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The Precision Medicine Revolution

Welcome to the world of precision medicine.

That sounds futuristic, like science fiction, or a cool exhibit, something that promises great things for tomorrow, something that’s not here yet.

But this is different. We have new knowledge which has given us new targets for a smarter, more scientific approach that is helping all men with prostate cancer – but particularly those who need it most, men with metastatic prostate cancer. Even a year ago, many of these men had to endure the discouraging trial-and-error process of finding drugs that work for them. We hate trial and error; it takes up valuable time and wears you down.

One day, there won’t be trial and error for prostate cancer drugs. Thanks to research funded by the Prostate Cancer Foundation, we have new targets – genes we now know to look for – that have led to new tests, which point us to specific drugs. Some of these drugs may not even be intended for prostate cancer, but for colon cancer or breast cancer; yet they are likely to work in your cancer if you have those same faulty genes, too.

One great thing about these drugs is that because they are gene-targeted, they don’t poison your body, make you vomit, deplete your white blood cells or hurt your bone marrow.

In the past, because chemotherapy was so harsh, doctors did something that seems kind of odd now: they waited until nothing else worked before they gave it. This meant that by the time a man with metastatic prostate cancer got chemo, he was already very sick, and his cancer was very advanced. Now, because precision testing can give us a glimpse several years into the future, we know which men are likely to have their cancer come back, and we’re not waiting around for that. When it comes to treating cancer cells, sooner is better than later.

It’s not your father’s prostate cancer anymore.

We’re not done yet, not by a long shot. There’s much more work to do. Already, the death rate is half of what it used to be 20 years ago. Many men who have metastatic prostate cancer are not going to die of it; with these new approaches, we are putting them into long remissions.

Our goal is cure, and we’re not there yet. But we can see it; it’s not just some vague hope, not wishful thinking. We’re getting there, thanks to precision medicine. This is why we have raised and pushed $630 million dollars into research over the last two decades: to stop men from dying of prostate cancer.

Precision Drugs: If you have advanced prostate cancer and conventional hormonal therapy is no longer working, you might be helped by enzalutamide or abiraterone – but you might not. Now, instead of spending thousands of dollars and enduring months of trial and error, you can find out ahead of time if you should take one of these drugs. A simple blood test is just becoming widely available. It targets AR-V7, a particular androgen receptor variant (basically, AR-V7 allows the cancer to create an antidote to these drugs, canceling out their effects). If you are AR-V7 negative, then abiraterone or enzalutamide can put you into remission. If you are AR-V7 positive, then you will do better with another form of treatment.

I believe that every man should be asking his oncologist, “What’s my AR-V7 status?” You need to help drive your treatment. This is so new, your oncologist may not know about it.

Precision Diagnosis. We call this clonotyping: basically, your cancer is one dot on the big data map of prostate cancer, and exactly where you are depends on the specific genes that are mutated in your cancer.

We now know that you don’t just have prostate cancer: you have a very particular type of it – one of over 27 different kinds (scientists call them clones) of prostate cancer. This is not as crucial to understand if you have localized, low- or intermediate-risk disease. But it is very important to understand if you have high-risk or advanced disease. Just as we all have different fingerprints, cancer has different fingerprints, too – except these fingerprints are genetic. The genes that are mutated in your piece of the prostate cancer jigsaw puzzle are most likely different from the genes involved in the prostate cancer of the man sitting next to you in the doctor’s waiting room. Your cancer is literally programmed differently from that guy’s; it’s driven by slightly different software, because the DNA code is different.

This means that when it comes to advanced or high-risk prostate cancer, we know that the treatment that works on one man’s cancer may not work on yours, and now we know why. So we shouldn’t treat you both the same. We need custom-tailored treatment, and that begins with custom-tailored diagnosis.

To show you where we’re headed, it’s like the difference between buying a suit off the rack and getting one crafted by an expert tailor: precision medicine is individualized. You need custom-tailored treatment, and that begins with custom-tailored diagnosis.

The old way – and by this I mean what we did even six months ago – was to treat the average. This means that if 100 men got treatment, some would benefit, and the rest would have cancer that keeps right on growing. We did our best to give patients odds, because all we could do was estimate that they might be in the group of men who are helped by a particular drug. The new way, precision medicine, means treating the right patient with the right disease at the right time with the right amount of drug. It’s about understanding the genes. This approach works: 25 years ago, everyone who got HIV died of AIDS. Now, nobody has to die of AIDS, because we have medicines to treat it. Even the smallest genetic variant in that disease is so well-defined, we know what medicine will work best.

We shouldn’t be treating prostate cancer; we should be treating you. Precision medicine also means that your prostate cancer may have more in common with colon cancer, or breast cancer, than with some other man’s prostate cancer, because you may share the same genetic mutations.

Precision testing. There is a new blood test called the Cascade Genetic Test that could change your life. Your doctor may not know about it; it’s that new. But if you have metastatic prostate cancer, or your father had it, you should know about it; so should your sons and daughters, and your grandchildren. The “cascade” part of the test is the domino effect to the next generations; that’s the part that will save lives and stop the cycle of lethal cancer from bad genes. A patient recently asked, “Why didn’t my urologist tell me?” Because it’s very new.

This test, developed by PCF-funded research, tells you if you have a mutation in one of 16 genes called “DNA damage-repair” genes. These genes are little mechanics; their job is to fix problems in the DNA. When they break down, errors don’t get fixed, and over time, this can lead to cancer. Some of these genes are pretty famous: BRCA1 and BRCA2 are well-known causes of breast and ovarian cancer.

Another is a gene called WNT. It’s mutated in 100 percent of colon cancers and a target in more than 25 percent of ovarian cancers that are chemotherapy-resistant. If you have a faulty WNT gene, then what makes most sense is a drug that has WNT as its bullseye.

Still another gene is called PTEN, and it is mutated in more than 40 percent of all lethal breast cancers, more than 60 percent of lethal ovarian and uterine cancers, and 40 percent of brain tumors. PTEN is like the emergency brake on a car; if it doesn’t work, you’re in trouble. Now, imagine that car is parked on a hill: just as the car rolls downhill and picks up speed, so does cancer start growing unchecked without this gene.

So what we need – and are actively working on – are PTEN-targeting drugs that act like a caltrop. This is an ancient, highly effective weapon, used by the Romans to deter chariots and still used today in the form of spike strips that puncture your tires if you go the wrong way. If the brake is off and the car is rolling, this will slow it down and eventually stop it. When – not if – these drugs become available, they will not only help men with prostate cancer, but many men and women with different cancers, as well.

Now, a PTEN-targeting drug is not going to help a man with a faulty BRCA1 gene; but a drug like olaparib or rucaparib – both of which target BRCA1 – could help that man get his cancer into remission.

Have you heard of an “orphan disease?” That’s what we’re dealing with here. Orphan diseases affect just a few people compared to heavy-hitters, diseases like lung cancer or diabetes that affect millions. They tend to languish when it comes to funding for research and treatment. But if those orphan diseases could be combined somehow, the numbers of people affected would really go up, and the pharmaceutical industry would have a lot more incentive to develop drugs to treat them.

We now know that advanced prostate cancer is a bunch of orphan diseases.

Here’s another example: 3 percent of men with metastatic prostate cancer have a mutated MMR gene. A young PCF-funded investigator named Julie Graff has had amazing results in some men with metastatic prostate cancer using a drug called pembrolizumab, which is in a new class of drugs called checkpoint inhibitors. These drugs help the immune system recognize cancer as the enemy, and use the body’s own powerful T cells to kill the cancer. Specifically, pembrolizumab is a “PD-1” inhibitor, and is approved by the FDA to treat melanoma. Melanoma is not prostate cancer, but some people in both categories have precisely the same MMR mutation, and for them, pembrolizumab produces results that have been called miraculous. In some men, the cancer that lit up their scans when the study started either shrank significantly or disappeared entirely just a few months later. Their PSA dropped dramatically – from more than 2,000 down to 0. They stopped taking pain medication.

Graff’s protocol is laid out. If you have the right genetic mutation for this study, you should be able to get this drug, and you shouldn’t have to fly to Oregon, where she is, to get it. It’s not chemo. No one has ever seen metastases in the liver disappear like this – yet they really do, and you can see the images for yourself here. Over the next few months, as soon as it’s available, we will have information on hospitals that are offering these drugs in clinical trials. This is precision oncology.

Precision family genetics. Another PCF-funded investigator, Dr. Heather Cheng, has started a program at the Fred Hutchinson Cancer Research Center in Seattle, Washington that is the first of its kind in the country. She is offering treatment based on the genetics of your cancer. If it involves a gene (like the ones we talked about above) that might be carried by your sons and daughters, she offers them genetic counseling – so your daughter can get high-risk screening for breast and ovarian cancer if she needs it. Every man treated for prostate cancer there will have custom-tailored treatment based on an understanding of the genes that need to be targeted to make him better. Reach out to Seattle Cancer Care Alliance (URL: seattlecca.org/contact/feedback) to inquire. We hope to see similar programs starting at centers of excellence around the country.

Precision biopsy. Pathologists can’t get this kind of genetic information just from looking at prostate biopsy tissue under a microscope and determining the Gleason grade. So just as it’s not your father’s prostate cancer treatment anymore, it’s not his biopsy, either. Pathologists today look at the DNA of prostate cancer cells. We are also working toward what we call a “liquid biopsy,” where pathologists can isolate some prostate cancer cells that are circulating in the blood and look at that DNA, as well.

Precision patients as partners. Everything I’m talking about right now is not going to become widespread without men and their families driving the standard of care. There is a frontier, a leading edge of medicine, and that’s what you need to be seeking. Ask your doctor for the AR-V7 test. Ask your doctor for the Cascade Genetic test. Ask your doctor if you are eligible for a clinical trial of a checkpoint inhibitor. This is all so new. But we have turned a corner on prostate cancer, and there’s no going back. We’ve seen it with HIV. We are seeing amazing results in metastatic prostate cancer, and in other metastatic cancers. We have momentum.

You are an essential part of this. It is crucial that we have men with prostate cancer willing to help other men with prostate cancer: sharing your stories, sharing the latest news about treatments and research – so they can ask their doctors whether it will be right for them.

What kind of prostate cancer do you have? Let’s figure it out and go from there.

Welcome to precision medicine.