A full-on assault of high-risk prostate cancer with intensive neoadjuvant hormonal therapy before surgery marks a huge shift in medical thinking.  Instead of doing things in a well-ordered sequence, oncologists like UCSD’s Rana McKay are launching many weapons earlier than ever, when cancer is less prepared for battle, and they’re going for a cure.

Why the No-Holds-Barred Approach Now?

Which scenario would you prefer:  “I’ve got high-risk prostate cancer.  I sure hope it doesn’t come back after surgery or radiation!  Fingers crossed!  My doctor and I are really hoping for the best!” or,

“I’ve got high-risk prostate cancer that has a chance of coming back after initial treatment.  So, my doctor is going after it relentlessly, like Inspector Javert hunting Jean Valjean in Les Mis.

High-risk prostate cancer is formidable: it will spread if not treated and is more likely to recur after initial treatment.  That’s why doctors like Rana McKay, M.D., medical oncologist and PCF-funded Young Investigator at the University of California San Diego (UCSD) are now throwing the proverbial kitchen sink at high-risk prostate cancer as soon as it is diagnosed.

This marks a huge shift in medical thinking.  Advanced prostate cancer treatment in the past has been like a methodical series of “if: then” statements in math, like, “If A, then B,” or “C if and only if B.”  If cancer spreads beyond the prostate, then the traditional next step has been androgen deprivation therapy (ADT), shutting down testosterone and other male hormones that drive prostate cancer’s growth.  If the cancer becomes resistant to ADT, then other medications are added: chemotherapy and/or androgen receptor (AR)-targeting drugs (also called androgen-directed therapies, or AR-signaling inhibitors).

Over the last few years, doctors have been compressing this time frame, giving these AR-targeting drugs at the time that ADT is initiated – based on studies such as STAMPEDE, LATITUDE, suggesting that the cancer, which evolves and mutates as it spreads, is more vulnerable to treatment sooner rather than later.   Although these treatments can extend survival, they are not a cure.

What’s different about this new, full-on, kitchen-sink approach?  First, a high-intensity burst of hormonal suppression (ADT plus an androgen-directed drug, such as enzalutamide or abiraterone) is finite, given as neoadjuvant therapy for a few months before surgery and for up to a year afterward.  Then it’s over, and within a year, testosterone comes back.

Second:  “We are going for a cure,” says McKay.  This is worth repeating:  Going for a cure!

Early results of exciting clinical trials, with more on the way, are highly encouraging.  One Phase II trial still in progress, led at UCSD by McKay in collaboration with Mary-Ellen Taplin, M.D., of the Dana-Farber Cancer Institute, grew out of a 2014 PCF Challenge Award study, led by Taplin.  The investigators tested two combinations of drugs given for six months before surgery:  abiraterone and prednisone plus leuprolide (Lupron), vs. abiraterone and prednisone, Lupron, and apalutamide.  After surgery, “men were randomized to continue therapy for one year, or simply to be monitored.”  The initial results of this trial were presented at the American Society of Clinical Oncology meeting in 2020.

“We showed that about one out of five men who received intensive hormonal therapy up front demonstrated very residual amounts of tumor, or no tumor at all, in their prostatectomy specimen” when the surgically-removed tumor was thoroughly examined by a pathologist under the microscope.   This “pathologic response,” seen in the surgically removed tissue, “hasn’t yet been proven in prostate cancer to be associated with long-term outcome,” notes McKay.  “But in several other tumor types – breast, bladder, rectal cancer, and others – evidence demonstrates that the pathologic response is associated with overall survival.”  In follow-up data from this and two other neoadjuvant studies, recently published in the Journal of Urology, McKay and colleagues showed that “of those patients who had no tumor or very little tumor left behind in their prostate, the rate of recurrence (the average follow-up time so far is 3.6 years)  was significantly lower.  In our cohort of 117 patients, only two patients who had a pathologic response and minimally residual disease had a recurrence, and no man died of prostate cancer.  Our hope is that we will develop data to prove that a pathologic response is associated with long-term outcomes in prostate cancer.”

 In Some Responders at Prostatectomy, Cancer’s Already Dead!

Over time, prostate cancer acquires genomic alterations that help it to be more aggressive.  Each tiny mutation gives the cancer extra protection, maybe starting out with the genetic equivalent of a bullet-proof vest or stronger helmet, then becoming much more sophisticated – imagine a fighter jet deploying decoy flares or chaff as missile countermeasures.

Is it more vulnerable, and easier to kill, early on?  McKay and colleagues believe the answer is yes, and they’re testing this idea in several clinical trials.  One phase II study at UCSD still in progress, in collaboration with Taplin, involved 119 men with “unfavorable intermediate or high-risk disease.  “More than 90 percent of the patients had high-risk disease, and all of them, from the get-go, had very aggressive tumors,” says McKay.  “Over one-third of patients had Gleason 9 or 10 disease, and about 60 percent of patients had stage 3 cancer,” that had spread slightly beyond the prostate but with no evidence of distant metastases.  Men in the trial received either neoadjuvant abiraterone and prednisone plus leuprolide (Lupron), vs. abiraterone and prednisone, Lupron, and apalutamide.

One major reason why McKay and colleagues are testing this approach with surgery rather than radiation is to study the pathologic response: looking at how much residual tumor is present in the surgical specimen that has been removed after treatment.  Have they seen any changes?  Not in all men, but in about 20 percent, there’s a remarkable change:  “The primary tumor was dead and necrotic.”  The pathologists “looked at every little sliver of the prostate,” and found that these exceptional responders had either “less than 5 mm of tumor left behind, or no tumor left behind.”

Just think about that for a minute:  the surgeon removes the prostate, gives the tissue to the pathologist, who starts looking at it under the microscope and sees only corpses of cancer cells!

One patient who participated in this study is Pat Sheffler, who was diagnosed at age 53 with stage 3 prostate cancer and a PSA of 37.  He received abiraterone and prednisone, Lupron, and apalutamide for six months before prostatectomy, and started to see results right away.  In monthly blood tests before his surgery, his PSA levels dropped:  “34, 27, 21, 10, 4, 2, and 0.2.”  At surgery, he had “very minimal remaining tumor,” says McKay.  Then he underwent one more year of hormone therapy after surgery.  Two months after he stopped taking the trial medications, not only was his PSA undetectable, but his testosterone levels were coming back to normal.  “My hope for Pat is that he’s cured, that he can go on just being an amazing dad, husband, and advocate for prostate cancer awareness.”

In another phase II study led by Taplin, published in the Journal of Clinical Oncology, McKay and colleagues at UCSD, Dana-Farber, Beth Israel Deaconess Medical Center, Johns Hopkins, and the University of Washington reported a complete pathologic response (no remaining live cancer cells in the prostate) or minimal residual disease in 30 percent of patients treated with neoadjuvant enzalutamide, Lupron, abiraterone and prednisone before prostatectomy.

But what about the men who were not exceptional responders to big-gun hormone therapy?  The scientists have identified some key genetic changes in men who were non-responders, and they have some ideas about how to help these men, as well.

In several clinical trials, including this one, an intense blast of neoadjuvant androgen deprivation therapy (ADT) and androgen-directed treatment (drugs such as abiraterone and enzalutamide) has shown promising results in some men – but not all men.  Why is this?

McKay, Taplin, and colleagues have found an explanation:  Men who have not responded (who had a significant amount of tumor remaining after neoaduvant treatment) in these clinical trials have certain genetic differences in their prostate cancerloss of PTEN (a tumor suppressor gene, which is knocked out in as many as 70 percent of men with prostate cancer) or alterations in ERG (an oncogene that fuses with another gene, called TMPRSS2, in as many as half of all men with prostate cancer).

“Very few of the men who responded had PTEN loss,” says McKay, “and ERG positivity was also associated with lack of response.”  But these men also seem to have something else that might render AR-blocking drugs unhelpful: lower AR expression, compared to other men.  Basically, if a tumor does not seem to have a lot of androgen receptor activity, then a medicine that targets these receptors won’t have much to work with.

This information is not discouraging, McKay hastens to add:  it’s helpful!  It has taught the scientists that “the responders have a certain tumor profile, and non-responders have a certain profile.  Similarly, responders had mutations in a gene called SPOP” (which is mutated in about 10 percent of primary prostate tumors).

Knowing this, McKay adds, could be an opportunity:  a springboard for additional or different therapy – perhaps neoadjuvant chemotherapy, for example.  Remember:  you’re still ahead of the game here.  You don’t have metastatic cancer, and many scientists believe that high-risk cancer, when it’s localized, is still vulnerable enough to be cured, if it’s hit hard with multiple weapons.

“This is an opportunity for us to develop and design a personalized treatment strategy for these men,” says McKay.  “It would be awesome if we could use somebody’s own genomics to help design the best treatment for him – similar to what’s being done in the breast cancer I-SPY trials, neoadjuvant studies with multiple treatment arms, some determined by biomarkers (specific genetic alterations that show up in a blood or tissue test).

Some men with high-risk prostate cancer might respond better to a PARP-inhibiting drug, such as olaparib and rucaparib.  This is the focus of another study that will be starting soon, McKay says.  “In men who have germline (inherited) alterations, such as a BRCA1 or BRCA2 mutation, we hypothesize that giving a PARP inhibitor in a neoadjvant setting before prostatectomy might significantly improve pathologic response.  We are finalizing the protocol for NEPTUNE, a biomarker-focused neoadjuvant trial testing PARP inhibitors in localized prostate cancer.”

“It is really exciting to be part of this paradigm shift,” says McKay.  “We have the opportunity to improve outcomes for men with high-risk localized disease, and we’re in the midst of trying to prove that through well-organized, thoughtful clinical trials.

“At the end of the day, the question is, how can we help our patients live longer and live better?  That’s really the big driver.  The good thing about localized disease is that we can try to cure more men of prostate cancer – not just extend life for metastatic disease, but can we develop a pathway so they don’t ever develop metastatic disease, and so they can be cured?  That’s what we’re aiming to do.”  And, bonus:  after the big blast of intense hormonal treatment, most men get their testosterone back.  “Most patients actually recovered their testosterone fully within the first year of discontinuation of treatment.”

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

 ©Janet Farrar Worthington

 

 

 

 

 

 

 

 

You have metastatic prostate cancer, and your doctor has said you’re doing all you can do.  How can you be sure?  This is a post that’s very close to my heart, because I have met many men over the years who hear this from their doctors and they just accept it.  Maybe you truly are doing all you can do.  But maybe you aren’t.  With the hope of fighting the spirit of complacency or worse, despair, that can overtake anyone with an illness so easily, I recently interviewed Duke oncologist Andrew Armstrong for the Prostate Cancer Foundation (PCF).  He proved to be a kindred spirit, who wants to encourage men not to give up.

“This is all we can do” is a phrase no cancer patient wants to hear, especially someone with metastatic disease.  Medical oncologist and PCF-funded investigator Andrew Armstrong, M.D., M.Sc., hears those six words a lot – from patients who have come to see him at Duke University’s Cancer Center, a comprehensive cancer and clinical trial center.  The patients are hoping their local doctor was wrong – that this is, in fact, not all that can be done.

And here’s some good news:  Often, there is something more, and the list of options is growing even as we speak.  “The FDA has approved many new therapies for advanced prostate cancer,” says Armstrong.  The challenge, he adds, is in knowing which of these might be helpful for you – and which are likely a waste of your time and money.

Why don’t all of these drugs work for everyone?  Because underneath the umbrella diagnosis of metastatic prostate cancer are many factors that make the response to treatment different in each man.  Understanding whether or not you have some of these factors could not only save you thousands of dollars, but could point you away from treatment that is not going to work, and toward better, more promising options.

Do you need a “liquid biopsy?”  Armstrong and investigators at five centers recently completed the PROPHECY trial, funded by a Movember-PCF Global Challenge Award.  The study’s goal was to use a “liquid biopsy” – a blood test that can detect circulating tumor cells (CTCs) shed by prostate cancer – to evaluate a biomarker called AR-V7 as a predictor of response to androgen receptor-blocking drugs such as abiraterone (Zytiga) and enzalutamide (Xtandi).  AR-V7 is a variant androgen receptor that some men develop over time.  “AR-V7 does not show up when you’re first diagnosed with prostate cancer,” says Armstrong, “and it generally does not show up before you start hormonal therapy.  It only shows up when a patient has developed resistance to commonly used hormonal therapies like leuprolide or degarelix, and more commonly after he has been taking an androgen receptor pathway inhibitor like enzalutamide or abiraterone.”

The results of the PROPHECY study, published in the Journal of Clinical Oncology and updated this past year in JCO-Precision Oncology, showed that AR-V7 is a “negative predictive biomarker” for response and outcomes to abiraterone or enzalutamide.  In other words, if a blood test shows that your cancer cells have detectable AR-V7, these drugs are not likely going to be helpful for you.  There are two blood tests for AR-V7:  one is an mRNA assay developed at, and offered by, Johns Hopkins, and the other is a more widely available CTC protein-based assay made by Epic Sciences.  Both tests are good, says Armstrong.  “It’s common practice,” he explains, “that if a man has been on enzalutamide and his cancer has progressed, to try another hormonal agent such as abiraterone, and vice versa.  But that strategy can lead to cross-resistance,” where neither drug is effective in this patient.  “These drugs are very expensive.”  Abiraterone is now available in a much less expensive generic form, but enzalutamide can cost more than $10,000 – per month!   That’s a lot of money, particularly if it’s not going to help you.

New Strategy:  Shotgun and Sniper Rifle! 

If you have AR-V7, what should you do instead?  Think shotgun – many pellets aimed at the disease – and sniper rifle – a highly focused, precision medicine approach.  “The answer is not to give up, but also not to give therapies that don’t work,” says Armstrong.  “Right now, drugs that are more effective would be chemotherapy: docetaxel and cabazitaxel, and radium-223,” a drug that mimics calcium – and, like calcium, gets absorbed into areas of bone with a lot of cell turnover, particularly areas where bone metastases are forming.”  Treating cancer in the bones not only improves quality of life, but has been shown to increase survival.   Another experimental way to treat areas of metastasis is with stereotactic ablative radiotherapy (SABR, or SBRT), an intense, focused dose of radiation directly to a metastatic site.

Gene-targeted treatment is another option for some men.  “I look at AR-V7 as not the only blood test you’re going to do, but as part of a broader plan to find a therapy that fits the patient,” says Armstrong.  A small percentage of men have microsatellite unstable (MSI-high) prostate cancer – defects in one or more “spell-checker” genes involved in DNA mismatch repair.  This can be identified by tumor genomic sequencing biomarker tests.  “About 5 percent of men have microsatellite unstable prostate cancer, and those patients can do very well on immunotherapy such as pembrolizumab– and may even get complete remission of their cancer!”

Another small percentage of men – those who have a defective BRCA1 or BRCA2 gene – may have an excellent response to a PARP inhibitor drug like olaparib or rucaparib and to off label platinum-based chemotherapy.   “Ongoing trials are exploring a range of combination approaches of both immune therapies and these targeted agents, as well.”

Armstrong is an investigator in clinical trials for still other treatments: newer immunotherapies, targeted molecular agents, newer AR degraders and other inhibitors of hormone signaling, and PSMA-targeted radionuclides, which can detect and attack areas of prostate cancer throughout the body.  “A negative test (such as a blood test finding AR-V7) doesn’t mean you close all doors.  It just means that other doors may open to you, and if those doors are more likely to help, those are the doors you should open.  But the first step is going to see an expert who can open those doors for you.” Look for a Comprehensive Cancer Center or a PCF-VA Center of Excellence (for Veterans).

And don’t forget:  you can help your body fight prostate cancer, as well!  As we’ve discussed previously, exercise can help minimize side effects and maximize the effectiveness of treatment.  The stress hormone, cortisol, plays a role in some forms of prostate cancer, and lowering stress can help slow down cancer’s growth.  Diet can do a lot:  foods that lower inflammation and insulin resistance can also slow cancer’s growth, and new evidence suggests that caloric restriction can decrease metastasis and increase overall survival.

To sum up:  Don’t accept complacency.  “I see it all the time,” says Armstrong, “and I’ve heard stories you wouldn’t believe,” of patients who have been told there is nothing more that can help them.  “Sometimes, if you just do some of these tests, you can find really actionable results.”  There is almost always something else you can do.  There are clinical trials under way and entirely new avenues of treatment, such as PSMA-targeting radionuclides, that offer tremendous promise.

“Andy Armstrong and his team are making tremendous strides towards precision medicine for men with advanced prostate cancer,” says medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of PCF.  “If your doctor doesn’t mention new tests or experimental treatments – or even different uses for existing treatments that might be helpful for you, then it’s up to you to start this conversation.  And even during the pandemic, some clinical trials are still enrolling patients.”

It never hurts to ask.  Don’t give up! 

In addition to the book, I have written 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

 

 

 

We’ve talked about PSMA-PET before, but now it has gotten FDA approval for use in imaging prostate cancer.  This is just the start: more approvals are expected.  PSMA-targeting is also being used in Europe and Australia, and in clinical trials in the U.S., as a means of treating prostate cancer, not just showing where it’s hiding in the body.  For the Prostate Cancer Foundation (PCF), I recently interviewed Thomas Hope, M.D., part of a team of scientists at UCSF and UCLA whose PCF-funded research led to the FDA approval for PSMA-PET imaging.  The possibilities here are truly exciting:

“If we can see it on PSMA-PET, we can treat it, right?”

 “My PSA is no longer undetectable after surgery, but cancer didn’t show up on a PSMA-PET scan.  Do I still need radiation therapy?”

 “I’m at high risk of cancer recurrence.  A bone scan was negative, but the PSMA-PET scan shows a few spots of cancer outside the prostate.  Do I have metastatic prostate cancer?”

 These are just some of many new questions that men with prostate cancer and their doctors are starting to deal with after recent FDA approval of PSMA-PET, a new kind of scan that can show, for the first time, the needles in the haystack – tiny spots of prostate cancer hiding in the body that are too small to be picked up by standard imaging.

PSMA stands for prostate-specific membrane antigen, a molecule identified in the late 1980s that sits on the surface of prostate cancer cells.  Supported by many years of PCF funding, scientists have managed to link PSMA to radioactive tracers that can home in on this very specific molecule wherever it happens to be:  think of heat-seeking missiles locking onto a target.  Depending on the radioactive molecule linked to PSMA, it can either detect prostate cancer by shining a virtual spotlight on areas as small as a BB – the imaging technique the FDA has just approved – or detonate it with chemotherapy or tiny doses of radiation delivered by radionuclides at the cellular level.  In Europe and Australia, and in clinical trials in the U.S., PSMA-PET is being used to target and kill cancer in just those tiny outposts, leaving nearby cells unscathed.

“The PCF saw the potential of PSMA targeting way back in 1993,” says medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of PCF.  “Over nearly 30 years, we have invested more than $26 million in research on PSMA, with the goal of finding cancer that has escaped the prostate when it is very early and at a very small volume, because we believe that the sooner we can target it, the sooner we will be able to treat it and change the course of metastatic prostate cancer.”

The particular PSMA-targeted contrast agent that just got approved – a remarkable achievement in itself, based on five years of research by investigators Thomas Hope, M.D., at the University of California-San Francisco, and Johannes Czernin, M.D., and Jeremie Calais, M.D., MSc., at the University of California-Los Angeles – is called 68Ga-PSMA-11.  (The “Ga” stands for gallium; other PSMA agents are in various stages of getting FDA approval.)  And this particular FDA approval, for now, is for use on a very small scale:  only in California, at UCSF and UCLA.  But it’s a start – and it marks an important milestone in prostate cancer detection and treatment.  

This FDA approval is for use of PSMA-PET imaging in two main groups of patients (for now), says Hope, who is Director of Molecular Therapy in the Department of Radiology and Biomedical Imaging at UCSF: “in high-risk men before treatment with prostatectomy or radiation therapy, and in men who have already been treated for localized prostate cancer who have a rising PSA.

The strong collaboration among the PCF-funded scientists at UCLA and UCSF undoubtedly helped secure the FDA’s approval – itself a bit of a milestone.  “This is really unusual,” Hope notes.  “The FDA has never approved a drug at two manufacturing centers before, and both centers were approved on the same day.”

Achieving a PSMA-PET scan is more labor-intensive and expensive than patients might realize, Hope adds.  “We have to make the imaging agent ourselves in small batches,” a high-tech process that requires a gallium generator, and the solution can’t be stockpiled for long-term storage, because gallium has a half-life of a little more than an hour.  “For now, there is no commercially available PSMA-PET contrast agent,” but Hope believes this will change soon; two new drug applications for PSMA agents are under review by the FDA, and more are expected.

Note:  Many men won’t ever need PSMA-PET.  If you have a small amount of Gleason 6 prostate cancer and you are enrolled in active surveillance, or you were diagnosed with low- or intermediate-risk cancer that was treated with surgery or radiation and your PSA is undetectable, then PSMA-PET is probably not something you will need to consider.  But for other men – those with a rising PSA after treatment, for instance; men at high risk of cancer recurrence; or some men with metastatic prostate cancer – PSMA-PET can help determine what to do next.  As Hope says, “Now we know where it is.  The question then becomes, what’s the best way to treat it?”

Smarter Treatment

Having this extra insight shouldn’t be a scary prospect, he adds.  “It’s never bad to know; instead, what can we do with this knowledge?” One exciting thing is to treat men with oligometastasis, as oncologist Phuoc Tran, M.D., Ph.D., is doing at Johns Hopkins: and he’s going after a cure!   Another thing is to actually put the treatment where the cancer is, instead of where it is not.  Hope explains:  Many men who have a rising PSA after prostatectomy “get radiation therapy blindly to the prostate bed; 30 percent of those patients have a recurrence of cancer after about two years.  But with PSMA-PET, we know that about 30 percent of these patients have disease outside the radiation field.  Those are the patients who are recurring!  Now we can expand the radiation field to include known sites of cancer.  We assume the patient will benefit – we just haven’t proven it yet.  Do we not want to know where the disease is, and treat them blindly?” No! And this could be a game-changer for some men.

It’s also important to note that PSMA-PET is not the perfect crystal ball; it can’t detect areas of cancer that are really tiny.  Hope says that “some patients take a negative PSMA-PET to mean they don’t need any treatment,” and that’s not always correct.  “If you have biochemical recurrence (a rising PSA), and PSMA-PET doesn’t show any evidence of disease, the cancer is going to continue to progress.  Don’t think you don’t need treatment, particularly if you’re a candidate for salvage radiation therapy.”

These and other issues will become increasingly clear as PSMA-PET becomes incorporated into the standard of care.  As Hope notes, “It’s early days yet.”

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

Limiting Prostate Cancer’s Fuel by Restricting Calories and Changing the Diet:  Just when it seems like the picture of diet and prostate cancer is finally coming into focus, Nicole Simone, M.D., a radiation oncologist at Thomas Jefferson University, has added a new dimension.  It may not be just a question of the good foods you do eat, and the bad foods you don’t eat:  It also appears to matter, very strongly, how much you eat at all.

Simone’s research in prostate cancer and also in breast cancer suggests that restricting calories has many anti-cancer effects in the body – including, in mice, decreasing the likelihood of metastasis.  Early research in humans has shown, so far, that it lowers inflammation, changes the gut microbiome, may decrease the side effects of systemic therapy and generally seems to slow down cancer.  In effect, caloric restriction gives cancer a “brown-out,” limiting its energy.  “We’re just beginning to understand the promise and the power of caloric restriction,” says medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation (PCF), which funded this research.  “If there were a drug that could do all these things, we’d prescribe it in a heartbeat.”

Wait… aren’t people with cancer supposed to keep their calories upIf you’re thinking that limiting calories when someone’s fighting cancer seems like the opposite of the common wisdom – well, you’re right!  “This is not what we were all taught in medical school,” says Simone.  And she’s not entirely sure why this approach produces as many good effects as it does – but here’s a clue:  One way to look for various forms of cancer is with a PET scan, which involves injecting a radioactive dye.  “That dye is actually a radio-labeled glucose,” which is eagerly taken up by tumor cells because “cancer loves to eat.  Cancer is metabolically active, and sugar is one of its favorite foods!”

Simone’s laboratory has been investigating caloric restriction for several years.  “Initially, we were looking for a way to increase the effectiveness of radiation and chemotherapy in tumors that have a poor response to standard therapies.”  In mouse models of hormone-sensitive breast cancer, Simone found that simply restricting the mice’s daily caloric intake made a big difference:  it not only altered cell metabolism and made cancer cells more vulnerable to radiation and chemotherapy.  It also “decreased metastasis and increased overall survival.”

If this worked in breast cancer, would it work in prostate cancer?  Yes!  “In several models of hormone-sensitive prostate cancer, we found the same,” she says.  “We were able to decrease tumor growth, decrease metastasis, and increase survival.”  Then Simone’s lab tested caloric restriction in mice with castrate-resistant prostate cancer (CRPC), cancer that is no longer controlled by androgen deprivation therapy (ADT).  Again, caloric restriction affected how tumors responded to radiation.  “We saw some really interesting systemic, molecular changes,” Simone says.  “We wanted to take it a step further, and use that preliminary data as a launching pad to see what would happen in patients with prostate cancer if we put them on a caloric restriction diet.”

Eating 25 percent less:  In a pilot study, 20 patients – men diagnosed with localized prostate cancer who were scheduled to have prostatectomy – underwent caloric restriction for 21 days.  Simone individually tailored each man’s daily calorie total, based on what he had reported eating for several days ahead of time.  “We figured out their average caloric intake and then decreased that by 25 percent.”  Simone’s team also gave the men some dietary guidelines, encouraging (but not requiring) an anti-inflammatory diet with less refined sugar and processed food, more fruits, vegetables and complex carbohydrates.  “The men were able to stick to the diets really nicely,” she says.  “We went over their diet logs and calculated their dietary inflammatory index.   They did increase their anti-inflammatory foods!  They also lost an average of 12 pounds each.”

Could just three weeks of restricted-calorie, pretty much anti-inflammatory diet make a difference?  Yes, in several ways:

A decrease in systemic inflammation.  Men had changes in inflammatory markers in the blood, including a lower sedimentation rate (a blood test that measures inflammation).

Changes in the gut microbiome.  Rectal swabs, taken before the men started the diet and three weeks later, were sent to PCF-funded investigator Karen Sfanos, Ph.D., at Johns Hopkins, who performed in-depth analysis.  In the swabs taken at three weeks, Sfanos found a significant change in what the gut microbes were producing:  more butyrate!  Butyrate is an important fatty acid that helps control inflammation and is made by beneficial bacteria.  The fact that butyrate increased suggests that the population of bacteria in the gut changed for the better, simply with caloric restriction and an anti-inflammatory diet.

Less inflammation in the gut wall, as measured by lipopolysaccharides (LPS) in the blood.  “When there is inflammation in the gut, it creates spaces between the epithelial cells in the gut wall.”  Inflammatory cells can “leak” out of the gut into the blood, and increase inflammation elsewhere.

Less inflammation in the tumor.  “We saw a decrease in inflammatory markers such as NF-κB (an inflammatory pathway) in the tumor itself, and in MIR21.”  MIR21 is a microRNA gene (which makes RNA instead of proteins) that is believed to drive cancer development, growth, metastasis, and resistance to treatments.  Simone is discussing this aspect with another scientist she met at PCF’s Scientific Retreat, Shawn Lupold, Ph.D., of Johns Hopkins, who is a pioneer in the study of MIR21.

Ultimately, Simone believes, caloric restriction can play an important role for men with all stages of prostate cancer – but to make it even more effective will also require precision nutrition, based on precision oncology.  In this case, that means figuring out whether someone’s cancer prefers a diet that is sweet or savory.  “Prostate cancer can metabolize through the glucose pathway, or through lipid pathways,” says Simone.  Understanding which pathway really appeals to a particular cancer – some prefer sugar, some really go for fat– “can tell us how your cancer is driving its own energy.”

Thus, “if the tumor’s feeding on lipids, we change the dial on fat content in the diet.”  And if the tumor prefers sugar, then a diet aimed at keeping sweets and simple carbohydrates to a minimum will foil the cancer’s gustatory pleasure.

One of the biggest challenges with chemotherapy, ADT, or even radiation therapy, is resistance to treatment:  the cancer evolves to minimize the damage of attempts to kill it.  “Diet can almost be a more powerful tool,” says Simone.  “Cancers get smarter; a drug will work well for a while, then all of a sudden, cancer will figure out a way around it.  The power of restricting food is that it provides less energy for the cancer to use up.”

In addition to the book, I have written 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

Part One:  Live Your Best Life!

What can you do to live your best life?  You might say, quite reasonably, that your best life does not include prostate cancer.  True.  But no matter where you are in your journey – prevention, treatment, recovery, or survivorship – what can you do to maximize the good, to help your physical and mental wellbeing?  There’s actually quite a lot!

For example: Exercise not only helps you lose weight; it helps fight depression, and it even can help slow down prostate cancer!  And eating the right diet – as opposed to eating a lot of junk and chemicals – can boost your spirits, your energy level, and just generally make you feel better.  Even better:  it can help lower inflammation and insulin, and this can help your body fight prostate cancer, and can help prevent diabetes, cardiovascular disease, and other chronic illnesses.

There is growing evidence that the lifestyle choices that help prevent or fight other diseases – like, eating low sugar for diabetes, or exercising for your heart – can also help prevent or slow down prostate cancer.

Here are three basic principles:

What lowers inflammation helps fight prostate cancer.

What fights diabetes and insulin resistance helps fight prostate cancer.

What is good for the heart is good for the prostate.  We will cover all of this here and in part two.

Studying Diet is Hard

For the Prostate Cancer Foundation (PCF), I interviewed two scientists who study lifestyle factors and their effect on prostate cancer:  Epidemiologist June Chan, Sc.D., of UCSF, and epidemiologist Lorelei Mucci, M.P.H., Sc.D., of Harvard.

Right off the bat, both of these experts note that studying food is hard, and the answer to staying healthier is not one single thing.  There is no dietary magic bullet, and if you see one advertised and choose to take it, do so with a huge proverbial grain of salt!  In many studies over the years, scientists have tried to isolate specific foods to see if they promote or prevent cancer – but they did it by asking people to recall what they ate over certain periods of time.  And most people don’t have ideal memories:  “Yes, I ate that fairly regularly.  No, I didn’t eat this – wait, maybe I did.”  See the difficulty?

Okay, so what if people keep a food journal?  That’s more helpful, although these kinds of studies, done right, take many years.  Even then, if you isolate certain foods that seem promising, you still don’t know exactly what’s happening!  Let’s say you are studying what people eat and you notice a trend in those who didn’t get cancer:  they eat apples (hypothetically).  What kind of apples?  Is it all apples, or just Granny Smiths?  Were they all grown in the same type of soil?  Were they cooked, or eaten raw?  Peeled or not?  Organic or not?  How many did people eat a day?

But wait!  Did these people even have an actual benefit from eating the apple – say, one they brought to work from home – or did they benefit from not eating a bag of cheese puffs or Twinkies from the vending machine instead?

And wait some more!  Do the people who benefited have genetic or molecular differences that make them more likely to be helped by apples?  Or… are people who eat apples also more likely to exercise and take better care of their health in general – so maybe it’s not even the apples but their whole lifestyle that made the difference, and we’re back to the drawing board!

This is why science around nutrition takes time.  Remember back in 2010 when coffee was bad?  And now, here we are in 2020 and coffee is good?  This stuff evolves.  The good news is, we’ve learned a lot.

Broad Strokes are Better

Scientists don’t have a Paint-by-Number approach to food science, with every single food accounted for.  But they are able to paint with broad, but definitive, strokes.

In our interviews, June Chan and Lorelei Mucci both cited work led by Harvard scientists Fred Tabung, Ph.D., M.S.P.H., and Edward Giovannucci, M.D., Sc.D., that look at the relationship between diet and inflammation.  In one, the scientists tracked inflammatory markers in the blood and whether inflammation was raised or lowered by what people ate, based on data from thousands of participants in the Nurses’ Health Study and the Health Professionals Follow-Up Study.  The key for us is the foods they found that reduce inflammation:  dark yellow vegetables (carrots, winter squash, sweet potatoes, etc.); leafy green vegetables (like spinach, broccoli, kale, etc.), coffee, and wine.  Beer (one bottle, glass, or can) was in this category, too.  So was tea, but its effect was not very strong.

The pro-inflammatory (bad) category, included processed meats (hot dogs, bacon, pepperoni, lunch meat, etc.), red meat, refined grains, high-energy beverages (with additives and sweeteners), and “other vegetables,” like potatoes and corn.  Interestingly, not all fish is equal:  canned tuna, shrimp, lobster, scallops, and “other” fish were more inflammatory than “dark-meat” fish like salmon or red snapper.

But if you love canned tuna, and if you love a baked potato or corn on the cob, don’t freak out:  remember, broad strokes!  The key seems to be to make sure you do eat the anti-inflammatory foods.  For example, the anti-inflammatory effects of leafy green vegetables, dark yellow vegetables, wine and coffee are more powerful than the very mild, pro-inflammatory effect of “other fish” or “other vegetables.”  If you feel that you just can’t give up meat entirely, that’s okay – just aim for smaller portions of meat, surrounded by anti-inflammatory vegetables.  Example:  instead of regular fries, try sweet potato fries.  They’re really good, and they fight inflammation!  You can have your burger, but still help counteract inflammation:  it’s a win-win!

So:  what about foods that are bad for diabetes and insulin resistanceTabung and Giovannucci led another study, also using data from the thousands of participants in the Nurses’ Health Study and Health Professionals Follow-Up Study, to assess the “insulinemic potential” of diet and lifestyle – basically, how foods and exercise affect blood sugar and insulin resistance, as measured by certain biomarkers in the blood.  Foods that did not raise blood sugar or insulin resistance included wine, coffee, whole fruit, high-fat dairy (whole milk, sour cream, a half-cup of ice cream, a slice of cheese, etc.), nuts, and leafy green vegetables.  Physical activity was also good for lowering insulin resistance and blood sugar.

What do the experts make of this?  Benjamin Fu, a postdoctoral fellow in Lorelei Mucci’s lab at Harvard has been looking at these two different dietary patterns: “a diet associated with hyperinsulinemia, and a hyper-inflammation diet.”  The two diets have some overlaps, but are not identical.  Neither is good for men worried about prostate cancer, Mucci says, “particularly the hyper-insulinemia (blood sugar-raising) diet, which is associated with a 60-percent risk of more advanced or fatal prostate cancers.”  Let’s just let that sink in for a second:  if you eat a lot of carbs and sugar and you get prostate cancer, you’re more likely to have a serious form that could kill you.  Okay, let’s go on:

Mucci continues:  “The hyper-inflammatory diet also is associated with an increased risk of prostate cancer,” particularly in men who develop cancer at a younger age, in their forties and fifties.  “It may be that earlier-onset cancers are more susceptible to the effect of diet and lifestyle.”

What does heart health have to do with it?  A lot, for many reasons.  It turns out, says Mucci, that “cardiovascular disease and other chronic diseases are the major cause of death in many men who have prostate cancer.  If you look at men with localized prostate cancer and survival outcomes over 10 years, three-fourths of the deaths in those men will be due either to cardiovascular disease or another chronic disease.  Only one-fourth of the mortality is due to prostate cancer.”  Now, you may be thinking, we all have to die of something, right?  This is true, but “these men are dying sooner than they should, and eating a plant-based diet rich in cruciferous vegetables will help lower that risk of cardiovascular disease.”

Which brings us to the Mediterranean Diet:  Not only do people in Mediterranean countries, as compared to Americans, eat more vegetables and fruits, fewer fatty foods, less processed junk, and less red meat – “which increases insulin resistance, increases inflammation, raises cardiovascular risk and also is part of a dietary pattern that may increase obesity, as well,” as Mucci notes.  You know what else they eat a lot of?  Olive oil.  Greater than 30 ml a day, which is a little over two tablespoons.  “There’s really good evidence that extra virgin olive oil (EVOO), either on its own or as part of the Mediterranean diet, substantially lowers the risk of cardiovascular disease and lowers the risk of overall mortality.  The evidence specifically for men with prostate cancer is much more limited, but given the strong benefits for overall death and cardiovascular death in particular, not only using EVOO, but using it to replace butter or margarine, is something that is worth doing.”

 

Coming up:  Part 2:  What’s Good for the Prostate is Good for All of You!


In addition to the book, I have written 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

 

 

 

If, as we have seen, inflammation can lead to prostate cancer, could anti-inflammatory agents help protect against it?

The jury’s still out.  However:  Johns Hopkins epidemiologist Elizabeth Platz, Sc.D., has been intrigued by this possibility for many years.  She is senior author of a new study on the use of aspirin and statins, published in Cancer Prevention Research.  The study, of men in the placebo arm of the Prostate Cancer Prevention Trial, doesn’t answer this question once and for all – but adds more weight to the idea that, for lowering the risk of developing potentially fatal prostate cancer, fighting inflammation is a good thing.

Evidence from observational studies has suggested that when taken regularly over time, aspirin may lower the risk of prostate cancer.  These drugs block enzymes that play a key role in the body’s inflammatory response.  Other studies have linked long-term use of statins, prescription drugs that are used to lower cholesterol but that also are anti-inflammatory, to a lower risk of advanced and metastatic prostate cancer.

In this most recent study, the investigators looked for inflammation markers in benign prostate tissue samples.  “We compared the use aspirin and statins with the presence and extent of inflammation in the prostate tissue,” says Platz.  They also looked at prostate biopsy slides for the presence of certain immune cells that are involved in inflammation.

“Of 357 men, 61 percent reported aspirin use, and 32 percent reported statin use,” Platz continues.  “Aspirin users were more likely to have low FoxP3, a T regulatory cell marker, and statin users were more likely to have a low CD68, a macrophage marker.”  “Our results suggest these medications may alter the immune environment of the prostate. A next step is to determine whether these immune alterations may underlie the epidemiologic observations that taking an aspirin or statin may protect against getting advanced prostate cancer, and dying from it.”

Prostate Cancer Loves Fats          

Here’s some more recent research out of Johns Hopkins, a neat bit of  basic science that may help explain the findings of Platz’s recent study:  “Our work is mechanistic,” says investigator Marikki Laiho, M.D., Ph.D., director of the Division of Molecular Radiation Sciences, “and provides insight into how the tumor microenvironment senses the excess load of the lipids.  Diet and statins obviously relate to the amount and regulation of the lipids, and have shown those clear correlations to prostate cancer.  However, we need to understand why to be able to correct the problem. Our work provides at least one explanation how the lipids fuel cancer. One part of the work was just to feed the prostate cancer cells with cholesterol, which made them more invasive.”

It turns out that even on a cellular level, prostate cancer gravitates to its own kind of junk food – the tiny version of deep-fried Oreos with a side of chili cheese fries.  Laiho and colleagues have just figured out how the body enables prostate cancer’s terrible diet.

The culprit is a lipid-regulating protein called CAVIN1, the scientists reported in the journal, Molecular Cancer Research.  In lab studies, when CAVIN1 was removed from cells in and around the prostate tumor, the fatty acid that was in those cells spilled into the tumor’s microenvironment.   The effect on prostate cancer cells was dramatic:  the cancer cells soaked up the lipids, which then acted as turbo fuel to make the cancer spread more aggressively.

“In every prostate cancer cell line we tested,” says research fellow Jin-Yih Low, Ph.D., the study’s first author, “tumor cells universally had an appetite for the lipids, using them to strengthen the protective membrane around the cell, synthesize proteins and make testosterone to support and fuel the cancer’s growth.  The tumor cells then behaved more aggressively, exhibiting invasive and metastatic behavior.  Just having access to the lipids gave the tumor cells more power; the tumor’s behavior changed.”

But wait!  There’s more:  nearby cells changed, too.  Deprived of their lipids, normal stromal cells started to churn out inflammatory molecules, adding fuel of their own to the fire. 

Laiho’s team then confirmed their findings in mouse models, comparing tumors with and without CAVIN1 in the stromal cells.  In the mice, Laiho says, “although the presence or absence of CAVIN1 did not affect the speed of tumor growth, lack of CAVIN1 definitely caused the cancer to spread.  All of the mice with tumors that lacked CAVIN1 had a twofold to fivefold increase in metastasis.  The tumors also had a fortyfold to hundredfold increase in lipids and inflammatory cells.”

The investigators were surprised at these results, Laiho adds.  “We suspected CAVIN1 was important, but we didn’t realize how important.  The tumor’s microenvironment matters, and the amount of lipids matters a lot.”  Just changing the level of lipids “created a situation of rampant metastasis.”

What could come from this research?  One possibility is development of a new biomarker:  a loss of CAVIN1 in local or locally advanced cancer, for example, could signal a higher risk of metastasis.  The next step is to understand more about the inflammatory process in the tumor’s microenvironment.  “We want to understand why the inflammation brings in macrophages, immune cells that further exacerbate the inflammatory process, instead of T cells, which should attack the cancer.”  The more scientists know about how inflammation does its nasty work to inflame cancer, the closer we are to finding a way to stop it.

 

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

Why does it matter if you eat right and exercise?  Everybody knows the answer; in fact, we’ve all heard it so many times, it’s easy to tune it out:  diet and exercise are good for you.  Duh!  Who’s going to argue with that? Having a healthy lifestyle is right up there with world peace as a worthy goal!

Bear with me here:  With a topic such as this, I know I’m either preaching to the choir – people who are already exercising and eating a pretty good diet – or I run the risk of turning off the people I really want to hear this message, by seeming to preach at all: people who might think, “Go ahead, tell me what to do.  I really enjoy that.  Micromanage my life.  Maybe you’d like to come over and look at my closet and tell me what shirt to wear today.”

Okay, fine!  I’m not here to tell you what to do.  But I am going to try really hard to tell you why you might want to do certain things, and how good diet and exercise – or the lack thereof – can affect prostate cancer.

Please pardon the long set-up, but let’s begin with some facts, with plenty of links for further reading:

If you exercise, you are less likely to have cancer return after treatment, less likely to get metastatic prostate cancer and die of it.  What does exercise do?  A lot of good things for your vascular system, which, in turn, can help slow down prostate cancer metastasis.  But you know what it also does?  It helps you lose weight.

And it just so happens, men who lose weight are less likely to die of prostate cancer.

And sugar can make cancers grow faster.

And men who stop smoking are less likely to have cancer come back after treatment, and less likely to die of prostate cancer.

Exercise also helps control stress, and the stress hormone, cortisol, affects adrenal receptors, and can play a role in making cancer grow and spread faster.

Now, here’s why all this matters so much:  smoking, not exercising, quaffing sugary drinks, eating processed, fatty foods, and being overweight all contribute to inflammation.

I’m going to be writing a lot about inflammation in the next few posts, because it is becoming increasingly evident that inflammation can lead to cancer – and it’s quite possible that if we can prevent inflammation, we may prevent or at least slow down cancer.

What Inflammation Does

In a landmark study, Karen Sfanos, Ph.D., and scientists at Johns Hopkins have shown for the first time that bacterial infection can cause prostate cancer.  The study was led by Sfanos and her former graduate student, Eva Shrestha, Ph.D., in collaboration with Angelo De Marzo, M.D., Ph.D., Jonathan Coulter, Ph.D., and colleagues.  Infection? That’s not the same as inflammation!  True… but bear with me.

The bacterial culprit found in this study belongs to the family Enterobacteriaceae, which includes E. coli. Better known as a nasty gastrointestinal bug, E. coli causes inflammation in the urinary tract and is a known cause of bacterial prostatitis.  As the scientists discovered, colibactin, a genotoxin produced by some strains of E. coli, can also instigate a series of unfortunate events in the prostate.  Bacterial infection leads to acute and chronic inflammation, which can lead to the development of a lesion in the prostate called proliferative inflammatory atrophy (PIA), first described by pathologist De Marzo, oncologist William (Bill) Nelson, M.D., Ph.D., and other Johns Hopkins scientists; it can also cause DNA damage. The presence of colibactin is even more ominous, because it can directly lead to double-stranded DNA breakage. 

Sfanos suspects that this combination leads, in turn, to another development:  fusion of two genes, TMPRSS2 and ERG, that normally should remain separate, but in this case get abnormally spliced together.  Now, it may be that by themselves, TMPRSS2 and ERG are like Robert Leroy Parker and Harry Alonzo Longabaugh:  put them together, and they became Butch Cassidy and the Sundance Kid, and together, they got into much worse trouble than either one managed alone.  This TMPRSS2/ERG fusion – found in as many as half of all prostate cancers – is thought be an early event leading to the development of prostate cancer.

“We found evidence in human tissues (from prostatectomy specimens) that bacterial infections are initiating the TMPRSS2/ERG fusion,” says Sfanos.  “We don’t think this is the only way bacterial infections contribute to cause prostate cancer.  But in this particular study, the way we looked at it was by tracking the presence of these TMPRSS2/ERG fusions.”

It is entirely possible, notes De Marzo, “that other types of mutations or events could also be caused by bacterial infections or inflammation.  But looking at these fusions gave us ‘smoking gun’ evidence that bacterial infection was the initiating event.”  Sfanos adds that “the colibactin-producing bacteria, TMPRSS2/ERG fusions, PIA, and tiny buds of cancer were all there, in the same place at the same time, a snapshot of prostate cancer being born.”  The team’s early findings are available online in BioRxiv, a scientific data-sharing website, and a manuscript for publication is undergoing peer review.

Bacterial infection is a known cause of other cancers.  H. pylori, for example, is a well-established cause of stomach cancer.  “We believe that many different types of microorganisms, certain types of sexually transmitted infections (STIs), and other infections in the prostate can certainly cause the same chain of events,” says Sfanos.

How did the bacteria get into the prostate?  They could have come from the urethra.  “These bacteria are good crawlers,” Sfanos says.  De Marzo recalls what the late Don Coffey, Ph.D., the longtime director of the Brady’s scientific labs, used to say: “The urethra is like the Holland Tunnel for bacteria.”

Note:  These tiny cancers are not the cancers that were biopsied and that led to the diagnosis of prostate cancer; they’re too young even to achieve a Gleason grade.  They’re just baby sites of cancer cropping up, in addition to the more mature cancer that was already there.  Prostate cancer is multifocal:  in most men with prostate cancer, several sites of cancer develop at the same time.  But because of the unique molecular tools used in this study – looking for TMPRSS2/ERG fusions and “ERG-positive PIA” – Sfanos, De Marzo and colleagues were able to catch the formation of these invasive cancers in real time.  “This might start to explain the multifocal nature of prostate cancer,” says Sfanos. “There might be multiple infections or other inflammatory events that occur throughout a man’s lifetime.”

Sfanos suspects that the men whose tissue was used for this study “likely all had undiagnosed infections.”  These findings may lead to development of a new test, using urine or prostatic fluid, to look for colibactin or markers of inflammation in the prostate.  Future studies may look at urine samples along with prostate tissue for such markers, and  new imaging technology may one day be able to detect inflammation, as well.

For more than 20 years, De Marzo and Sfanos, with Brady scientists Bill Nelson, Srinivasan Yegnasubramanin, M.D. Ph.D., Elizabeth Platz, Sc.D., and William Isaacs, Ph.D., have studied inflammation as a risk factor for prostate cancer, particularly looking at PIA.  Sfanos “has also been the major champion of infection” as a risk factor, De Marzo says.  Now, these two paths of investigation have come together.

Could dietary changes make a difference?  “Bill Nelson showed years ago that loss of expression of the GSTP1 gene rendered prostate cells more susceptible to DNA damage caused by a chemical compound that is found in charred meat,” says De Marzo.  “Infection plus a bad diet might make this worse, and then combine that with the underlying genetics.  There might be multiple culprits, a constellation of things over years.”  We’re going to look more at diet in future posts.

Coming up next:  Could anti-inflammatory drugs help?

 

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