A ‘New’ Type Of Breast Cancer? Practice-Changing Results? New Study Says Yes, And Provides Hope For Patients With HER2 ‘Low’ Breast Cancer

Oncologists at Memorial Sloan Kettering Cancer Center say this is one of the biggest advancements in breast cancer since the adoption and use of the drug Herceptin, which was almost 15 years ago. The study on Enhertu in HER2-low patients was “groundbreaking,” according to the group of medical professionals. Results showed that women taking the drug had improvements in overall survival, despite having received multiple lines of prior treatment. This is not commonly seen in the metastatic setting; SurvivorNet’s physician experts tell us that these results should give hope to thousands of patients.

Enhertu is designed to target HER2, a protein that promotes the growth of cancer cells. Trial researchers analyzed more than 500 patients with metastatic breast cancer who were categorized as HER2-low (having few HER2 cells).

Dr. Sylvia Adams, who directs breast cancer care an NYU Langone Health, tells SurvivorNet that the findings, presented at this year’s American Society of Clinical Oncology (ASCO) Annual Meeting, address “a major unmet need for patients who have metastatic breast cancer.” For patients with a minimal expression of a protein called HER2, the findings are “practice-changing,” she said.

But before we learn more about the promising Enhertu findings, it’s important to understand the patients that were being studied.

Deciding How to Treat Breast Cancer

For starters, let’s take a look at what goes into the decision making process for breast cancer treatments.

Like most cancer patients, people with breast cancer are treated according to the stage of the tumor and factors specific to the tumor such as hormone receptors. Some of the most common factors in breast cancer that help physicians determine treatment include the presence or absence of the estrogen receptor, progesterone receptor and the presence of HER2 over-expression.

"These receptors, I like to imagine them like little hands on the outside of the cell, they can grab hold of what we call ligands, and these ligands are essentially the hormones that may be circulating in the bloodstream that can then be pulled into this cancer cell and used as a fertilizer, as growth support for the cells," Dr. Elizabeth Comen, a medical oncologist at Memorial Sloan Kettering Cancer Center, tells SurvivorNet.

“What we've learned is that some of these patients we thought were HER2 negative are actually HER2 low, which means that in this trial, they actually responded to targeted medications called T-DXd, or Enhertu, that targets the HER2 receptor, goes into the cancer cell, and kills it,” Dr. Comen adds.

The Unique Features of Breast Cancer: Deciding the Right Course of Treatment

If you have or a loved one has been diagnosed with breast cancer, it’s important to ask physicians about receptor status. All breast cancers should be routinely tested for these biomarkers as they are critical in helping the multidisciplinary team decide the best treatment for each patient.

For example, women with estrogen-receptor-positive breast cancers are typically treated with a combination of surgery, radiation therapy, hormonal therapy and sometimes chemotherapy.

In other women, with HER2-positive tumors, patients may also receive an additional drug called trastuzumab. Trastuzamab is a monoclonal antibody that specifically targets the HER2 receptor and typically is only given to patients with HER2 positive tumors.

Learning More about HER2 Status in Breast Cancer Patients

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 in The New England Journal of Medicine reported on the use of Enhertu in women with metastatic hormone receptor-positive or negative, HER2 "low" breast cancer who had received multiple prior lines of treatment.

RELATED: New Hope for Breast Cancer Warriors: ENHERTU Therapy Is A 'Big Game Changer' for HER2 Positive Metastatic Breast Cancer Patients

Enhertu 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.

Clinical Trials for Breast Cancer

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 study speaks to the impact of antibody-drug conjugates, likely stimulating further research to identify targets beyond HER2 on breast cancers as well as other malignancies. It is an exciting field of scientific advances improving lives of many patients,” Dr. Adams said.

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.'”

Women who have metastatic disease, and have been treated as HER2 negative, should immediately consult their oncologists about whether they meet the criteria for HER2 low, as some may benefit from therapy with Enhertu. This group of patients may be as large as 10,000, and would include patients previously labeled as HER2-negative, or triple-negative.

SurvivorNet’s experts tell us that it’s not often that a study can so rapidly change practice, but with the results of the Destiny Breast-04 trial, this seems to be the case.

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."

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