ASCO: New Study Provides Hope For Patients With HER2 ‘Low’ Breast Cancer

• A new study presented at ASCO on the drug ENHERTU gives hope to women with metastatic HER2 “low” breast cancer.
• HER2 “low” may become a new commonly classified subtype of breast cancer.
• HER2 “low” as a breast cancer type would include approximately 50% of all patients and opens the door for new treatments and research.

Breast cancer is treated according to the unique qualities of each case. And now the drug ENHERTU may be just the right option for a group of patients that traditionally have struggled to fit into a category.

But before we learn more about the ENHERTU study that was recently presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, it’s important to understand the patients that were being studied.

Traditionally, the presence of HER2 has been divided into two groups, either positive or negative, leaving about 50 percent of patients somewhere in the middle. These groupings are based upon the way the tumors appear under a microscope when graded by the pathologist or with additional testing a pathologist may perform.

Patients with HER2 positive tumors have tumors that show HER2 over-expression while patients with HER2 negative tumors show minimal or no expression.

Recently, however, researchers have looked to further expand this definition to include patients that have a minimal amount of HER2 expression but do not meet the classic definition for HER2-positive tumors. This group has been called HER2 “low” and is very important as it represents approximately 50 percent of all patients with breast cancer.

The New ENHERTU Study

So what does all this mean, and why is this relevant to the ENHERTU study?

Well, this clinical trial, the results of which were recently published in The New England Journal of Medicine, reported on the use of a new drug called ENHERTU in women with metastatic hormone receptor-positive or negative, HER2 “low” breast cancer who had received multiple prior lines of treatment.

The drug called ENHERTU (trastuzumab deruxtecan) had previously shown success in women with HER2 positive breast cancer, but validation in the newly defined HER2 “low” cohort had not been established in a large study. What this means is that in patients who had HER2 positive tumors, the drug ENHERTU had shown success, but it was unknown what would happen in patients with only minor HER2 expression – the HER2 “low” group.

What Is ENHERTU?

ENHERTU is not traditional chemotherapy, but is a unique type of medication termed an antibody-drug conjugate.

In this type of therapy, an antibody is linked to chemotherapy or another drug to provide a targeted approach to cancer treatment. The antibodies serve as the vehicle and the drug serves as the payload once the antibody reaches the cancer cell. The benefits of this type of therapy include decreased side effects and a more targeted approach compared to systemic chemotherapy.

Durexecan is the payload, or chemo, for ENHERTU, and trastuzumab is the antibody.

In the setting of ENHERTU, the drug is bound to an antibody that targets the HER2 receptor. Once the antibody reaches the cancer cell it will interact with the HER2 receptor which causes a release of the payload. When the payload is released it diffuses a very short distance to kill the cancer cell without harming additional surrounding cells.

Results from the Study

Taking a closer look at the study presented at ASCO, which is called DESTINY Breast-04, patients with pretreated metastatic hormone receptor-positive or negative, HER2 “low” breast cancer were randomized to receive either ENHERTU or traditional cytotoxic chemotherapy.

The study showed remarkable results including reducing the risk of tumor progression or death by 49 percent. And the trial’s primary endpoint of progression-free survival – the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse – was improved nearly doubling (10.1 months vs 5.4 months) in patients receiving ENHERTU.

This drug also impacted overall survival with patients who received ENHERTU living longer than patients who received traditional chemotherapy. More specifically, it improved overall survival by 36 percent compared to women who received chemotherapy alone.

When asked about the trial results Dr. Allison Zibelli, MD, FACP Vice-Chair, Oncology and Assistant Professor of Medicine at the Sidney Kimmel Cancer Center at Thomas Jefferson University says, “the outcomes for the trial patients were very impressive, especially given that they were all heavily pretreated.”

These results are groundbreaking for several reasons. First, this offers additional hope to women with hormone receptor-positive or negative, HER2 “low”, metastatic breast cancer treated on multiple prior therapies. By using ENHERTU, patients now have an additional option before resorting to chemotherapy.

Secondly, this drug further proves the concept of the HER2 “low” state. As discussed, HER2 low patients would represent approximately 50 percent of all patients with breast cancer. As the definition expands from HER2 positive, HER2 negative now to include HER2 low, this opens the door for multiple new treatment pathways and future research. This would represent a large step forward in the thinking around breast cancer biomarkers and treatment.

When asked about HER2 “low” as a new class of breast cancer, Dr. Zibelli said it’s changing her practice.

“I have already changed the way I think about the care of my patients,” Dr. Zibelli said. “Many more patients will now be eligible for treatment with trastuzumab-deruxitecan (ENHERTU), including many patients who were previously labeled ‘triple negative.’”

Overall, this trial represents a major step forward in the treatment of breast cancer. The results of the study were promising by not only extending the lives of patients with metastatic hormone receptor-positive breast cancer but also defining a new category innovating the classification of breast cancer. The HER2 “low” class of breast cancer continues to be defined and this will hopefully bring new research and treatments for patients with HER2 “low” breast cancer.

Per Dr. Zibelli, in the future “every patient with breast cancer will want to know if they are HER2 low.”