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HR+ Breast Cancer: Risk-Stratifying to CDK4/6 Inhibitors

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: Tuesday, Aug 21, 2018



Transcript: 

Matthew P. Goetz, MD: As we think about the different CDK4/6 inhibitors and how we might choose to use them in patients who present with metastatic disease, one of the things we do know is that there appear to be some tumors that are exquisitely driven by the estrogen receptor. These are patients who come in with perhaps a long treatment-free interval, high levels of ER [estrogen receptor] and PR [progesterone receptor], lower-grade disease, and a lack of visceral metastases. These are patients who clearly do well with endocrine monotherapy, such as fulvestrant. And then we have a group of patients who have higher-risk characteristics, and these are patients who exhibit tumor features that are more concerning. These are tumors that are higher grade and have absence of the progesterone receptor, short treatment-free interval, and of course the presence of visceral crises. One of the things that’s important to note as we looked across the CDK4/6 inhibitors is that it appeared these drugs have activity in these patients. Specifically, with the drug abemaciclib, substantial or significant increases in response rates were seen in these patients with these high-risk features.

One of the questions that comes up is, Why did the drugs work so well for these high-risk features? Well, if the tumor is not driven only by the estrogen receptor, are there other ways that these drugs could potentially work? Certainly, one of the things that is quite interesting is the recent data that have come out of the Harvard group demonstrating that abemaciclib and some of the other CDK4/6 inhibitors can activate the immune system. This might be very critical in a tumor with genomic instability that is driven by factors other than the estrogen receptor. The observations that the response rates are this high in patients with poor prognostic features—high-grade disease with absence of PR but liver metastases—suggest that these drugs may be doing things other than just targeting CDK4/6. The bottom line is that patients who present this way are excellent candidates for drugs such as abemaciclib or the other CDK4/6 inhibitors.

Stephen Johnston, MA, PhD, FRCP: The pooled analysis from MONARCH 2 and MONARCH 3, which has shown the level of benefit in different subgroups, is really important for clinicians to understand. What we’ve seen in the analysis is that there are certain baseline characteristics that we know are prognostic and can actually help you differentiate those patients who get the biggest degree of benefit from the addition of a CDK4/6 inhibitor. If clinicians are thinking about whether they should offer the combination to patients who present with metastatic disease, then I think an understanding of this is helpful.

Patients who have tumors that are of a higher grade, tumors that lack progesterone receptor expression, and patients who have an early onset of relapse within 3 years since diagnosis have a poorer prognosis with endocrine therapy alone and are set to gain the most from the addition of a CDK4/6 inhibitor.

On the other hand, patients who relapse many years later perhaps have a very hormone-driven cancer that is strongly ER- and PR-positive, perhaps with a lower-grade tumor, and distribution of disease that might be just in the bone alone. We know that those patients can do fantastically well with endocrine therapy alone. While the addition of a CDK4/6 inhibitor might give a little bit more benefit, there is an option for patients to be treated with endocrine therapy alone and reserve the addition of these agents for when they progress on their aromatase inhibitor, as shown in the PALOMA-3 trial or the MONARCH 2 trial with this class of agents.

Transcript Edited for Clarity
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Transcript: 

Matthew P. Goetz, MD: As we think about the different CDK4/6 inhibitors and how we might choose to use them in patients who present with metastatic disease, one of the things we do know is that there appear to be some tumors that are exquisitely driven by the estrogen receptor. These are patients who come in with perhaps a long treatment-free interval, high levels of ER [estrogen receptor] and PR [progesterone receptor], lower-grade disease, and a lack of visceral metastases. These are patients who clearly do well with endocrine monotherapy, such as fulvestrant. And then we have a group of patients who have higher-risk characteristics, and these are patients who exhibit tumor features that are more concerning. These are tumors that are higher grade and have absence of the progesterone receptor, short treatment-free interval, and of course the presence of visceral crises. One of the things that’s important to note as we looked across the CDK4/6 inhibitors is that it appeared these drugs have activity in these patients. Specifically, with the drug abemaciclib, substantial or significant increases in response rates were seen in these patients with these high-risk features.

One of the questions that comes up is, Why did the drugs work so well for these high-risk features? Well, if the tumor is not driven only by the estrogen receptor, are there other ways that these drugs could potentially work? Certainly, one of the things that is quite interesting is the recent data that have come out of the Harvard group demonstrating that abemaciclib and some of the other CDK4/6 inhibitors can activate the immune system. This might be very critical in a tumor with genomic instability that is driven by factors other than the estrogen receptor. The observations that the response rates are this high in patients with poor prognostic features—high-grade disease with absence of PR but liver metastases—suggest that these drugs may be doing things other than just targeting CDK4/6. The bottom line is that patients who present this way are excellent candidates for drugs such as abemaciclib or the other CDK4/6 inhibitors.

Stephen Johnston, MA, PhD, FRCP: The pooled analysis from MONARCH 2 and MONARCH 3, which has shown the level of benefit in different subgroups, is really important for clinicians to understand. What we’ve seen in the analysis is that there are certain baseline characteristics that we know are prognostic and can actually help you differentiate those patients who get the biggest degree of benefit from the addition of a CDK4/6 inhibitor. If clinicians are thinking about whether they should offer the combination to patients who present with metastatic disease, then I think an understanding of this is helpful.

Patients who have tumors that are of a higher grade, tumors that lack progesterone receptor expression, and patients who have an early onset of relapse within 3 years since diagnosis have a poorer prognosis with endocrine therapy alone and are set to gain the most from the addition of a CDK4/6 inhibitor.

On the other hand, patients who relapse many years later perhaps have a very hormone-driven cancer that is strongly ER- and PR-positive, perhaps with a lower-grade tumor, and distribution of disease that might be just in the bone alone. We know that those patients can do fantastically well with endocrine therapy alone. While the addition of a CDK4/6 inhibitor might give a little bit more benefit, there is an option for patients to be treated with endocrine therapy alone and reserve the addition of these agents for when they progress on their aromatase inhibitor, as shown in the PALOMA-3 trial or the MONARCH 2 trial with this class of agents.

Transcript Edited for Clarity
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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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