HER2-Low Classification Is a ‘Big Leap Forward’ for Breast Cancer Treatment

It has been nearly 25 years since the approval of Herceptin (trastuzumab), a breakthrough therapy targeting the human epidermal growth factor receptor 2 (HER2) oncogene, ushering in a new phase of targeted therapy that has saved thousands of lives .

Ongoing research into the biology of the HER2 pathway has led to many new research directions that continue to yield new successful treatments and further improve the life expectancy of patients with HER2-positive breast cancer.

As detailed in this issue of CURE® a major leap forward was made just this summer with coverage of the DESTINY Breast04 study. This study was a first because it targeted a group of patients with tumors that were technically HER2-negative—in that they expressed low levels of HER2 that fell below the threshold for a response or benefit of Herceptin would be expected.

The story began when the antibody-drug conjugate Enhertu (fam-trastuzumab deruxtecannxki), which had recently been approved by the Food and Drug Administration as a late-line therapy for advanced HER2-positive breast cancer, had been shown in a pilot study to break the activity barrier in patients with HER2-negative tumors who demonstrated low levels of HER2 in the cell membrane using standard HER2 antibody staining techniques.

We are still trying to understand this newly coined class of “HER2-low” tumors.

It is not clear that these are biologically distinct from HER2-negative tumors. However, since Enhertu is an antibody-drug conjugate designed to bind to HER2-expressing cells regardless of their biology, HER2-low cells could be vulnerable due to the mode of action of antibody-drug conjugates.

The HER2 antibody portion of the antibody-drug conjugate binds to the HER2 receptor on the cell surface and is drawn into the cell along with the attached toxic drug.

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Like a Trojan horse, the “soldiers” – a drug called deruxtecan, which inhibits cell growth by interfering with DNA division – are released into the cell. The design of this antibody-drug conjugate differs from that of previous versions such as Kadcyla (T-DM1 or Ado-Trastuzumab Emtansine), which only kills HER2-positive but not HER2-low cells.

The DESTINY-Breast04 study compared Enhertu to standard chemotherapy for patients with HER2-low breast cancer and showed such remarkable improvement in time to tumor progression and overall survival that it was included in the presentation at the American Society of Clinical Oncology meeting Standing ovation was rewarded June 2022.

Given that more than half of all breast cancers are HER2-low, this greatly expands the possibilities when hormonal or chemotherapy drugs stop working.

Additionally, it lays the groundwork for a whole new generation of antibody-drug conjugates, consisting of antibodies that can be engineered to bind to proteins expressed by certain tumors and linked to drugs that are not used as prior therapy, thereby maximizing the chances of success.

Debu Tripathy, MD


Professor of Medicine
Chairman, Division of Medical Oncology of the Breast

The University of Texas MD Anderson Cancer Center

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