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Understanding Genetics and Genomics in Prostate Cancer



Kristie L. Kahl: What are genetics and genomics?

Dr. Charles Ryan: In reality, when we, in a clinical situation, are talking about genetics we're talking about genes associated with a cancer. Genes that we inherit from our mother and our father are germline genes or there can be genes in the tumor itself. While many of the genes that are in your normal non-cancer body are in the cancer itself, the cancer itself may have its own set of mutations and other genes.

Family genetics, or germline genetics, are an important part in prostate cancer. Some of it is known and some of it is not known. Some of it is clinically relevant and some of it is not clinically relevant in terms of decision making. The most important observations in recent years, because they hit both of those criteria, would be the observations around DNA repair genes and their risk for prostate cancer. The most known about is the BRCA1 or BRCA2 gene. They’re different genes but they're very similar in terms of what they do. These genes were first discovered in breast cancer, that's why they have the name that they do but they are associated with a number of endocrine cancers, such as breast cancer, ovarian cancer, endometrial cancer, uterine cancer and prostate cancer, even pancreas cancer. A person who has a familial mutation in one of those genes is at higher risk of prostate cancer as they age. If a person who is not a cancer patient who has a strong family history or knows that they carry one of these genes, they should be talking to their doctor about getting screened for the cancers that apply to it. So, that's really genetics. There are other familial genes that are associated with prostate cancer but they're much less common and we're still kind of sorting out the link between family genes and prostate cancer risk. There is another gene called S-POP. But BRCA is really the one that receives the most coverage and is probably the most common.

With regards to genomics, that's a different story. So, genomics refers to the genes in the cancer and how they may correspond to the biology of that particular cancer. For example, a patient has metastatic prostate cancer and I’m wondering what his prognosis is. I’m wondering what types of treatment options might I have available for him. So, if I do a genomic test, I take his prostate biopsy or or the whole prostate if it's been removed from him and I send it to a lab where they look at a panel of mutations. They might look at somewhere between 50 and 500 genes to see if they are mutated. They look at commonly mutated genes in in cancer patients. Then I’ll get a report that will say this patient has two or three or four mutations or maybe no mutations. Not all of those are going to be helpful to me. Some of them are going to be something I don't know what it does and maybe nobody does. Some of them are going to tell me about the patient's prognosis and saying this is a gene that is mutated in a higher risk cancer situation. And some of them are going to tell me not only about prognosis but they might tell me something about a treatment that I might find available. So, for example, I just mentioned BRCA2. If I find a BRCA2 mutation in a cancer specimen, it means a fairly high likelihood that that patient may benefit from that class of drugs that target it, which are called PARP inhibitors.

Kristie L. Kahl: Why is it important for men who have a history of prostate cancer to make sure that they're getting genetic testing done?

Dr. Charles Ryan: It used to be that genetic testing was really only necessary for family counseling but now it's going to help a patient and a doctor make treatment decisions individually. So, that's what's important about it. And there are certain cases where the genetic mutation in the cancer can drive a very significant difference in outcome when these drugs are used. It doesn't occur in everybody, but it can make a critical difference. The setting in which we think about the cancer genetics, we think about doing the genomic testing in anybody who has metastatic prostate cancer. Certainly, in a patient who develops metastatic cancer, at the first sign of the disease – in other words you have someone who gets surgery and then it recurs as metastatic disease – and in others whose first sign of the disease is metastatic disease. Those are situations in which most guideline panels recommend that genetic testing be done. Subsequently, patients who develop resistance to the standard hormonal therapies, what we call castration resistant prostate cancer, or CRPC, is going to need more therapy. In that setting,

genetic testing would be indicated.

Kristie L. Kahl: How does genomic testing affect treatment?

Dr. Charles Ryan: Genomics can change over time. So, we have seen cases where patients have had prostatectomy, their prostates removed, and four years later their cancer recurs. Three years after that, they're developing resistance to the therapy that we give them. When we do a genomic test on a tumor specimen from the more advanced form of a cancer and we compare it to the prostatectomy specimen, we see different mutations. So, those are acquired mutations. The term that we use for tumor-associated mutations is somatic. What

somatic means is it's in the body of the tumor. That’s different from the germline mutations. For example, if we find a patient who has a germline BRCA2 mutation that means he probably inherited it from his parents and his siblings. But if we find a patient who has a somatic acquired or a somatic BRCA2 mutation, that's not in his germline. He's not going to pass that to his children, and he didn't get that from his parents. The mutation occurred spontaneously in his cancer and that is something that is a typical phenomenon that occurs with cancer. It is this kind of genetic instability and the development of new mutations.

The root of your question is when is the best time to do this test? The most frequent time that we test it or the most frequent specimen we use is the prostate biopsy; however, it is not unreasonable for us to be doing biopsies of the bone or of a lymph node in a patient who has developed metastatic disease because it's more up-to-date. With genetic information, the problem is it's really hard to get those tissues sometimes and we can't be biopsying every patient you know every three months. It's just too much to put a person through that.

Potentially, an answer to that question would be if we can look at mutations through the blood and there are tests that are called cell-free DNA tests or circulating tumor DNA tests. Both of those tests apply and basically what that is is that you put a tube of blood in the arm of the patient and then you capture some of the DNA that's circulating in the blood. We all have DNA circulating in our blood because there's just so much DNA in all of our cells that some of it just is escaping into the blood. But if a person has cancer, some of that circulating DNA is from the tumor and some of those mutations that are in the tumor can show up in the circulation. So that is a potential solution to this problem, which is that we can look at cell-free DnA testing.

It is not uncommon for us to detect mutations that come from the cancer that we detect in the blood.

Kristie L. Kahl: If this testing hasn't been done, why is it important to make sure that patients are asking their doctors about genomic testing?

Dr. Charlees Ryan: It’s important for two reasons. Those of us who treat cancer patients, we can tell a lot just by looking at the types of mutations that we see in these tumors. There are tumors that we know are corresponding to a higher risk, a higher likelihood of death from this disease. So, for me, whenever I get a genomic test back, I’m answering two questions: What does this tell me about the biology of this patient's disease and what does it tell me about his prognosis? And what does it tell me about these select PARP inhibitors or these targeted therapies that we might be able to use?

There are some other genetic panels that are out there. There's one called Decipher, for example, which is done on a prostate tissue and it's about 50 genes that they look at. They look at a combination of genes and they can they can tell basically through mathematical models using the combination of these genes where the patient is on a spectrum of risk. So, it's not just looking at one gene, it's looking at a whole family of genes and how they interrelate with one another. I neglected to mention that before, but that's a panel that's done on the prostate. Then there are genetic germline genetics that are done on the germline tissue that we inherit

mom and dad and pass on to our children, perhaps. And then there are somatic mutation panels that we can do on tumor specimens that can be metastatic tumor specimens. Then, there's the cell-free DNA that we can do from the blood. So, there's all kinds of different ways we can get at the genetics of this tumor.

Kristie L. Kahl: What would you say is the number one thing that patients should know about genetics and genomics?

Dr. Charles Ryan: The first question a patient should ask is how can genetics and genomics help me to make a decision for my case? If you have localized disease and you're thinking about having a radical prostatectomy or thinking about having radiation therapy, you might want to think about one of the studies like the Decipher panel or others that are done that can give a sense of the patient's place on the spectrum of risk. This tells us a little bit more information than the Gleason score, for example, because we do occasionally see patients who have a low Gleason score suggesting low risk but they have a high Decipher score suggesting higher risk. That might tell them maybe we should have radiation and hormonal therapy as opposed to surgery or maybe we just need to be watching this carefully more carefully or maybe I shouldn't be doing active surveillance. Maybe I should move ahead with surgery. And that's a complicated decision-making process that involves the patient and the physician talking through this. For the patient who has recurrent disease or metastatic disease, then they should be asking the question: Should I be checking my germline genes so that I can counsel my family? The big issue there is should I be checking my somatic or my tumor genes to help see if it can help my doctor with assessing my prognosis and with potentially assessing for for future treatments?

Transcription edited for clarity.

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