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Extended Aromatase Inhibitor Risk/Benefit

Insights From:Ruth O’Regan, MD, University of Wisconsin;Hope S. Rugo, MD, UCSF
Published: Tuesday, Nov 08, 2016


Transcript:

Hope S. Rugo, MD:
The toxicities seen with aromatase inhibitors are fairly well understood now. Many women have joint stiffness and muscle aching. Hot flashes occur early, but usually get better much more quickly than they do with tamoxifen. It’s interesting. Joint stiffness occurs with tamoxifen, it just occurs less frequently, so it’s important to keep in mind. Vaginal dryness is an issue. Some women note that they have thinning of their hair. There is bone loss that can be accelerated in particular women. So, some women, particularly if they start with low bone density, are at higher risk for bone density loss. Many studies have shown an increased risk of these osteoporotic-type fractures in women who have been on long, long-term suppression of estrogen production.

And then, there are some other funny side effects which it’s hard to associate and they’re very much determined by your individual risk. So, women often have an increase in bad cholesterol, so the LDL (low-density lipoprotein) versus the HDL (high-density lipoprotein), when they go into menopause. Women who have that genetic profile will have a higher cholesterol if you suppress their estrogen production even further. It’s not directly caused by the aromatase inhibitor, but tamoxifen provides more protection against cardiovascular risk than aromatase inhibitors do. Then, there are these other difficult side effects, like libido, where we don’t have good ways of treating it. Women note that they have less libido, and that’s a really big issue for women who are in menopause, anyway. And, so, it can be enhanced with hormone therapy.

The risk-benefit profile for aromatase inhibitors is going to always be the greatest in years 1 to 5. At least 50% of your recurrence risk, if you just take an ER-positive, HER2-negative patient population—and to some degree, even ER-positive, HER2-positive, depending on the subset—the greatest risk of recurrence is in the first 5 years. So, aromatase inhibitor therapy is critical. It’s also important to remember that there’s a carryover effect. If you take an aromatase inhibitor for 5 years or take tamoxifen, you still have a reduced risk of recurrence out, at least for the tamoxifen data, to 15 years compared to those women who didn’t take it or took a shorter course. By all factors, that’s most important. For the second 5 to 10 years, as we’ve been discussing, it’s very much dependent in terms of the risk-benefit profile on what your risk is. If your risk is high, a stage III cancer and ER-positive, then that’s going to be very much a benefit rather than a risk. If you have a 0.4 cm low-grade tumor, it’s all going to be for risk, not benefit. And then, there’s going to be women where it’s very much a wash and we don’t know well. Again, we’re going to be really looking for genomic tests that will help us differentiate out those populations in addition to the clinical pathologic factors I just mentioned.

The risk-benefit ratio from year 10 to 15 is more complex, and I think that we need more research and data from upcoming studies to really understand that better. Right now, I think that you can really see there would be a benefit in women who have an extremely high risk of recurrence. But, for the average risk, it’s hard to see that benefit right now.

Ruth O’Regan, MD: I would say we probably underreport the number of patients that have to discontinue aromatase inhibitors because of side effects. Certainly, if you look at the analyses that are out there, they’re reasonably high, and some reports can be as high as 20%. There are actually some data with endocrine therapy, both tamoxifen and aromatase inhibitors, indicating that there is almost 40% of patients who are not compliant through 5 years of treatment. So, in my practice, it’s variable. The most common reason patients stop aromatase inhibitors for sure is joint pain, which we don’t really understand the mechanisms of, so it’s very hard to treat and it’s very hard to predict. Sometimes, if you change to another aromatase inhibitor, the joint pain tends to improve. I would say in the main setting, patients don’t stop it because of bone loss. We can certainly use a bisphosphonate in that setting to try and help with their bones. I would say, overall, the most common thing is joint pain, also probably menopausal symptoms. Some patients just can’t tolerate that either, but I think joint pain is by far the most common. And, my guess is there are some patients that probably don’t even tell me they’ve stopped it and they have.

For patients on aromatase inhibitors, we know because they cause such profound estrogen loss that they are at risk of developing further bone loss, osteopenia, and osteoporosis. And, we know the fracture rate is increased with these drugs. What I typically do is a baseline bone density study, and if that looks like they’ve got osteoporosis, I might consider using tamoxifen for a few years. If it looks like their bones are in reasonably good shape, I’ll go ahead with an aromatase inhibitor. Then, I try and check the bone density every year if we can get it covered. If we see a considerable loss in bone density, then I would consider using a bisphosphonate or another bone-directed agent to try and help with their bones. It certainly is an issue for patients, but I think as long as you’re proactive in checking the bone density, you can pick up bone loss before they’re really at risk of developing fractures. So, I think determining it would be through a bone density study, how we manage it would really depend on how much bone they’re losing, how quickly they’re losing the bone, and how long you’re planning to have them on the aromatase inhibitor.

Transcript Edited for Clarity
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Transcript:

Hope S. Rugo, MD:
The toxicities seen with aromatase inhibitors are fairly well understood now. Many women have joint stiffness and muscle aching. Hot flashes occur early, but usually get better much more quickly than they do with tamoxifen. It’s interesting. Joint stiffness occurs with tamoxifen, it just occurs less frequently, so it’s important to keep in mind. Vaginal dryness is an issue. Some women note that they have thinning of their hair. There is bone loss that can be accelerated in particular women. So, some women, particularly if they start with low bone density, are at higher risk for bone density loss. Many studies have shown an increased risk of these osteoporotic-type fractures in women who have been on long, long-term suppression of estrogen production.

And then, there are some other funny side effects which it’s hard to associate and they’re very much determined by your individual risk. So, women often have an increase in bad cholesterol, so the LDL (low-density lipoprotein) versus the HDL (high-density lipoprotein), when they go into menopause. Women who have that genetic profile will have a higher cholesterol if you suppress their estrogen production even further. It’s not directly caused by the aromatase inhibitor, but tamoxifen provides more protection against cardiovascular risk than aromatase inhibitors do. Then, there are these other difficult side effects, like libido, where we don’t have good ways of treating it. Women note that they have less libido, and that’s a really big issue for women who are in menopause, anyway. And, so, it can be enhanced with hormone therapy.

The risk-benefit profile for aromatase inhibitors is going to always be the greatest in years 1 to 5. At least 50% of your recurrence risk, if you just take an ER-positive, HER2-negative patient population—and to some degree, even ER-positive, HER2-positive, depending on the subset—the greatest risk of recurrence is in the first 5 years. So, aromatase inhibitor therapy is critical. It’s also important to remember that there’s a carryover effect. If you take an aromatase inhibitor for 5 years or take tamoxifen, you still have a reduced risk of recurrence out, at least for the tamoxifen data, to 15 years compared to those women who didn’t take it or took a shorter course. By all factors, that’s most important. For the second 5 to 10 years, as we’ve been discussing, it’s very much dependent in terms of the risk-benefit profile on what your risk is. If your risk is high, a stage III cancer and ER-positive, then that’s going to be very much a benefit rather than a risk. If you have a 0.4 cm low-grade tumor, it’s all going to be for risk, not benefit. And then, there’s going to be women where it’s very much a wash and we don’t know well. Again, we’re going to be really looking for genomic tests that will help us differentiate out those populations in addition to the clinical pathologic factors I just mentioned.

The risk-benefit ratio from year 10 to 15 is more complex, and I think that we need more research and data from upcoming studies to really understand that better. Right now, I think that you can really see there would be a benefit in women who have an extremely high risk of recurrence. But, for the average risk, it’s hard to see that benefit right now.

Ruth O’Regan, MD: I would say we probably underreport the number of patients that have to discontinue aromatase inhibitors because of side effects. Certainly, if you look at the analyses that are out there, they’re reasonably high, and some reports can be as high as 20%. There are actually some data with endocrine therapy, both tamoxifen and aromatase inhibitors, indicating that there is almost 40% of patients who are not compliant through 5 years of treatment. So, in my practice, it’s variable. The most common reason patients stop aromatase inhibitors for sure is joint pain, which we don’t really understand the mechanisms of, so it’s very hard to treat and it’s very hard to predict. Sometimes, if you change to another aromatase inhibitor, the joint pain tends to improve. I would say in the main setting, patients don’t stop it because of bone loss. We can certainly use a bisphosphonate in that setting to try and help with their bones. I would say, overall, the most common thing is joint pain, also probably menopausal symptoms. Some patients just can’t tolerate that either, but I think joint pain is by far the most common. And, my guess is there are some patients that probably don’t even tell me they’ve stopped it and they have.

For patients on aromatase inhibitors, we know because they cause such profound estrogen loss that they are at risk of developing further bone loss, osteopenia, and osteoporosis. And, we know the fracture rate is increased with these drugs. What I typically do is a baseline bone density study, and if that looks like they’ve got osteoporosis, I might consider using tamoxifen for a few years. If it looks like their bones are in reasonably good shape, I’ll go ahead with an aromatase inhibitor. Then, I try and check the bone density every year if we can get it covered. If we see a considerable loss in bone density, then I would consider using a bisphosphonate or another bone-directed agent to try and help with their bones. It certainly is an issue for patients, but I think as long as you’re proactive in checking the bone density, you can pick up bone loss before they’re really at risk of developing fractures. So, I think determining it would be through a bone density study, how we manage it would really depend on how much bone they’re losing, how quickly they’re losing the bone, and how long you’re planning to have them on the aromatase inhibitor.

Transcript Edited for Clarity
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