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

You’ve got a lot of antibodies floating around in your blood – to every cold or virus you’ve ever had, plus all the antibodies your body has made after you got a shot to prevent the flu, measles, mumps, chicken pox, or tetanus, etc.

If results of a clinical trial are as promising as scientists believe they will be, we may soon be entering an era where every man diagnosed with prostate cancer gets a combined vaccine to help his body fight it off.

The idea is to “harness the tremendous power of the immune system to augment what your body has done your whole life, which is fight off infections,” says medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation. “Prostate cancers grow because the immune system misses them, or mistakes them for something normal instead of a foreign invader.”

It’s all about the flags: The immune system uses a very effective communication system that’s a lot like semaphore – using handheld flags to send messages, spelling out words by changing the position of the flags. Cells that hoist the “friend,” or “self,” flags get to sail freely; the immune system leaves them alone.   But enemy invaders – viruses, infectious bacteria and other harmful pathogens – announce their nefarious intentions by flying the body’s version of the Jolly Roger, the skull and crossbones: the flag that screams, “foreign!” or “enemy!” These flags are called antigens.

Unfortunately, prostate cancer cells often trick the body by waving a false flag. They get safe passage; the threat is unrecognized by the immune system.

The goal of all immunotherapy – vaccines and checkpoint inhibitors – is to teach the immune system to recognize cancer as the enemy: to rip off the false flag and show cancer’s true evil colors. It’s similar to unmasking the creepy reptilian aliens in “V,” if you remember the TV miniseries from the 1980s.

It’s also like a toddler’s shape sorter: What’s happening in immunotherapy research right now is incredibly complicated, intimidatingly dense and confusing to understand, even for doctors. If you were to pick up an immunotherapy journal and skim through it, you might think somebody had gotten the “caps lock” stuck on the typewriter, because just about any article you might read is chock full of words like PD1 and GM-CSF and CTLA4.

Don’t let the jargon throw you. We’re going to try to cut through all the alphabet soup for you because you need to know this stuff: immunotherapy is going to be increasingly important in prostate cancer. One day, it may even be the way we cure advanced prostate cancer.

Basically, what scientists are trying to do here is very simple – something your kids, grandkids, or maybe even you learned to do at a very early age: match the target with the right block.

Yes, immunotherapy has a lot in common with a toddler’s shape sorter; except instead of finding the right place for the star, crescent moon, triangle or oval blocks, scientists are finding drugs that target extremely tiny points of vulnerability in the body’s immune system. They’re finding the chinks in our armor, and filling them very precisely to help us not only withstand the attack of cancer, but launch a counterstrike.  Level one of immunotherapy here is a prostate cancer vaccine.

Provenge: Provenge (also known as sipuleucel-T) is the only immunotherapy that has been approved by the Food and Drug Administration for prostate cancer. It is usually given to men who have early metastasis after they have been on androgen deprivation therapy (ADT). (This is called castrate-resistant prostate cancer, or CRPC.)

“The vaccine is made from a man’s own cells,” says physician-scientist Charles G. Drake, M.D., Ph.D. In addition to being a renowned expert on immunotherapy, Chuck Drake is the director of genitourinary oncology and an associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at New York Presbyterian/Columbia University Medical Center.

The immune cells are collected in a process called leukapheresis – blood goes out through a needle in one arm, some white blood cells, platelets and red blood cells are taken out, and the rest of the blood is pumped back into the other arm. Then, those cells are put in a culture with an engineered protein that links prostatic acid phosphatase (PAP) with what Drake calls a “special sauce” that activates the immune system. PAP is an enzyme that, like PSA, is made by prostate cells. That special sauce – think of Miracle Gro for plants, or maybe baking soda to activate the yeast in bread dough – is designed to kick-start the immune cells: it’s called GM-CSF (granulocyte-macrophage colony-stimulating factor).

In multiple clinical studies, Provenge has been shown to increase average survival by a few months – but don’t just look at those statistics. Provenge might be able to achieve much more than that if given earlier, in men with a “lower tumor volume” (in other words, not a lot of cancer) or less aggressive disease. It also might achieve a kind of synergy or extra momentum if it’s combined with other treatments.

“It’s a good start,” in the sense that the Mercury and Gemini space programs prepared the way for the Apollo rockets, says Simons; before astronauts walked on the moon, pioneers like John Glenn had to escape gravity and orbit the Earth. “You can’t have immunotherapy unless your body can see the foreign flags. Provenge is about using GM-CSF,” which Simons pioneered as a young faculty member at Johns Hopkins, “to activate the dendritic cells to educate the immune system. The vaccine is actually against a flag that prostate cancer cells fly: PAP.” Other vaccines in the works recognize other flags such as PSA and PSMA (a molecule on the surface of prostate cells).

In men with metastatic cancer, Provenge is able to slow down cancer, but not stop it. “This is a big clue that we could do more in at least 30 to 40 percent of patients if we had something better than the Mercury program,” says Simons. “It’s great to extend life, but what we want to do is eradicate the cancer.” That said, Provenge is “exceptionally safe,” with “the fewest side effects of anything we give to prostate cancer patients. There’s no nausea, no vomiting; you may feel like you’ve got the flu, but most of the time men don’t even feel that.”

Give it sooner? If Provenge works better when a man is healthier in general, then why not give it before there’s any evidence of metastasis? Maybe after surgery or radiation in a man who is otherwise healthy, except that his PSA is going up? “We agree with that idea so much, we started a trial” involving about 60 patients, says Chuck Drake. “Men with a rapidly rising PSA after surgery or radiation were randomized to get either a year of ADT with vaccine starting about month after the ADT began; or the vaccine first, followed by a year of ADT. Men got a better immune response when they got the vaccine first, and then the ADT.”  This was just a small study, Drake notes, and a larger randomized trial is needed. “But our trial helped us figure out the right order – the vaccine first, and then the ADT – and that you could do it safely. A few of the men who got both the vaccine and ADT recovered their testosterone, but never got their PSA back. They have done very well.”

Like so many scientists and physicians working to help men with prostate cancer, Drake hates the side effects that go along with ADT and hopes one day that we’ll find an effective way to treat advanced cancer without taking away the male hormones. For now, he would be happy to put men on ADT for the briefest amount of time necessary, along with immunotherapy, to get their cancer into remission, perhaps continuing with “maintenance immunotherapy, potentially forever.”

However, because the main goal is to cure the cancer and save the man’s life, Drake is also looking at a different group – men who have doubled down on hormonal therapy, who are still on ADT but who have added an androgen receptor-targeting drug such as enzalutamide or apalutamide.

Other vaccines that target other flags: Other vaccines are in the works. One is based on a modified version of listeria (a bad kind of bacteria that, in its unaltered state, can give you food poisoning). Another, called PROSTVAC-VF (also called PSA-TRICOM), developed with PCF funding, uses a modified smallpox virus as its means of entry into the body and targets any cell that makes PSA. “There’s no good cell in your body making PSA once you have prostate cancer,” says Simons. “If we could get your T cells to recognize and destroy everything that makes PSA, you’d be cancer free.”

PROSTVAC is being tested along with GM-CSF in a worldwide clinical trial called the Prospect Trial, involving 1,200 men with metastatic CRPC from about 200 centers. It’s designed to test whether early treatment with this vaccine improves survival. Investigators are waiting for the results, and if it performs as well as they expect, then men could start getting this vaccine in addition to Provenge. “These vaccines are so safe,” explains Simons, “that you could get more than one. When you get the hepatitis vaccine, you’re really getting four vaccines in one. You can get multiple antigens, or flags. The whooping cough vaccine has seven flags in it, and it works a lot better than if you just got one. We will be combining these prostate cancer vaccines down the road if each one shows a benefit. The great promise of all these vaccines is, if you can figure out all of the antigens you need, you might be able to vaccinate right after surgery or radiation,” and one day, men might not need ADT, or they could delay it for many years.

If the PROSTVAC trial is successful, Simons believes, “every man with prostate cancer should get vaccinated, and should get GM-CSF. Antigen-specific immunotherapy is already curing the most fatal form of lymphomas, because scientists perfected the way to make a T cell kill off that antigen. Now lymphoma is a disease where they just give a little chemo to beat down the numbers of cancer cells, and then they activate the T cells and they destroy the cancer.”

Still another vaccine, called GVAX, is being tested by Drake and Antonarakis in men with high-risk prostate cancer undergoing surgery. Here, men are getting either a short course of ADT alone, or GVAX vaccination followed by a short course of ADT. The benefit here is that a pathologist can examine the surgically removed prostate to see whether the immune system has been activated – whether there’s evidence that the immune cells have begun to attack the cancer.

Combining vaccines and checkpoint inhibitors: In another clinical trial, Doug McNeel, M.D., Ph.D., at the University of Wisconsin, is testing a combination of a vaccine called MVI-816 that, like Provenge, targets PAP, plus a checkpoint inhibitor (see below). This particular checkpoint inhibitor, called pembrolizumab, blocks PD-1, and in early data, the combination looks encouraging: PSA levels have dropped and some men’s tumors have shrunk. The idea here is to educate the T cells – to fly the Jolly Roger on the cancer cells – and then unleash the T cells to attack them. “Immune checkpoints are natural compounds that cells make to protect themselves, and they’re the reason why we aren’t just rejected by our mothers when we’re conceived,” says Drake, “because babies in the womb are half ‘foreign’ with the father’s DNA. Once a killer T cell starts attacking something that it thinks is foreign, it won’t stop unless brakes are put on it. Checkpoint inhibitors basically take the brakes off T cells; that’s their job. Checkpoint inhibitors release the hounds.”

Can the immune system go from oblivious pacifism to DEFCON 1, with alarms sounding and the military being deployed? And if the military – the immune system’s enemy-killing T cells, or antibodies made by B cells – gets involved, is it enough to stop the cancer?

The key is to alter the balance, says Drake. “For a lot of tumors, there’s an ongoing battle with the immune system. The immune system smacks the tumor down, the tumor gets around it.”

The ultimate goal of immunotherapy is to tip the balance toward the immune system. To unleash the hounds.

 

Who’s Who in the Immune System: A Primer for You!

Making sense of some very complicated stuff only a few scientists truly understand: A guide to the immune system for the rest of us

                

Let’s think of the immune system as a Broadway musical. The star of the show is the T cell (actually, there are a bunch of different types of T cells, but let’s just focus on the Killer T cell, not to be confused with the “natural killer” cell; see below).

Killer T cells: These cells live up to their name: they’re precision assassins. When they are on their “A game,” they are merciless, and nothing, not even cancer, stands a chance. Killer T cells have a large and growing fan club:  “They’re my personal favorite cell in the world,” says Drake. “They’re incredible. They can go anywhere, and kill any other cell if it has the right target,” or flag.  “T cells are amazing,” agrees Simons. “They can move out of the bloodstream and go in the bone marrow, the lungs, the liver, and start attacking cancer wherever it is. They have little sensors on their surface that can recognize viruses you haven’t even been affected with yet – just because they’re foreign.”

However:   Cancer knows how to snake-charm these cells, to put them into a trance, or a straitjacket, or to put the “boot” on their tires so they can’t go anywhere – pick your metaphor, but the bottom line is that cancer temporarily takes the T cells out of commission. Cancer cells secrete a substance that puts T cells to sleep – but don’t kill them – on a large scale. If you’re a James Bond fan, think of that scene in “Goldfinger,” when planes fly over Fort Knox and cropdust entire platoons – soldiers with loaded guns at the ready – with gas that makes them drop instantly. Or that moment in “Sleeping Beauty” when the entire kingdom plunges into a 100-year slumber, waiting for the handsome prince to come save the day. One of prostate cancer’s first official functions is to deactivate the T cells with molecules that act as brakes, or checkpoints.

Checkpoint inhibitors are like the handsome prince: they allow the kingdom of T cells to wake up. There are several checkpoints, or sleeping potions. One is PD-1. Another is CTLA-4. In their proper role, checkpoints are good. “Nature doesn’t want a T cell to kill off your kidney or gastrointestinal tract,” says Simons. In an autoimmune disease, for instance, T cells are misdirected; they mistake good and decent cells for the enemy, and destroy tissue. When someone gets an organ transplant, unless the immune system is suppressed, the body will reject the foreign organ. “The reason transplants are rejected is that T cells realize that these cells are foreign, and within days or even hours destroy every last one.” Thus, the body’s checkpoints. “Nature is very sophisticated about keeping T cells from going crazy. T cells that make a mistake can be fatal.”

But cancers that successfully keep T cells from doing their job can be fatal, too, and cancer cells co-opt checkpoints so successfully that there can be a T cell sitting right next to a cancer cell and the T cell does nothing, because the cancer is sending a signal saying, “I’m normal, don’t kill me.”

Checkpoints such as PD-1 are tiny molecules sitting on individual T cells. And incredibly, there are several drugs that can deactivate them. Pembrolizumab and Nivolumab target PD-1. A drug called ipilimumab targets CTLA-4. For each checkpoint – and it’s still not clear exactly how many there are – potentially, there is some way to block it, and the Prostate Cancer Foundation is actively funding this research.

From what we know right now, it seems that a minority of men with prostate cancer respond to PD-1 blocking drugs. Only a few men with prostate cancer respond to ipilimumab. Scientists aren’t sure why. But maybe the men with prostate cancer who don’t respond to those drugs will respond to different checkpoint inhibitors.

Now, back to that Broadway musical: There don’t seem to be any bit players in the immune system. Yes, T cells are the stars, but there are plenty of potential stars waiting in the wings. These include:

Natural Killers. These sound like something Quintin Tarentino would write about, but really, they’re foot soldiers, under the command of the T cells. “T cells don’t fight alone; they bring reinforcements,” says Simons. “Natural killer cells poke a big hole in a cancer cell or a virus, but they need direction. They need to be told where the fight is. But they’re really good at killing.” Checkpoint inhibitors aimed at helping unleash natural killer cells are being developed.

Macrophages. When cancer cells die, there’s carnage. Macrophages are early responders to the crime scene, and they chew up the debris. GM-CSF activates macrophages. Physician-scientist Pam Sharma, M.D., Ph.D., of MD Anderson Cancer Center, suspects that some types of prostate cancer may be more susceptible to immunotherapy drugs that activate the macrophages, rather than, or in addition to, the T cells. But macrophages aren’t just scavengers. “They do something very important: they put cancer cell flags on the surface of cancer cells,” explains Simons, “so they’re like educator garbage men.” T cells eventually reproduce, and then die. Their offspring cells need macrophages to show them the ropes – so they can find the flag and kill whatever is flying it.

Some cancers have more macrophages than T cells. Some of these macrophages are counter-productive: not only do they not help, they may also secrete substances that make the tumors grow more quickly.

Mast cells. These are immune cells involved in the allergic response. What do they have to do with prostate cancer? Apparently something, because scientist Karen Sfanos, Ph.D., at Johns Hopkins, and colleagues just discovered that men who have more mast cells are less likely to have a recurrence of prostate cancer after radical prostatectomy.

Dendritic cells: These are the cells that stand in the wings and give the T cells stage directions, pointing out which flags are for “self” and which are for “foreign.” They encourage the T cells that target foreign invaders to get out there and do their thing – multiply, attack, kill!

B cells. If T cells are the stars, B cells are the co-stars. They make Y-shaped antibodies, which grab onto the flags on a cancer cell. Antibodies attract the macrophages to come and clear away the debris. B cells are like a Neighborhood Watch on steroids. Think of the nosy neighbor on “Bewitched,” Mrs. Gladys Kravitz, watching for suspicious activity through her binoculars, spying in the bushes, or peeping through the window. Now imagine Mrs. Kravitz on steroids – as a drone, maybe – flying around the body looking for anything that’s not supposed to be there. They don’t do the actual killing of the enemy cells, but they aim the laser at it so the T cells can see it.

“B cells are the least studied immune cells in cancer, but they’re incredibly promising,” notes Simons. “Prostate cancer generally shuts them down with checkpoints, too. But we think we have identified a checkpoint inhibitor for them, as well. It would be a very good thing to have prostate cancer cells making antibodies.” As a matter of fact, Drake’s team published a paper showing that if men taking Provenge make more and better antibodies, they seem to live longer.

Vista. “Vista may be a major switch” that really puts T cells to sleep, Simons explains. If checkpoints like PD-1 put a T cell into a trance, Vista might put it into a deep sleep – think of Juliet faking her own death in Shakespeare’s play, sleeping so deeply that her heart barely pumped and her lungs barely breathed. When cancers make Vista, T cells are exceptionally sleepy. A drug that blocks Vista might make those cells be exceptionally wide awake. An anti-Vista drug “just went into clinical trials for prostate cancer.” It might take a cocktail of antidotes – anti-PD-1, anti CTLA4, anti-Vista – to allow T cells to achieve maximum killing potential against prostate cancer.

Helper T cells. We weren’t going to talk about other T cells, but these cells help the B cells that make antibodies to do their jobs.

IDO: Indolamine amase (IDO) is the reason your mother’s body didn’t reject you in the womb. It’s a gene made in the placenta. Cancer cells stole the recipe; they make it, too, to keep your body from rejecting them.

 

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

 

 

Here’s some news about coffee, the good, the bad – actually, there is no bad to this story. Coffee is good! If you can’t drink caffeinated coffee, decaf is good, too! Here’s why:

Although most scientists are not yet willing to step out on a limb and proclaim definitively that drinking coffee prevents cancer (this story is mostly about prostate cancer, but beneficial effects have been seen in other types of cancers, too) or makes you less likely to have aggressive, high-grade disease if you do get it, undeniable evidence from several new studies suggests that this may indeed be the case.

Best of all, there’s no downside. If you drink coffee, keep right on drinking it. Fill it to the brim! And if you don’t already drink it, you may want to consider it.

What’s going on here? What about coffee has us so – pardon the pun – perked up? Well, there’s a latte to consider, so let’s look at the grounds for optimism starting with these findings, published in the International Journal of Cancer:

In a study from the Moli-sani Project, investigators looked at coffee consumption in nearly 7,000 men, age 50 and older, in the Molise region – a mountainous, mostly rural part of Italy. They followed them, on average, for more than four years, and during this time 100 of these men were diagnosed with prostate cancer. (Note: unlike many American men, these men were not getting routine screening, so it’s possible that some of them may have had not-yet diagnosed prostate cancer.) The average age at diagnosis was 67, and of these men, half had cancer that was Gleason grade 7 or higher; 8 percent had distant metastases, and 6 percent had local metastases. In separate studies, the Italian investigators also showed that both coffee and caffeine can slow down the growth rate and spread of prostate cancer cells in the laboratory.

But what about actually drinking coffee? It turns out that there was an inverse association between coffee intake and prostate cancer risk. In other words, the more coffee the men drank every day, the less likely they were to develop prostate cancer. In this study, the men who drank more than three cups a day had the lowest risk of getting prostate cancer.

Note: The investigators define more than three cups as drinking 90 grams or more per day. This actually turns out to be just 3.17 ounces; in Italy, coffee consumption tends to be in cute little espresso cups, and the cultural tendency is not to sit for hours nursing a cup at a café, but to just knock it back and get on with your business. So a dose of coffee here is more like a shot of espresso to us. In comparison, the smallest size at Starbucks, a Short, is 8 ounces; a Tall is 12 ounces, and a Grande is 16 ounces.   At Dunkin’ Donuts, a Small is 10 ounces, a Medium is 14 ounces, and a Large is 20 ounces.

It’s also worth noting that these men most likely took their coffee black, or maybe with a bit of milk or cream. In other words, they didn’t have a pump of hazelnut, five shots of whipped cream, ice cream, soy milk, almond milk, sugar, stevia, Nutrasweet, Sweet & Low, or any of the many things we can think of in America to add to our coffee.

So just think pure coffee here. Also, their coffee was unfiltered – not brewed or instant, as coffee is for many of us on this side of the pond.   This means that it may have some other prostate cancer-suppressing molecular components that get filtered out in other forms of coffee.

Still, the results are striking. Of all the foods and potential things you could take to lower your risk of getting prostate cancer – scientists believe the most promising of these include taking a baby aspirin a day, eating lots of tomatoes cooked in olive oil, taking vitamin D, or being on statins to lower cholesterol; all of these lower the inflammatory environment in your body and make it less likely for cancer to develop – coffee in this and other studies seems to have the best hazard ratio; that’s a scientific term that ranks the probability of being true in real life, and not just in the study.

So why aren’t we standing from the rooftops shouting: Coffee for everyone! Run, don’t walk, to the nearest percolator! Because, says Harvard nutritional epidemiologist and PCF-funded investigator Kathy Wilson, Sc.D., it is just so darn hard to know exactly what’s going on when you look at things in the diet. I recently interviewed her for the Prostate Cancer Foundation’s website.

For example: How do we know that the vast majority of these men didn’t get prostate cancer just because they downed a lot of coffee? Maybe it was what they were eating – which was almost certainly the Mediterranean diet, high in fruits and vegetables and olive oil, and low in red meat? Did they drink tea or eat chocolate? Both of these substances are chock full of antioxidants, as well.

Or maybe it was what they were not eating – high-fat, high-carb stuff like bacon cheeseburgers and chili fries. Or maybe it was what they were not drinking – super-sized sodas, energy drinks, or sweet tea?

“The Italian investigators adjusted for other factors in their study – such as total energy intake, smoking, BMI (how fat the men were) – and found that the coffee benefit was independent of those things,” says Wilson.

Wilson’s work focuses on understanding the role diet plays in prostate cancer, and she has been zeroing in on coffee for years. In fact, she was first author of a large Harvard-led study published in the Journal of the National Cancer Institute in 2011, in which investigators also showed an inverse association between coffee and prostate cancer. “The Italian authors put a lot of weight on the unfiltered coffee that’s consumed in Italy, but I don’t think we can rule out that the lowered risk is just an effect of coffee itself, filtered or unfiltered.”

In their study, Wilson and colleagues also found that coffee was associated with a lower risk of getting prostate cancer, and of developing aggressive, potentially lethal cancer. Men who drink one to three cups a day 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. “The findings were similar for caffeinated and decaffeinated coffee,” says Wilson.  This was perhaps even more remarkable because they also found that heavy coffee drinkers also tended to be smokers – and smoking cigarettes is known to raise the risk of getting prostate cancer, and of developing a more aggressive form of the disease.

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

What does coffee do in the prostate? This is very difficult to study. Ideally, in men who decide to have their cancer treated with surgery, scientists might look at the biopsy tissue from men at the diagnosis of prostate cancer, then have those men drink several cups of coffee every day until their surgery, and compare the tissue from the entire removed prostate with the biopsy. Maybe they would find a change in aggressiveness, or in inflammatory markers, or in some other measurable thing that might show more precisely what coffee does in the prostate.

What’s in coffee, anyway? Well, that’s another tough one. There are actually thousands of compounds. Metabolites found at high concentrations in caffeine. Roasting products. Polyphenols. Diterpenes, products in the oil of the coffee bean (these are strained out in filtered coffee). Which one is the golden ticket to better health? There may be more than one, maybe more than a hundred. Nobody knows for sure.

Okay, well then, maybe the key is in what coffee does in the body. Just what does it do, anyway?

Coffee has powerful antioxidant effects. As Wilson notes, “coffee is the number one source of antioxidants in the diet of the American man.” This is very interesting, and also pretty sad; it means the average American man is not loading up on antioxidants in fruit and vegetable form in his daily meal plan.

Coffee is also anti-inflammatory, says Wilson. “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. “It reduces blood glucose levels, reduces intestinal glucose absorption, and reduces liver glucose output.”

Coffee cuts lipids, the body’s fatty acids. “It reduces fasting cholesterol and triglyceride levels.”

Coffee helps the gut’s microbiome. It increases diversity in the microbiome, the millions of bacteria living happily in your gut. “There are a lot of immune cells along the gut, and the increased diversity in the microbiome may inhibit inflammation elsewhere in the body.” There may be some important interplay between the gut flora and inflammation, and it may be that coffee tips the balance away from inflammation and the development of cancer.

How much coffee should you drink? For how long do you need to drink coffee to be protected from cancer? Do men who cut down on caffeine later in life because of urinary problems (from BPH, benign enlargement of the prostate) lower this protective shield and somehow open the door to cancer?

Add these and a whole bunch of other questions to the large list of things nobody knows the answers to – for now. But scientists are working on it, and the Prostate Cancer Foundation is funding studies in four labs in the UK and U.S., says medical oncologist Jonathan Simons, M.D., CEO of the PCF. “Scientists who have expertise in pharmacology, biochemistry are curious about this unfiltered Italian coffee phenomenon. They’re undertaking the detective work needed to figure out the biochemistry and gene signaling of it.” Such work has paid off before, he adds. “Two of the most important drugs in internal medicine, digoxin and aspirin, come from leaves and tree bark plus intensive and persistent detective work by pharmacologists who were sure the clinical effects were real.”

One thing does seem pretty clear, notes Wilson: “There’s a perception that coffee is not good for you, that it’s a habit you should kick, or that you should cut back. But all the evidence is that if anything, coffee is beneficial. It’s really quite striking.”

And yet, she adds, “it’s probably premature to actively recommend coffee, or tell guys who don’t drink coffee that they should start drinking it. But coffee is not bad for you in terms of chronic health. If people are already drinking coffee, they should feel fine about it – not, ‘this is bad for me in the long run.’ In long-term health, coffee seems like it’s doing good things.”

One group not particularly well represented in the Harvard Health Professionals study or the Italian study is men of African descent. Prostate cancer is different in these men; it is more aggressive, it develops in a harder-to diagnose part of the prostate, different genes are involved in its development and progression, and some of the biomarkers that help monitor the disease do not work as well in these men. However, Wilson notes: “It is interesting that in overall U.S. diet data, black men do drink less coffee than white men.” File that one away for future studies; it’s hard to know what to make of that one fact on its own.

Because trying to find the magic pill – whether it’s beta carotene or selenium, or any of the millions of compounds that could potentially be isolated from the diet and sold as a supplement – has not worked yet, your best bet is just to err on the side of healthy. Eat lots of fruits and vegetables, particularly tomatoes, don’t eat a lot of red meat, don’t load up on carbs and sugar. Watch your weight; obesity is linked to a higher risk of prostate cancer. Don’t smoke.

And feel free to have another cup of Joe.

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

Remember these letters:  PSMA.  If you haven’t heard of PSMA-targeted agents yet, you probably will soon.

Imagine a heat-seeking missile – except the tiny target locked onto by this particular missile is PSMA (prostate-specific membrane antigen), a protein that sits on the surface of prostate cancer cells.  The weapon itself is a small molecule, originally designed as an imaging agent by a team led by Johns Hopkins investigator Martin Pomper, M.D., Ph.D., and scientists are still discovering what it can do.

How specific is it? Imagine a bit of tissue the size of a teardrop.  Two of the cells inside it are prostate cancer cells; the rest are not.  With a PSMA-targeting tracer, like Pomper’s small molecule or any of its next-gen relatives, only those two cells would light up.

We’re talking molecular LEGOs here: With Pomper’s small molecule, PSMA can be linked to different chemical bricks.  One kind of brick is a radioactive tracer that can show on a PET scan exactly where small bits of cancer are hiding.  But wait!  There’s more:  PSMA can also be hooked up to a radiopharmaceutical agent, called a radionuclide, that can seek out and kill those tiny pockets of cancer and potentially even stop metastatic disease.

It’s like the old commercial for the miracle product called Shimmer on “Saturday Night Live.” It’s a floor wax! It’s a dessert topping! No, it’s both!

“It truly has excellent potential and we are just scratching the surface here of what PSMA-targeting can do,” says medical oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation, “in metastatic disease and also in localized disease.”   I recently interviewed Simons and Pomper for the PCF’s website, and Pomper for the newly released Fourth Edition of my book with Patrick Walsh.

This momentum has been building for two decades. “We started working on PSMA-based imaging agents back in the late 1990s,” says Pomper, Director of Nuclear Medicine and Molecular Imaging at Johns Hopkins. Pomper’s team was not the first to try to harness PSMA as a way to get to prostate cancer; in 1996, scientist Neil Bander created an antibody that can target PSMA and used SPECT imaging to see hidden prostate cancer cells.  But antibodies are cumbersome; it takes several days from the time they are administered until they clear the bloodstream and reach the target cells. They are also very large. Continuing the building-block theme here, it’s like trying to attach toddler-friendly DUPLO blocks to the much more svelte LEGOs. “We want to be able to scan within an hour or so after injection,” Pomper explains. “We prefer the small molecules for therapy, too.”

Pomper’s versatile small molecule and derivatives of it have galvanized the field of nuclear medicine. PSMA-targeted imaging and therapy has generated huge interest worldwide – especially in Europe, where scientists have linked the small molecule to radionuclides (both alpha- and beta-emitting particles) and are reporting long-term remissions in some men with metastatic prostate cancer. “You just switch what’s attached to the small molecule, and you can go from imaging to irradiating the cancer – cancer you can’t even see, potentially. This would be impossible using external-beam radiation.”

German doctors – who, thanks to a regulatory loophole were able to move right into using PSMA-targeted radiotherapy without having to conduct the clinical trials required in the U.S. – have even reported cures in a few men – but also some side effects, including the loss of the salivary gland, where some PSMA-bearing cells also live. That’s because, although scientists called it “prostate-specific,” PSMA is not solely confined to prostate cancer.

Scientists worldwide are trying to figure out how to tackle the “collateral damage” problem of PSMA. Is there some way to protect the salivary gland, like using potassium iodide to protect the thyroid in the event of a nuclear attack? Some of the salivary-protecting options being explored include botox and anticholinergic drugs.

The Great Promise of PSMA-Targeting Agents

“PSMA is present in the normal prostate, present in the brain, the kidney and the intestines,” Pomper notes, “but it’s really expressed much higher in malignant prostate tissue. It’s also expressed in the neovasculature – the vessels tumors need in order to grow in place or metastasize.”

PSMA is present in many different cancers, too. “Renal cell carcinoma, glioblastoma, pancreas cancer and other cancers have PSMA in the blood vessels around them – not in the tumor itself,” and this is an exciting potential avenue for future research: finding a way to target and kill PSMA-bearing areas around some terrible cancers that desperately need effective treatment.

Pomper keeps tinkering with the molecule and agents that link to it.. Recent work with Hopkins colleagues in Radiology and Radiation Oncology has led to the first published small-molecule alpha-particle emitting agent to treat prostate cancer. A team led by radiation oncologist Ana Kiess, M.D., Ph.D., linked an alpha-particle emitter to Pomper’s small molecule. “Alpha particles are emitted from certain molecules as a consequence of radioactive decay,” explains Pomper. “They are useful for treating cancer because they provide a lethal punch to the DNA of malignant cells – more so than other forms of radiation. The key is to enable the alpha emitter to reach the cancer cells selectively, leaving normal tissues unharmed.”

In the lab, “using this agent, we were able to prolong the lives of immunocompromised mice bearing human prostate tumors,” says Pomper. This study lays the groundwork for future clinical trials in men with prostate cancer, and for the design of even safer, next-generation alpha particle agents. Also, it “represents a pivot by our group from developing imaging agents to finding better agents for therapy.” The group is now leading a phase I clinical trial for beta particle-emitting agents it has developed.

The very good news for men with advanced prostate cancer is that numerous clinical trials are opening in the U.S. and Australia to test similar PSMA-targeted radiopharmaceutical agents. In fact, the PCF is funding three research projects – in Australia, at UCLA, and Weill Cornell – and all of these have clinical trials.

PSMA-PET Can Help Clarify Localized Prostate Cancer, Too         

So far, efforts with PSMA-targeting molecules have mostly been focused on what ancient Romans called the disjecta membra, the scattered bits and pieces of cancer that started out in the prostate and moved to the lungs, bone, liver, or someplace else.

But what about the cancer that’s right there in the prostate – cancer that hasn’t spread yet?  That’s what investigator Steve Cho, M.D., has been working to find out.  Cho, on the faculty at Johns Hopkins before joining the faculty at the University of Wisconsin, led the first human imaging study of Pomper’s PSMA-targeting agent.   He showed how well PSMA-PET could pick up metastatic prostate cancer – better than a bone scan and CT combined. Then he thought: “There’s a low level of PSMA in the prostate itself. How well does this agent pick up primary prostate cancer?”   With Movember funding through the Prostate Cancer Foundation, Cho led another study for prostatectomy patients – men with localized prostate cancer who have it taken out surgically. The benefit here is that Cho and colleagues could compare what they saw on the PSMA-PET images with what the pathologists found in the needle biopsy tissue and in the actual removed prostate specimens. They learned a couple of very important things:

One, in localized disease “this specific agent doesn’t show up in all prostate cancer patients.” (Note: other PSMA-targeting molecules might be found to work better in this situation.) But “it does show up in men with higher-grade cancers,” Gleason grade 8 or 9 tumors.

As it turns out, PSMA-targeting molecules have discernment.

This is really important, because many men need some extra help. “One of the problems with MRI,” Cho explains, “is that it can pick up a lot of lesions – but sometimes they are benign.” Calculi, stones in the prostate (like kidney stones, but tiny), and enlargement of the prostate (BPH) can show up on an MRI, too, and it’s not always apparent what needs to be treated and what doesn’t.

MRI is sensitive, but not always very specific; it’s “user-dependent, in terms of interpretation and experience.” Understandably, a radiologist who looks at nothing but prostate images all day probably has more expertise at spotting prostate cancer than does a radiologist who looks at images of all sorts of body parts. “PSMA-PET was specific in our study,” says Cho. “If you see a signal by PSMA-PET in the prostate, it typically ends up being a site of prostate cancer, and ends up being clinically significant.

This could be particularly helpful for men with an elevated PSA but a negative biopsy (or biopsies), or men considering Active Surveillance for prostate cancer. Men who are told they have low-grade disease – because the biopsy needle hasn’t picked up anything different – could have extra peace of mind if a PSMA-PET comes up negative for high-grade disease. Or, men who have had one or more inconclusive biopsies may decide to undergo surgery or radiation therapy if PSMA-PET shows high-grade cancer that the needles missed.

Even if a biopsy shows cancer, “the biopsy needle is not always accurate,” Cho notes. “It might show Gleason 6 disease, but maybe there’s Gleason 8 cancer somewhere hidden. ” Similarly, during a rectal exam, “the urologist’s finger can’t always feel cancer in the apex or anterior of the prostate. That’s where I think this technology can really help: it can provide a better way of targeting a specific region of the prostate so the needle has a higher probability of a true hit.”

Combining PSMA-PET with MRI may result in even more accurate and predictive scans, as well.

But wait again! There’s even more! Cho is exploring PSMA-PET in several different studies, aimed at helping men with different stages of prostate cancer.

One of these is for men with high-risk prostate cancer, “we currently have a clinical trial here at the University of Wisconsin, a Department of Defense-supported grant, with medical oncologist Joshua Lang, M.D., urologist David Jarrard, and biomedical engineer David Beebe, Ph.D., who studies the microenvironment of tumor cells. “In these high-risk patients, at the time you take the prostate out, they already have a high probability of having cancer outside the prostate.” But if the disease could be attacked systemically, with three months of hormonal therapy (Degarelix) and chemotherapy (Docetaxel) before prostatectomy, would that help – and could PSMA-PET images show that tiny bits of cancer have disappeared?

In future studies of men with advanced prostate cancer, Cho envisions using PSMA-PET to monitor treatment – any kind of treatment – to make sure it’s working. “Can we tell early on whether a patient is responding or not responding well, so we don’t have to continue to give treatment that’s not working, and we can quickly change course?” Molecular imaging can help doctors “be more nimble” and respond more quickly – either to intensify treatment or, if it’s working, perhaps to dial it back and spare the patient multiple cycles of hormonal therapy or chemotherapy. This is already happening in other cancers, such as lymphoma.

“This whole area is evolving,” says Cho. “We have barely scratched the surface.”

We’ll be talking more about PSMA in future posts.

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

 

 

 

What does your poop reveal about your gut bacteria (called the gut “microbiome”), and what does this have to do with your immune system’s ability to fight off cancer? Just how important is this gut flora, or bacteria, anyway?

Let’s look at the last question first. How important is your gut bacteria? It’s very important to your whole body: your brain, your heart, your immune system – and, although no one has proven it yet, we suspect that it is also very important to your prostate. Being able to empower the gut bacteria – to increase certain “good” bacteria that, in turn, 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. In still other work, scientists studying melanoma found that the presence of certain gut bacteria can change how cancer patients respond to immunotherapy.

I have written about understanding and tapping the power of the gut bacteria here, and here, as it relates to irritable bowel and depression. But cancer! This article mainly applies to prostate cancer, but the implications are rich for many types of cancer.

Could treating the bacteria help prevent cancer, make it less likely to spread, or make immunotherapy more effective against it? I recently interviewed Johns Hopkins scientist Karen Sfanos, Ph.D., whose work is shedding light on the role bacteria play in cancer – particularly, in prostate cancer – for the Prostate Cancer Foundation (PCF), which has invested $1 million in research to help explain the gut microbiome’s role in metastatic prostate cancer.  Call it a “gut feeling.”

Eight Pounds of Your Body Is Just Bacteria

Here’s something to consider about the megapopulation of bacteria in your gut: A lot of us have been exposed to bad bacteria, but these bugs don’t kill us. In our large intestine, we have about eight pounds or so of trillions of bacteria; in fact, we have more bacteria than cells in our bodies. Some of them are good, and some of them are not so good.

But some people die from bacterial infections in the gut; what happens to make them more susceptible? Dysbiosis: an imbalance, where the bad bacteria take over. For example: say you have an upper respiratory infection, and you get antibiotics. Antibiotics wipe out bacteria. They don’t distinguish between good and bad species; they just kill ‘em all. The good bacteria are collateral damage, and sometimes this scorched-earth result creates an opportunity for very bad bacteria to thrive in your gut. What’s going to fix that, more antibiotics? Maybe, but not always. In fact, when you wipe out the gut flora with antibiotics, an even worse form of bacteria – something nasty like C. difficile, for instance – can take over.

Again, what does this have to do with cancer? Here we go: If antibiotics fail, the most effective way to cure intractable C.difficile is with a fecal transplant: basically, taking the poop of someone who does not have C. difficile, who has a healthy gut microbiome, and inserting it in your colon. It’s gross, but it can also save someone from chronic, miserable illness.

Karen Sfanos is one of a few pioneering cancer researchers wondering if the same principle could apply to treating prostate cancer.   With colleagues at Hopkins and Thomas Jefferson, she is looking at gut bacteria – a heck of a lot of it, in at least a thousand patients undergoing various treatments for advanced prostate cancer. As principal investigator of the PCF grant, Sfanos is stockpiling gut bacteria and building a microbiome specimen repository that will serve as an international database for research.

Sfanos, a molecular microbiologist, has long been interested in the relationship between bacteria and prostate cancer; in fact, she is among a growing number of scientists who are proving that urine is not (as scientists supposed for decades) sterile, and was the first to describe the urinary microbiome in men with and without prostate cancer. Bacteria in the urinary microbiome may shed light on the presence of microbes that can cause prostate infections, including some that are sexually transmitted infections. These microbes may produce no symptoms but may lead to chronic inflammation – and this, in turn, may cause prostate cancer in some men.

Meanwhile, a few studies looking at other forms of cancer “started to indicate that the gut microbiome could have an influence on treatment response,” Sfanos says, “and that really got us thinking about whether the gut microbiome could influence how well men respond to prostate cancer treatment.”

In studies with medical oncologist Julie Graff, M.D., of Oregon Health & Science University, Sfanos has been working to see if there is a difference in the gut microbiome of men with widely metastatic prostate cancer who have responded dramatically well to the checkpoint-inhibiting immunotherapy drug, pembrolizumab.

Originally, Graff and colleagues suspected that the men in their studies who were exceptional responders to this drug had cancers with “microsatellite instability” (they had tumors with many genetic mutations) – which made the cancer cells stand out and be more easily recognizable as enemies to the immune system. And this is undoubtedly true, but it’s not the whole story.

In Graff’s initial small study, published in Oncotarget, three men out of 10 had dramatic responses: their metastatic tumors in the liver, brain, and elsewhere disappeared, and their PSA levels plunged. Tumor tissue from two of these men was available for further analysis and, indeed, one of the men’s tumors had microsatellite instability. But the other man’s tumor did not. The number of tumor mutations, explains Sfanos, “cannot fully explain those responses to immunotherapy,” in Graff’s and other studies. “People who do not have that phenotype are still having dramatic responses.”

For these men, “the gut microbiome could be contributing in several ways. If the immune system is blocked from recognizing the tumors,” because the cancer uses sneaky tricks and devious disguises to hide itself from the body’s roving immune system soldiers that would kill it, “the right mix of bacteria could help stimulate the immune system – and combining that with the immune checkpoint inhibitor might drive a robust anti-tumor immune response. So that could explain what’s happening in patients who do have this high mutational burden.”

What about the other people with various forms of cancer who do have microsatellite instability – the weird-looking, multi-mutated tumors that the immune system can see and say, “Hey, that’s not supposed to be here!” Why do only some of them respond well to immunotherapy? The gut may be helping them, too.   Is it diet? Do these people just eat better, and thus have a healthier gut microbiome?

“Certainly, diet does have a profound influence on the composition of your gut flora,” says Sfanos. To understand more, it’s time to look at your poop – or rather, at the poop of men with advanced prostate cancer who are contributing to this repository – in a very high-tech way. With each fecal sample, Sfanos and colleagues extract all of the bacterial DNA and RNA. They’re generating “microbiome profiles” that include bacteria, viruses, fungi, and protozoa. Then, they are correlating the gut flora with the treatment the men are receiving – and hoping to find answers to so many questions.

“I am extremely interested in the interplay between bacteria and circulating hormones,” says Sfanos. Does ADT – androgen-deprivation therapy, which deprives prostate cancer of the androgens, or male hormones, that nourish it – change the makeup of bacteria in the gut? “It’s an underappreciated relationship: they influence each other. The gut bacteria influence the circulating androgen levels, and vice versa. They’re talking to each other.”

In one ongoing study, “we looked at the gut flora of men across the prostate cancer spectrum,” Sfanos notes – men without prostate cancer, men with localized prostate cancer, men with recurrent prostate cancer, and men with metastatic prostate cancer. “We were really interested in determining if there are differences based on what treatments the men were being given. Oral anti-androgens, including abiraterone and enzalutamide, “may directly interact with the gut flora. We found that these men in our study had measurable differences in the composition of their gut flora. Something specific is going on in the men taking oral anti-androgens.” In further analyses, Sfanos and colleagues found that in men taking these drugs, “there are bacteria capable of hormone biosynthesis in the gut: microbes able to synthesize and metabolize precursors that can be hormones. This could potentially influence treatment response.” In other words, some gut bacteria can synthesize androgens that “could maybe even continue to nourish the tumor. We are very actively studying this right now.”

The gut flora, she adds, are “absolutely linked” to some of the other health problems that can accompany ADT, particularly metabolic syndrome. “This is very understudied in men with prostate cancer.” (Sfanos’s most recent work is currently in press, to be published soon in Nature’s journal, Prostate Cancer and Prostatic Diseases. In the meantime, here’s a link to a related study she did.

What might this research lead to? How could it help men with advanced prostate cancer fight their disease? Here’s one example Sfanos can envision. “Let’s say we discover a species of bacteria that’s capable of metabolizing an androgen,” a nasty bug that could counteract the effects of abiraterone by whipping up its own homemade batch of male hormones. “If depriving men of androgens leads to an outgrowth of some bacteria that can make their own androgen, we could check for them in a patient’s stool sample and try to get rid of them.”

Boosting the immune system: The epithelial barrier, the thin lining of the intestinal wall, is a virtual Checkpoint Charlie for immune system activity. This is a gateway with “a massive amount of immune cells on one side, and bacteria on the other side,” Sfanos notes. “Several studies have shown that certain species of bacteria are overrepresented in the gastrointestinal tract of people who respond to immunotherapy.” One research group has focused on a group of bacteria called Ruminococcaceae, and another is studying a microbe called Akkermansia muciniphila. Either of these, or both, may turn out to be very important. “The idea is that if, for whatever reason, the presence of these microbes is essential to generate a response to immunotherapy, you would want to introduce these bacteria,” in a fecal transplant or perhaps in the form of a targeted prebiotic or probiotic.

There probably won’t turn out to be one “magic bullet” form of bacteria, which is why a fecal transplant might be helpful. It is an intriguing idea: taking the gut bacteria from someone who responds extremely well to immunotherapy, and transplanting that – in poop form – into the colon of someone whose gut bacteria is not as beefed up for cancer-fighting. Would this stimulate the immune system so that it would knock out the cancer? Could it turn flabby, couch potato bacteria into ripped, mighty, cancer-fighting bacteria? And could this beefed-up bacteria help put your cancer into remission?

It’s early days yet. But if the bacteria within our bodies can shape how our immune system functions, if it can help determine how we respond to cancer treatment – or even whether we get cancer at all – then understanding the very complicated interplay between gut bacteria and cancer could be a game-changer.

“Historically, many prostate cancer biobanks have not included fecal samples,” says Sfanos. This means that nobody has correlated the other markers for how prostate cancer develops or progresses – PSA, Gleason score, genetic mutations, or clinical outcomes – with what’s happening in the gut.

Thanks to Sfanos and colleagues, that’s not the case anymore. 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