Risk Stratification in Metastatic Prostate Cancer: The Genomic Approach - Leanne Schimke
January 11, 2022
Diane Newman hosts Leanne Schimke to explore the complexities of metastatic prostate cancer with a focus on the role of genomics and PARP inhibitors. Dr. Schimke delves into how advancements in genomics are providing new avenues for personalized treatment, although the field lags about a decade behind breast cancer research. She highlights the importance of differentiating between indolent and aggressive prostate cancers, pointing out that genetic mutations can offer clues for targeted treatments. Germline mutations, which are hereditary, not only affect treatment plans but also have familial implications, warranting genetic counseling for family members. Dr. Schimke points out that current NCCN guidelines recommend genetic testing for any patient with metastatic or high-grade prostate cancer. Both Drs. Newman and Schimke express concern over the persistence of late-stage diagnoses, attributing it partly to skepticism around PSA testing among primary care providers.
Biographies:
Leanne Schimke, CRNP, CUNP, dual certified Family Nurse Practitioner and Urology Nurse Practitioner at Lancaster Urology, Lancaster, PA
Diane K. Newman, DNP, ANP-BC, FAAN, Adjunct Professor of Urology in Surgery, Perelman School of Medicine, University of Pennsylvania and Former Co-Director of the Penn Center for Continence and Pelvic Health
Biographies:
Leanne Schimke, CRNP, CUNP, dual certified Family Nurse Practitioner and Urology Nurse Practitioner at Lancaster Urology, Lancaster, PA
Diane K. Newman, DNP, ANP-BC, FAAN, Adjunct Professor of Urology in Surgery, Perelman School of Medicine, University of Pennsylvania and Former Co-Director of the Penn Center for Continence and Pelvic Health
Read the Full Video Transcript
Diane Newman: Welcome, everyone. I'm Diane Newman. I'm a Nurse Practitioner at the University of Pennsylvania, and I'm here on UroToday to introduce our speaker Leanne Schimke. She's a Urology Nurse Practitioner in Lancaster, and she's going to talk to us about metastatic prostate cancer.
Thank you, Leanne.
Leanne Schimke: Thank you, Diane. So today, I'm going to be talking about metastatic prostate cancer and the role of genomics and PARP inhibitors in this patient population. So let me just flip over to my slideshow real quick here. Thank you.
So genetics and genomics have come a long way in prostate cancer. Initially, when you talk to women who have had breast cancer, this has been around for about 10 years for them, and they have precision medicine treatment for them. But prostate cancer is about 10 years behind where breast cancer is in treatment and genetics and genomics. So what we've learned is that about 10 to 15% of prostate cancer is hereditary, and if they inherit these mutated genes, it increases their risk for aggressive prostate cancer.
Our problem right now with prostate cancer is knowing which one is going to be indolent and that we really can observe them through active surveillance versus one that is going to be very aggressive and cause the man's death in a short period of time if it's not treated. So knowing the germline mutations can give us an idea of which patients can be on active surveillance versus other treatments. We can target chemotherapy and oral medications for the mutations, and also, we can help prevent some cancers hopefully in the family, because, with the germline, if they have a BRCA2 or a BRCA1, that will have implications for their daughters, their sisters, their sons; all of them can have an increased risk of ovarian, pancreatic, colon cancer. If it's BRCA1, it might be male breast cancer, that could be possible.
So, when we do this, we're not only just looking at the man and what we can do to treat him, but also if there is something that shows up, then we can also have the family see genetic counseling, and have some proactive surveillance with them to help hopefully prevent other cancers with them. And the current NCCN guidelines do recommend genetic testing on any patient with metastatic prostate cancer, or if they have a high-grade Gleason 7 or higher with a specific family history. And I will talk about that in a few minutes here.
So I just want to go over some definitions because sometimes people get a little confused with this. So, the germline is basically the genetic DNA that we pass on to our offspring. It's the DNA that is passed down in families. It's present in every cell in our body, and it's fixed throughout our life; it doesn't change. We can test this through blood, sputum, or cheek swab testing. And this is some of the things that you see with that 23andMe, and some of those ancestry things that they say, "do you want to find out about your ancestry"? They are looking at germline with that.
When we talk about somatic, that's actually the tumor cells, the prostate cancer tumor cells. And this can be obtained by the actual prostate biopsy. If they had surgery, it can be from the surgical pathology we have, or if they have a new metastasis that we can get to, to get a new biopsy, we can get it biopsied at that area. This can change over time. It is not passed on to any of our family members, so if the patient has a somatic change but not a germline change, we can reassure them that their family member is not at a higher risk for any disease. And one of the newer things is liquid biopsy testing, plasma free, just by a blood test. That is still in the early stages, and there are questions about how accurate it is, and if we can do that instead of biopsying the actual sites in the body of a new metastasis.
So for prostate cancer, who do we test? If they have a family history of a lot of cancers at early ages of diagnosis, with the females in the family having breast cancer at under 45 years of age, uterine or colon cancer under 50 years of age, ovarian cancer, or prostate cancer 60 years or under, if the patient themselves has had multiple prior cancers... They may have had colon cancer and now they have prostate cancer, this would be someone that we would test.
If you have a male that has breast cancer... this may be a BRCA2 or a BRCA1, so this is someone you definitely want to test because males typically do not get breast cancer, it's very rare, but it happens. An Ashkenazi Jew, we know they are at higher risk for having mutations in the germline.
And if they have a personal history, obviously, of metastatic prostate cancer, even if there's no real family history, if they have multiple generations of prostate cancer... so if their grandfather and their father and themselves, and maybe a brother had prostate cancer, this is someone you want to say, "Okay, there might be something in the genetic makeup that is causing this prostate cancer;" and if they have sons, then we can talk to the sons about getting earlier testing for prostate cancer and not waiting as long as we would do for maybe generalized testing.
If they have high-grade prostate cancer that is Gleason 7, and two or more syndrome-related cancers: pancreatic, melanoma, breast, colon, uterine... this is when I'm talking to a patient, getting their family history and the hair on my neck starts standing up when they say, "My mom had pancreatic cancer. My sister had ovarian cancer. My dad had colon cancer. My grandmother..." You start hearing these multiple cancers in the family, and you're going, "Okay, if this guy doesn't have a genetic mutation, I would be surprised."
And when you look at the prevalence estimates, so when you are looking at germline versus somatic, basically it's 50/50 between the two. It can be either germline or somatic or you can have it combined. They can both be germline and somatic. So you can have BRCA2 in a germline test and a BRCA2 in their somatic test, and they can agree with each other, or you can have it just in one or the other.
And this slide just shows you what other diseases it goes along with. A lot of this is breast cancer and ovarian cancer. Lynch Syndrome is a big one for mismatch repair. And these patients are at a higher risk of colon, endometrial cancer, and multiple cancers with Lynch Syndrome. Usually, the Lynch Syndrome was probably picked up previously, because if they've had colon cancer or some other cancers, they usually pick this up. So we haven't picked up a Lynch Syndrome patient, we've inherited Lynch Syndrome patients, and we already know that they've got that issue.
So let's just go over another case study. This is a 45-year-old male. He was diagnosed with metastatic prostate cancer in 2017 after he presented to the hospital with back pain. Now you would think in today's age that this would never happen. But unfortunately, we are seeing one to three patients a week that this is happening in. And a lot of this came about because PSA testing was said to be worthless basically, and the US Preventive Services Task Force in 2012 said, "Don't do it," so all our family practice providers stopped doing it. And now, we are seeing our men with prostate cancer. Unfortunately, this guy's 45 years old. He wouldn't even meet the guidelines to have been screened at this point in time, but his PSA was 300 at diagnosis.
We did a staging evaluation, and he had multiple skeletal metastases, and multiple spinal lesions in the lumbar area, which was the cause of his back pain. Luckily, his CAT scan was negative for any visceral or lymphadenopathy. We did a prostate biopsy, it was a Gleason 8, so it's a more aggressive cancer. And then we did next-generation sequencing of his germline DNA, and he did have a BRCA2 mutation, and his somatic testing also agreed with this. He also had a BRCA2 in his somatic testing.
So we started out giving spot radiation to his lumbar spine to help with his pain. We followed that with docetaxel six cycles because he had high-volume bone metastases on presentation. We started him on leuprolide, which eliminates his testosterone level, his PSA nadir to 1.26 in August 2018. Then he had a rising PSA, so we put him on sipuleucel-T, which is immunotherapy. We followed that by abiraterone. His PSA went from 5.9 back down to 1.6 in October 2019.
His PSA is again rising. We treated him with radium-223 in November 2020. His PSA was 63.21, and that was in January 2021. It rose to 106 in March, and at that point in time, we started him on olaparib. Why did we start him on olaparib? Because a PARP inhibitor is recommended for BRCA2 mutations.
So this is just a question I put out for nursing: what counseling would you give regarding the potential side effects of olaparib? Would you talk to them about nausea with or without vomiting that occurs in the first two months after starting the medication, and recommend the use of ondansetron and a bland diet prior to taking the medication? Would you tell them they may have a macular pruritic rash, and how to treat that? Would you tell them they would gain weight or have an increased appetite? Or would you tell them there are really no dietary restrictions needed? You may eat grapefruit or Seville oranges for your vitamin C intake to keep things up.
So with olaparib, nausea, in the PROfound trial, occurred in 41% of the participants. So very few, I mean, 18% reported vomiting. So usually, it resolves at about two months after being on the medication. Proactive counseling and treatment with the patient with antiemetics and diet really helps compliance with this medication. The rash is not a known side effect with olaparib. Altered taste and decreased appetite or weight loss are side effects of the medication. Grapefruit, grapefruit juice, Seville oranges, or juice intake are moderate to strong CYP3A inhibitors, which cause the increase in the olaparib circulating doses. So you would tell them to actually avoid those medications.
What questions do you have, Diane? I'm sure you have some.
Diane Newman: Yeah, thanks so much for that case study. What a kind of complex, but sad case, 45-year-old. You mentioned the fact that we are seeing more of these cases. Do you think that is changing at all, as far as maybe now that... are we seeing your primary care physicians picking up men with their PSAs and referring them on, or how many more... Are you still seeing these metastatic diseases?
Leanne Schimke: And I wish I could tell you that I wasn't. I wish I could tell you it was slowing down. But we are still seeing one to three every week. A lot of times, they are going into the hospital with back pain, and that's how prostate cancer has been found. I've had patients tell me that their family practice provider recommended they not get a PSA test because it would lead to unnecessary testing and it's not accurate...
We know the PSA test isn't perfect. We have other tests that we can do to amplify the PSA testing, to see if they have a high risk for high-grade aggressive disease or not. So, we keep trying to get the message out, but it's not there yet.
Diane Newman: Yeah, it's really sad. I mean, we're seeing that also, but I keep waiting for it to change. Now, you did a really nice review of the germline testing, Leanne. Now, do you use genetic counselors, or do you and your physician communicate those results with a patient?
Leanne Schimke: So, we do use genetic counselors. We have a cancer center that we refer to, with genetic counseling. They are very happy to have us do all this testing because if they are negative, those patients do not need genetic counseling, and genetic counselors are at a premium. So if we can eliminate some of the people that see them because they're negative, they are very happy. So we will usually tell the man what the results are, and then tell them that we are referring him to genetic testing and counseling for further counseling for their family and themselves. But we tell them, for their specific mutation, how it's going to help them in their prostate cancer.
Diane Newman: Now, also on this case, did you prescribe bone health agents with him?
Leanne Schimke: Yes, he is on Xgeva, which is denosumab. I say the brand name because denosumab has two different names and they are of different usage, so Xgeva is used for metastatic prostate cancer. So yes, he's been on that.
Diane Newman: And then, I was really surprised that, even with the radium, his PSA still rose, huh? Is that usual?
Leanne Schimke: It's not unusual. With radium-223, we do not expect a decrease in the PSA. We expect it to go up while they're on it. We know that radium is treating bone metastasis, so we usually will use it in between our ARIs. So if they were on Xtandi first or abiraterone or one of the other drugs, we will put Xofigo in between, because we think it does a little change in the body's reaction to the medications. Then we would put him on another medication afterward.
Diane Newman: What would you do next now? You're going to continue to monitor his PSA, right? And how often would you have him back?
Leanne Schimke: We have this gentleman back every month because he's young, and if you let this go three to six months, his PSA can start doubling every month. It would go up very quickly, and he would get in trouble very quickly. So for him, we are monitoring him every month. And because he's on olaparib, which does have side effects, and what would we do next with this patient? His next step is probably chemotherapy with the second-line therapy, cabazitaxel.
Diane Newman: Well, thank you very much for this presentation, this really excellent case study. So I appreciate you sharing your knowledge with us. You are such a wealth of information in this area. Thanks, Leanne.
Leanne Schimke: Thanks, Diane. Glad to have you have me. I appreciate it.
Diane Newman: Welcome, everyone. I'm Diane Newman. I'm a Nurse Practitioner at the University of Pennsylvania, and I'm here on UroToday to introduce our speaker Leanne Schimke. She's a Urology Nurse Practitioner in Lancaster, and she's going to talk to us about metastatic prostate cancer.
Thank you, Leanne.
Leanne Schimke: Thank you, Diane. So today, I'm going to be talking about metastatic prostate cancer and the role of genomics and PARP inhibitors in this patient population. So let me just flip over to my slideshow real quick here. Thank you.
So genetics and genomics have come a long way in prostate cancer. Initially, when you talk to women who have had breast cancer, this has been around for about 10 years for them, and they have precision medicine treatment for them. But prostate cancer is about 10 years behind where breast cancer is in treatment and genetics and genomics. So what we've learned is that about 10 to 15% of prostate cancer is hereditary, and if they inherit these mutated genes, it increases their risk for aggressive prostate cancer.
Our problem right now with prostate cancer is knowing which one is going to be indolent and that we really can observe them through active surveillance versus one that is going to be very aggressive and cause the man's death in a short period of time if it's not treated. So knowing the germline mutations can give us an idea of which patients can be on active surveillance versus other treatments. We can target chemotherapy and oral medications for the mutations, and also, we can help prevent some cancers hopefully in the family, because, with the germline, if they have a BRCA2 or a BRCA1, that will have implications for their daughters, their sisters, their sons; all of them can have an increased risk of ovarian, pancreatic, colon cancer. If it's BRCA1, it might be male breast cancer, that could be possible.
So, when we do this, we're not only just looking at the man and what we can do to treat him, but also if there is something that shows up, then we can also have the family see genetic counseling, and have some proactive surveillance with them to help hopefully prevent other cancers with them. And the current NCCN guidelines do recommend genetic testing on any patient with metastatic prostate cancer, or if they have a high-grade Gleason 7 or higher with a specific family history. And I will talk about that in a few minutes here.
So I just want to go over some definitions because sometimes people get a little confused with this. So, the germline is basically the genetic DNA that we pass on to our offspring. It's the DNA that is passed down in families. It's present in every cell in our body, and it's fixed throughout our life; it doesn't change. We can test this through blood, sputum, or cheek swab testing. And this is some of the things that you see with that 23andMe, and some of those ancestry things that they say, "do you want to find out about your ancestry"? They are looking at germline with that.
When we talk about somatic, that's actually the tumor cells, the prostate cancer tumor cells. And this can be obtained by the actual prostate biopsy. If they had surgery, it can be from the surgical pathology we have, or if they have a new metastasis that we can get to, to get a new biopsy, we can get it biopsied at that area. This can change over time. It is not passed on to any of our family members, so if the patient has a somatic change but not a germline change, we can reassure them that their family member is not at a higher risk for any disease. And one of the newer things is liquid biopsy testing, plasma free, just by a blood test. That is still in the early stages, and there are questions about how accurate it is, and if we can do that instead of biopsying the actual sites in the body of a new metastasis.
So for prostate cancer, who do we test? If they have a family history of a lot of cancers at early ages of diagnosis, with the females in the family having breast cancer at under 45 years of age, uterine or colon cancer under 50 years of age, ovarian cancer, or prostate cancer 60 years or under, if the patient themselves has had multiple prior cancers... They may have had colon cancer and now they have prostate cancer, this would be someone that we would test.
If you have a male that has breast cancer... this may be a BRCA2 or a BRCA1, so this is someone you definitely want to test because males typically do not get breast cancer, it's very rare, but it happens. An Ashkenazi Jew, we know they are at higher risk for having mutations in the germline.
And if they have a personal history, obviously, of metastatic prostate cancer, even if there's no real family history, if they have multiple generations of prostate cancer... so if their grandfather and their father and themselves, and maybe a brother had prostate cancer, this is someone you want to say, "Okay, there might be something in the genetic makeup that is causing this prostate cancer;" and if they have sons, then we can talk to the sons about getting earlier testing for prostate cancer and not waiting as long as we would do for maybe generalized testing.
If they have high-grade prostate cancer that is Gleason 7, and two or more syndrome-related cancers: pancreatic, melanoma, breast, colon, uterine... this is when I'm talking to a patient, getting their family history and the hair on my neck starts standing up when they say, "My mom had pancreatic cancer. My sister had ovarian cancer. My dad had colon cancer. My grandmother..." You start hearing these multiple cancers in the family, and you're going, "Okay, if this guy doesn't have a genetic mutation, I would be surprised."
And when you look at the prevalence estimates, so when you are looking at germline versus somatic, basically it's 50/50 between the two. It can be either germline or somatic or you can have it combined. They can both be germline and somatic. So you can have BRCA2 in a germline test and a BRCA2 in their somatic test, and they can agree with each other, or you can have it just in one or the other.
And this slide just shows you what other diseases it goes along with. A lot of this is breast cancer and ovarian cancer. Lynch Syndrome is a big one for mismatch repair. And these patients are at a higher risk of colon, endometrial cancer, and multiple cancers with Lynch Syndrome. Usually, the Lynch Syndrome was probably picked up previously, because if they've had colon cancer or some other cancers, they usually pick this up. So we haven't picked up a Lynch Syndrome patient, we've inherited Lynch Syndrome patients, and we already know that they've got that issue.
So let's just go over another case study. This is a 45-year-old male. He was diagnosed with metastatic prostate cancer in 2017 after he presented to the hospital with back pain. Now you would think in today's age that this would never happen. But unfortunately, we are seeing one to three patients a week that this is happening in. And a lot of this came about because PSA testing was said to be worthless basically, and the US Preventive Services Task Force in 2012 said, "Don't do it," so all our family practice providers stopped doing it. And now, we are seeing our men with prostate cancer. Unfortunately, this guy's 45 years old. He wouldn't even meet the guidelines to have been screened at this point in time, but his PSA was 300 at diagnosis.
We did a staging evaluation, and he had multiple skeletal metastases, and multiple spinal lesions in the lumbar area, which was the cause of his back pain. Luckily, his CAT scan was negative for any visceral or lymphadenopathy. We did a prostate biopsy, it was a Gleason 8, so it's a more aggressive cancer. And then we did next-generation sequencing of his germline DNA, and he did have a BRCA2 mutation, and his somatic testing also agreed with this. He also had a BRCA2 in his somatic testing.
So we started out giving spot radiation to his lumbar spine to help with his pain. We followed that with docetaxel six cycles because he had high-volume bone metastases on presentation. We started him on leuprolide, which eliminates his testosterone level, his PSA nadir to 1.26 in August 2018. Then he had a rising PSA, so we put him on sipuleucel-T, which is immunotherapy. We followed that by abiraterone. His PSA went from 5.9 back down to 1.6 in October 2019.
His PSA is again rising. We treated him with radium-223 in November 2020. His PSA was 63.21, and that was in January 2021. It rose to 106 in March, and at that point in time, we started him on olaparib. Why did we start him on olaparib? Because a PARP inhibitor is recommended for BRCA2 mutations.
So this is just a question I put out for nursing: what counseling would you give regarding the potential side effects of olaparib? Would you talk to them about nausea with or without vomiting that occurs in the first two months after starting the medication, and recommend the use of ondansetron and a bland diet prior to taking the medication? Would you tell them they may have a macular pruritic rash, and how to treat that? Would you tell them they would gain weight or have an increased appetite? Or would you tell them there are really no dietary restrictions needed? You may eat grapefruit or Seville oranges for your vitamin C intake to keep things up.
So with olaparib, nausea, in the PROfound trial, occurred in 41% of the participants. So very few, I mean, 18% reported vomiting. So usually, it resolves at about two months after being on the medication. Proactive counseling and treatment with the patient with antiemetics and diet really helps compliance with this medication. The rash is not a known side effect with olaparib. Altered taste and decreased appetite or weight loss are side effects of the medication. Grapefruit, grapefruit juice, Seville oranges, or juice intake are moderate to strong CYP3A inhibitors, which cause the increase in the olaparib circulating doses. So you would tell them to actually avoid those medications.
What questions do you have, Diane? I'm sure you have some.
Diane Newman: Yeah, thanks so much for that case study. What a kind of complex, but sad case, 45-year-old. You mentioned the fact that we are seeing more of these cases. Do you think that is changing at all, as far as maybe now that... are we seeing your primary care physicians picking up men with their PSAs and referring them on, or how many more... Are you still seeing these metastatic diseases?
Leanne Schimke: And I wish I could tell you that I wasn't. I wish I could tell you it was slowing down. But we are still seeing one to three every week. A lot of times, they are going into the hospital with back pain, and that's how prostate cancer has been found. I've had patients tell me that their family practice provider recommended they not get a PSA test because it would lead to unnecessary testing and it's not accurate...
We know the PSA test isn't perfect. We have other tests that we can do to amplify the PSA testing, to see if they have a high risk for high-grade aggressive disease or not. So, we keep trying to get the message out, but it's not there yet.
Diane Newman: Yeah, it's really sad. I mean, we're seeing that also, but I keep waiting for it to change. Now, you did a really nice review of the germline testing, Leanne. Now, do you use genetic counselors, or do you and your physician communicate those results with a patient?
Leanne Schimke: So, we do use genetic counselors. We have a cancer center that we refer to, with genetic counseling. They are very happy to have us do all this testing because if they are negative, those patients do not need genetic counseling, and genetic counselors are at a premium. So if we can eliminate some of the people that see them because they're negative, they are very happy. So we will usually tell the man what the results are, and then tell them that we are referring him to genetic testing and counseling for further counseling for their family and themselves. But we tell them, for their specific mutation, how it's going to help them in their prostate cancer.
Diane Newman: Now, also on this case, did you prescribe bone health agents with him?
Leanne Schimke: Yes, he is on Xgeva, which is denosumab. I say the brand name because denosumab has two different names and they are of different usage, so Xgeva is used for metastatic prostate cancer. So yes, he's been on that.
Diane Newman: And then, I was really surprised that, even with the radium, his PSA still rose, huh? Is that usual?
Leanne Schimke: It's not unusual. With radium-223, we do not expect a decrease in the PSA. We expect it to go up while they're on it. We know that radium is treating bone metastasis, so we usually will use it in between our ARIs. So if they were on Xtandi first or abiraterone or one of the other drugs, we will put Xofigo in between, because we think it does a little change in the body's reaction to the medications. Then we would put him on another medication afterward.
Diane Newman: What would you do next now? You're going to continue to monitor his PSA, right? And how often would you have him back?
Leanne Schimke: We have this gentleman back every month because he's young, and if you let this go three to six months, his PSA can start doubling every month. It would go up very quickly, and he would get in trouble very quickly. So for him, we are monitoring him every month. And because he's on olaparib, which does have side effects, and what would we do next with this patient? His next step is probably chemotherapy with the second-line therapy, cabazitaxel.
Diane Newman: Well, thank you very much for this presentation, this really excellent case study. So I appreciate you sharing your knowledge with us. You are such a wealth of information in this area. Thanks, Leanne.
Leanne Schimke: Thanks, Diane. Glad to have you have me. I appreciate it.