Gynecomastia – How to Assess and Treat? "Presentation" - Lisa Horvath
November 15, 2024
At the 2024 Advanced Prostate Cancer Consensus Conference (APCCC), Lisa Horvath discusses the diagnosis and management of gynecomastia in prostate cancer patients undergoing ARPI therapy. The presentation compares preventive approaches, highlighting tamoxifen's superior prophylactic efficacy over radiotherapy, while noting surgery as the definitive treatment for established cases and emphasizing several unresolved questions about newer treatment combinations and the importance of patient perspectives.
Biographies:
Lisa Horvath, MBBS, PhD, Chris O’Brien Lifehouse, Professor of Medical Oncology (Genitourinary Cancers), University of Sydney, Sydney, Australia
Biographies:
Lisa Horvath, MBBS, PhD, Chris O’Brien Lifehouse, Professor of Medical Oncology (Genitourinary Cancers), University of Sydney, Sydney, Australia
Read the Full Video Transcript
Lisa Horvath: I did think I was getting a topic that was going to be a little bit vanilla perhaps. That all changed yesterday. And clearly, I have walked into the lion's den, and we'll just see how things go. These are my disclosures, none of which are relevant to the presentation.
So how do we diagnose gynecomastia? And in particular, how do you work out the difference between gynecomastia and chest fat, also known as pseudo gynecomastia? Essentially, it is about enlargement of the breast tissue in a nodular mass under the nipple. And there is often enlargement of the nipple and areola with sensitivity, which you don't see in chest wall fat. This can be diagnosed radiologically through ultrasound and mammogram, which is, of course, one of the questions for the panel.However, most of us can diagnose this clinically. The main reason to use radiology is to assess for malignancy. And that's most relevant in patients who have germline BRCA1 and BRCA2 mutations and some of the other DDR mutations. I'm going to give a disclaimer that I am giving a very sanitized version of the biochemistry.
So essentially, there is a balance between estrogen and testosterone, with estrogen promoting growth of the male mammary tissue and testosterone inhibiting that. Of course, when you have an LHRH agonist, you remove the testosterone that pulls the brakes off, and then you also have adrenal androgens that are aromatized in the fat tissue and increase the estrogen load promoting breast growth. However, when you have an RP, the testosterone—not only do we switch off the effect of the testosterone, we also increase it and increase the aromatization of the androgens in the fat tissue, increasing the estrogen, thereby also increasing the incidence of gynecomastia.
So what is the incidence of gynecomastia? Most of these—the studies I will be talking about today—were all done with high dose bicalutamide. And the studies vary from around 49% to 85% in terms of the incidence. However, this is very much a problem as we have already heard in enzalutamide, but it is also a problem in darolutamide and apalutamide. All of these studies have substantial arms using monotherapy androgen receptor pathway inhibitors with incidence of, again, around 40% and sometimes above 50%.There is a similar rate of nipple and breast pain. Although it does seem to vary between drugs, I'm not convinced this is a true representation but may be how the questions were asked and what AEs were looked at. What is unclear is how much of an effect does this have on patients as to whether they will discontinue treatment.
In the historical data, it is thought to be around 16% treatment discontinuation. I found it very difficult in the current data to work out how many treatment discontinuations were actually due to gynecomastia. And it is a very important issue when we talk about will this be a negative factor in patients staying on treatment.
So as was mentioned yesterday, the best way to do this is with prophylaxis. These are three studies of prophylactic radiotherapy. All of the studies that I will show you today are on bicalutamide. The radiation was given on the day the patient started the bicalutamide.
When radiation is compared to sham, there is a significant reduction from 85% to 52% in the incidence of gynecomastia, very little effect on nipple pain. The next study, same issue. Radiation was given with no treatment to arm B. There was a slightly different schedule of radiation, but again, a significant reduction in the incidence of gynecomastia, a little bit of effect on breast pain, but not substantial.
The last study in this table looked at 10 milligrams of tamoxifen daily for two years versus a single dose of radiotherapy versus no treatment. And you can see a substantial difference in the incidence of gynecomastia, with the tamoxifen down to 8% compared to 34% for radiation, 68% for no treatment. It also affected the incidence of breast pain. The side effects from radiation are what we would expect, erythema in the skin. And these things tended to improve very rapidly.
So we've touched now on tamoxifen. Now we'll delve into it in a bit more detail. The first study looked at the dose effect of tamoxifen, giving patients prophylactic tamoxifen from 1 milligram up to 20 milligrams, with a decrease in the incidence of breast events from 86% at 1 milligram to 88% at 20 milligrams. There were hot flashes and dizziness, which we've discussed yesterday.Other studies looked at whether you could get away with, rather than continuous daily, have an induction period of eight weeks of daily treatment, followed by weekly tamoxifen. Unfortunately, the daily tamoxifen works a lot better with 31% incidence of gynecomastia versus 74%.
And finally, there have been studies looking at anastrozole. And this one in particular looked at tamoxifen versus anastrozole versus placebo. Not only did anastrozole not work very well either for gynecomastia or breast pain, there were some reductions. It doubled the incidence of adverse events. It is interesting to note, given the discussion yesterday, that there was no evidence of thromboembolic AEs reported in these studies, but there may not have been enough follow-up.
So this is a meta-analysis looking at the prevention of gynecomastia. And I think it's very clear from this that the prophylactic tamoxifen not only appears to be a better treatment, there is a smaller number needed to treat in order to prevent gynecomastia. The same thing is seen in breast pain, with a number needed to treat of two versus five in the tamoxifen compared to the radiotherapy.
So what happens if you don't treat prophylactically, and you wait for the patient to develop gynecomastia? In this top study, it was actually a study of prophylaxis. But in the placebo arm, they then treated patients with tamoxifen when they developed gynecomastia. And this certainly did improve the gynecomastia.
In the second study, they looked very specifically at treatment versus prophylaxis. And the incidence of breast events was pretty similar at 27% versus 35%. But when you dig into the grade of the breast events, it becomes obvious that treating at the time of gynecomastia, in this case, within a month, resulted in a greater incidence of grade two and three gynecomastia and breast pain and much worse outcomes for the patients.
The other thing we need to consider in the new era of ARPIs is drug, drug interactions, especially with enzalutamide and apalutamide. With CYP3A4 metabolism, we may need a higher dose of tamoxifen. Darolutamide does not seem to have these problems.
Finally, what is the role of surgery? This is certainly used for symptomatic gynecomastia and, as stated by Neal Shore yesterday, is the gold standard for this. Very hard to find. There's certainly no randomized trials, but there's a meta-analysis of 17 trials of all comers with gynecomastia. Looking at a variety of different surgeries, the majority that are used for prostate cancer treatment-related gynecomastia are the minimally invasive liposuction and skin-sparing mastectomies, with a complication rate of around 5% for hematomas and 2% for seromas.
So what is the conclusion? Well, gynecomastia is very prevalent when we're giving androgen receptor pathway inhibitor monotherapy. The audience already knows this. Tamoxifen is a better prophylactic treatment in the current trials that have been reported than radiotherapy. And it is certainly better to treat prophylactically than treat a diagnosis. And surgery is the definitive treatment for symptomatic disease.
But there are lots of questions. As I delved into this rabbit hole of gynecomastia, which became increasingly fascinating, I would say, there are more questions than answers, I feel. Will the tamoxifen work as well with our more modern drugs? Do we need to adjust the dose? Do we need a new dose-finding study? But a lot of these studies were 12 months. Only a couple were out to 24 months. Can patients tolerate tamoxifen and an ARPI combination beyond the 12 months? We will improve their gynecomastia, but we will increase their hot flashes, which Anthony is about to talk about in more detail.
And what is the role of radiotherapy in surgery, especially if we can do these as one-off treatments if we're going to use long-term therapy? I think it's crucial. And many of our speakers have talked about this. What is the patient perspective? What is important to them? And that needs to be factored into the trials that we design. Thank you.
Lisa Horvath: I did think I was getting a topic that was going to be a little bit vanilla perhaps. That all changed yesterday. And clearly, I have walked into the lion's den, and we'll just see how things go. These are my disclosures, none of which are relevant to the presentation.
So how do we diagnose gynecomastia? And in particular, how do you work out the difference between gynecomastia and chest fat, also known as pseudo gynecomastia? Essentially, it is about enlargement of the breast tissue in a nodular mass under the nipple. And there is often enlargement of the nipple and areola with sensitivity, which you don't see in chest wall fat. This can be diagnosed radiologically through ultrasound and mammogram, which is, of course, one of the questions for the panel.However, most of us can diagnose this clinically. The main reason to use radiology is to assess for malignancy. And that's most relevant in patients who have germline BRCA1 and BRCA2 mutations and some of the other DDR mutations. I'm going to give a disclaimer that I am giving a very sanitized version of the biochemistry.
So essentially, there is a balance between estrogen and testosterone, with estrogen promoting growth of the male mammary tissue and testosterone inhibiting that. Of course, when you have an LHRH agonist, you remove the testosterone that pulls the brakes off, and then you also have adrenal androgens that are aromatized in the fat tissue and increase the estrogen load promoting breast growth. However, when you have an RP, the testosterone—not only do we switch off the effect of the testosterone, we also increase it and increase the aromatization of the androgens in the fat tissue, increasing the estrogen, thereby also increasing the incidence of gynecomastia.
So what is the incidence of gynecomastia? Most of these—the studies I will be talking about today—were all done with high dose bicalutamide. And the studies vary from around 49% to 85% in terms of the incidence. However, this is very much a problem as we have already heard in enzalutamide, but it is also a problem in darolutamide and apalutamide. All of these studies have substantial arms using monotherapy androgen receptor pathway inhibitors with incidence of, again, around 40% and sometimes above 50%.There is a similar rate of nipple and breast pain. Although it does seem to vary between drugs, I'm not convinced this is a true representation but may be how the questions were asked and what AEs were looked at. What is unclear is how much of an effect does this have on patients as to whether they will discontinue treatment.
In the historical data, it is thought to be around 16% treatment discontinuation. I found it very difficult in the current data to work out how many treatment discontinuations were actually due to gynecomastia. And it is a very important issue when we talk about will this be a negative factor in patients staying on treatment.
So as was mentioned yesterday, the best way to do this is with prophylaxis. These are three studies of prophylactic radiotherapy. All of the studies that I will show you today are on bicalutamide. The radiation was given on the day the patient started the bicalutamide.
When radiation is compared to sham, there is a significant reduction from 85% to 52% in the incidence of gynecomastia, very little effect on nipple pain. The next study, same issue. Radiation was given with no treatment to arm B. There was a slightly different schedule of radiation, but again, a significant reduction in the incidence of gynecomastia, a little bit of effect on breast pain, but not substantial.
The last study in this table looked at 10 milligrams of tamoxifen daily for two years versus a single dose of radiotherapy versus no treatment. And you can see a substantial difference in the incidence of gynecomastia, with the tamoxifen down to 8% compared to 34% for radiation, 68% for no treatment. It also affected the incidence of breast pain. The side effects from radiation are what we would expect, erythema in the skin. And these things tended to improve very rapidly.
So we've touched now on tamoxifen. Now we'll delve into it in a bit more detail. The first study looked at the dose effect of tamoxifen, giving patients prophylactic tamoxifen from 1 milligram up to 20 milligrams, with a decrease in the incidence of breast events from 86% at 1 milligram to 88% at 20 milligrams. There were hot flashes and dizziness, which we've discussed yesterday.Other studies looked at whether you could get away with, rather than continuous daily, have an induction period of eight weeks of daily treatment, followed by weekly tamoxifen. Unfortunately, the daily tamoxifen works a lot better with 31% incidence of gynecomastia versus 74%.
And finally, there have been studies looking at anastrozole. And this one in particular looked at tamoxifen versus anastrozole versus placebo. Not only did anastrozole not work very well either for gynecomastia or breast pain, there were some reductions. It doubled the incidence of adverse events. It is interesting to note, given the discussion yesterday, that there was no evidence of thromboembolic AEs reported in these studies, but there may not have been enough follow-up.
So this is a meta-analysis looking at the prevention of gynecomastia. And I think it's very clear from this that the prophylactic tamoxifen not only appears to be a better treatment, there is a smaller number needed to treat in order to prevent gynecomastia. The same thing is seen in breast pain, with a number needed to treat of two versus five in the tamoxifen compared to the radiotherapy.
So what happens if you don't treat prophylactically, and you wait for the patient to develop gynecomastia? In this top study, it was actually a study of prophylaxis. But in the placebo arm, they then treated patients with tamoxifen when they developed gynecomastia. And this certainly did improve the gynecomastia.
In the second study, they looked very specifically at treatment versus prophylaxis. And the incidence of breast events was pretty similar at 27% versus 35%. But when you dig into the grade of the breast events, it becomes obvious that treating at the time of gynecomastia, in this case, within a month, resulted in a greater incidence of grade two and three gynecomastia and breast pain and much worse outcomes for the patients.
The other thing we need to consider in the new era of ARPIs is drug, drug interactions, especially with enzalutamide and apalutamide. With CYP3A4 metabolism, we may need a higher dose of tamoxifen. Darolutamide does not seem to have these problems.
Finally, what is the role of surgery? This is certainly used for symptomatic gynecomastia and, as stated by Neal Shore yesterday, is the gold standard for this. Very hard to find. There's certainly no randomized trials, but there's a meta-analysis of 17 trials of all comers with gynecomastia. Looking at a variety of different surgeries, the majority that are used for prostate cancer treatment-related gynecomastia are the minimally invasive liposuction and skin-sparing mastectomies, with a complication rate of around 5% for hematomas and 2% for seromas.
So what is the conclusion? Well, gynecomastia is very prevalent when we're giving androgen receptor pathway inhibitor monotherapy. The audience already knows this. Tamoxifen is a better prophylactic treatment in the current trials that have been reported than radiotherapy. And it is certainly better to treat prophylactically than treat a diagnosis. And surgery is the definitive treatment for symptomatic disease.
But there are lots of questions. As I delved into this rabbit hole of gynecomastia, which became increasingly fascinating, I would say, there are more questions than answers, I feel. Will the tamoxifen work as well with our more modern drugs? Do we need to adjust the dose? Do we need a new dose-finding study? But a lot of these studies were 12 months. Only a couple were out to 24 months. Can patients tolerate tamoxifen and an ARPI combination beyond the 12 months? We will improve their gynecomastia, but we will increase their hot flashes, which Anthony is about to talk about in more detail.
And what is the role of radiotherapy in surgery, especially if we can do these as one-off treatments if we're going to use long-term therapy? I think it's crucial. And many of our speakers have talked about this. What is the patient perspective? What is important to them? And that needs to be factored into the trials that we design. Thank you.