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Treatments Emerging to Combat Endocrine Resistance in ER+ Breast Cancer

Danielle Bucco
Published: Friday, Apr 06, 2018

Heather Han, MD
Heather Han, MD
Most patients with ER-positive breast cancer will develop resistance to treatment with endocrine therapy, said Heather Han, MD, which makes understanding causes of resistance an important area of study.

CDK 4/6 inhibitors have emerged as a potential tool for overcoming endocrine resistance. The efficacy is similar for the 3 CDK4/6 inhibitors approved for the treatment of patients with metastatic breast cancer, as they have all demonstrated improvement in progression-free survival (PFS) in the first- and second-line settings.

Abemaciclib (Verzenio) joined palbociclib (Ibrance) and ribociclib (Kisqali) as the third CDK 4/6 inhibitor for patients with hormone receptor (HR)-positive, HER2-negative breast cancer. Most recently, abemaciclib was approved by the FDA in February 2018 for use in the frontline setting in combination with an aromatase inhibitor (AI), based on results from the phase III MONARCH 3 trial. This study showed that the the addition of abemaciclib to anastrozole or letrozole reduced the risk of progression or death by 46% compared with a nonsteroidal AI alone.

Han said the next step with the CDK 4/6 agents will be combination approaches, including with PD-1/PD-L1 inhibitors, as early research suggests CDK 4/6 inhibitors increase tumor immunogenicity, likely enhancing the impact of immune checkpoint agents.

In an interview during the 2018 with OncLive® State of the Science SummitTM on Breast Cancer, Han, research director, medical oncologist, Department of Breast Oncology, Moffitt Cancer Center, discussed emerging approaches for combating endocrine resistance in patients with ER-positive breast cancer.

OncLive: Please provide an overview of your presentation on ER-positive breast cancer.

Han: In my presentation, I discussed hormone therapy and the main mechanisms of endocrine resistance. HR-positive breast cancer is the most common subtype of breast cancer. The main treatment is endocrine therapy, but unfortunately resistance is universal to endocrine therapies. Patients end up having recurrence and progressive disease. Understanding the mechanism of endocrine resistance is critical in order for us to find targeted therapy to try and overcome the resistance.

I reviewed some of the mechanisms that have been identified in recent studies, so we can see what is FDA approved for use in routine clinical practice along with ongoing new therapies and novel combinations for these patients. I also reviewed attempts to identify the predicative markers for targeted therapies that have been studied. 

Can you elaborate on these mechanisms of resistance?

Many genetic and epigenetic alterations have been identified to explain the mechanisms to endocrine resistance. For example, a reduction or loss of ER expression explains some of the required resistance to endocrine therapy. Also, cell cycle regulation and deregulation have been the important mechanisms of endocrine resistance—not to mention to the cell itself and its interaction to the microenvironment, extracellular metrics, and immune cells.

What percentage of patients develop resistance?

In the metastatic setting, resistance to endocrine therapy is universal for patients with ER-positive breast cancer. Most patients end up developing resistance to endocrine therapy throughout their courses of therapy. That is why it is very important to understand this resistance mechanism—to find potential targets and reverse this resistance. 

What are some combination approaches being explored?

The approved agents that we are using in this setting include an mTOR inhibitor, such as everolimus (Afinitor), and 3 approved CDK 4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib. These are approved agents, but there are also many ongoing studies investigating new agents being studied in this subset, such as including PI3K inhibitors. Specifically, combinations with PI3K inhibitors, CDK 4/6 inhibitors, and new checkpoint inhibitors are actively being investigated. Some of the results show promising efficacy. 

Can you specify the differences between the different CDK 4/6 inhibitors?

Published and presented data suggest that efficacy across the 3 different agents are similar and are significantly improving PFS in the first- and second-line settings. However, what we have seen is that the toxicity of the 3 agents is slightly different. For example, abemaciclib has more diarrhea, gastrointestinal toxicities, and fatigue. Ribociclib and palbociclib have similar toxicities with neutropenia. 

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