I’ve had a lot of requests to print a talk I recently gave. Here it is. — Janet
Recently, I took part in a large, two-day community cancer seminar in Prescott, Arizona, presented by Prescott United Methodist Church. Many people have asked for copies of my talk, so here it is. Readers of this blog will find some of this material familiar, but I’ve collected it all into one place. I would call it “Prostate Cancer in a Nutshell,” but that doesn’t sound very good… I’m sharing it with you now because I want you to know that there really is hope.
I’m not a doctor. But I have been writing about the very latest in prostate cancer research and treatment for more than 25 years. What I hope to do today is give you kind of a “state of the union” talk on the latest advances. Some of these are not yet available, but they are coming. Everything I have to talk about is very hopeful.
I started writing about prostate cancer when my father-in-law died of it at age 53. I was the editor of the Johns Hopkins medical magazine at the time, and so I arranged to interview Patrick Walsh, Director of the Brady Urological Institute at Hopkins. I had no idea that he was the surgeon who invented the nerve-sparing radical prostatectomy, the operation to remove the prostate but preserve continence and potency. We wrote an article about prostate cancer in 1993, it got 3,000 requests for reprints, and when my daughter, Blair, was born, I left Hopkins and Pat Walsh and I wrote our first book. We’re now on our sixth book. At that time, PSA, prostate-specific antigen, was new, and although there was a PSA blood test, nobody knew what to do with the results. I made my dad start getting the PSA test, and my mom and I made him start getting his prostate checked. He did not appreciate it, especially the rectal exam. But he did it, and in 1997 was diagnosed with prostate cancer, even though his PSA was very low – 1.2. Patrick Walsh took out his prostate. He had no complications from the operation, and his PSA remains undetectable today. That was 21 years ago, and he just happens to be visiting today. Dad, hold up your hand. (VJ readers, my dad got a big round of applause here!)
SCREENING
I’m starting with screening, because it just makes me mad. Screening is the best thing you can do to avoid dying of prostate cancer. But ever since 2012, millions of American men haven’t been screened for prostate cancer because their doctor said they didn’t need it, because that’s what the U.S. government told them. And yet: About one out of seven American men – about 160,000 this year alone – will be diagnosed with prostate cancer at some point in his life. Not all prostate cancer needs to be treated; many men with low-risk cancer can safely do Active Surveillance. But many men do need treatment.
American men need a baseline PSA test and rectal exam to check for prostate cancer in their forties, and then they need follow-up screening at regular intervals. Men who are at higher risk – men with a family history of prostate cancer and other cancer, and African American men – need to start screening earlier, ideally at age 40.
In 2012, the government – the Congressionally funded Band of Geniuses known as the U.S. Preventive Services Task Force, USPSTF for short –recommended against routine screening for “men of average risk” for prostate cancer. There was not a single urologist on this panel, by the way. The USPSTF placed fear of overtreatment over the value of detecting curable disease.
Many urologists and oncologists believe the USPSTF made some bad assumptions. One is that many men are treated overzealously; that men who have slow-growing disease are subjected to surgery or radiation and suffer side effects from treatment they didn’t need. And it is absolutely true that, back in the 1990s when scientists were just beginning to figure out PSA, many men were treated who probably didn’t need it.
But that’s not the case today.
The other bad assumption was that all men are the same. They’re not. Some men are a lot more likely to develop the kind of prostate cancer that really needs to be treated. These include men with a family history of prostate cancer and men of African descent. Also, we now know that just having a history of cancer in your family – even if it’s not prostate cancer – raises your risk of getting prostate cancer. Also, all men of average risk are not alike: men who smoke cigarettes, for example, are at higher risk; so are men who are obese. We’ll get to that.
This summer, my boss at the PCF, medical oncologist and molecular biologist Jonathan Simons, sent me an article in the World Journal of Urology. The senior author was Jim Hu, urologist and urologic oncologist at Weill Cornell Medicine.
The title: “Unintended Consequences of Decreased PSA-based Prostate Cancer Screening.” The article begins: “In May 2012, the USPSTF issued a grade D recommendation against PSA-based prostate cancer screening,” which is why so many family doctors stopped screening men for prostate cancer.
So, how is that working out for us?
To find out, Hu and colleagues looked at nearly 20,000 men at nine high-volume referral centers in the U.S. from 2008 to 2016. They broke these men into two groups– from 2008-2012, and 2012-2016. Before and after the Band of Geniuses. From 2012-2016, they found fewer men were diagnosed with low-grade cancer, the kind that is easiest to kill. Unfortunately, what this really shows is that these cancers were not caughtwhen they were low-grade. They also found across the board that high-grade cancers increased by 24 percent.
Between 2008 and 2012, 6.2 percent of men had a biochemical recurrence, a return of PSA after treatment, which is not supposed to happen. Between 2012-2016, that number had nearly tripled to 17.5 percent. All centers experienced consistent decreases of low-grade disease and absolute increases in intermediate and high-risk cancer.
The new guidelines give a grade of C, which is not exactly encouraging but is better than a D, to prostate cancer screening in men aged 55 to 69. This is still not good enough.
If you want to know the value of PSA screening, ask the 45-year-old guy diagnosed with metastatic prostate cancer who’s just starting ADT, androgen deprivation therapy, the suppression of male hormones including testosterone. Oh, wait – 45-year-old men aren’t even mentioned in these guidelines. Some men are diagnosed with prostate cancer in their early forties, and a few are diagnosed in their late thirties. For many men, age 55 is too late to start screening. And 69 is too early to quit.
Pat Walsh and other Hopkins scientists recently reported that even using age 75 as a blanket cutoff for PSA screening is missing some significant prostate cancer. Men diagnosed at 75 or older account for 48 percent of metastatic cancers and 53 percent of prostate cancer deaths. So basically, if you’re in good health and are 75 and over and you don’t want to die of prostate cancer, you should keep getting screened.
Also: many men don’t know their family history. You may be at higher risk and not know it.
Do you need screening for prostate cancer? Well, Do you want to know, or not? If you do, ask your doctor to start checking you for prostate cancer, with a PSA blood test and a physical exam. If you don’t, then don’t.
But remember: If you are diagnosed with prostate cancer, that doesn’t necessarily mean that you need treatment. You may be that guy who can safely live his life with a little bit of cancer that will never spread beyond his prostate.
If you are diagnosed with cancer that needs to be treated: Prostate cancer that’s localized, confined to the prostate, can be cured with surgery or radiation; however, both treatments have a risk of side effects, including erectile dysfunction (ED) and, with surgery, the risk of incontinence. With an experienced surgeon at a high-volume center, the risk of complications is much lower. These side effects are often temporary, and they can be treated. With ED, where there’s a will, there’s a way: in other words, if you want to have your sex life back, there are treatments that will restore it. And don’t let anyone tell you that men who get radiation instead of surgery dodge the ED bullet. They don’t. But again, there are good treatments, and I have specifics in the book and on my website.
Incontinence is usually temporary after surgery, and gets better as your muscles get stronger. If it persists, there are treatments for this, as well.
Maybe you’re thinking, “The treatment is not worth it. I don’t want the side effects. I’ll take my chances and just deal with cancer if I have to.” If it turns out that you do have it, and that the cancer has spread outside the prostate, it may not only be very difficult to cure: In this case, side effects aren’t just a “maybe.” You will definitelyhave side effects from ADT– androgen deprivation therapy, the shutting down of male hormones including testosterone. These can include impotence, breast swelling, weight gain, bone density changes, a higher risk of metabolic syndrome, diabetes, heart attack, stroke, or cognitive changes. Note: These side effects can and should be fought with diet and exercise, and many men do very well on ADT for decades. But catching the disease early and treating it while it’s confined to the prostate, is better.
DIAGNOSIS
Very briefly: The whole point of getting regular PSA tests is to watch what the number does. It should not be going up. If it is, you should have a prostate biopsy.
Biopsies are not infallible. Even with 12 or 14 cores of tissue (it used to be 6), cancer can still be missed. Why? Prostate cancer is multifocal– that means, there’s not one obvious tumor that sticks up like a marbleand screams, “Here I am, I’m cancer!” The average prostate that has cancer in it has seven individual spots of cancer– and if you think of the prostate as a strawberry, these spots of cancer are like the little black seeds on it. Just little dots. They’re easy to miss. African American menhave an even tougher situation; their prostate cancer tends to develop in an out-of-the-way place at the apex of the prostate – the attic, instead of the basement, where the needle comes in, so it’s harder to reach.
Several new forms of MRI can help target a biopsy and detect cancer. I recently wrote about a man named Rob who was a human pincushion; he had endured five prostate biopsies, some saturation biopsies – all inconclusive. But his PSA kept rising. In fact, he had developed scar tissuein his prostate that masked the presence of cancer. But a fusion biopsy, guided by MRI and ultrasound, found cancer. Robhad his prostate out, the cancer turned out to be intermediate grade; it was confined within the prostate, and he’s fine now. Rob is just 49 years old.
MRI is even more effective when combined with PHI – the Prostate Health Index. This is a “second-line” blood test that combines three molecular forms of PSA into a single score. There are other “second-line” biomarker tests, and more on the horizon, including tests for circulating tumor cells in the blood, urine tests, and molecular and genetic tests of biopsy sample tissue. One of these, developed by Hopkins pathologist Angelo De Marzo, is called the PTEN IHC test. IHC is immunohistochemistry, and it involves using antibodies to stain cells. PTEN is a “tumor suppressor” gene; it puts the brakes on cancer. But cancer doesn’t like brakes, so in about half of all lethal prostate tumors, PTEN is knocked out. The loss of PTEN is a powerful predictor of aggressive cancer. This test is not widely available yet.
Second opinion on pathology:
Another thing you can do is get a second opinion on your biopsy slides. You can send your biopsy tissue to an experienced tertiary-level hospital to have a urologic pathologist take a look at it. At Hopkins, world-class pathologist Jon Epstein and colleagues do second opinions on 15,000 cases a year, sent from all over the world. They can also do IHC and other tests.
WHAT CAUSES PROSTATE CANCER?
Chronic Inflammation. One cause of chronic inflammation is charred meat.
When meat is cooked at a high temperature – when a steak, burger, hot dog, or even a piece of cooked fish gets those grill marks that most of us really like to see – it produces a bad ingredient called PhIP. PhIP is a “pro-carcinogen,” a chemical that turns into something that can attack and mutate your DNA. PhIP is known to cause prostate and other cancers in rats. However, when scientists feed rats tomatoes and broccoli along with PhIP, the rats live longer and have fewer prostate and other cancers than the rats that ate the PhIP alone. Vegetables help counteract PhIP. In the entire world, those least likely to get prostate cancer are men in rural Asia, who eat the traditional anti-inflammatory diet – low in meat, high in fruits and vegetables, with hardly any processed carbs. No soda, lots of green tea. No fries, lots of rice. No burgers, lots of vegetables. However,when those same men with their low risk come to America, over time, their risk goes up to the level of an American man’s. You are what you eat.
Good news: Men of any age can benefit from eating anti-inflammatory foods.
The opposite is also true: Obesity and one of its consequences, diabetes, make these flames of inflammation burn even higher. This may be one reason why ruralAsian men are less likely to get prostate cancer: they have a lower body mass index, BMI, which means less stress on their cells. If you are overweight or borderline diabetic, you turn on more insulin to try to control your blood sugar. Insulin secretes molecules called cytokines, which can encourage inflammation. This can put added stress on the body and perhaps tip the balance toward cancer.
The prostate is particularly vulnerable to inflammation because it’s just chock full of inflammatory cells called prostaglandins. So the prostate is already a tinderbox.
Bad genes: We’ll cover this more in a minute, but the good news even with bad genes is that they are not automatically your destiny: we know this from studies of identical twins. There are many cases where one twin gets cancer, and one does not. Their genes are the same, so it must be something in their diet or lifestyle, too.
High blood sugar: Men who have diabetes are not more likely to getprostate cancer, but they are three times more likely to die of it if they do get it. Nondiabetic men who have high blood sugar have almost a five-times greater risk of dying from prostate cancer. If you are pre-diabetic or diabetic, you can lower your risk of lethal prostate cancer by getting your blood sugar under control, improving your diet, and exercising.
Smoking: Men who smoke, even if they don’t have a diagnosis of prostate cancer, are more likely to die of prostate cancer in the future. Men who have been treated for prostate cancer who keep smokingare more than twice as likely to die of it, too, because cancer is more likely to recur. The good news: Recent smoking matters more than if you smoked 30 years ago. Your risk of dying of prostate cancer starts going down the day you stop smoking! In 10 years, it’s the same as if you had never smoked! Quitting now can make a big difference. If you smoke, you should quit, and if you have prostate cancer, you should definitelyquit. There is no point in the spectrum of prostate cancer where quitting smoking is not helpful.
No drug protects against prostate cancer as much as having a healthy weight and being physically active.
Lose that gut. Like smoking, obesity is linked to more aggressive disease and death from prostate cancer. For men who have prostate cancer, being obese and continuing to gain weight is associated with higher disease recurrence and death. Among 2,500 men with localized prostate cancer in the Physicians’ Health Study, a one-unit increase in body mass before cancer diagnosis was associated with a 10-percent increase in a man’s risk of dying of prostate cancer. A five unit increase raised the risk of dying of prostate cancer by 20 percent.
If you’re a young man, losing weight might stop prostate cancer from developing. If a tumor is already there, but very small and not detectable, losing weight may delay the growth of cancer. If you have a diagnosis of cancer, losing weight can slow cancer or help prevent it from spreading. “It’s never too late to lose weight.”
Drink coffee. Coffee is good! Regular or decaf! Let’s look at this study from Italy, published in the International Journal of Cancer: In the Moli-sani Project, investigators looked at coffee consumption in nearly 7,000 men, age 50 and up in rural Italy. They followed them, on average, at least four years, and during this time 100 of these men were diagnosed with prostate cancer. It turns out that the more coffee the men drank every day, the less likely they were to develop prostate cancer. Men who drank more than three cups a day had the lowest risk of getting prostate cancer.
Note: these men took their coffee black, or maybe with a bit of milk. In other words, they didn’t have five shots of whipped cream, etc. Also, their coffee was unfiltered– not brewed or instant.
A Harvard study published in the Journal of the National Cancer Institutefound that coffee was associated with a lower risk of gettingprostate cancer, andof developing aggressive, potentially lethalcancer. Men who drank one to three cups a day, regular or decaf, had a 29-percent lower risk, and the risk went down as the coffee drinking went up. Men who drank at least six cups a day had a 60-percent lower risk. Amazingly, the heavy coffee drinkers also tended to be smokers – so coffee seems to have helped counteract cigarettes.
In other studies, coffee has been linked to a lower risk of developing Type 2 diabetes; liver cancer, endometrial cancer, postmenopausal cancer and colorectal cancer.
Coffee has powerful antioxidant effects. Coffee is the number one source of antioxidants in the diet of the American man. This is sad.
Coffee is also anti-inflammatory. Many studies have shown that heavy coffee drinkers have lower levels of circulating inflammatory markers in their blood.
Coffee has helpful effects on insulin and glucose metabolism.
Coffee cuts lipids, the body’s fatty acids. It reduces fasting cholesterol and triglycerides.
Coffee helps the gut’s microbiome. It increases diversity in the microbiome, the eight pounds of bacteria living happily in your gut. Bad gut flora may promote inflammation, and vice versa.
Exercise: Your prostate doesn’t care about six-pack abs and “gun show” biceps. But your cardiovascular health matters a lot. Cardiovascular exercise can lower your risk of getting lethal prostate cancer, or of having cancer come back if it’s already been treated. UCSF scientistJune Chan and colleagues found that vigorous exercise (jogging or bicycling) after diagnosis was associated with a lower risk of prostate cancer death in men with localized cancer. “Three or more hours a week of vigorous activity was associated with a 60 percent reduction in the risk of dying of prostate cancer.” Now they are looking to see if moderate exercise, the kind anybody can do, can lower the risk of dying of prostate cancer. “Biochemically, exercise could help deter metastasis, spread of cancer, by changing the environment for the cancer.” This is like spraying fire retardant on the tumor. Not necessarily extinguishing the flame altogether, but making it burn slower, and helping the body set up fire breaks to keep the cancer from spreading.
Here’s an odd thought: Exercise seems to make prostate cancer fat and happy. “Prostate cancer may be the most common cancer where exercise, used like a drug, can confer an increase in survival,” says Jonathan Simons. “There is no form of treatment that has this effect.” It may be that just as it improves blood flow in the arteries, exercise gives cancer a better blood supply that keeps it happy where it is, “so the tumor has no motivation to leave.” So basically, exercise makes cancer feel like it’s at a nice hotel, with free cable TV and a pool. It’s content to stay there indefinitely. “When tumors are stressed” – when they’re in a bad neighborhood, in effect – “they have genes that are programmed to help them survive by getting them to crawl away to someplace that better serves their needs.” One of those genes, Simons discovered, not only pipes in more blood to supply the tumor; it gets rid of waste products – the cancer cells’ sewage. “When tumors build a supply line of blood vessels, to bring in more nutrients, they also build their own plumbing system. Once they have this infrastructure, they launch a genetic program that lets them grow and spread. But giving the cancer a better blood flow might sabotage the cancer’s need to boost its own blood supply. It just may be that exercise makes cancer, rather than head for the door, sit back in the recliner and reach for the remote. A contrary notion, isn’t it – that in order to turn your prostate cancer into a couch potato, your best chance is not to be one yourself?
This doesn’t mean that men who exercise are immune to prostate cancer. “There are very fit athletes who have had forms of prostate cancer that are so aggressive, so genetically mutated, that they have proved fatal. However, those men are at one end of the spectrum of prostate cancer. There are many thousands of men at the other end or in the middle, for whom exercise may make a real difference.
Here are some other things that can lower your risk, which I cut out of this talk to save time.
Oligometastasis: Is the Window of Curability Wider Than We Thought? Now: What if you have cancer that is confined to the prostate, with just a little tiny bit somewhere else? Are you doomed? It used to be that doctors thought, “Oh, man, he’s a goner, the cancer’s spread.” But scientists are learning that just because a spot of cancer has popped out of the prostate, this doesn’t necessarily mean that it can’t still be cured.
Here’s the old-school thinking: You’re lying on a chair at the dentist’s office, and the dentist says, “You’ve got a cavity, decay is inevitable. We’ll just wait and pull all your teeth in a few years.” Like the poor guy in “Monty Python” who is mistakenly left for dead:” “I don’t want to go on the cart!”
Until very recently, the dividing line between prostate cancer that was considered curable and cancer that might not be was the prostate itself. That’s not the case anymore, says Johns Hopkins radiation oncologist Phu Tran, also a contributor to our book.
New evidence suggests that in men with oligometastasis – just a few spots of cancer outside the prostate – by treating “not only the primary disease in the prostate or the pelvis, but alsothe few metastatic spots, perhaps men can actually live a long time without disease progression and even be cured.” It’s the difference between being reactive – waiting for the next shoe to drop, the rise in PSA or development of symptoms – and being proactive. In other words: not just suspecting cancer is there, but knowing its precise location and going after it.
Now, how do they know where these little bits of cancer are? There is a new form of technology called PSMA PET scanning,which can showbits of cancer as small as a BB. There is also highly focused radiation, called: SBRT (stereotactic body radiation therapy) or SABR (stereotactic ablative radiation). Tran says it’s like spot welding—focused on a small area, very intense, and theoretically ablative, meaning it kills all the cancer in that spot.” Tran is testing this in clinical trials at Hopkins.
PSMA-PET:
Hopkins scientist Marty Pomper, who was one of my husband’s interns when he was Chief Resident at Hopkins, figured out how to engineer a small molecule that binds to PSMA, prostate-specific membrane antigen, which sits on the surface of prostate cells. He then used innovative biochemistry to glue F18, the radioactive fluorine that glows in a PET scan, to that small molecule. What he achieved is a way to see cancer that no one could see before.
This is very exciting for two reasons: PSMA-targeting molecules can find prostate cancer. But if you switch out the radioactive tracer for a radionuclide – a little grenade of radiation that is targeted precisely to PSMA – then this technology can also be used to kill prostate cancer. This is in clinical trials in the U.S., but it has been used for several years in Europe and Australia. Germany got the leap on everyone, because they don’t have to go through all the rigorous testing that we do. Some doctors in the U.S. are sending patients with widely metastatic disease out of the country for these treatments, and some of these men have gone into long-term remission. There are still some bugs to be worked out. There are different radionuclides, and we need to know which is better. Also, it turns out that PSMA didn’t know that its name was prostate-specific… it is also in the salivary glands, and so there has been a problem with men getting their cancer into remission but having no salivary glands, so this is not ready for prime time yet. But it is extremely hopeful.
IF YOU HAVE ADVANCED PROSTATE CANCER
If you need to start ADT, androgen-deprivation therapy, thanks to several recent studies, you also need to start taking an androgen receptor blocker. There are three: abiraterone (which you also take with prednisone), enzalutamide, and apalutamide.
The LATITUDE study, released last summer at the ASCO meeting, showed that giving abiraterone (Zytiga) and prednisone along with Lupron to men who are just starting ADT increased survival by an average of 18 monthslonger than ADT alone. But the study found that 25 percent of men showed an increased survival of four years, and a small percentage of those men appear to be “exceptional responders” who have had no progression of cancer for at least six years.
In real estate, it’s location, location, location. With cancer drugs, scientists are learning, the key to success may be timing, timing, timing. Starting abiraterone earlier, while the cancer is more vulnerable – before it has had a chance to mutate, to develop resistance and strengthen its armor – makes a huge difference.
Who should be interested in these findings? Between 50,000-60,000 American men just this year alone. Men who are on ADT, whose PSA is rising rapidly and doubling every 10 months or less. And men who are just starting ADT.
Apalutamide (Erleada) is the newest FDA-approved drug for advanced prostate cancer. Enzalutamide (Xtandi) is the third. These are game-changers, and the game they are changing is a terrible one, the agony of wait-and-see, played out with each PSA test by men whose cancer looks like it’s going to metastasize. This game sucks. Until now, men who did not yet have metastatic cancer did not have access to the next level of treatment.
The idea is that now, not only do you nothave to wait for metastasis, you may very well change the course of the cancer, delaying the time to metastasis by more than two years longer than ADT alone. Again, for some men, doctors aren’t even sure how longmetastasis can be delayed, because their cancer stillhasn’t progressed. The SPARTAN study, of apalutamide, was published February 2018 in the NEJM. Its senior author, Eric Small of UCSF, told me that the idea behind this study was actually to see if we could somehow put advancing cancer in a holding pattern. Maybe metastasis is not a done deal. In fact, he says, “this was really the first metastasis prevention study.”
For the men in the apalutamide group, the average metastasis-free survival was 40.5months – and some of these men stillhaven’t developed metastasis.
“We are talking about a 72-percent reduction in the risk of metastasis,” Small says. What nobody knows yet is whether earlier treatment will lengthen overall survival. “We believe it will,” says Small, “but it’s way too early.” For now, though, “We’re having a dramatic impact on delaying metastasis.” At nearly four years, “50 percent of men in the apalutamide group still have not developed PSA progression. They are doing well, they don’t have metastatic cancer, and haven’t been ravaged by extensive disease. That’s remarkable.”
In July 2018, the FDA approved enzalutamide (Xtandi) for men with non-metastatic CRPC. Same thing: this used to be second-line hormonal therapy, recommended only in men who developed metastatic cancer afterbeing on ADT. This decision is based on the PROSPER clinical trial, led by oncologist Maha Hussein, M.D., of Northwestern. In this study, 1,400 men with non-metastatic CRPC whose PSA levels were doubling every 10 months or sooner were randomly given either ADT with a placebo, or ADT plus enzalutamide.
Men who received enzalutamide had a delay in time to metastasis or death by an average of 21.9 months longerthan men in the placebo group, and some men haven’t had metastasis at all.
And now we get to Bad Genes and Immunotherapy
In 2016, a breakthrough study came out. It was led by Fred Hutchinson Cancer Research Center medical oncologist Pete Nelson, and published in the New England Journal of Medicine. The study found that:
Prostate cancer is a lot more of an inherited disease than anybody thought;
There are 16 bad genes that we now know to look for; and
If you have a mutation in one of these genes, your sons and daughters and their children should get tested, so they can be considered high-risk for certain types of cancer, screened vigilantly, treated aggressively, and live to a ripe old age and not die of cancer.
These particular genes, called DNA-repair genes, are tiny quality control specialists; they’re the spell checkers.
Nelson’s study looked at 20 DNA-repair genes, in 692 men with metastatic prostate cancer in the U.S. and United Kingdom. They found mutations in 16 of them, including some unexpected ones, like BRCA1 and BRCA2.
“Now wait,” you may be thinking, “aren’t they the breast cancer genes?” Yes, and for years, nobody linked these genes to prostate cancer. Now we know that the very same mutation that can cause breast and ovarian cancer in women can cause lethal prostate cancer in men.
Other bad DNA-repair genes include one that sounds like it should be at a bank, called ATM; and one that sounds like a roadie making sure the microphones work at a concert, called CHEK2; there’s also one that sounds friendly but isn’t at all, PALB2, which is strongly involved in pancreatic cancer.
Nelson and colleagues estimate that one in nine – 12 percent – of men with metastatic cancer have one of these bad genes.
In another study led by William Isaacs of Johns Hopkins, investigators did a genetic analysis of 96 men who died of prostate cancer at an early age – younger than 65. Billy Isaacs says: “Surprisingly, we found that more than 20 percent of these patients carry inherited mutations in genes responsible for repairing damaged DNA.”
Why Genes Matter: There are entirely new kinds of cancer-fighting drugs that target specific genes. One class of drugs is known as PARP inhibitors like Olaparib, which is being used to treat women with BRCA mutations in ovarian cancer. It has now been approved as a treatment for advanced prostate cancer in some men. Men with BRCA mutations also respond well to carboplatin, nota standard drug in prostate cancer.
What should you do? If you have high-risk or metastatic prostate cancer, or if you have a strong family history of prostate or other cancers, ask your doctor about genetic testing. One of them is made by Color Genomics, and it costs $250. You just spit into a test tube.
Checkpoint Inhibitors
In July 2016, a small but very exciting study led by investigators at the Oregon Health & Science University and Johns Hopkins, was published in the journal, Oncotarget. It involves checkpoint inhibitors.
Basically, your immune system can do great and powerful things: like cause an autoimmune disease to devastate your body. Ideally, it should only attack bad things, like cancer. But cancer has a lot of devious tricks.
T cells are some of the body’s most powerful warriors. They kill enemy cells. But prostate cancer basically makes a nice cup of chamomile tea for these T cells, and puts them to sleep. If you look at a sample of prostate cancer tissue, you can see the T cells right there next to cancer cells, and the T cells are asleep. They have checkpoints on them; these are like a straitjacket. Here, the cancer is hijacking a normal process that happens in every pregnant woman, so she doesn’t make an immune reaction to her unborn child.
Checkpoint inhibitors are a class of drugs, invented by Jim Allison with funding from the Prostate Cancer Foundation; in fact, he just shared the Nobel Prize for this work this month! Checkpoint inhibitors take off the straitjacket and unleash the T cells.
But not every checkpoint inhibitor works for every cancer. Also, compared to other kinds of cancer, prostate cancer looks pretty normal. It doesn’t have many mutations. Some forms of cancer have so many mutations – think of any villain in Batman – that the immune system says, ‘Hey, that guy looks weird. Let’s kill him.” But prostate cancer can blend in, so this is one problem: getting the immune system to recognize prostate cancer as the enemy.
There’s a lot of work that needs to happen. However: some people have had spectacular success with checkpoint inhibitors. Tumors that should have killed people with metastases in their lungs, liver, and brain, have melted awayinstead.
In this study, led by Julie Graff of Oregon, they used a checkpoint inhibitor called a PD-1 inhibitor. The results were so dramatic, and so unexpected, that they published the results early. Julie Graff was working with immunologist Chuck Drake, of Columbia University. Previously, she had seen two men with advanced prostate cancer who responded exceptionally well to a PD-1 inhibitor: their PSA went away, and their cancer appeared to be undetectable. Chuck Drake suggested that maybe enzalutamide, which targets the androgen receptor, might stimulate the immune system to make the PD-1 inhibitor work better.
So they did this study, of men who were taking enzalutamide but whose cancer was still progressing. The men continued to take enzalutamide as they receive four doses of a PD-1 inhibitor called pembrolizumab. The first 10 patients were enrolled from March 2015 to January 2016. Their ages ranged from 61 to 80, and their PSA ranged from a little over 4 to nearly 2,503.
In three men, the disease did not change; it did not get noticeably better, but it didn’t get noticeably worse, either. Four men did not have any evidence of a benefit, and one of these men died of his cancer. So that’s seven men; what about the other three? Their response blew the investigators away: Their PSA – including the man with the PSA of nearly 2,503 – dropped to the undetectable rangeof less than 0.1. Two of these men had been on narcotics for pain, and stopped taking them. One man’s liver metastases went away. “These three men had a complete response,” says Graff. “Their tumors shrank radiographically” – meaning that they couldn’t be seen in imaging – “in the lab” – their PSA falling to nearly nothing – “and clinically,” with the need for pain medication going away. “None has had a recurrence.”
Another very promising form of immunotherapy, on the horizon, is Tumor-targeting CAR T cell immunotherapy. This is custom-tailored for each patient: they take a patient’s T cells, and engineer a gene that enables the T cell to pick a cancer cell out and kill it.
Now here’s a question you are probably wondering: How is cancer affected by my gut bacteria? It may be that being able to increase “good” bacteria will help the immune system do a better job of fighting off disease – may soon help people with some types of cancer respond better to immunotherapy. Recently, scientists studying colon cancer found that certain bacteria are found in half of all colon tumors and when the cancer spreads, the bacteria spread right along with them. In another study, scientists found that two different forms of bacteria work together, like fertilizer, to help colon cancers grow. Scientists studying melanoma found that the presence of certain gut bacteria can change how cancer patients respond to immunotherapy. Karen Sfanos of Johns Hopkins is working on this in prostate cancer. It may be that special probioticsor even a fecal transplantmay help immunotherapy work better.
Gene-Targeted Therapy
Already, at major academic medical centers, getting treatment for advanced prostate cancer involves a talk with a genetic counselor. Heather Cheng, a medical oncologist at the University of Washington and Fred Hutchinson, was the first one. She started the world’s first prostate cancer genetics clinic. Here is a story about one of her patients, an amazing guy I interviewed named Mark Meerschaert.
In a matter of weeks, Mark went from being an athlete to someone who could barely walk; metastatic prostate cancer had come from nowhere and spread like wildfire throughout his body. Mark is a university math professor – the kind who fills up the blackboard in his classroom with calculations to answer questions of probability, and statistics. So when he got sick, he did what he does best: looked at the numbers. Men with widespread prostate cancer that is not responding very well to standard treatment don’t live very long.
So then Mark did what I hope everyone with a challenging diagnosis will do: He became his own advocate. He did some research and found Heather Cheng.
It turns out that Mark has a mutated BRCA2 genethat runs in his family. Cheng immediately focused on this gene and suggested a very different type of treatment – off-label use of olaparib, approved by the FDA to treat ovarian cancer. Olaparib is a PARP inhibitor; it blocks a protein that cancer cells need to repair themselves, and works especially well in people with defects in the BRCA2 gene. Olaparib and other PARP inhibitors are being studied in clinical trials for prostate cancer.
Cheng also got genetic sequencing of tissue from Mark’s metastatic cancer.
Cancer can change over time. If you have metastatic cancer, there may be different mutated genes than in the cancer that was originally diagnosed from the needle biopsy. This matters because there may be a new medicine that works well with your particular mutated gene or genes. She told him it could get worse before it got better.
It did. Mark said: “I started olaparib in October 2016. Two months later, “we did a bone scan, and saw that there was cancer all over the place: my ribs, hips, legs, some lymph nodes.” He became very weak. He used a cane, then a walker, then a wheelchair. He took a leave of absence from his job. Now he is looking forward to going back.
Starting early in 2017, he says, “I just slowly started to feel better and better. At some point, I said, ‘Maybe I can go for a walk again. I had a little numbness in my foot, but I said, ‘I’m going to keep walking,’ so I did. I walk my dog every day, a couple of miles. Now even the numbness is gone.” In a matter of six months, he said, “I’ve gone from shockingly, disastrously ill to feeling – I’m still cautious, still waiting for the other shoe to drop; nobody knows how long this is going to work. There’s no data on people like me. Now I feel great.”
Mark had known he was BRCA2 positive; after his brother was diagnosed with breast cancer several years earlier, he got genetic testing. But he never expected to get prostate cancer. In fact, although he’d gotten a PSA test every year, he had stopped. “My doctor said, ‘We don’t need to do PSAs.’ For two years I didn’t get a PSA.” Which brings us full circle to the Band of Geniuses.
In 2013, Mark developed some urinary symptoms and went to see a urologist. Cancer was found. He also learned that his father had been treated for prostate cancer when Mark was away in college, and his parents never said a word. “Had I known, I would have kept PSA screening.”
Mark underwent external-beam radiation therapy and a two-year course of ADT, which ended in March 2016. “By July of 2016, something just felt a little off. I went to see a urologist. A biopsy showed high-grade cancer.
When Mark went to Seattle, Heather Cheng got that biopsy tissue and sequenced it. Cheng told him, ‘Your cancer is very aggressive, but that might work in your favor.’ That turned out to be absolutely correct. It got bad really fast, and it got better really fast.” He says: “The question is, what happens next? I’m very interested in the five-year survival rate for people like me. They’ve only been using this since 2015, and the studies were on ovarian cancer. My God, what if this had happened five years ago?”
So, right now, immunotherapy drugs only help men with certain mutated genes: mainly BRCA 1 and 2, and ATM. But this is just the beginning.
Imagine a waiting room full of 100 men with advanced prostate cancer. Some of those men have mutated BRCA genes; those genes can also cause breast and ovarian cancer, so let’s color them pink.
Some have a mutated PALB2 gene, also the bad gene in pancreatic cancer. Let’s color them green.
For about eight of those men, the bad gene is WNT. That’s also the gene involved in 100 percent of aggressive colon cancers. Let’s color those men blue.
About half have a bad ERG gene. This is found in children’s leukemia and in sarcoma. Let’s color those men purple.
About one-fourth have a mutated PTEN gene. That can also cause some brain cancers, endometrial cancer, breast cancer, and ovarian cancer. Let’s color those men orange.
One guy has a mutated IDH1 gene; this only affects 1 percent of men with prostate cancer, but it affects 100 percent of people with a glioblastoma, like Senator John McCain. Let’s color that man red.
Eventually, our imaginary waiting room looks like an Easter Egg hunt.
Each color represents a subgroupof advanced prostate cancer. The drug that works best on the men with the bad BRCA genes probably won’t work best on the men with the faulty ERG genes. The drugs work differently because the men’s cancers are different – but they’re different in groups. A man in the yellow group may not be helped by a drug that works well for the guy in the purple group. But he probably will be helped by a drug that helps other men in the yellow group.
You know who else will be helped? People with other cancers who have that same mutated gene. So very good things are happening, and there has never been so much hope for prostate cancer, and cancer in general, as there is now.
In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.” As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.
©Janet Farrar Worthington