Conversations With Prostate Cancer Experts

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The Genomic Revolution Comes To Prostate Cancer

Dr. Oliver Sartor, the Laborde Professor of Cancer Research in the Medicine and Urology Departments of the Tulane School of Medicine, is one of the leading researchers in advanced prostate cancer today. He is also the editor-in-chief of Clinical Genitourinary Cancer and the author of more than 300 scientific papers.

Dr. Sartor puts this month’s conversations about prostate cancer genomics into context for us.

“We can divide genomics into two different categories. The first category is germline genomics, which is the DNA with which you’re born. It’s clear that about 12% of people with advanced prostate cancer will have alterations in their inherited DNA, in particular in genes involved with DNA repair. Most common of these alterations are BRCA2. There are a variety of others that are somewhat prevalent, including ATM, CHEK2, and BRCA1. There are others that are more rare.

The implications of these germline mutations are significant for the patient: in certain configurations they may predispose a cancer to be sensitive to certain therapies, such as PARP inhibitors or platinum-based chemotherapy or (rarely) immunotherapy. There is more complexity, but knowing the germline mutation helps the informed clinician make decisions. In my practice, we test all patients with advanced prostate cancer for these germline mutations. (A National Comprehensive Cancer Network guideline suggests the same approach.)

These germline mutations represent the DNA with which you’re born. That DNA is going to have repercussions if also mutated in your family members. Men who have some of these DNA repair mutations have an increased risk of prostate cancer. In addition, there is a small increased risk of pancreatic cancer and male breast cancer for those with some of the germline mutations. Around 30% of men with BRCA2 will be diagnosed with prostate cancer in their lifetime, but that cancer is more likely to be aggressive if diagnosed. With regards to females, it’s particularly important. Females with DNA repair defects are more likely to have breast and ovarian cancer. Female with DNA repair mutations, in particular BRCA1/

BRCA2, ought to consider having their breasts or ovaries removed at an appropriate time. Prophylactic surgery has been demonstrated to be potentially life-saving for those individuals. The risk of breast cancer may be as high as 70% and the risk of ovarian cancer may be as high as 40%.

Thus, for these germline mutations there are implications for treatment and implications for the patient’s family.

We should be doing prostate cancer screening earlier in men with these DNA repair defects for prostate cancer; we should be doing biopsies at a PSA of 3 or higher, and perhaps even lower, for younger men known to be at risk. Starting screening at age 45 has been suggested by some. In addition to germline genomics, we need to also talk about somatic genomics. Data indicates that about 60% of individuals who have a DNA repair germline mutation are likely to have another second genetic mutation occur within their tumor. In addition, many of the tumors can acquire an alteration in their tumor DNA even when the germline is normal.

Taken together, about 20 to 25% of men may have DNA repair mutations in their tumor’s DNA. That makes them particularly sensitive to certain therapies such as the PARP inhibitors, as I mentioned earlier, or platinum chemotherapy. When you have two DNA repair mutations in the same cell, the likelihood of response to these agents appears fairly high.

There are also other DNA defects of considerable interest, such as alterations of the mismatch repair genes MSH-2 and MSH-6. When these alterations do occur, there is a potentially increased probability of responding to immunotherapy such as the new PD-1 inhibitors.

Overall, the guiding light today in genetics in my practice is to look at both the germline DNA and the tumor DNA. I choose to look at the tumor DNA circulating free DNA (cfDNA) tests, in particular the Guardant Health assay. The ability of other assays to corroborate the Guardant Health findings is not yet clear. There is clear data to indicate that different assays give different results, but nevertheless, I think in the early exploratory phase we’re in now, it’s important to begin to test patients in order to better understand their genomics and hopefully guide us towards better therapies. This will happen part of the time but certainly not all of the time.

There is more to the story of prostate cancer genetics. We’ve looked at androgen receptor mutations that can have implications for a response to Androgen Receptor directed therapy, such as Xtandi (enzalutamide), Zytiga (abiraterone), and Erleada (apalutamide). We’re dissecting a number of permutations that occur. It’s a complex scenario, because very few men have only one mutation. Most have multiple mutations. And in most cases, these mutations are not targetable with current therapies. This is very important for people to know.

Everybody thinks if they get a genomics test that means they’ve got a treatment. It’s not the case. Many times we get the genomics results and find that there are no known treatments we can use for that man’s particular alteration. That said, there is a subset of men who will have informative genomics while many more people will have non-informative genomics.

There is a final issue I’d like to discuss. There is currently a bit of a debate amongst physicians over the utility of PARP inhibitors such as Lynparza (olaparib) as compared to platinum chemotherapy. But it is noteworthy that platinum-based chemotherapies are inexpensive compared to PARP inhibitors. This does not require a clinical trial. (Most men will access PARP inhibitors through a clinical trial, although sometimes insurance companies are willing to try.)

As it turns out, neither the platinum-based chemotherapies nor the PARP inhibitors will be effective forever, so we do need strategies to manage patients after PARP inhibitors or platinum-based chemotherapies fail. Currently, that space is unexplored. We have to gather much more data before we can make conclusions about those with underlying DNA repair defects who have failed platinum-based chemotherapy or PARP inhibitors.

This is an area of active and important investigation that represents a conundrum for many patients today. I’ve got a patient right now going through this. We’re debating what to do next. I’ve tried to be as honest as I can when I say, “I don’t know what to do, but we’ve got to try something.”

We are in the middle of a revolution, but the parts and pieces are not yet clear. For some, understanding tumor genetics at the current level is helpful. For others, it is perplexing and expensive.

Join us to read this month’s conversations about prostate cancer genomics.

(Already a member? You can read all conversations in your copy of April’s Prostatepedia.)


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Targeted Prostate Cancer Screening

Jeffrey_SwensenDr. Jeffrey Swensen is the Associate Director of Molecular Genetics at Caris Life Sciences in Phoenix, Arizona.

Prostatepedia spoke with him recently about prostate cancer screening for men with BRCA2 mutations. (See Prostatepedia March 2017 for a discussion with Dr. Swensen about molecular profiling for prostate cancer.)

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Should a man with a BRCA2 inherited mutation be screened earlier for prostate cancer?

Dr. Swensen: Carrying a pathogenic BRCA2 mutation increases the risk for prostate cancer, and that cancer is more likely to be aggressive and earlier onset. There are recommendations that suggest male BRCA2 carriers should be screened more aggressively for prostate cancer. Male BRCA2 and, to a lesser extent, BRCA1 mutation carriers are also at increased risk for other cancers, including male breast cancer and pancreatic cancer. Screening male BRCA2 mutation carriers for breast

cancer is generally recommended; screening for pancreatic cancer is generally not unless there is a family history of that cancer.

Would it make sense to offer prostate cancer screening to male children of a prostate cancer patient earlier?

Dr. Swensen: No. A man with a BRCA2 mutation tends to get prostate cancer at an earlier age than the standard person in the population. But it’s generally not really early onset.

A female with a BRCA1 or BRCA2 mutation is at higher risk for breast and ovarian cancer and the onset can be at a considerably younger age. However, screening is typically not performed on these women until they’re adults.

Male BRCA2 mutation carriers are at increased risk for cancers, but the risk is not the same magnitude as the risk for the women. The lifetime risk has been estimated to be around 20% for prostate cancer in a male BRCA2 mutation carrier; a female carrier of a BRCA2 or BRCA1 mutation has a lifetime risk of breast cancer that may be up to 80%.

A female BRCA1 or BRCA2 mutation carrier will be counseled and followed extensively. After they reach a certain age and have had children, they can have their breasts and ovaries removed to significantly reduce their risk.
That is what Angelina Jolie did.

Are there any other mutations that are significant for prostate cancer?

Dr. Swensen: There is a mutation
in another gene that has been shown to be a risk factor for prostate cancer: G84E in the HOXB13 gene.

This mutation is carried by about 0.5% of individuals of European ancestry. It is not a high-risk mutation. Male carriers have a two to threefold increased risk of prostate cancer. The mutation is not known to be therapeutically significant.

Is that mutation associated with an increased risk of getting prostate cancer or of getting aggressive prostate cancer?

Dr. Swensen: That has still not been clearly defined.

Does it make sense to offer prostate cancer screening earlier to men with the G84E germline mutation in HOXB13?

Dr. Swensen: It is one of many genetic factors that will influence an individual’s risk of cancer.
At this time, though, screening is not warranted.


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Prostate Cancer Screening For Men With BRCA


Dr. Preston Sprenkle is an Assistant Professor of Urology at Yale University.

Prostatepedia spoke with him about a trial he’s running on targeted prostate cancer screening.

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Why did you become a doctor?


Dr. Preston Sprenkle: My father was a physician. I liked the idea of helping people and doing something that was both intellectually challenging, yet also socially and intellectually rewarding.

I wasn’t sure, though, so after college I worked in consulting for a little while also volunteering in an ER and in some free clinics. I really valued those experiences with patients and the one- on-one interactions. I recognized how much good you can do and how much you can help someone by just listening and being attentive to their needs and concerns. Those experiences solidified my desire to go into medicine.

When I started medical school, I quickly realized that I really enjoyed anatomy and surgery. Urology is a fantastic specialty because you come in contact with a wide variety of patients—from children to very old patients, men and women. Even though most people think urology just centers on men, we actually take care of a lot of women too.

Urology involves a lot of surgeries that can be complicated and take a lot of time and energy, but there is also a lot of one-on-one patient-based care dealing with very personal things like sexual function or urinary function. Urology is somewhat unique among surgical specialties in that we not only operate on patients, but very often follow them for many years, allowing for long-term relationships with our patients.

I then became interested in cancer care. The current challenge is to improve the way we take care of cancer patients. Cancer is scary. Fortunately, in many cases it is very treatable and even curable. But hearing the C-word can be terrifying. Most people shut down and don’t really hear much after learning they’ve been diagnosed, so it can be a little longer process to help them understand that there are opportunities for cure.

What is the thinking behind the clinical trial you’re running?

Dr. Sprenkle: We opened this trial to better understand the relationship between the BRCA2 mutation, or BRCA2 deletion, in men and the incidence of prostate cancer.

There have been several studies showing that men with prostate cancer who have a BRCA2 mutation have a more aggressive prostate cancer more likely to have lymph node positivity.

What we have not been able to identify is where that starts. These men were arguably diagnosed with prostate cancer because they had an elevated PSA. Is their risk higher because they were diagnosed later in the course of their prostate cancer, or is their risk higher because the BRCA2 deletion causes them to have higher-grade prostate cancer?

When we started this trial, there was no information and no long- term prospective studies. (I believe there recently has been a trial that suggests that on a stage-for-stage basis it actually may not be much worse to have BRCA2, but that was not around when we started this trial.)

We are trying to understand the incidence of prostate cancer in this population of men with the BRCA2 mutation. This is, in part, a registry for all men who have a known BRCA2 mutation. We offer them prostate cancer screening with standard techniques: PSA blood tests, DRE, etc. But we also offer an MRI and MR-targeted biopsy to evaluate if there are any radiologic characteristics that could be used.

If 28-30% of men in a general population have prostate cancer with a PSA cut-off of 4, is that the same for men with a BRCA2 mutation?
 Or should we be screening men with this mutation earlier? Or biopsying them with a lower PSA? Do men with this mutation have a 30% rate of prostate cancer with a PSA of 2?

There is a famous trial called the Prostate Cancer Prevention Trial that used a medication to shrink the prostate. During the trial, they biopsied men 
if they had an elevated PSA and then at the end of that trial. Even men who didn’t get treatment were biopsied
 at the end, independent of what their PSA was. The trial gave a tremendous amount of information about what the likelihood is of developing prostate cancer when your PSA is as low as 1. Based on the results of this trial,
 we know that approximately 8%
 of men with a PSA of 1 or less have prostate cancer on a random biopsy—even though we typically don’t biopsy those men.

This current trial is an opportunity
 for us to gain information about how—or if—the incidence of prostate cancer is different in a population of men with a BRCA2 mutation.

Are you just looking for men without prostate cancer with the BRCA2 mutation?

Dr. Sprenkle: Yes. Any man who
 has at least a 10-year life expectancy qualifies to be screened.

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