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HR+ Breast Cancer: Prognostic Subgroups in MONARCH Trials

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: Thursday, Aug 16, 2018



Transcript: 

Joyce A. O’Shaughnessy, MD: In abemaciclib, 2 very large randomized trials—MONARCH 2 with fulvestrant and MONARCH 3 with aromatase inhibitors—both showed significant benefit for abemaciclib with endocrine therapy. There was a deep dive done into the patient phenotypic subsets: patients with bone-only disease, patients with very long natural histories, patients with very short natural histories, and patients with liver metastasis. The grade of the cancer. Interestingly, what was found is that abemaciclib’s greatest benefits in terms of patient subsets were those with more aggressive biology. It worked in all the subsets of patients, as all the CDK4/6 inhibitors have. But there seemed to be a differential benefit in those with liver metastases, for example. Those with shorter treatment-free intervals who stopped endocrine therapy or recurred on endocrine therapy in the adjuvant setting and manifesting endocrine therapy resistance really benefited. It just may be that these cancers are more highly proliferative and may have multiple mechanisms of endocrine therapy resistance.

Abemaciclib, of course, is a very potent CDK4 inhibitor. It’s the most potent of the 3 CDK4/6 inhibitors, particularly against CDK4. In these full-throttle cancers, you need continuous target inhibition, potentially. That really has to be put to a randomized trial, but it’s a hypothesis. You need very strong inhibition of the target with a potent inhibitor. Abemaciclib also inhibits more than just CDK4/6. It does have some inhibition of CDK2, potentially even CDK9: some of the other CDKs that can cause resistance to a CDK4/6 inhibitor.

We know that some of these cancers have higher levels of cyclin E. There were some recent data from Nick Turner looking at PALOMA-3, looking at the tumors of the primary breast cancers in patients who ultimately developed metastatic disease and were randomized to fulvestrant plus or minus palbociclib—patients whose primary breast cancers had higher levels of cyclin E, which complexes with CDK2 and is not inhibited by CDK4/6 inhibitors. Those patients didn’t do as well with palbociclib as those who had lower levels of cyclin E, where the cancer was more driven by CDK4/6. Those patients did extremely well. We don’t know those data for abemaciclib, but we do know it has some inhibition of CDK2. A broader mechanism of action, as well, may potentially help these patients with more aggressive cancers that recur more quickly, probably because they have multiple mechanisms of resistance against endocrine therapy.

Transcript Edited for Clarity 
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Transcript: 

Joyce A. O’Shaughnessy, MD: In abemaciclib, 2 very large randomized trials—MONARCH 2 with fulvestrant and MONARCH 3 with aromatase inhibitors—both showed significant benefit for abemaciclib with endocrine therapy. There was a deep dive done into the patient phenotypic subsets: patients with bone-only disease, patients with very long natural histories, patients with very short natural histories, and patients with liver metastasis. The grade of the cancer. Interestingly, what was found is that abemaciclib’s greatest benefits in terms of patient subsets were those with more aggressive biology. It worked in all the subsets of patients, as all the CDK4/6 inhibitors have. But there seemed to be a differential benefit in those with liver metastases, for example. Those with shorter treatment-free intervals who stopped endocrine therapy or recurred on endocrine therapy in the adjuvant setting and manifesting endocrine therapy resistance really benefited. It just may be that these cancers are more highly proliferative and may have multiple mechanisms of endocrine therapy resistance.

Abemaciclib, of course, is a very potent CDK4 inhibitor. It’s the most potent of the 3 CDK4/6 inhibitors, particularly against CDK4. In these full-throttle cancers, you need continuous target inhibition, potentially. That really has to be put to a randomized trial, but it’s a hypothesis. You need very strong inhibition of the target with a potent inhibitor. Abemaciclib also inhibits more than just CDK4/6. It does have some inhibition of CDK2, potentially even CDK9: some of the other CDKs that can cause resistance to a CDK4/6 inhibitor.

We know that some of these cancers have higher levels of cyclin E. There were some recent data from Nick Turner looking at PALOMA-3, looking at the tumors of the primary breast cancers in patients who ultimately developed metastatic disease and were randomized to fulvestrant plus or minus palbociclib—patients whose primary breast cancers had higher levels of cyclin E, which complexes with CDK2 and is not inhibited by CDK4/6 inhibitors. Those patients didn’t do as well with palbociclib as those who had lower levels of cyclin E, where the cancer was more driven by CDK4/6. Those patients did extremely well. We don’t know those data for abemaciclib, but we do know it has some inhibition of CDK2. A broader mechanism of action, as well, may potentially help these patients with more aggressive cancers that recur more quickly, probably because they have multiple mechanisms of resistance against endocrine therapy.

Transcript Edited for Clarity 
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