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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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Oligometastasis in Prostate Cancer: Curable?

What if you have cancer that is confined to the prostate, with just a little tiny bit outside of it? Are you doomed? It used to be that doctors thought, “Oh, man, he’s a goner, the cancer’s spread outside the prostate.” But scientists are learning that not all out-of-the-prostate cancer is the same, and just because a spot of cancer has popped out of the prostate, doesn’t necessarily mean that it can’t still be cured.

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

This is pretty much the way it’s been for men were treated for localized prostate cancer with surgery or radiation who have a rising PSA.   The options have been: salvage radiation or surgery, maybe a short course of androgen deprivation therapy (ADT), a vaccine, maybe a clinical trial, and then… waiting for metastases, long-term ADT, and other forms of treatment.

But here’s some promising news:  The window of curability may be wider than anybody thought. Until very recently, the dividing line between prostate cancer that was considered curable and cancer that might not be was the prostate itself – whether the cancer was confined to the prostate or had spread beyond it to a distant site. That’s not the case anymore, says Johns Hopkins radiation oncologist Phuoc Tran, M.D., Ph.D. In the most recent (2018) edition of our book, Patrick Walsh and I wrote the section on radiation oncology with expert opinion from Tran, an innovative scientist working hard to save lives from prostate cancer.

“Clinically speaking, we prescribe treatments for men with prostate cancer as though prostate cancer presents in clear clinical states,” he says.

Think of a Venn diagram: in one circle are “men we believe to have purely localized disease, and they are curable by surgery or radiation.” In the other circle are men with metastatic disease, men who are considered “treatable but not curable with our current therapies.  In general, this old treatment paradigm says that men with localized disease benefit mostly from local therapies like surgery and radiation and very little from systemic treatment like hormones and chemotherapy.”

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

This is a dramatic and very exciting change in scientific thinking, and it’s happening because several key advances have come together all at once. PSMA PET scanning now allows bits of cancer as small as a BB to be seen – and SBRT (stereotactic body radiation therapy) or SABR (stereotactic ablative radiation) make possible precision treatment. “SBRT and SABR are highly focused radiation given in an intense fashion,” says Tran. “I tell patients it’s like spot welding—focused on a small area, very intense, and theoretically ablative, meaning it kills all the cancer in that spot.”

The Baltimore ORIOLE Trial

Can this new SABR technology plus treatment of localized cancer help men with oligometastatic cancer? “We wanted to test our idea in a rigorous way,” says Tran.  “Our Baltimore ORIOLE trial is a randomized clinical trial in patients with oligometastatic prostate cancer (defined as three or fewer metastases).” To be eligible, men must have received either surgery or radiation for the primary prostate disease, and have had no hormonal therapy for their metastatic disease. “They can have had hormonal therapy in conjunction with treatment for their primary disease,” such as a short course of androgen deprivation therapy (ADT) with external-beam radiation therapy, “but not for their metastatic disease.”

Men are randomly assigned either to receive SABR to up to three metastatic sites, or to a short observation period of three to six months – but this doesn’t mean that the men assigned to observation can’t get SABR, Tran states. “The randomization is two to one to SABR, versus a short – no longer than one- to six-month – observation period, after which they can cross over to the SABR treatment.”

Other criteria for eligibility: small metastatic sites (less 250 cc) and a PSA doubling time of less than 15 months. “We chose less than 15 months because there are men who have biochemical failure or low-volume metastatic disease with long PSA doubling times, sometimes many years,” explains Tran. “These men probably don’t need any treatment immediately – or possibly, ever.  A PSA doubling time of less than 15 months allows us to zero in on patients for whom SABR treatment may make a difference.”

This study was funded by the Movember Foundation and the Prostate Cancer Foundation (PCF).   “The Baltimore ORIOLE trial had no preliminary data when we funded it, and without private funding, it would not have been possible. says medical oncologist Jonathan Simons, M.D., CEO of the PCF. “Generally, the federal government requires that you have one-third of the work done in advance, then they fund the other two-thirds of it. That’s a real deterrent to highly innovative projects, and this one goes after a central and potentially practice-changing question: Can these men be cured now, and be spared ADT and metastases later?”

The potential implications here are huge: “The data suggest that two-thirds of men – or perhaps even more – who progress from biochemical failure to metastatic disease progress first with oligometastatic disease,” says Tran. “The number of men who could be helped by this could be as high as 20,000 to 25,000 every year.”

Because of the possibility of long-term remission or even cure, the study has filled up fast, Tran adds. “Thus far, as expected, we have seen only minimal side-effects from the SABR, and all men continue to work and are able to resume their normal activities during the short treatment,” which generally lasts less than three weeks.  Early results “look promising.  The trial also has a number of cutting-edge genetic, blood and imaging studies associated with it that men would not have access to otherwise.”

The Baltimore ORIOLE trial is a collaborative effort involving Hopkins radiation oncologists Theodore DeWeese, Danny Song, Curt DeVille and Stephen Greco; medical oncologists Mario Eisenberger, Ken Pienta, Emmanuel Antonarakis, Michael Carducci, Sam Denmeade Channing Paller and Mark Markowski; urologists Ashley Ross and Michael Gorin; radiologists Steven Rowe and Martin Pomper; and statisticians Hao Wang from Johns Hopkins and Adam Dicker from Thomas Jefferson University.

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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ADT and Cognitive Impairment

Part Three of Four

Does ADT cause cognitive impairment? This question seems simple, but really, it’s more like opening a medical can of worms. So let’s ask a different question. Do men on ADT get cognitive impairment? Yes, some do. But many don’t. It is hard to pin down definitive facts here – like, how many men get it? What’s the risk at one year, two years, five years, and ten years?

Nobody knows the exact statistics, and there are several reasons why.

  • There are probably many more men on ADT with cognitive impairment than we know about. But they don’t spend enough time with their doctors, at 5- and 10-minute follow-up visits to renew their Lupron prescription, for their mental status to be evaluated. Cognitive impairment doesn’t always show up in casual conversation.
  • Scientists looking to answer this question aren’t using standardized criteria. For example, does hormonal therapy mean only ADT, or ADT plus another drug, like enzalutamide? Also, are we talking about actual Alzheimer’s disease here, or just an inability to find the right word quickly on a crossword puzzle?

Well, what about men who are actually showing signs of cognitive impairment? That’s not much easier; there are still more questions:

  • Would they have gotten it anyway?
  • Did they start ADT with some risk factors for dementia already on board?
  • If they are showing signs of dementia, is it because when they got on ADT they stopped exercising, gained weight, and experienced depression – and could one of those those factors actually be the tipping point?

I recently interviewed medical oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation (PCF), and medical oncologist Alicia Morgans, M.D., of Northwestern University, about ADT for the PCF’s website.  “We have reached a crossroads, and in some ways, it’s actually a sign of progress,” notes Simons. Long, long ago, heart disease wasn’t a big health problem – because people died of other things, like accidents and infections, and diseases that we now get routinely vaccinated for. Diabetes wasn’t a huge risk for many people; sugar wasn’t widely available, there was no such thing as soda, obesity was rare, and people were more physically active. Prostate cancer wasn’t that big a deal, either, because most men didn’t live long enough to get it.  “Not too long ago, men with metastatic cancer died within months or a few years of their diagnosis. Today, men with metastatic prostate cancer are living long enough to develop other problems, and doctors – who previously had just been focused on keeping these patients alive – are trying to figure out how best to keep them alive and well.”

What we have here is an issue of survivorship – living with metastatic prostate cancer, and dealing with the side effects and challenges of treatment.   Medical oncologist Alicia Morgans, M.D., M.P.H., of Northwestern University, is a pioneer in studying survivorship. Cognitive issues have not been much studied in prostate cancer, and scientists are playing catch-up. “It’s not fair for us just to look at the benefits of treatment anymore,” she says, “now that we are starting to understanding the risks better.”

One easy place to start is to make sure that all men who are put on ADT really need it.   Next, men on ADT need better follow-up to monitor their cognitive function.   Morgans believes cognitive impairment in men on ADT is “underreported, underappreciated, and underdiagnosed.” In a PCF-funded study, Morgans’ patients are taking brief neuropsychological tests; the tests look for changes in verbal memory, visual memory, attention, and executive function. She hopes to develop reliable tests that can be done online – tests that could be given to many more patients in clinical trials, so that investigators can get an idea of the scope of the problem.

Family and friends can help: Someone who is having cognitive impairment may not be aware of changes, or may not be able to articulate them well. But his family and friends can help bring worrisome symptoms to the doctor’s attention.

Layers of medication: One of Morgans’ patients, a 76-year-old man, had been doing fine on Lupron for years. But when his PSA started to rise, Morgans added abiraterone, and then enzalutamide. For this man, enzalutamide might have been the tipping point, “one thing on top of another thing, on top of another thing. He was experiencing confusion and forgetfulness,” she says. The man, a minister, was not able to write or deliver sermons anymore. “We decided, despite the fall in his PSA, to stop the enzalutamide.” Four weeks later, his cognitive function had improved, and “he continues to give sermons today.”

For this man, the key to cognitive issues seemed to be enzalutamide. For another man, it could be something different. It could be a different kind of domino effect – the higher risk of diabetes and cardiovascular disease, for instance; maybe these other health problems, in turn, affect the vitality of the brain. “There may be subclinical strokes or cerebrovascular disease that we don’t know about,” Morgans says.

Loss of estrogen? Morgans suspects that a change in cognitive function might also have something to do with a man’s estrogen levels. Women aren’t the only ones who make estrogen; men make it, too, at lower levels. But ADT causes men to have “very low levels of estrogens, lower than postmenopausal women have.”  In studies of women with breast cancer, she points out, “low estrogen levels on their own can be associated with cognitive decline. It’s not ‘chemo brain,’ it’s something different.”

Men with prostate cancer don’t need to have low estrogen levels in order for their cancer to be treated; it just happens as a byproduct. Normally, men need some level of testosterone in order to make estrogens. “Estrogen doesn’t have to fall for us to treat prostate cancer, but it does fall with the method we use – we know testosterone drops to a place it’s never been since puberty.” Would giving some type of estrogen along with the ADT be helpful? No one knows.

Depression is a risk factor for dementia; big changes in sleep habits can also be a risk factor. It may be that addressing each of these separately – with an antidepressant, with exercise, and with melatonin to help with sleeping – could help keep the brain working better.

What about changes in the way ADT is given? Intermittent therapy may be an option. This could mean giving ADT, stopping it for a few months, and then starting back up again. “When men go off ADT, their testosterone comes back, they feel better, think better, their executive function is better – their ability to do a crossword puzzle, or find a synonym, or find the word they’re searching for – and they feel more like themselves again.” Another approach, as investigator Samuel Denmeade is testing at Johns Hopkins, is “bipolar” hormonal therapy: alternating ADT with its polar opposite – high-dose testosterone.

Could “brain exercise” help? Maybe. Crossword puzzles and mind-challenging games may indeed act as mental push-ups and sit-ups, says Simons.

The ultimate goal for treatment, scientists and doctors agree, is to find a way around ADT altogether, or to change it somehow so that the prostate cancer is affected, but the brain is not. Until then, it’s up to doctors to use ADT wisely, only when it is medically appropriate. “Using hormonal therapy has to be more than just a reflex, like giving people penicillin for a head cold,” Simons states. “The PCF, in fact, is actively funding research for other ways to treat metastatic cancer that don’t involve hormones at all.”

It’s also up to you, too, to make sure you start ADT only if and when you need it. If you are at intermediate- to high-risk of recurrence, or if you have a rising PSA but no evidence of metastatic disease and your doctor wants to put you on ADT, get a second opinion. You may also be eligible for a clinical trial of a different kind of therapy that does not affect your hormones, including treatment for oligometastasis — SBRT radiation to a few spots of cancer in your bones, or surgery to remove cancer that is just in one lymph node.

If you do have metastatic disease, right now ADT is the standard of care, and it could put your cancer into remission for many years. There is a lot you can do to help mitigate the side effects – which, in turn, may help protect your brain.

———

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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Gene-Targeted Treatment for Prostate Cancer

In a matter of weeks, Mark Meerschaert went from being an athlete to someone who could barely walk; metastatic prostate cancer had come from nowhere and spread like wildfire throughout his body.

A highly respected mathematics professor and researcher – the kind who fills up the blackboard in his classroom with labyrinthine calculations to answer questions of probability, statistics, physics and the like – he did what he does best: looked at the numbers. Men with widespread prostate cancer that is not responding very well to standard-of-care treatment don’t live very long.

So then Mark did what I hope everyone with a challenging diagnosis will do: He became his own advocate. He did some research and found a different doctor, Heather Cheng, M.D., Ph.D., a medical oncologist at the Seattle Cancer Care Alliance, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center. She also started the world’s first prostate cancer genetics clinic.

It turns out that Mark has a mutated gene that runs in his family. It’s called BRCA2, and when it is not working as it should, it’s more notorious for increasing the risk of breast and ovarian cancer; recently, scientists discovered that it increases the risk of prostate cancer, too.

Because of Mark’s bad copy of BRCA2, Cheng immediately focused on this gene and suggested a very different type of treatment – off-label use of a drug called olaparib, currently approved by the FDA to treat ovarian cancer. Olaparib is a PARP inhibitor; basically, it blocks a protein that cancer cells need to repair themselves, and has worked especially well in people with defects in the BRCA2 gene. Olaparib and other PARP inhibitors such as rucaparib and niraparib are currently being studied in clinical trials for prostate cancer patients.

I want to pause here just for a moment to make two points. First, among the many very smart things Cheng did was to get genetic sequencing of tissue from Mark’s metastatic cancer.   This is because cancer can change over time. We’ll talk more about this in a minute, but if you have metastatic cancer, there may be different mutated genes than in the younger cancer that was originally diagnosed from the needle biopsy of your prostate. This matters because there may be a new medicine that works well with your particular mutated gene or genes. The other really important point is that, because these new drugs are so specific, they don’t work for everybody. One drug might only help a small percentage of men. But another new drug might help a different small percentage, and a third new drug might target still another small percentage – and you might fit into one of those groups. So take heart! There are entirely new drugs being developed.

“She said, ‘Let’s try something else,’” Mark recalls. Cheng told him that the medicine may take a few months to kick in fully. “I started olaparib in October of 2016. At the end of 2016, we did a bone scan, and saw that there was cancer all over the place: my ribs, hips, legs – I can’t remember all the places – some lymph nodes. One day, I walked my dog, and I had to sit down,” right in the middle of the walk, “and rest for 20 minutes.”   That fall, Mark – on the faculty in the Department of Statistics and Probability at Michigan State University in East Lansing – organized a conference.   He was the moderator, and was supposed to stand up for five minutes between talks and moderate discussions. “I couldn’t stand up for five minutes.”

He used a cane, then a walker, then a wheelchair. He took a leave of absence from his job. Now he is looking forward to going to work. “The great thing is,” starting early in 2017, “I just slowly started to feel better and better,” he says. “At some point, I said, ‘Maybe I can go for a walk again. I had a little numbness in my foot, but I said, ‘I’m going to keep walking,’ so I did. I walk my dog every day, a couple of miles. Now even the numbness is gone.

“In the last six months, I’ve gone from shockingly, disastrously ill to feeling – I’m still cautious, still waiting for the other shoe to drop; nobody knows how long this is going to work,” Mark told me when I interviewed him for the Prostate Cancer Foundation’s website, pcf.org. “There’s no data on people like me. Now I feel great.”

Unexpected Family History

Mark is one of the pioneers of gene-targeted treatment for prostate cancer – medicine that, as Cheng explains, “is tailored to the weakness of his cancer resulting from a specific gene mistake in that cancer, rather than just treating it the same as all prostate cancers.” In other words, treating the gene, not the cancer.

“I knew that I was BRCA2 positive before I was diagnosed with prostate cancer,” he says; after his brother was diagnosed with breast cancer, several members of Mark’s family got genetic testing. But he never expected to get prostate cancer. In fact, although Mark had gotten a PSA test every year, he had stopped. “My doctor said, ‘We don’t need to do PSAs.’ For two years I didn’t get a PSA.”

Mark believes the policy of not screening men – which recently was revised – because of a fear of overtreatment is misguided. “A PSA costs almost nothing. To me it’s a misreading of the statistics,” somehow saying it’s worse for some men to get unnecessary biopsies than for other men to miss their shot at an early cancer diagnosis.

In 2013, Mark developed some urinary symptoms and went to see a urologist. Cancer was found.  Around this time, he received some bombshell news: “My dad had prostate cancer. But I never knew that until after I was diagnosed. Had I known, I would have kept PSA screening.” Mark’s father had been treated for prostate cancer when Mark was away in college, and his parents never said a word. “I’m a big fan of sharing knowledge with your family, even though it might be a little embarrassing. You might not feel comfortable talking to your kids about things like impotence, but they really need to know.”

Mark underwent external-beam radiation therapy and a two-year course of androgen deprivation therapy (ADT), which ended in March 2016. “By July of 2016, something just felt a little off. I went to see a urologist. He said, ‘I don’t think it’s anything to worry about, I saw something kind of weird, so I sent it off for a biopsy.’ It came back as high-grade cancer,” Gleason 9. The prostate cancer had come back with a vengeance.

Genetic tumor sequencing: When Mark went to the Seattle Cancer Care Alliance, “they got the tissue from last July and sequenced it.” As Cheng suspected, the genetic makeup of the cancer in Mark’s first prostate biopsy in 2013 was not the same as the tissue removed in 2016, after the cancer had time to mutate and become more dangerous. “They found out that I have the BRCA2 mutation in one of the two copies in my germline, but in the metastatic cancer cells, it was mutated in both copies.

“Dr. Cheng said, ‘Your cancer is very aggressive, but that might work in your favor going the other way.’ That turned out to be absolutely correct. It got bad really fast, and it got better really fast.” He is still taking the olaparib. “I guess I’ll keep taking it as long as it works.   The question is, what happens next?

“I’m very interested in things like the five-year survival rate for people like me. Nobody knows. They’ve only been using this since 2015, and the studies were on ovarian cancer.”

So there are no guarantees. However, Mark says, “I can deal with that. I do feel like this is something pretty remarkable. My God, what if this had happened five years ago?”

Update:  I wrote this in 2017.  It is now 2021, and I just learned that Mark passed away in August 2020.  I don’t know any of the details, but the obituary said “after a courageous battle with cancer.”  I can only assume that the prostate cancer came back, although it’s possible it could have been a different cancer linked to a BRCA mutation.  If Mark had gotten this treatment today, and the cancer had come back, it might have been possible to hit it from another angle with PSMA-targeted treatment.  I am just devastated to hear this.  He was an inspiration to many.

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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Surviving Cancer and Beyond

I had the privilege of meeting Paul Calobrisi through my work with the Prostate Cancer Foundation.   He is a prostate cancer survivor, and also a bladder cancer survivor. Basically, he is someone who has seen way, way too much cancer – in himself and in his family. He is also a remarkable person who has gotten through really awful things by being a smart partner in his own care. Somehow, he has managed to keep his sense of humor, too. Read more

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Hope for the Future:  An Engineered Bladder 

health tissue “Tissue engineering is the ultimate in reconstruction,” says David McConkey, Ph.D., Director of the Greenberg Bladder Cancer Institute at Johns Hopkins, “and we have a fantastic team” working to create a new bladder out of a patient’s own cells.

Using a scaffold to layer stem cells and similarly “plastic” cells called progenitor cells – kind of like chameleons, they can become different types of cells, depending on their environment, urologist Trinity Bivalacqua, M.D., Ph.D., and colleagues are doing “3-D chemistry,” McConkey explains.  Getting these cells to take their proper places on the scaffold has been a huge challenge, “but Trinity solved it.”  If this work proves successful, one day instead of crafting a neobladder (artificial bladder to replace a cancerous one) out of bowel tissue, surgeons will simply remove the old bladder and put in a brand new one. 

I interviewed McConkey and Bivalacqua recently for Discovery, a magazine published by the Brady Urological Institute at Johns Hopkins.   “We envision developing a clinically functional, tissue-engineered bladder by the end of 2025,” Bivalacqua told me.  He and a “regenerative urology” research team are working hard toward this goal, buoyed by recent breakthroughs in the practical mechanics of how to do it.

The key is the organic framework that allows the patient’s own cells to grow over it.  Bivalacqua is the first investigator to successfully complete a Phase 1 clinical trial in bladder cancer patients using this “autologous cell-seeded scaffold” to replace the urinary system after radical cystectomy, the surgical procedure to remove a cancerous bladder.  “Although the Phase 1 trial demonstrated regeneration of urinary tissue, the neo-urinary conduit was not durable,” so the team brainstormed and “outlined a road to success,” Bivalacqua says.

The interdisciplinary team includes Bivalacqua, a surgeon-scientist, Anirudha Singh, Ph.D., a biomaterials and tissue engineer, and Nikolai Sopko M.D., Ph.D., a stem cell biologist.  Their strategy begins with designing more durable materials “that will function as urinary tissue for a long time.  The use of regenerated urinary tissue is necessary.”  Currently, replacement bladders are made using part of the patient’s own intestine; this is not ideal and complications are common.

Singh’s laboratory recently developed a novel process to make collagen scaffolds for “urological neo-organs.” Collagen, Bivalacqua explains, “is one of the most suitable biomaterials, and is a natural choice here.”  But developing a good scaffold proved a tough challenge, “until Singh’s laboratory created a simple yet elegant collagen molding technology, which resembles synthetic polymer processing methods, to create neo-organs.” The versatile design has “unprecedented features and user-controlled mechanical and biological properties.”  A patent is pending.  “Specifically, this process developed hollow and tubular collagen systems ranging from ureter-like micro-sized tubings to tubes with designer lumen that resembles intestinal villi, to complex seaweed-like structures as multiple mini-bladders for regenerative urology applications.”

This research was published in Nature Biomedical Engineering.  As Singh continues to refine the scaffolds, Bivalacqua and Sopko’s laboratories are developing animal models for testing them. 

©Janet Farrar Worthington

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Prostate Cancer and Your Genes

If your mom had breast cancer, that could raise your risk for prostate cancer.  If you have aggressive prostate cancer, your daughter might be at higher risk for ovarian or breast cancer.  Some “bad apple” genes run in families; doctors know what they are, and there’s a blood test to look for them.

For the last two decades or so, doctors and scientists have talked a lot about genes and genetic testing, and about gene-fixing medicines that can stop cancer in its tracks. Until recently, with a few exceptions, that’s mostly what it has been: talk, and frankly, a fair amount of hype.

That’s changing.  I recently interviewed Jonathan Simons, M.D., medical oncologist and molecular biologist, and also President and CEO of the Prostate Cancer Foundation, which has funded some of the most exciting research in this area.   “Everybody talks about genes,” he says.  “But what really matters is, how does it help you?  How can it help your children and grandchildren?” 

medical laboratoryA new blood test called the Cascade Genetic Test looks for mutations in several known “bad apple” genes.  These are genes that are supposed to repair DNA damage. When they malfunction, it is easier for cancer to develop. 

What does this mean to you?  Well, say you’re a man with a rising PSA, and a biopsy shows just a small amount of low-grade cancer.  Your doctor might want to wait and do another biopsy in six months to a year, and you might decide to get yet another biopsy a few months after that.  But what if you could add a very important piece of extra knowledge to the puzzle?  What if you could find out whether you have one of these bad genes?  That might lead you to seek treatment right away, before the cancer has a chance to get established outside the prostate. 

Another thing: “If a man tests positive for one of these genes, his sisters, brothers, and children will need genetic testing, as well, because of the high probability that their cancer risk has been significantly elevated,” says Simons.  “Men on active surveillance should have these genes tested.”

Very important: Testing positive is not a cause for alarm, or for making panicky, hasty decisions.  “Genes don’t have to be your destiny,” notes Simons. 

In other words, if you have one or more of these genetic mutations, cancer is not a done deal.  But it’s on the table.

A man diagnosed with prostate cancer who has one of these mutated genes needs to take that cancer diagnosis very seriously, even if it seems to be low-level, “safe” prostate cancer. 

It turns out that more than half of American men are carrying a gene that they inherited from either their mother or their father that increases their chances of getting prostate cancer.  “We now know that prostate cancer is perhaps the most heritable of all the major cancers,” says Simons.  Again, having one of these bad genes doesn’t mean that cancer is inevitable – which also means that having a healthy diet and lifestyle may help prevent cancer from ever getting started – but it can make it easier for cancer to spread and become difficult to treat.

“The genes tell their story,” says Simons.  The good news is that, for the first time, a test can provide the Cliff’s Notes preview of what that story might be.   For more on this test, keep reading.

Bad “Spell-checker” Genes

mindless wanderingAn important study, led by Fred Hutchinson Cancer Research Center medical oncologist Peter Nelson, M.D., funded in part by the Prostate Cancer Foundation, and published in the New England Journal of Medicine, is changing how we think about prostate cancer. What Nelson has found can be summed up like this: 

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

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

If you have a mutation in one of these genes, your sons and daughters, and their children need to know about it, because they are more likely to develop cancer, too.

Every gene has a job.  Some of them act like brakes that control cell growth; some do just the opposite, and instead of curbing growth, they step on the accelerator and speed it up in a bad way.  Some genes are tiny Xerox machines, making genetic copies.  And some genes are little quality control specialists; they’re the spell checkers. 

The genetic mutations we are born with are called germline mutations.  Those are different from the kind of incremental gene mutations that develop over time – through exposure to carcinogens in cigarettes, for example, or eating a bad diet, or drinking too much alcohol.   

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

“Now wait,” you may be thinking, “aren’t they the breast cancer genes?”  Yes, and for years, these genes were not significantly linked to prostate cancer.  Now we know that the very same mutation that can cause breast and ovarian cancer in women can cause lethal prostate cancer in men. 

Other bad DNA-repair genes include one that sounds like it should be at a bank, called ATM; and one that sounds like a roadie making sure the microphones work at a concert, called CHEK2; there’s RAD51D; and one that sounds friendly but isn’t at all, called PALB2, which is strongly involved in pancreatic and breast cancer.

These gene mutations are rare in the general population, but startlingly common in men with metastatic prostate cancer:  Because of this work, Nelson and colleagues estimate that one in nine – 12 percent – of men with metastatic cancer have them, even if they have no family history of prostate, breast, or ovarian cancer. 

And this last part is actually hopeful because it means that cancer is not inevitable if you carry one of these mutations.  It may well be that if you live your life doing some things that we know help prevent or delay prostate cancer – not eating a lot of red meat and dairy products, eating foods like broccoli and tomatoes, not smoking, not drinking an excessive amount of alcohol, and not being overweight, which adds stress to your cells and makes them less resistant to cancer – that you will never develop prostate cancer.  And if you start getting screened for prostate cancer at age 40, and if you are then screened every year to look for changes in your PSA and other markers, that if you do develop cancer, it will be caught early and you will be cured.

headacheSo don’t despair.  But if you have metastatic prostate cancer, Nelson recommends that you get genetic testing, because your kids and grandkids need to know if one of these bad genes runs in the family – so they can be considered high-risk for certain types of cancer, screened vigilantly, treated aggressively if cancer is found, and most important of all, live to a ripe old age and not die of cancer.

Other hopeful news:  There are entirely new kinds of cancer-fighting drugs that target specific genes.  One class of drugs is known as PARP inhibitors, and the standout in this class is Olaparib, which is being used to treat women with BRCA mutations in ovarian cancer.  It has now been approved as a treatment for advanced prostate cancer in some men. 

What should you do?  If you have high-risk or metastatic prostate cancer, or if you have a strong family history of prostate or other cancers, ask your doctor about this test. It costs $250 at Color Genomics.

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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