Mark Meerschaert is alive today because of a genetic counselor, a medical oncologist in Seattle named Heather Cheng, M.D., Ph.D. (You can read more about Mark’s story here.) Less than a year ago, Mark was desperate: hormonal therapy had failed, and traditional chemotherapy was not going to save his life. His body was riddled with cancer, and he could barely walk.
After getting a grim prognosis from his doctors, Mark did some research and found Cheng at the Seattle Cancer Care Alliance; she is on the faculty at the University of Washington School of Medicine and the Fred Hutchinson Cancer Research Center, and she opened the country’s first genetic counseling clinic for men with prostate cancer.
One of the first things Cheng did was to study the biopsy results of Mark’s metastatic cancer. This is different from the prostate biopsy that all men get when their cancer is diagnosed, and it’s necessary because the cancer that was first diagnosed – in Mark’s case, back in 2013 – is not the same as the cancer that later spread throughout his body; it’s a different animal.
If you remember the 1984 movie, “Gremlins,” what happens as cancer spreads is like the Jekyll-Hyde transformation that happens to the cute, furry cinematic creature when it gets wet – it multiplies, producing destructive, evil offspring that, in turn, reproduce like crazy and cause a lot of harm.
At the genetic level, there is a huge difference between early cancer, even if it has the potential to become aggressive, and metastatic cancer, which has lived up to that potential and become a deadly disease.
Sure enough, Cheng saw something Mark already knew about – an inherited bad copy of BRCA2, which runs in his family – in his normal tissue. But she also found that in Mark’s metastatic cancer cells, both copies of BRCA2 were mutated. Because of this extra mutation, his cancer was especially aggressive. Cheng suspected that it also had great potential to respond to off-label use of a drug called olaparib, approved by the FDA to treat ovarian cancer and known to work especially well when there is a bad BRCA2 gene.
She was right. Mark, who had been in terrible pain and unable to walk, slowly started to feel better. He now walks his dog two miles a day, is able to babysit his grandson, and is planning on going back to his job as a college mathematics professor.
The Right Treatment for Your Own, Individual Cancer
Together, genetic testing and cancer sequencing are the very best examples we have right now of precision diagnosis and precision treatment. This means finding the right treatment for your own, individual cancer. It also means, says medical oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation, “the beginning of the end of traditional chemotherapy.”
It is high time, he adds. Traditional chemotherapy hardly ever works equally well on everyone. Doctors prescribe it because it helps some, or even most people who have cancer – but not everyone. Its approach is basically scorched-earth – imagine killing a fly with a flame thrower.
But until recently, that was the best we could do. “For years, we had no way of knowing who would be helped and who wouldn’t by standard chemotherapy,” Simons adds. “Even worse, we didn’t understand why a drug helped some people, but didn’t help others. Imagine there are eight men in a waiting room, they all have metastatic prostate cancer – but maybe only two people will respond the same way to the same drug.”
There are molecular reasons why these men all respond differently. Their cancers might have the same effects – say, metastases in the bone – but each one may have its own very different genetic roadmap for reaching the same destination.
Cookie-cutter chemo is going the way of the dinosaur – and what a coincidence: paleontologists are doing something very similar! Years ago, they used to say, “This looks like a likely spot where dinosaurs used to roam. Let’s dig it all up and sift for clues.” Today, they look at aerial photographs, and use sonar, x-rays, and other clues so they dig smarter; they dig where they know a skeleton is.
Cheng began the Prostate Cancer Genetics Clinic at the Seattle Cancer Care Alliance in 2016 because she saw a great need, particularly for younger men – in their 40s and 50s – diagnosed with metastatic cancer or at high risk of developing it. Some of them have a family history of prostate cancer, and some of them have a family history of other kinds of cancer – cancer of the colon, pancreas, ovary, or breast.
Her timing could not have been better. Cheng’s University of Washington/Fred Hutchinson colleagues, Colin Pritchard and Pete Nelson, were making discoveries at around this same time that would result in a landmark paper published in the New England Journal of Medicine. In the world of prostate cancer, their article was a bombshell: it showed that about one in 10 men with metastatic prostate cancer has at least one inherited mutation that raises his risk of getting cancer. They also found that, for many men, having a family history of other cancers – in the breast or pancreas, for example – was just as important as, and maybe even more important than, having a family history of prostate cancer. Pritchard and Nelson’s team identified 16 key genes – genes such as BRCA1 and BRCA2, notorious for their role in breast and ovarian cancer, and other genes linked to colon cancer, pancreatic cancer, and melanoma. These genes have very similar jobs: to repair damaged DNA. If they are mutated, the DNA damage doesn’t get fixed. These are “germline” genes – genes that can be passed on to sons and daughters, and to their children.
Is genetic counseling for you? Maybe. “At present, genetic counseling is not necessarily for every man diagnosed with prostate cancer,” says Cheng, “but if you have metastatic disease – or someone in your family has had it – I would strongly consider at least discussing your situation with your doctor and/or a genetics specialist.” There are several excellent reasons why:
Gene-targeted treatment: It may be that, like Mark Meerschaert, you have a mutation in a particular gene that is known to be susceptible to a certain drug – even if that drug is approved for a different type of cancer. For example, olaparib is in a new category of drugs called PARP inhibitors, which have been shown to work well in tumors with faulty BRCA1, BRCA2, or PALB2 genes. These and other DNA damage-repair genes can be tested in the biopsy of metastatic cancer tissue or, in relatives of someone with metastatic cancer, in a blood or saliva test.
PARP is a tool in the DNA damage repair kit. It’s a protein that works like a styptic pencil when you cut yourself shaving: it stops nicks in a strand of DNA from getting worse. Some of these same genes are also more sensitive to platinum chemotherapy; in fact, a few men have been exceptional responders to it.
One day, it may be possible to test for defective genes by looking at circulating tumor cells (CTCs) – bits of cancer that have broken off from the cancer and floated into the bloodstream. For now, though, the best way to know what’s going on in the genes of a man with advanced prostate cancer is to look at a metastatic biopsy (from the newly spread tumor). “That’s the gold standard,” says Cheng, “but it’s not standard of care quite yet, either.” This means that not all insurance plans cover metastatic tumor biopsies, but she hopes that will be changing soon as more men are helped by precise knowledge and treatment of the genes in their tumor. New gene-targeted drugs are under development.
Smarter treatment of high-risk disease. If you have one of these inherited mutations and you get prostate cancer, “even at the time of original diagnosis, it may be more aggressive,” says Cheng. But there’s more than prostate cancer on the table here: Let’s say a man has metastatic prostate cancer, and he is found to have inherited a BRCA2 mutation. “We now know his family members may also carry the same mutation. Let’s say the man’s sons get tested and find out that they have the BRCA2 mutation and are at higher risk. This doesn’t mean they will definitely get cancer, but it’s an opportunity to be extra careful and tailor their prostate cancer screening – because they’re at a higher risk of developing aggressive prostate cancer.”
Along the same lines, she notes, “If the man’s daughters and granddaughters are tested and found to have the BRCA2 mutation, they would be at higher risk for breast or ovarian cancer, and could get the best preventive screening and care. The whole family can have a much better chance of not even getting cancer, or of curing it.
“There’s a lot of misconception that these genes just involve men, or with the BRCA genes, that they just involve women’s cancers,” Cheng adds. “Someone might think, ‘There’s no one on my mom’s side of the family with prostate cancer, just breast cancer.’ The cancer risk can come from both sides of the family. This is a great opportunity to educate families in a way that’s really valuable.”
Should any men consider taking the “Angelina Jolie” route, and getting their prostates taken out before they get cancer? A radical prostatectomy is definitely not something to be undertaken lightly, because of the risk of side effects. “If you are at extremely high risk, if you have a very strong history of prostate cancer-related deaths and are a known carrier of a faulty gene, that might be a situation where – maybe in the future – it would become a standard option. However, we’re not recommending that at this time.”
Men who have been treated for localized prostate cancer who are at a higher risk of having it come back might get extra precautions, as well, depending on their genes – neoadjuvant or adjuvant treatment, for example, or a short course of ADT with radiation therapy.
Genetic testing is still very new in prostate cancer. “In another five years, we will have a much more comprehensive list of genes,” notes Cheng. What if you get genetic testing and it’s negative – but your family has a lot of cancer, so how to explain it? “That may mean we just don’t know what the cause of your family’s risk is yet.” For example, men of African descent undoubtedly have unique genetic differences in their prostate cancer compared to Caucasian or Asian men, but much more study is needed to come up with a definitive list. The PCF is funding research in this area. “Our molecular tools are getting better all the time,” says Cheng. She hopes new genetic knowledge will lead to more thoughtful screening for early detection.
So maybe, when you or your sons and grandsons get screened for prostate cancer, testing will include a DNA assessment along with biomarker tests for the blood or urine – and if you turn out to have a genetic Achilles’ heel, there will be a way to attack it strategically. “So many things are coming together. It is really very exciting.”