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Immunotherapy for Prostate Cancer, Part 2

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

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Immunotherapy for Prostate Cancer, Part 1

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

 

 

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Living in Prostate Limbo

Ask Rob Gray* to talk about how prostate cancer came into his life, and he has the best possible response: “I prefer to talk about how it came out of my life.”

For nearly a decade, among other tests and procedures, Rob underwent 17 PSA tests, five PCA3 tests, and nine MRIs. He endured five prostate biopsies, some of them saturation biopsies, that made him feel like a human pincushion.   He remained steadfast in prostate limbo – when doctors couldn’t find cancer, but they couldn’t rule it out, either, because of some abnormalities in his MRIs and biopsies. Because he kept looking for answers when it would have been so easy to assume everything’s okay and leave it alone for a few years, Rob is cancer-free today.

He is only 49 years old – the age when many men just start to think about prostate cancer.

Rob’s ordeal started back when he was in his thirties. When he asked for a PSA test, his family doctor thought he was worrying too much: “We don’t traditionally order that test until you’re 50,” he told Rob. Note: The National Comprehensive Cancer Network recommends that men start getting screened for prostate cancer in their forties, and at age 40 if they have a family history of the disease. But Rob didn’t have a strong family history of prostate cancer, just a slight one. His grandfather developed it in his eighties, and wasn’t even treated for it because he had other significant health problems.

All Rob had at first was a minor urinary problem and the need to know why it was happening, which led him to read about possible causes, which led him to the prostate, which led him to the PSA test.

He also had a heck of a lot of persistence and maybe was even a bit of a pain in the medical butt because he wouldn’t just let it go. Thank goodness he didn’t. He is cancer-free because of his tenacity.

Over a remarkable nine-year gauntlet, Rob basically did hyper-vigilant active surveillance before the disease was ever diagnosed. He and his doctors followed his prostate, as best they could, in real time. He had so many biopsies that scar tissue developed in his prostate, which made it more difficult to interpret the abnormal MRI results, and if it weren’t for technology that recently became available, an MRI-guided fusion biopsy, his cancer still might not have been found.

When it was finally diagnosed, and when his prostate was removed – with more difficulty than it should have been for a man his age because of all that scar tissue – his Gleason grade turned out to be a 7 (3+4), higher than the Gleason 3 + 3 score found on his biopsy.

And here’s the really amazing part: During this time, Rob developed a strong family history of prostate cancer which did not exist before he began his active surveillance, the kind that should make most doctors take notice and say, “You need to be screened early for prostate cancer.” His father developed it at age 70, and a few years later, so did his maternal cousin, at age 56. In just a few years, he went from having hardly any family history to having three men (and maybe four, if Rob himself developed it) in the family with prostate cancer. It is very important to tell your doctor when your family history changes for exactly this reason: it should upgrade your risk, and you should be followed more closely.

Prostate Purgatory

It all started in 2005 with a drip; actually, a few drips after urination from time to time. “It wasn’t substantial,” he says, “but it was enough to raise an eyebrow for any guy,” particularly an active, otherwise healthy, 38-year-old man. “It started to weigh on me so much, so that I would need to be conscious about what I would wear.” Rob started reading up on his symptoms, trying to figure out what could be the cause.

In 2008, at his yearly physical, Rob asked his family doctor for a PSA test. “It came back at 1.6,” higher than it should have been.   The doctor said, “’I thought you would have been below 1.0. This may be something we want to explore,’” and referred Rob to a local urologist. His urologist in Connecticut performed several diagnostic tests for urinary problems, including a Uroflow test, a renal ultrasound, and a cystourethroscopy, in which a lighted tube is threated through the penis to examine the urethra. This was his least favorite, says Rob, of all the tests he’s had. “It was like Alien Autopsy,” he laughs. “I’d never experienced anything in my life like that, and it was just the beginning of the barbaric things I had to experience!”

And so it began. Five months later, in March 2009, the next PSA test came back with 1.9 and a rectal exam detected some swelling of the prostate, which the urologist suspected was prostatitis.   Rob had his first biopsy that same month, and three of the 12 samples showed high-grade PIN (prostatic intraepithelial neoplasm); this pathological finding is not cancer, but it’s not normal, either. In fact, where high-grade PIN is found, cancer is often lurking nearby – except the needle didn’t find it.

The next two PSAs were 1.9 and 1.8, taking us to 2010, and at this point, Rob decided to go to an academic medical center with expertise in treating prostate cancer. “I’ve been known to research things ad nauseam and then research them again to validate my original findings,” he says. “I thought, ‘if there’s any possibility that something’s developing, I have got to find who’s the best in this field.’” He sought a second opinion on his biopsy slides at Columbia University in New York; the results were confirmed.

The next few years saw more PSA tests, with the results ranging from a high of 2.3 down to 1.36. Ash Tewari, M.D., now Director of Urology at Mount Sinai, ordered Rob’s first PCA3 test. PCA3, like PSA, is a blood test and it is not a replacement for PSA, but an adjunct to it. The PCA3 test is more cancer-specific; the lower the score, the lower the odds of a positive biopsy. In Rob’s case, however, the PCA3 was not the crystal ball he’d hoped for; the first result was a false score of 58.8; the second was 18.3, the third was 18.7, and the fourth was 12.4. Another PSA test showed a free PSA ratio of 27 percent – again, not terribly helpful in Rob’s case. Generally, in men with a PSA lower than 4, a free PSA greater than 25 percent is more likely related to benign enlargement of the prostate, or BPH.

Rob had his first of nine MRIs – three of them endorectal – in 2010 before moving to the 3T MRI. It was not until he had a fusion biopsy conducted by urologist Ardeshir Rastinehad, M.D., at Mount Sinai – in which the needle biopsy is guided by MRI and ultrasound combined – done in June 2017, that cancer was finally detected – just a little, low-grade, Gleason 6. Rob had his prostate removed by urologist Ketan Badani, M.D., director of robotic surgery at Mount Sinai. His surgical margins were negative – no cancer was left behind. His nerve bundles were preserved. When the pathologist examined the prostate specimen after surgery, Rob’s cancer turned out to be of a slightly higher grade, Gleason 7 (3 + 4) – a finding that “validated my decision to have the surgery,” Rob notes.

“Literally, the first thing out of my mouth when I woke up in recovery from surgery was, ‘Was it contained?’ I was still groggy, and I must have asked my wife that question a dozen times. She was at my bedside when I awoke, and she said that it was – with a smile that said more than you could imagine for me and my family. I knew it had taken longer than it should have, based on when I went into surgery and the time estimated to wake up in recovery, which contributed to my concern. But this delay turned out to be because of the extra time it took to work around and cut away the buildup of scar tissue from all the biopsies. “There was so much scar tissue that it also contributed to the abnormal MRI results, which led to the increased number of biopsies. If I hadn’t had the fusion biopsy, it might not have been found. I would be living with it in me undetected and with a false sense of security – the thought of which is truly unsettling for me.”

We just fast-forwarded through years of worry, of waiting, of inconclusive tests – none of which Rob probably would have gotten if his pesky PSA had been where it should have been. As the volatility in his PSA persisted, so did Rob’s mission to stay ahead of anything that might have been developing.

In the meantime, because Rob and his wife didn’t have children during the early days of his ordeal, he banked his sperm just in case he ended up with prostate cancer. “Here I was, still young, and I didn’t know what tomorrow was going to bring. I had this sense of urgency to be prepared for the worst.” He even duplicated PSA tests with different doctors just to double-check; or as Rob puts it, “stress-test the results against one another.” A recent family photo, taken outside, shows Rob, his lovely wife and three beautiful young children, all looking healthy and happy.

Why was he so worried? Because of his dad and his cousin. Both developed prostate cancer. In tests in 2011, his dad’s PSA showed up as 10.3 and 7.56 – both numbers much higher than they should have been for a 70-year-old man. By this point, Rob knew the drill, and he plugged his father into the best system he could, with the same doctors he had come to know so well. An MRI and two biopsies later, Rob’s dad was diagnosed with Gleason 6 prostate cancer. He had a prostatectomy in 2013. In 2016, Rob’s cousin had a PSA of 8.9, was diagnosed with Gleason 9 disease, and once again, Rob’s experience helped him show his cousin the path forward; he, too, had a prostatectomy.

There are several take-home messages here:

  • It’s up to you. Many doctors don’t order PSA screening during a routine physical, especially in men who don’t have a family history of the disease or in men younger than 50. If you’re age 40 or over, you should get a baseline PSA test, and then get it checked regularly afterwards. It’s easy: if you’re getting your blood checked anyway for cholesterol, lipids, etc., adding PSA to the list of things to be looked at is just a matter of your doctor checking a box on the lab form.

  • Do what you need to do. Rob really needed to know what was going on. At one point, his family suggested that he “was becoming a bit of a PSA junkie,” Rob recalls, and he asked himself: “Am I actually losing my mind? Am I looking for a problem?” But when his father and cousin were diagnosed with prostate cancer, “suddenly everyone in the family realized this was genetic” and appreciated Rob’s efforts.

  • Find doctors you have confidence in, and go to the best place you can. Many studies have shown that if you get treated for a disease – any disease – at a large-volume hospital where they treat a lot of people with this same problem, you will do better. Your cancer will be less likely to return, and you are less likely to have complications from treatment because they are really good at treating it there.

  • PSA fluctuates. There are many reasons why; if you have an infection in your prostate, engage in some form of intense physical activity, or have intercourse one to three days before your blood is drawn it could result in a higher PSA than normal. BPH and prostatitis can also drive up the PSA level.

  • Be prepared, or as Rob says, “Stay in front of the 8 ball.” Rob not only banked sperm ahead of time just in case he had his prostate removed; he researched various forms of treatment and – very important – got himself in the best possible shape for surgery. During the almost two months between his conclusive biopsy and prostatectomy, “I worked out every day as if I was training for a marathon,” he said. “I never missed a day at the gym. So when it was game time, aka the surgery, I was going to be in the best possible shape I could be and ultimately recover faster. In fact, just two hours after I was in my hospital bed post-surgery, I was up and walking laps around the unit in the hospital while some men were literally unable to get out of bed for a day or two because of their physical condition going into surgery.”

  • Take care of your family. “I have a brother, and three young sons, ages six, four, and two. God willing, nothing will happen to them,” but Rob will be on guard, making sure they get regular PSA screenings. He also made his sister aware that her risk of breast cancer may be higher, too, “once I started reading about the correlation between breast and prostate cancer I recommended that both she and my brother take the germline test. ”

  • Help your friends. Rob didn’t tell many friends before surgery that he had been diagnosed with prostate cancer. “I didn’t want it to become a ‘Woe is me’ situation and I certainly didn’t want to expend any energy fielding dozens of phone calls asking how I was doing, even though I know it was because they genuinely cared. I just needed to focus on preparing for the surgery and the recovery process.” He also told his wife, “I want to be the guy you can confidently point to regardless of where we are after you overhear somebody saying, ‘I’m scared, my husband is scared; he’s just been diagnosed with prostate cancer.’ It’s at that very moment you can say, ‘See that guy over there? Go talk to him. He had his prostate out X months ago and you would never know it.’ That’s the value I can take away from this recent journey: an experience I can share with others who find themselves in a similar situation.

“I was fortunate enough to dodge a bullet, and I want to – I feel obligated to – pay it forward. Any chance I can get to alleviate the fear that is most often fueled by uncertainty is something I want to offer. The anxiety that people are living with because they simply don’t know what to expect, where to start, or better yet, the incredible resources that are available to them as long as you know where to look;; the playbook, if you will. I did the Kegel exercises religiously as prescribed before and after surgery, which led to my getting off the pads after just two months, Sexual function is also fine, which was a welcome surprise.”

  • Reach out. Rob, who couldn’t let it go during the search for prostate cancer, isn’t about to let go now; in fact, he hopes that other men will be helped by his story. “This disease affects one in eight men over a lifetime – and more specifically, my grandfather, my father, my cousin, and me.   When I talk to friends who don’t know what a PSA test is, it proves there needs to be an even louder rally call and greater effort to educate and increase awareness around prostate cancer – so that like me, others can stay ahead of it, make the right decisions, and live long, healthy lives after detection and surgery.”

*Name has been changed, at Rob’s request, to protect his privacy.  The names of the doctors in this story have not been changed.

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

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Coffee and Prostate Cancer: Go Ahead, Have Another Cup

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

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PSMA-PET and Prostate Cancer

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

 

 

 

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ED After Prostate Cancer Treatment: Old School Approach Not Good Enough

Just when everything should be getting better – you’ve been diagnosed with prostate cancer, gotten curative treatment with surgery or radiation, and now you’re looking forward to getting your life back – there’s another bump in the road: ED (erectile dysfunction). You don’t need that!

Darn it, here’s yet another “reluctant brotherhood” – a club, like that of prostate cancer, that you never wanted to join. Take heart: You’re not alone, and it’s going to get better.  But your road to success may not be a little blue pill.

Maybe you’re like a lot of men who, before treatment, envisioned themselves boldly striding forward toward recovery of potency – perhaps temporarily using Viagra, Cialis, or another pill in the class of PDE5 inhibitors as a crutch until erections returned on their own.

Unfortunately, for some men, these might as well be sugar pills. They just don’t work as promised. And instead of striding forward boldly, they find themselves making uncertain progress like the Wayfarer, a character painted by Renaissance artist Hieronymous Bosch: a poor guy just trying to get somewhere down a troubled path.

For too many men, the road back to potency is a lot more difficult, confusing, and frustrating than it has to be. This makes me mad, because I have talked to men and their families who just don’t need another health burden to deal with. It makes Johns Hopkins urologist Arthur Burnett, M.D., mad, too, and he is doing something about it.  

Burnett is a surgeon-scientist, a neuro-urologist and pioneer in the understanding of erectile dysfunction (ED). His research on the biochemical mechanisms of nitric oxide in erectile tissue contributed to the development of Viagra and other PDE5-inhibiting drugs.

Burnett is also a world-recognized authority on treating the problems in sexual function that can occur after surgery or radiation for prostate cancer – and there are several. “ED is one thing,” he says, but it’s not the only potential roadblock to sexual recovery. “Some men also develop scarring in the penis, a condition known as Peyronie’s syndrome. Some men have climacturia, where they may release a little urine during sexual stimulation or climax, so that’s problematic. There’s a whole host of things that can go wrong,” and all of these problems can be treated.

By far the most common problem after prostate cancer treatment is ED, difficulty achieving or maintaining a penile erection. The American Urological Association has just revised its guidelines on treating this. Burnett, who co-chaired the committee to change these recommendations, says they were brought about by an evolution in thinking. “Treatment should be based on shared decision-making,” he states. “Patients should have the opportunity to have a full discussion on ED with their doctor – the variety of options to treat it, the likelihood of success – and options should exclude those that may have contraindications,” that aren’t recommended in their particular case, or that probably won’t help them.

Makes sense, right? And yet, Burnett has seen thousands of patients from all over the world who have not had such a discussion with their doctor, or whose doctor has continued treatment that not only isn’t working, but never was going to work.  

The old model – the one that emerged close to two decades ago with availability of PDE5 inhibitors – had well-defined steps to follow.   “We initiated therapy along the lines of first line, second line, and third line,” explains Burnett.   The first-line treatment was the pills, “the least invasive form of therapy.”

Erection is a vascular event; it involves blood flowing into the penis, being held inside there, and then flowing back out. The nerves that are responsible for erection lie in fragile neurovascular bundles on either side of the prostate, a discovery made by my co-author on the books, Johns Hopkins surgeon Patrick Walsh, M.D., who found that if men had one or both bundles preserved during prostatectomy, it was still possible for them to recover erectile function. However, he reported that patients who were older or who had one bundle were not always successful in recovering erections, and even men who had both bundles preserved, if they had vascular problems or other health issues, were more likely to have trouble.

Burnett has spent years studying these nerves, and he has found that the surgery itself – the traction on the nerves, and the stress of having an invasive procedure – can damage them. Often they recover, but sometimes they don’t. So even if, theoretically, a man should be able to produce an erection, it’s not guaranteed.

Many men – even though their nerves have been spared – “are not likely to respond to PDE5 inhibitors,” Burnett notes. These patients, particularly men with significant vascular disease, “need to be counseled in realistic terms on their likelihood of responding to these pills, balanced with their preferences, to try to get to the most effective therapy sooner rather than later,” says Burnett.   “Vacuum pumps and injections have traditionally been second-line treatments, but perhaps that should just be put on the table up front. Even penile prosthesis surgery should be put on the table early on for patients with more severe forms of ED. If men are already struggling with erections before surgery, after radical prostatectomy, they’re going to have even more trouble, and more frustration.” In other words, if you were relying on Viagra before treatment, the pill probably isn’t going to have the same effect that it used to.

“I see patients in my clinic who might best have been fast-tracked to a penile prosthesis early.” Burnett even sees men who had “non nerve-sparing” surgery – that is, both neurovascular bundles were removed (which is the right thing to do if cancer has reached these nerves) – who have been “done a disservice,” by being offered medicine that is simply not going to work for them. “Oral therapy depends on a necessary degree of intact nerve function,” Burnett explains. In other words, the pills augment what the nerves are already trying to do. “Their doctor says, ‘Let’s just try PDE5 inhibitors,’ but there are no nerves for penile erection. They start the first-line therapy. Then it’s, ‘Let’s wait another six months; keep trying.’” And that is not acceptable, in Burnett’s opinion. “We have to understand how these different therapies work, think about the clinical presentation of the patient, the variables that may impact his erectile physiology.”

Just having “all guys get first-line treatment, no matter what, and seeing how they do, then ‘maybe we’ll consider vacuum pumps and see how that goes for several months, and if it doesn’t work, we’ll consider injections’ – that’s not good enough. “It’s a much more practical model we’re evolving, one that’s focused on the patient’s desires and what is most likely to be effective.”

Make no mistake, Burnett adds, “if the patient has undergone a good-quality nerve-sparing radical prostatectomy, we should give his nerves the opportunity to recover function,” and not just jump to the third-line treatment, the penile prosthesis, right away. Nerves can continue to recover and erections can continue to improve even as long as four years after surgery. But that doesn’t mean a man should just stoically wait to resume his sex life until the day he achieves a decent erection, either. Maybe try a PDE5 inhibitor and a vacuum erection device, for instance.

Why do so many doctors insist on starting with the pills? Maybe they don’t take the time to find out how well the man’s erections were before surgery; maybe they don’t take heart disease or other health problems (again, some illnesses can hinder blood flow to the penis) into consideration – or maybe, as Burnett suspects, “they think, ‘the pills don’t have much of a negative impact,’ even though the patient will be frustrated for months.” Or maybe “they think, ‘More invasive therapies carry risks. Let’s see how he does,’ and they don’t consider that his sexual dysfunction can have a real impact on his health and wellbeing.” Too many doctors, he adds, “just pat ‘em on the back and say, ‘Things will be fine; you’ll be all right.’”

            But months and months of an unrestored sex life can be demoralizing, Burnett continues. “That’s why I think it’s more humane and appropriate to proceed with effective management of patients – not just treating ED by recipe. If somebody really is not predisposed to do well with PDE5 inhibitors, why push that on him?”

Similarly, injections work very well for some men, but not for others; men who have a large belly or who have poor hand-eye coordination, for instance, have difficulty. Other men simply “don’t feel that doing a needle injection is something that appeals to them. Why would we tell a man that’s all he’s got, instead of referring him to a penile prosthetic surgeon?”

Vacuum erection devices also have their pros and cons. “On the pro side, it’s noninvasive, and it’s fully under the control of the patient,” says Burnett. “But on the downside, it’s cumbersome and mechanical, it involves trying to draw blood into the penis, there’s a constriction band, it feels cold, and it can feel unnatural. Just put it on the table, and try to figure out what will work for one patient at a time – not some rote approach.”

Most men who get a penile prosthesis are happy with the result, says Burnett. “The erection feels natural, and they wonder why they didn’t get it sooner.” Why don’t more men with severe ED choose this option? “Part of it depends on how we in the medical community have presented it to patients.” Many of Burnett’s patients come to him after years of feeling frustrated with the first- and second-line treatments. “All too often, I hear patients say, ‘My internist said never get a penile implant; they get infected, and mechanically they don’t work.’ That’s unfortunate that this is what they’re being told.” In the 1970s and 1980s, penile prosthetics were not as reliable and were more prone to malfunction, but they have vastly improved since then.  

“Just like every other option, the prosthesis has its pros and cons. There is a 1 percent infection risk with prosthetic devices.” Burnett notes that doctors who are “infrequent implanters” tend to have higher infection rates, while “for expert surgeons, high-volume implanters, the infection rate is very low.” Burnett implants 80 or more penile prostheses a year, and “if I see an infection even once a year, it’s very rare.”

Patrick Walsh has told his patients for years, “if there’s a will, there’s a way,” and if they want to have a sex life after surgery, they can. Burnett, Walsh’s longtime colleague, adds to that message of hope from the doctor’s standpoint: “Never give up on a man who wants to preserve and restore his opportunity to be intimate with his partner.   We should try to explore options to help him achieve that.”

There’s one other important message here: Watch out for shysters. “Don’t waste your time or money with over-the-counter treatments or supplements,” says Burnett. They don’t work. Also, be very suspicious of high-cost experimental treatments. “The Sexual Medicine Society has taken a stand about some of this, and in our new ED guidelines for the AUA, we make it very clear that some things are investigational and require further evidence to show that they work.” These include shock wave therapy, stem cells, and platelet-enriched plasma injected into the penis. “Guys are being told, we’ll give you a couple of shots, and you’ll be fine. They pay out of pocket – $10,000 for as yet unproven therapy. It’s reprehensible, people out there trying to exploit these men. It is really terrible.”

It’s particularly terrible when there are medically proven approaches that Medicare and insurance will pay for that can actually restore a man’s sex life.

 

How Common Is ED After Surgery or Radiation?

 

Answering this question is more difficult than you might think, for two reasons: First, every surgeon and radiation oncologist has different results, based on expertise and the number of times the doctor has performed the procedure. So that’s one variable. The other variable is huge – and that’s your personal health. Start with the SHIM score, which is based on a few simple questions. You must be honest here. No one else will see these answers but you and your doctor.

After surgery: “In general,” explains Burnett, “erections are temporarily lost in many men who have a radical prostatectomy. Even with nerve-sparing, the nerves can be traumatized.   It takes a while for these nerves to recover. Although men may have some sporadic erections, it is very common for men not to be able to have consistent erections during the first nine to 12 months after surgery, without help.”

In men who are able to be sexually active without the help of a PDE5 inhibitor before nerve-sparing surgery, the potency rate after surgery gets better over time. “The potency rate at six months is different than at 12 months, and it’s even better at 24 months,” says Burnett. “Most men who had nerve-sparing surgery are going to recover erections in the second year.” Over the long term, he continues, “probably 80 to 90 percent of men who have pre-operative erections have the potential to recover erections without PDE5 inhibitors – if they have no other co-morbidities.”

This is the key. Co-morbidities are other health problems that could affect blood flow – particularly, blood flow to the penis. Major risk factors for not recovering erections, even if you have nerve-sparing surgery, include being a cigarette smoker (cigarettes are vasoconstrictors; they cause your blood vessels to contract); having diabetes, and having cardiovascular disease. There are other conditions and medicines that can affect erections, as well; this is why you need to have an honest discussion with your doctor about your current health and sexual function before treatment.

What about after radiation treatment? It’s kind of the opposite situation. “Unlike surgery, where you have a major loss and then you recover, with radiation you’re pretty much fine and then many men tend to lose erectile function over time,” says Burnett. For these men, PDE5 inhibitors may help. “As many as 50 percent of men who undergo radiation experience a general decline after two or three years – but for the first two to three years, men do not experience any true erection impairment.” Unless, of course, they were already having problems before treatment. The honest SHIM score is important here, too, and so is the discussion of any risk factors that you may already have with your doctor.

Note: None of this means that sex is impossible after you have surgery or radiation treatment for prostate cancer. If you want it, you can absolutely have it, Burnett says – but you may need more than PDE5 inhibitors, especially if you are already experiencing some ED before treatment.

False expectations are cruel. “Patients need to recognize if they aren’t the optimal guy to fully recover potency after surgery without any help,” says Burnett.   “Today, I had a 56-year-old professional athlete in my office, who had a perfect SHIM score and stage T1c cancer.” This man is highly likely to have full recovery of erections after surgery, because his cancer is minimal, and his cardiovascular system is in great shape.

But another man with that same stage of cancer who is diabetic and a smoker might not have such an easy recovery of potency.   That man can still have a full and wonderful sex life, Burnett says, but it might require a penile prosthesis. Knowing this before treatment could spare that man months of frustration.

 

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

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Cancer, Gut Bacteria, and Your Poop

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

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