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HER2 Low Advanced BC: Module

CME

Pushing the Boundaries of Unresectable or Metastatic HER2-Low Breast Cancer Treatment: New Insights and Innovations

Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™

Released: January 26, 2024

Expiration: January 25, 2025

Sara M. Tolaney
Sara M. Tolaney, MD, MPH
CME/CE Information

Activity

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Course Completed

Overview of the Therapeutic Landscape for Patients With HER2-Low Breast Cancer

The evolution of the HER2 spectrum to include patients with HER2-low expression has had a major impact on the current therapeutic landscape for patients with unresectable or metastatic HER2-low breast cancer, making the treatment of these patients challenging. In this space, we have seen the development of a spectrum of different antibody–drug conjugates (ADCs) targeting HER2, evolving from trastuzumab emtansine (T-DM1) to newer ADCs such as T-DXd.

Characteristic Differences Between T-DXd and T-DM1

ADCs comprise a monoclonal antibody linked to a small molecule cytotoxic drug via a linker.1-5 ADCs have the potential to selectively deliver a cytotoxic drug to antigen-expressing cells. This system of drug delivery to target cells is associated with improved efficacy and safety, in that the approach minimizes drug exposure to cells that do not express the antigen of interest. Following the binding of the ADC to the antigen on the tumor cell, it is internalized into endosomes/lysosomes, and this is followed by the release of the drug inside the cell once the linker is cleaved or the monoclonal antibody undergoes catabolism. The binding of the liberated drug to its target results in cell death. 

The first HER2-directed ADC to be approved for patients with breast cancer was T-DM1. T-DM1 comprises trastuzumab linked to the maytansinoid antimicrotubule cytotoxic payload, DM1, via a noncleavable linker, (N-maleimidomethyl)cyclohexane-1-carboxylate.5 The proteolytic degradation of the antibody portion of T-DM1 in cell lysosomes leads to the release of DM1. When DM1 binds to microtubules, polymerization is inhibited causing cell cycle arrest and cell death. The drug-to-antibody ratio for T-DM1 is approximately 3.5:1.6 

This is in contrast to what is seen with the newer ADCs such as T-DXd. With T-DXd, the technology is different, although both T-DM1 and T-DXd target HER2. With T-DXd, trastuzumab is linked via a cleavable peptide linker to a topoisomerase 1 inhibitor (DXd) payload, which is an exatecan derivative.2,3 Following the binding of T-DXd to HER2 on tumor cells, the cleavage of the linker results in the release of DXd. This in turn causes targeted DNA damage and cell death. Also, compared with T-DM1, T-DXd has a much higher drug-to-antibody ratio of approximately 8:1.2

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Classical ADC vs ADC With a Bystander Cell Killing Effect

As mentioned, an ADC uses a system that includes an antibody that binds to a specific target on the surface of the cancer cell and gets internalized into the cancer cell to release its cytotoxic payload, which results in cell death. However, for some ADCs, the payload is also able to penetrate the cell membrane, and so, it has the ability to get out of the cell into a neighboring cancer cell and function via a bystander effect to also kill the neighboring cancer cell.3,7 T-DXd is one ADC with bystander effects, so even if a neighboring cancer cell does not robustly express HER2, T-DXd is still able to trigger cell death via this bystander effect. On the contrary, the payload for T-DM1 does not have this capability.

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