your prostate doesn’t care about six-pack abs and “gun show” biceps.  But your cardiovascular health matters a lot.  Cardiovascular exercise can lower your risk of getting lethal prostate cancer, or of having cancer come back if it’s already been treated.   UCSF scientistJune Chan and colleagues found that vigorous exercise (jogging or bicycling) after diagnosis was associated with a lower risk of prostate cancer death in men with localized cancer. “Three or more hours a week of vigorous activity was associated with a 60 percent reduction in the risk of dying of prostate cancer.” Now they are looking to see if moderate exercise, the kind anybody can do, can lower the risk of dying of prostate cancer.  “Biochemically, exercise could help deter metastasis, spread of cancer, by changing the environment for the cancer.”  This is like spraying fire retardant on the tumor. Not necessarily extinguishing the flame altogether, but making it burn slower, and helping the body set up fire breaks to keep the cancer from spreading.

Here’s an odd thought:  Exercise seems to make prostate cancer fat and happy.  “Prostate cancer may be the most common cancer where exercise, used like a drug, can confer an increase in survival,” says Jonathan Simons. “There is no form of treatment that has this effect.”  It may be that just as it improves blood flow in the arteries, exercise gives cancer a better blood supply that keeps it happy where it is, “so the tumor has no motivation to leave.” So basically, exercise makes cancer feel like it’s at a nice hotel, with free cable TV and a pool.  It’s content to stay there indefinitely. “When tumors are stressed” – when they’re in a bad neighborhood, in effect – “they have genes that are programmed to help them survive by getting them to crawl away to someplace that better serves their needs.”  One of those genes, Simons discovered, not only pipes in more blood to supply the tumor; it gets rid of waste products – the cancer cells’ sewage.  “When tumors build a supply line of blood vessels, to bring in more nutrients, they also build their own plumbing system.  Once they have this infrastructure, they launch a genetic program that lets them grow and spread.  But giving the cancer a better blood flow might sabotage the cancer’s need to boost its own blood supply. It just may be that exercise makes cancer, rather than head for the door, sit back in the recliner and reach for the remote. A contrary notion, isn’t it – that in order to turn your prostate cancer into a couch potato, your best chance is not to be one yourself?

This doesn’t mean that men who exercise are immune to prostate cancer. “There are very fit athletes who have had forms of prostate cancer that are so aggressive, so genetically mutated, that they have proved fatal. However, those men are at one end of the spectrum of prostate cancer. There are many thousands of men at the other end or in the middle, for whom exercise may make a real difference.

Here are some other things that can lower your risk, which I cut out of this talk to save time.

Oligometastasis:  Is the Window of Curability Wider Than We Thought?  Now: What if you have cancer that is confined to the prostate, with just a little tiny bit somewhere else? Are you doomed? It used to be that doctors thought, “Oh, man, he’s a goner, the cancer’s spread.” But scientists are learning that just because a spot of cancer has popped out of the prostate, this doesn’t necessarily mean that it can’t still be cured.

Here’s the old-school thinking:  You’re lying on a chair at the dentist’s office, and the dentist says, “You’ve got a cavity, decay is inevitable. We’ll just wait and pull all your teeth in a few years.” Like the poor guy in “Monty Python” who is mistakenly left for dead:” “I don’t want to go on the cart!”

Until very recently, the dividing line between prostate cancer that was considered curable and cancer that might not be was the prostate itself. That’s not the case anymore, says Johns Hopkins radiation oncologist Phu Tran, also a contributor to our book.

New evidence suggests that in men with oligometastasis – just a few spots of cancer outside the prostate – by treating “not only the primary disease in the prostate or the pelvis, but alsothe few metastatic spots, perhaps men can actually live a long time without disease progression and even be cured.” It’s the difference between being reactive – waiting for the next shoe to drop, the rise in PSA or development of symptoms – and being proactive. In other words: not just suspecting cancer is there, but knowing its precise location and going after it.

Now, how do they know where these little bits of cancer are?  There is a new form of technology called PSMA PET scanning,which can showbits of cancer as small as a BB.  There is also highly focused radiation, called:  SBRT (stereotactic body radiation therapy) or SABR (stereotactic ablative radiation).  Tran says it’s like spot welding—focused on a small area, very intense, and theoretically ablative, meaning it kills all the cancer in that spot.” Tran is testing this in clinical trials at Hopkins.

PSMA-PET:  

Hopkins scientist Marty Pomper, who was one of my husband’s interns when he was Chief Resident at Hopkins, figured out how to engineer a small molecule that binds to PSMA, prostate-specific membrane antigen, which sits on the surface of prostate cells. He then used innovative biochemistry to glue F18, the radioactive fluorine that glows in a PET scan, to that small molecule.  What he achieved is a way to see cancer that no one could see before.

This is very exciting for two reasons: PSMA-targeting molecules can find prostate cancer.  But if you switch out the radioactive tracer for a radionuclide – a little grenade of radiation that is targeted precisely to PSMA – then this technology can also be used to kill prostate cancer.  This is in clinical trials in the U.S., but it has been used for several years in Europe and Australia. Germany got the leap on everyone, because they don’t have to go through all the rigorous testing that we do.  Some doctors in the U.S. are sending patients with widely metastatic disease out of the country for these treatments, and some of these men have gone into long-term remission.  There are still some bugs to be worked out.  There are different radionuclides, and we need to know which is better. Also, it turns out that PSMA didn’t know that its name was prostate-specific… it is also in the salivary glands, and so there has been a problem with men getting their cancer into remission but having no salivary glands, so this is not ready for prime time yet.  But it is extremely hopeful.

IF YOU HAVE ADVANCED PROSTATE CANCER

If you need to start ADT, androgen-deprivation therapy, thanks to several recent studies, you also need to start taking an androgen receptor blocker.  There are three:  abiraterone (which you also take with prednisone), enzalutamide, and apalutamide.

The LATITUDE study, released last summer at the ASCO meeting, showed that giving abiraterone (Zytiga) and prednisone along with Lupron to men who are just starting ADT increased survival by an average of 18 monthslonger than ADT alone. But the study found that 25 percent of men showed an increased survival of four years, and a small percentage of those men appear to be “exceptional responders” who have had no progression of cancer for at least six years

In real estate, it’s location, location, location. With cancer drugs, scientists are learning, the key to success may be timing, timing, timing.  Starting abiraterone earlier, while the cancer is more vulnerable – before it has had a chance to mutate, to develop resistance and strengthen its armor – makes a huge difference.

Who should be interested in these findings?  Between 50,000-60,000 American men just this year alone.  Men who are on ADT, whose PSA is rising rapidly and doubling every 10 months or less.  And men who are just starting ADT.

Apalutamide (Erleada) is the newest FDA-approved drug for advanced prostate cancer.  Enzalutamide (Xtandi) is the third.  These are game-changers, and the game they are changing is a terrible one, the agony of wait-and-see, played out with each PSA test by men whose cancer looks like it’s going to metastasize.  This game sucks.  Until now, men who did not yet have metastatic cancer did not have access to the next level of treatment.

The idea is that now, not only do you nothave to wait for metastasis, you may very well change the course of the cancer, delaying the time to metastasis by more than two years longer than ADT alone.  Again, for some men, doctors aren’t even sure how longmetastasis can be delayed, because their cancer stillhasn’t progressed.  The SPARTAN study, of apalutamide, was published February 2018 in the NEJM.  Its senior author, Eric Small of UCSF, told me that the idea behind this study was actually to see if we could somehow put advancing cancer in a holding pattern.  Maybe metastasis is not a done deal.  In fact, he says, “this was really the first metastasis prevention study.”

For the men in the apalutamide group, the average metastasis-free survival was 40.5months – and some of these men stillhaven’t developed metastasis.

“We are talking about a 72-percent reduction in the risk of metastasis,” Small says.    What nobody knows yet is whether earlier treatment will lengthen overall survival. “We believe it will,” says Small, “but it’s way too early.”  For now, though, “We’re having a dramatic impact on delaying metastasis.”   At nearly four years, “50 percent of men in the apalutamide group still have not developed PSA progression.  They are doing well, they don’t have metastatic cancer, and haven’t been ravaged by extensive disease.  That’s remarkable.”

In July 2018, the FDA approved enzalutamide (Xtandi) for men with non-metastatic CRPC.  Same thing: this used to be second-line hormonal therapy, recommended only in men who developed metastatic cancer afterbeing on ADT.  This decision is based on the PROSPER clinical trial, led by oncologist Maha Hussein, M.D., of Northwestern.  In this study, 1,400 men with non-metastatic CRPC whose PSA levels were doubling every 10 months or sooner were randomly given either ADT with a placebo, or ADT plus enzalutamide.

Men who received enzalutamide had a delay in time to metastasis or death by an average of 21.9 months longerthan men in the placebo group, and some men haven’t had metastasis at all.

And now we get to Bad Genes and Immunotherapy

In 2016, a breakthrough study came out.  It was led by Fred Hutchinson Cancer Research Center medical oncologist Pete Nelson, and published in the New England Journal of Medicine. The study found that:

Prostate cancer is a lot more of an inherited disease than anybody thought;

There are 16 bad genes that we now know to look for; and

If you have a mutation in one of these genes, your sons and daughters and their children should get tested, so they can be considered high-risk for certain types of cancer, screened vigilantly, treated aggressively, and live to a ripe old age and not die of cancer.

These particular genes, called DNA-repair genes, are tiny quality control specialists; they’re the spell checkers.

Nelson’s study looked at 20 DNA-repair genes, in 692 men with metastatic prostate cancer in the U.S. and United Kingdom.  They found mutations in 16 of them, including some unexpected ones, like BRCA1 and BRCA2.

“Now wait,” you may be thinking, “aren’t they the breast cancer genes?”  Yes, and for years, nobody linked these genes to prostate cancer.  Now we know that the very same mutation that can cause breast and ovarian cancer in women can cause lethal prostate cancer in men.

Other bad DNA-repair genes include one that sounds like it should be at a bank, called ATM; and one that sounds like a roadie making sure the microphones work at a concert, called CHEK2; there’s also one that sounds friendly but isn’t at all, PALB2, which is strongly involved in pancreatic cancer.

Nelson and colleagues estimate that one in nine – 12 percent – of men with metastatic cancer have one of these bad genes.

In another study led by William Isaacs of Johns Hopkins, investigators did a genetic analysis of 96 men who died of prostate cancer at an early age – younger than 65.  Billy Isaacs says: “Surprisingly, we found that more than 20 percent of these patients carry inherited mutations in genes responsible for repairing damaged DNA.

  Why Genes Matter:  There are entirely new kinds of cancer-fighting drugs that target specific genes.  One class of drugs is known as PARP inhibitors like Olaparib, which is being used to treat women with BRCA mutations in ovarian cancer. It has now been approved as a treatment for advanced prostate cancer in some men.  Men with BRCA mutations also respond well to carboplatin, nota standard drug in prostate cancer.

What should you do?  If you have high-risk or metastatic prostate cancer, or if you have a strong family history of prostate or other cancers, ask your doctor about genetic testing. One of them is made by Color Genomics, and it costs $250.  You just spit into a test tube.

Checkpoint Inhibitors

In July 2016, a small but very exciting study led by investigators at the Oregon Health & Science University and Johns Hopkins, was published in the journal, Oncotarget.  It involves checkpoint inhibitors.

Basically, your immune system can do great and powerful things: like cause an autoimmune disease to devastate your body.  Ideally, it should only attack bad things, like cancer. But cancer has a lot of devious tricks.

T cells are some of the body’s most powerful warriors. They kill enemy cells.  But prostate cancer basically makes a nice cup of chamomile tea for these T cells, and puts them to sleep.  If you look at a sample of prostate cancer tissue, you can see the T cells right there next to cancer cells, and the T cells are asleep.  They have checkpoints on them; these are like a straitjacket.  Here, the cancer is hijacking a normal process that happens in every pregnant woman, so she doesn’t make an immune reaction to her unborn child.

Checkpoint inhibitors are a class of drugs, invented by Jim Allison with funding from the Prostate Cancer Foundation; in fact, he just shared the Nobel Prize for this work this month!  Checkpoint inhibitors take off the straitjacket and unleash the T cells.

But not every checkpoint inhibitor works for every cancer.  Also, compared to other kinds of cancer, prostate cancer looks pretty normal.  It doesn’t have many mutations.  Some forms of cancer have so many mutations – think of any villain in Batman – that the immune system says, ‘Hey, that guy looks weird. Let’s kill him.”  But prostate cancer can blend in, so this is one problem: getting the immune system to recognize prostate cancer as the enemy.

There’s a lot of work that needs to happen. However: some people have had spectacular success with checkpoint inhibitors. Tumors that should have killed people with metastases in their lungs, liver, and brain, have melted awayinstead.

In this study, led by Julie Graff of Oregon, they used a checkpoint inhibitor called a PD-1 inhibitor.  The results were so dramatic, and so unexpected, that they published the results early.  Julie Graff was working with immunologist Chuck Drake, of Columbia University.  Previously, she had seen two men with advanced prostate cancer who responded exceptionally well to a PD-1 inhibitor:  their PSA went away, and their cancer appeared to be undetectable.   Chuck Drake suggested that maybe enzalutamide, which targets the androgen receptor, might stimulate the immune system to make the PD-1 inhibitor work better.

So they did this study, of men who were taking enzalutamide but whose cancer was still progressing.  The men continued to take enzalutamide as they receive four doses of a PD-1 inhibitor called pembrolizumab. The first 10 patients were enrolled from March 2015 to January 2016.  Their ages ranged from 61 to 80, and their PSA ranged from a little over 4 to nearly 2,503.

In three men, the disease did not change; it did not get noticeably better, but it didn’t get noticeably worse, either.  Four men did not have any evidence of a benefit, and one of these men died of his cancer.  So that’s seven men; what about the other three?  Their response blew the investigators away:  Their PSA – including the man with the PSA of nearly 2,503 – dropped to the undetectable rangeof less than 0.1.  Two of these men had been on narcotics for pain, and stopped taking them.  One man’s liver metastases went away.  “These three men had a complete response,” says Graff.  “Their tumors shrank radiographically” – meaning that they couldn’t be seen in imaging – “in the lab” – their PSA falling to nearly nothing – “and clinically,” with the need for pain medication going away.  “None has had a recurrence.”

Another very promising form of immunotherapy, on the horizon, is Tumor-targeting CAR T cell immunotherapy.  This is custom-tailored for each patient:  they take a patient’s T cells, and engineer a gene that enables the T cell to pick a cancer cell out and kill it.

Now here’s a question you are probably wondering:  How is cancer affected by my gut bacteria? It may be that being able to increase “good” bacteria will help the immune system do a better job of fighting off disease – may soon help people with some types of cancer respond better to immunotherapy.  Recently, scientists studying colon cancer found that certain bacteria are found in half of all colon tumors and when the cancer spreads, the bacteria spread right along with them. In another study, scientists found that two different forms of bacteria work together, like fertilizer, to help colon cancers grow.  Scientists studying melanoma found that the presence of certain gut bacteria can change how cancer patients respond to immunotherapy.  Karen Sfanos of Johns Hopkins is working on this in prostate cancer.   It may be that special probioticsor even a fecal transplantmay help immunotherapy work better.

Gene-Targeted Therapy

Already, at major academic medical centers, getting treatment for advanced prostate cancer involves a talk with a genetic counselor.  Heather Cheng, a medical oncologist at the University of Washington and Fred Hutchinson, was the first one.  She started the world’s first prostate cancer genetics clinic.  Here is a story about one of her patients, an amazing guy I interviewed named Mark Meerschaert.

In a matter of weeks, Mark went from being an athlete to someone who could barely walk; metastatic prostate cancer had come from nowhere and spread like wildfire throughout his body. Mark is a university math professor – the kind who fills up the blackboard in his classroom with calculations to answer questions of probability, and statistics.  So when he got sick, he did what he does best: looked at the numbers. Men with widespread prostate cancer that is not responding very well to standard treatment don’t live very long.

So then Mark did what I hope everyone with a challenging diagnosis will do: He became his own advocate. He did some research and found Heather Cheng.

It turns out that Mark has a mutated BRCA2 genethat runs in his family.  Cheng immediately focused on this gene and suggested a very different type of treatment – off-label use of olaparib, approved by the FDA to treat ovarian cancer. Olaparib is a PARP inhibitor; it blocks a protein that cancer cells need to repair themselves, and works especially well in people with defects in the BRCA2 gene. Olaparib and other PARP inhibitors are being studied in clinical trials for prostate cancer.

Cheng also got genetic sequencing of tissue from Mark’s metastatic cancer.

Cancer can change over time. If you have metastatic cancer, there may be different mutated genes than in the cancer that was originally diagnosed from the needle biopsy. This matters because there may be a new medicine that works well with your particular mutated gene or genes. She told him it could get worse before it got better.

It did.  Mark said: “I started olaparib in October 2016. Two months later, “we did a bone scan, and saw that there was cancer all over the place: my ribs, hips, legs, some lymph nodes.”  He became very weak.  He used a cane, then a walker, then a wheelchair. He took a leave of absence from his job. Now he is looking forward to going back.

Starting early in 2017, he says, “I just slowly started to feel better and better.  At some point, I said, ‘Maybe I can go for a walk again. I had a little numbness in my foot, but I said, ‘I’m going to keep walking,’ so I did. I walk my dog every day, a couple of miles. Now even the numbness is gone.”  In a matter of six months, he said, “I’ve gone from shockingly, disastrously ill to feeling – I’m still cautious, still waiting for the other shoe to drop; nobody knows how long this is going to work.  There’s no data on people like me. Now I feel great.”

Mark had known he was BRCA2 positive; after his brother was diagnosed with breast cancer several years earlier, he got genetic testing. But he never expected to get prostate cancer.  In fact, although he’d gotten a PSA test every year, he had stopped. “My doctor said, ‘We don’t need to do PSAs.’ For two years I didn’t get a PSA.”  Which brings us full circle to the Band of Geniuses.

In 2013, Mark developed some urinary symptoms and went to see a urologist. Cancer was found.  He also learned that his father had been treated for prostate cancer when Mark was away in college, and his parents never said a word. “Had I known, I would have kept PSA screening.”

Mark underwent external-beam radiation therapy and a two-year course of ADT, which ended in March 2016. “By July of 2016, something just felt a little off. I went to see a urologist.  A biopsy showed high-grade cancer.

When Mark went to Seattle, Heather Cheng got that biopsy tissue and sequenced it. Cheng told him, ‘Your cancer is very aggressive, but that might work in your favor.’ That turned out to be absolutely correct. It got bad really fast, and it got better really fast.” He says: “The question is, what happens next?  I’m very interested in the five-year survival rate for people like me. They’ve only been using this since 2015, and the studies were on ovarian cancer.  My God, what if this had happened five years ago?”

So, right now, immunotherapy drugs only help men with certain mutated genes: mainly BRCA 1 and 2, and ATM.  But this is just the beginning.

Imagine a waiting room full of 100 men with advanced prostate cancer.  Some of those men have mutated BRCA genes; those genes can also cause breast and ovarian cancer, so let’s color them pink.

Some have a mutated PALB2 gene, also the bad gene in pancreatic cancer.  Let’s color them green.

For about eight of those men, the bad gene is WNT. That’s also the gene involved in 100 percent of aggressive colon cancers.  Let’s color those men blue.

About half have a bad ERG gene.  This is found in children’s leukemia and in sarcoma. Let’s color those men purple.

About one-fourth have a mutated PTEN gene.  That can also cause some brain cancers, endometrial cancer, breast cancer, and ovarian cancer. Let’s color those men orange.

One guy has a mutated IDH1 gene; this only affects 1 percent of men with prostate cancer, but it affects 100 percent of people with a glioblastoma, like Senator John McCain.  Let’s color that man red.

Eventually, our imaginary waiting room looks like an Easter Egg hunt.

Each color represents a subgroupof advanced prostate cancer.  The drug that works best on the men with the bad BRCA genes probably won’t work best on the men with the faulty ERG genes.  The drugs work differently because the men’s cancers are different – but they’re different in groups. A man in the yellow group may not be helped by a drug that works well for the guy in the purple group.  But he probably will be helped by a drug that helps other men in the yellow group.

You know who else will be helped?  People with other cancers who have that same mutated gene. So very good things are happening, and there has never been so much hope for prostate cancer, and cancer in general, as there is now.

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

Believe it or not, there once was a time when the Grand Canyon was just a ditch.  Before that, it was a rough patch in the desert with a river running through it.  It took a very long time for that canyon to form, and the conditions had to be just right to allow water, blazing sun and wind to chip away through layers of fragile rock.

On a very much smaller scale, this is what happens to cause cancer when the conditions are just right.

Now, if you will:  While we’re thinking about the Grand Canyon, let’s pan the camera a few miles away. We’re near some tall pine trees, and there’s a campfire.  Some cowboys are sitting around it.  Let’s imagine that they all have white hats; they’re good guys.  (They’re also much quieter than the cowboys around the campfire in “Blazing Saddles,” so don’t go there!)

If you’ve ever sat around a fire, you know that wood sometimes pops unexpectedly and sends out sparks.  That’s exactly what happens at our little campfire, and it happens to hit one of the cowboys square on the arm.  He brushes out the sparks, then goes back to his seat.  Nothing’s really changed; he laughs it off.

Wouldn’t you know it, the fire sparks up again – right on that same poor guy.  This time, he’s a little more scorched; his shirt has a hole in it and his eyebrows got singed.  He’s also a little irritated.

It happens a few more times, and he is no longer the proverbial happy camper.  He’s moving around, no longer sitting quietly, he’s got some burns that will leave scars, and he’s angry.  His hat is so charred now that it’s almost black.  One last spark, and he’s out of there.  He leaves the campfire, saddles up his horse, and rides away, fighting mad and looking for trouble.

This little scene plays out a lot, every day, in our bodies.  There are countless campfires – like stars dotting the sky – that flare up, burn quietly, get snuffed out, and never cause harm.  The campfires are little flares of inflammation.  

Commenting on this analogy is medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation.  “The future of fighting prostate cancer,” he says, “is either to stop the sparks from flying, or to put fire retardant on the flames – or better yet, to bring in the fire retardant really early in life.  It’s all about the sparks, and what makes the sparks, and then spark interception or spark interdiction.”

Expect to Hear a Lot More About Inflammation

Inflammation is our own version of Dr. Jekyll and Mr. Hyde: When it works the way it’s supposed to – when you skin your knee or get a paper cut on your finger, for instance – inflammation is what protects your body from bacteria and germs that find their way through the open wound.  The immune system kicks in; zealous home soldiers like killer T cells spray chemicals on the intruders, puncture their armor, or even eat them whole.  You notice some redness, a little heat, maybe some swelling or even a bruise, and you know that your body is healing.  There’s a scab, new skin covering the hole or tear, and all is well. The inflammation goes away.

But what if it doesn’t go away?   Here’s where the dark side of Dr. Jekyll, his alter ego Mr. Hyde, starts to show itself.  Chronic inflammation is bad.  

“The story of inflammation is absolutely the heart of what causes prostate cancer,” says Simons.  “Inflammation lowers your defenses,” and changes the DNA.  Going back to the angry cowboy at our campfire scene: If only he had moved away from the fire, or if someone had poured a little water on the fire to cool it down and keep the flames low.  He might have had a few scars, but he would have been okay.  Instead, he began moving around, and eventually he left the campsite; if he were a prostate cell, he would have become cancerous – but still there at the site, still easily treatable.   But as he became more scorched, he became metastatic.  The continued exposure to those flames turned him from a cell sitting quietly into a metastatic cancer cell.

“We estimate that 30 percent of all cancers are caused by this kind of chemistry,” Simons adds.  The little fires hurt genes that are nature’s own tiny fire retardants, so without their subduing effect the flames burn hotter; the fires then go after the body’s normal first responders.  So the firefighters don’t stop the burning; the paramedics don’t heal the injured victims.  The inflammation draws other cells called macrophages and granulocytes to the scene; they’re supposed to be part of the body’s cleanup crew.  “Unfortunately, in cleaning up, they actually make the flames burn hotter and further damage the area.”

What causes the fires? 

One huge cause is our diet.  Fat, charred meat, processed carbohydrates, chemicals in junk food, and sugar.  Basically, what we know as the Western diet – high in meat and bad carbs, low in fruits and vegetables.   How do we know this?  Because the men in the entire world least likely to get prostate cancer are men in rural Asia, who eat the traditional Eastern diet – low in meat, high in fruits and vegetables, with hardly any processed carbs.  No soda, lots of green tea.  No fries, lots of rice.  No burgers, lots of broccoli.  But when those men come to America, their risk of getting prostate cancer goes up.  Diet matters. 

“The rural Asian diet is anti-inflammatory,” says Simons.  “It may be that these men would eventually develop prostate cancer if they lived to be 120.  But they don’t.”  If you think about our campfire analogy, maybe cells still get singed, but they’re few and far between.  That critical momentum never develops.

“We are now learning that it’s essential for men to have a healthy diet when they’re young – say, between 14 and 30.”  But men of any age can benefit from turning down the inflammation with “fire-fighting” foods.

The opposite is also true:  Obesity and one of its consequences, diabetes, make these flames burn even higher.   (In fact, this may be one reason why rural Asian men are less likely to get prostate cancer: because of their diet, they have a lower body mass index, which means less stress on their cells.) “If you are overweight or borderline diabetic, you turn on more insulin to try to control your blood sugar,” says Simons.  Insulin secretes molecules called cytokines, which – thinking of our cowboys at the campfire – are like the chuck wagon, bringing in oxygen, new blood vessels and nutrients to feed the cancer.

“Some men have more sparks flying around, and men who are overweight are in this group.  The good news is that you can reduce your insulin level with exercise,” says Simons.  “There’s a lot of evidence that just being sedentary is a terrible setup for trouble later, if you have a slightly inflamed prostate and higher insulin level.”

The prostate is particularly vulnerable to inflammation, Simons adds, because it’s just chock full of inflammatory cells called prostaglandins, most likely nature’s way of protecting the fluid that makes up semen.  So the prostate is already a tinder box.

What else makes it worse?  A big one is genetics.  Some men are born with  their own fire-starter – genes they inherited from their father or mother.  If you are of African descent, or if you have a family history of prostate cancer or cancer in general, you are at higher risk of developing prostate cancer.  That doesn’t mean that you’re bound to get it, and it may be that with cancer-fighting diet, exercise, not smoking, and plain old good luck that you will never have prostate cancer.

Other causes of sparks:  Infection.   Cigarette smoking.  Emotional stress.  Not being circumcised: several stories have shown that circumcision has a protective effect, lowering your odds of developing prostate cancer, and of dying from it.  This ties in with what we’re still just learning about the role infection plays in changing the prostate’s microenvironment, and making it more susceptible to cancer.

            Okay, then what puts out the fires?

We’re still figuring this out.  A good diet, exercise, and other flame retardants such as Vitamin D.  Dietary supplements such as turmeric seem to help, as do broccoli and tomatoes cooked in olive oil (which brings out the lycopenes).  Meditation: new research suggests that this may help calm the tiny sparks and lower the chances of cancer catching fire.

And finally, there’s a huge question mark. What else helps?  “This area of research is woefully underfunded,” says Simons. There may be a bacterial equivalent of H.pylori– the nasty bacteria found to cause stomach ulcers.   New research suggests that probiotics – “good” bacteria that change the microflora in the gut – may prove helpful in preventing cancer.  Does this mean that there are bad bacteria that do their share of causing it?  Could this be related to the link between infection and inflammation?

We don’t know.  Stay tuned.

 

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

 

 

 

Checkpoint Inhibitors

Miracle Drugs for Some, But Not Yet All

Checkpoint inhibitors have one mission: to unleash the immune system.  They wake up the sleeping T cells, and in some people with cancer, they have done this spectacularly well. But right now, they don’t help more than a fraction of patients. In other words, for every extraordinary responder – a man whose metastases in the liver and brain simply melt away, whose PSA drops from the thousands to undetectable – there are six or seven men who don’t get any better.

Doctors and scientists desperately want to change this.

A brilliant scientist and investigator named Jim Allison, with initial funding from the Prostate Cancer Foundation, was the first to discover molecules on T cells called checkpoints. He figured out that these molecules were putting T cells into an induced coma, stopping them from carrying out their mission as assassins of cancer cells, and he worked to develop the first checkpoint-inhibiting drug, ipilimumab, which has had great success in treating some cancers, particularly melanoma.  In fact, he just shared the  2018 Nobel Prize in Physiology or Medicine for this work.

Why don’t checkpoint inhibitors work better in prostate cancer? Chuck Drake, M.D., Ph.D., director of genitourinary oncology and the associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at New York Presbyterian/Columbia University Medical Center, explains: “When a T cell moves into tissue, it installs a brake.” It doesn’t necessarily apply the brake; it just has one ready to go.

I wish these brakes had convenient names, like “Bob,” or “Annette.”  But they don’t; they have pesky initials and numbers, so just hang in there and power through.  This is important:  One of those brakes is a molecule called PD-1, which sits right on the surface of the T cell. “Many tumors have T cells inside them, but they’re not working, because they have PD-1 on their surface.” The T cell with the PD-1 is just sitting there. But cancer cells make sure that cell isn’t going to move by adding a molecule called PD-L1. “That’s the foot on the brake. PD-L1 binds to the PD-1 on the T cell.” Imagine a car with several unpaid parking tickets under the windshield wiper; now imagine a traffic cop coming along and putting a parking boot on the car’s front tire. That car isn’t going anywhere.

So we’ve got our superhero in a stupor, like Superman staggering around or unconscious because Lex Luthor put a big chunk of Kryptonite in the room. But wait! Checkpoint inhibitors are coming to the rescue! “If you block either PD-1 or PD-L1 with a drug, a monoclonal antibody, you can wake up the T cell, take off the boot,” T cells can come roaring in and “do what they were designed to do, which is kill specific cells, including tumor cells.” And this is happening with checkpoint inhibitors in kidney cancer, bladder cancer, melanoma, and lung cancer.

Why not so much in prostate cancer? It may have something to do with the number of mutations on the prostate cancer cell. “Some melanomas have over 500 mutations; squamous cell lung cancer can have 200 to 500 mutations; garden variety lung cancer has 150 mutations, kidney cancer has about 70,” says Drake. “But prostate cancer only has about 30 mutations.”

Basically, the more mutations a cancer cell has, the more freakish it looks to the immune system, and the easier it is to recognize as an enemy. Think about any villain in Batman – the Joker, with his green hair and white pancake makeup, for instance. The villainous disguises are really helpful to crime fighters, because they say, “This guy’s dangerous.” But prostate cancers, even the very worst ones, are more like James Bond villains; they don’t look that much different from anybody else.

Timing may be a key factor, too.   Drake recalls a study he took part in when he was at Johns Hopkins, of a PD-1 blocker called nivolumab, which has worked well in other cancers. The patients were men with late-stage prostate cancer who had been through ADT and chemotherapy. “We had zero responses in 17 patients.” He recalled some anecdotal evidence from another trial, where a man who was on enzalutamide got Provenge , “his PSA went down to nearly undetectable, and his response lasted a very long time.”

In talking with Julie Graff, the lead investigator on a recent trial where Drake was a co-investigator, “we said, why don’t we try this same thing with pembrolizumab,” another PD-1 blocker. “We wanted to have patients who initially responded to enzalutamide but were progressing, and we didn’t stop the enzalutamide, but added on the pembro. Maybe there’s something funky about tumors progressing on enzalutamide that allows the immune system to recognize them. Whatever it is, maybe it’s better to stay on the enzalutamide and just add the PD-1 blocker.”  This strategy worked in a few men who were “exceptional responders.”

This study, published in Oncotarget, showed in just a few men with the most devastating prostate cancer – cancer that has metastasized, cancer that has invaded the bones, cancer that got better for a while on hormonal therapy but came back with a vengeance when the hormonal therapy stopped working – what might actually be cures.  It’s high time!  Why shouldn’t this happen in prostate cancer, number of mutations aside?  What is it, exactly, that has been happening in those other cancers:  Tumors that should have killed people with lung cancer, melanoma, kidney or bladder cancer have melted away instead, because checkpoint inhibitors allowed the T cells to recognize the cancer that’s been growing – invisibility-cloaked in plain sight – right beside them.  The results with pembrolizumab were so dramatic, and so unexpected, that the investigators decided to publish the early results.

Oncologist Julie Graff, M.D., at the Knight Cancer Institute of Oregon Health & Science University, explains:   “PD-1 inhibitors on their own have not seemed to have much of an effect on prostate cancer.”  But Graff, Drake and colleagues saw two exceptions to the rule, two men with “castrate-resistant prostate cancer” (their hormonal therapy stopped working) who responded exceptionally well to immunotherapy:  their PSA went away, and their cancer appeared to be undetectable.   “We wondered whether enzalutamide, which targets the androgen receptor, might stimulate the immune system to make the PD-1 inhibitor work better.”

The team designed a study of 28 men who are taking enzalutamide but whose cancer is still progressing.  The men continued to take enzalutamide as they received four doses of  pembrolizumab. The first 10 patients were enrolled from March 2015 to January 2016.  Their ages ranged from 61 to 80, and their PSA ranged from a little over 4 ng/ml to nearly 2,503.  Here’s what happened to them:  in three men, the disease did not change; it did not get noticeably better, but it didn’t get noticeably worse, either.  Four men did not have any evidence of a benefit, and one of these men died of his cancer.  So that’s seven men; what about the other three?  Their response blew the investigators away:  Their PSA – including the man with the PSA of nearly 2,503 – dropped to the undetectable range of less than 0.1 ng/ml.  Two of these men had been on narcotics for pain, and stopped taking them.  One man’s liver metastases went away.  “These three men had a complete response,” says Graff.  “Their tumors shrank radiographically” – meaning that they couldn’t be seen in imaging – “in the lab” – their PSA falling to nearly nothing – “and clinically,” with the need for pain medication going away.  “None has had a recurrence.”

With Emmanuel Antonarakis, M.D. of Johns Hopkins, Drake is looking at ipilimumab, which blocks a different checkpoint called CTLA-4.   “It turns out that within tumors there’s another population of bad guy lymphocytes (white blood cells), called regulatory T cells. These cells have a number of ways to turn off the immune response.”  In addition to blocking CTLA 4, ipilimumab interferes with the function of these regulatory T cells. Which begs the question: “What if you help the killer T cells by blocking PD-1, and at the same time block CTLA4?”  Blocking two checkpoints at once!  “In animal models, this works brilliantly,” says Drake. “The first data with melanoma were just magical; tumors shrank in four to six weeks.” Antonarakis and Drake “took turns petitioning the drug company” to do a clinical trial in prostate cancer for several years, with no luck. Then Antonarakis and Hopkins colleague Jun Luo, Ph.D., published an important paper in the New England Journal of Medicine showing that men who have a particular variant androgen receptor, called ARV7, don’t respond to enzalutamide and abiraterone. “We said, “If we can’t try this with everybody with prostate cancer, can we at least give it to guys who have the mutation? What if we took ARV7 patients and treated them with both anti-PD-1 and –CTLA 4 (blocks CTLA-4?),” says Drake.  “Emmanuel wrote the trial,” which just finished, and was published in Oncotarget.  “That’s the first clinical trial ever to combine anti PD-1 and anti-CTLA-4 in prostate cancer. It’s very promising.”  It’s also the first study to look at a specific, very bad, form of prostate cancer.  Let’s look at that study:

Combination Immunotherapy Combats AR-V7+ Prostate Cancer:  In this Hopkins-led study of men with very aggressive prostate cancer, this combo of two immunotherapy drugs has made a significant difference – shrinking tumors partially or completely – and two of 15 men have shown exceptional responses.

Once again, no one is suggesting that these drugs would produce the same promising results in all men with aggressive prostate cancer.   But this is an exciting example of precision oncology– finding the right drug (or combination of drugs) to work for the right patient and the right cancer.  The idea is that one drug might just help a few people; but another drug might help a few different people, and if we just keep chipping away at it, eventually we’ll help everybody, one subgroup of patients at a time.

The 15 men in the study had AR-V7-positive prostate cancer; AR-V7 is an aggressive variant of the androgen receptor, first discovered at Hopkins several years ago by Jun Luo and Antonarakis (this can be diagnosed by a blood test, available at Hopkins and through a company called EPIC Sciences).  They were given a combination of ipilimumab and nivolumab.  This specific form of prostate cancer, “can lead to fatal disease in only six to nine months and has inadequate treatment options,” says Antonarakis.

Patients received treatment by IV infusion:  3 mg per kilogram of nivolumab plus 1 mg per kilogram of ipilimumab every three weeks for four doses, followed by a maintenance regimen of 3 mg per kilogram of nivolumab alone every two weeks thereafter. The patients were enrolled between December 2016 and October 2017.

Two of the 15 men (13 percent) experienced a significant drop in PSA – by at least 50 percent.  “More encouragingly,” notes Antonarakis, “one-quarter of patients achieved an objective response, meaning that their tumors shrank partially or completely with combination immunotherapy.  These responses were durable and typically lasted more than nine to twelve months.”  But here’s the most exciting part:  “At least two of these patients remain alive for more than 18 months, which is much longer than expected for patients with AR-V7+ prostate cancer.”  Which means that Antonarakis and Luo don’t even know how long the response will last, because it’s still happening.

Genetic mutations affect response, too:  The men in this study were already different from many patients with advanced prostate cancer because of their AR-V7 variant.   Were there other differences that might help predict which men will respond best to this double checkpoint inhibitor approach?  Yes:  the specific genetic mutations are very important.

“Interestingly, six of 15 patients (40 percent) harbored damaging mutations in at least one DNA-repair gene,” notes Luo.  These mutations were either germline (inherited) or somatic (mutations that just developed spontaneously as the cancer advanced).  “In these six men, we detected gene mutations of BRCA2(3 men), ATM(2 men), and ERCC4(one man).

The job of DNA repair genes is to fix mistakes that occur in the DNA as cells divide – to keep a mistake from being repeated over and over again.  “Remarkably,” notes Antonarakis, “most of the benefit from ipilimumab plus nivolumab appeared to occur in patients who had one of these gene mutations, particularly in two men with BRCA2 mutations.”  If this proves true in larger studies, “it will have profound implications for other diseases such as breast and ovarian cancers, where these genes are more frequently mutated.”  An estimated 20 percent of men with metastatic prostate cancer have mutations in BRCA2or related DNA-repair genes. “This study suggests that these gene mutations may be even more common in men with the AR-V7+ form of prostate cancer, perhaps as high as 40 percent.”

The study also showed that the combination of nivolumab plus ipilimumab was safe and tolerable in men with AR-V7+ advanced prostate cancer.  “We did see some important side effects including colitis, pneumonitis and hepatitis – all caused by an over-activated immune system. These side effects were managed with prompt administration of steroids, which often resulted in reversal of these conditions.”

Encouraged by these preliminary findings, Antonarakis and his team are now expanding the study to include more patients.  This larger study is currently open to enrollment (https://clinicaltrials.gov/ct2/show/NCT02601014?cond=NCT02601014&rank=1), and is actively seeking participants.  If you are interested, please call Mrs. Rana Sullivan at (410) 614-6337.

So where do we go from here? Medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation, quotes Winston Churchill: “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.” In other words, it’s just getting good. “We are learning so much about the immune system.”

There may be a dozen or more potential checkpoints to block. “We only have drugs for about half, and we have a lot more being investigated.” It may be that for the T cells to eradicate prostate cancer, it will require one or more checkpoint inhibitors, plus one or more vaccines. “When we’ve really got a checkpoint inhibitor that allows these T cells to wake up, PSAs will fall, tumors will melt away. When one of these works, man does it work!”

Immunotherapy-induced changes in how we kill cancer are happening so fast, it’s hard to keep up. In lung cancer, for instance, 30 percent of patients now get a checkpoint inhibitor, nivolumumab, before they get chemotherapy, and about half don’t even need standard chemotherapy.   “We don’t even know what some of the antigens are,” says Simons. “We’ve got to make this work for every patient.”

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington