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HR+ Breast Cancer: CDK4/6 Inhibitors & Sites of Metastasis

Insights From: Joyce A. OShaughnessy, MD, Balor University Medical Center; Stephen Johnston, MA, PhD, FRCP, The Royal Marsden Hospital; Matthew P. Goetz, MD, The Mayo Clinic
Published: Monday, Aug 27, 2018



Transcript: 

Joyce A. O’Shaughnessy, MD: The most aggressive of the ER [estrogen receptor]–positive metastatic breast cancers will metastasize to the brain. This is a really important feature, particularly of these genomically unstable luminal B breast cancers. Ultimately, in the adjuvant setting, we’re going to need better and better therapies that will improve the disease-free survival of patients and prevent, hopefully, brain metastasis. In the metastatic setting, we’re very, very interested in which of the CDK4/6 inhibitors will be able to treat established brain metastasis in the hopes that eventually these will be moved into the adjuvant setting. Right now, these CDK4/6 inhibitors, palbociclib and abemaciclib, are in large adjuvant trials.

It turns out it was initially noted in patients with glioblastoma multiforme [GBM] who received abemaciclib preoperatively before they went to resection, and indeed there are very high levels of abemaciclib that actually get into GBMs. In fact, there’s some evidence of benefit from abemaciclib against GBM. It definitely penetrates. Similar work has been shown in patients with breast cancer brain metastasis who have been given abemaciclib before they go to surgical resection of a metastasis; there were also high levels of penetration of abemaciclib into brain metastasis.
There has been a study done with abemaciclib as a single agent where patients who were on an aromatase inhibitor could stay on it. There was evidence of some objective responses with abemaciclib in patients with heavily pretreated brain metastasis. So this is an agent we could consider for our patients who have ER-positive metastatic disease with brain metastasis. We have very few data about agents that can actually benefit patients, but abemaciclib does have activity against ER-positive brain metastases.

We don’t have data yet from palbociclib or ribociclib as to whether or not there will be any activity. I think with palbociclib, there haven’t been data emerging showing it penetrates into the CNS [central nervous system]. With ribociclib, I think there are some preclinical data that there may be some penetration into the CNS, so we await clinical data there. But it’s just going to be yet another factor for women with more aggressive types of breast cancer. It has to penetrate, and secondly, it has to work against that aggressive breast cancer. Certainly, with abemaciclib, it does. Now we need to move it up earlier in the course of treatment of brain metastasis with abemaciclib.

Matthew P. Goetz, MD: We do know that the CDK4/6 inhibitors are different in terms of not only their toxicity profile but also the fact that ribociclib and abemaciclib can cross the blood–brain barrier. There is now evidence that these drugs, when delivered for patients with CNS metastases, can result in CNS responses. The data are very early, but they’re quite encouraging. For those patients who present with CNS metastases who have been treated perhaps with SRS [stereotactic surgery] therapy, where otherwise one is continuing to use and thinking about using endocrine-based therapy, a choice such as abemaciclib or ribociclib would make quite a bit of sense. As I mentioned before, patients who present with bone metastases after a long treatment-free interval are patients who we know still benefit from the CDK4/6 inhibitors. But there is clearly a group of patients that we should never, based on the data right now, withhold CDK4/6 inhibitors in, and those are the patients with these very high-risk clinical characteristics, such as liver metastases.

Stephen Johnston, MA, PhD, FRCP: The other area of interest is management of brain metastases because although this is relatively rarer in ER-positive breast cancer, hitherto we’ve been concerned that an endocrine-based approach is an unlikely way of managing these patients. However, we do have data with abemaciclib that it may well cross the blood–brain barrier; there may be some penetration of CNS disease with this drug. So there may be evidence that it could be an effective combination to use systemically in patients who are presenting with some degree of brain metastasis spread.

Transcript Edited for Clarity 
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Transcript: 

Joyce A. O’Shaughnessy, MD: The most aggressive of the ER [estrogen receptor]–positive metastatic breast cancers will metastasize to the brain. This is a really important feature, particularly of these genomically unstable luminal B breast cancers. Ultimately, in the adjuvant setting, we’re going to need better and better therapies that will improve the disease-free survival of patients and prevent, hopefully, brain metastasis. In the metastatic setting, we’re very, very interested in which of the CDK4/6 inhibitors will be able to treat established brain metastasis in the hopes that eventually these will be moved into the adjuvant setting. Right now, these CDK4/6 inhibitors, palbociclib and abemaciclib, are in large adjuvant trials.

It turns out it was initially noted in patients with glioblastoma multiforme [GBM] who received abemaciclib preoperatively before they went to resection, and indeed there are very high levels of abemaciclib that actually get into GBMs. In fact, there’s some evidence of benefit from abemaciclib against GBM. It definitely penetrates. Similar work has been shown in patients with breast cancer brain metastasis who have been given abemaciclib before they go to surgical resection of a metastasis; there were also high levels of penetration of abemaciclib into brain metastasis.
There has been a study done with abemaciclib as a single agent where patients who were on an aromatase inhibitor could stay on it. There was evidence of some objective responses with abemaciclib in patients with heavily pretreated brain metastasis. So this is an agent we could consider for our patients who have ER-positive metastatic disease with brain metastasis. We have very few data about agents that can actually benefit patients, but abemaciclib does have activity against ER-positive brain metastases.

We don’t have data yet from palbociclib or ribociclib as to whether or not there will be any activity. I think with palbociclib, there haven’t been data emerging showing it penetrates into the CNS [central nervous system]. With ribociclib, I think there are some preclinical data that there may be some penetration into the CNS, so we await clinical data there. But it’s just going to be yet another factor for women with more aggressive types of breast cancer. It has to penetrate, and secondly, it has to work against that aggressive breast cancer. Certainly, with abemaciclib, it does. Now we need to move it up earlier in the course of treatment of brain metastasis with abemaciclib.

Matthew P. Goetz, MD: We do know that the CDK4/6 inhibitors are different in terms of not only their toxicity profile but also the fact that ribociclib and abemaciclib can cross the blood–brain barrier. There is now evidence that these drugs, when delivered for patients with CNS metastases, can result in CNS responses. The data are very early, but they’re quite encouraging. For those patients who present with CNS metastases who have been treated perhaps with SRS [stereotactic surgery] therapy, where otherwise one is continuing to use and thinking about using endocrine-based therapy, a choice such as abemaciclib or ribociclib would make quite a bit of sense. As I mentioned before, patients who present with bone metastases after a long treatment-free interval are patients who we know still benefit from the CDK4/6 inhibitors. But there is clearly a group of patients that we should never, based on the data right now, withhold CDK4/6 inhibitors in, and those are the patients with these very high-risk clinical characteristics, such as liver metastases.

Stephen Johnston, MA, PhD, FRCP: The other area of interest is management of brain metastases because although this is relatively rarer in ER-positive breast cancer, hitherto we’ve been concerned that an endocrine-based approach is an unlikely way of managing these patients. However, we do have data with abemaciclib that it may well cross the blood–brain barrier; there may be some penetration of CNS disease with this drug. So there may be evidence that it could be an effective combination to use systemically in patients who are presenting with some degree of brain metastasis spread.

Transcript Edited for Clarity 
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Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 16th Annual International Congress on the Future of Breast Cancer®Sep 29, 20182.0
School of Breast Oncology®: Mid-Year Video Update OnlineSep 30, 20182.0
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