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HER2-Low Breast Cancer Explained

By BCRF | July 8, 2022

The DESTINY-Breast04 trial at ASCO 2022 introduced many people to the term “HER2-low.” BCRF dives into this subtype and our investigators working on related research

For many people outside the breast oncology and research fields, the “unheard-of” and “breakthrough” results out of the DESTINY-Breast04 trial introduced them to the concept of “HER2-low breast cancer” and essentially added a new term to the breast cancer vocabulary.

For the first time in a clinical trial, DESTINY-Breast04’s exciting results showed that patients with low HER2-expressing metastatic breast cancer benefitted from a targeted therapy, trastuzumab deruxtecan (T-DXd/Enhertu®), an antibody-drug conjugate (ADC). Dr. Shanu Modi’s presentation on DESTINY-Breast04 at the American Society of Clinical Oncology (ASCO) Annual Meeting this year was met with a standing ovation, and the trial results went on to make headlines in major outlets.

RELATED: Watch an interview with Dr. Modi on BCRF’s Behind the Breakthroughs video series

Targeting and treating HER2-low breast cancer, which represents at least 55 percent of breast cancers, has long been a known challenge in the medical and scientific community—and the results of DESTINY-Breast04 have opened the door for a new standard of care for these patients. What’s more: T-DXd’s likely approval for HER2-low disease means that this drug will benefit an astonishing 75 percent of all breast cancer patients (the 55 percent of people with HER2-low breast cancer and the 20 percent of those who are HER2-positive).

Here, we explain HER2-low, highlight BCRF research on this emerging classification, and what’s to come.

What is HER2-low breast cancer?

Normally, human epidermal growth factor receptor 2 (HER2) proteins help control healthy breast cell growth and maintenance. In some breast cancers, however, breast cells have very high levels of HER2 on their cell surfaces, causing them to grow and divide uncontrollably.

Breast cancer patients are routinely tested for HER2 expression using a biochemical process that allows visualization of the protein. They then receive an immunohistochemical (IHC) score. Currently, HER2 status is binary: Patients usually either learn their breast cancer is HER2-positive or HER2-negative.

HER2-positive breast cancers, which meet a certain high threshold of HER2 molecules (3+ IHC score), can be treated with HER2-targeted therapies such as trastuzumab/Herceptin®, which dramatically improved prognoses for these patients after it was approved in 1998 and was the last breast cancer drug to get a standing ovation at ASCO. About 15 to 20 percent of breast cancer patients fall in the HER2-positive category, and their cancers tend to grow and metastasize faster. Conversely, breast cancers with HER2 levels below the threshold (IHC scores of 0 or 1+) are considered HER2-negative and are not treatable with these therapies.

A smaller subset of patients may find out their IHC score is borderline (2+), and this group requires additional classification with what’s called an in situ hybridization (ISH) test, which measures gene amplification.

“However, within the HER2 population there are tumors that have low levels of HER2 expression, which we have termed ‘HER2-low’ breast cancer, for which this HER2 receptor may still be targetable,” Dr. Modi explained in her presentation at ASCO. “Our currently available therapies are HER2-targeted therapies that have not proven effective in patients in this subgroup [HER2-low].”

This HER2-low category includes those who have IHC scores of 1+ and 2+ without amplification (as measured by that ISH test).

The DESTINY-Breast04 results showed that HER2-low breast cancer is now targetable with a novel HER2-targeted therapy. Estimates show that at least 55 percent of people with breast cancer fall into this HER2-low category—including some patients who have either hormone receptor–positive breast cancer or triple-negative disease, who will now have a new strategy to target and treat their disease.

DESTINY-Breast04’s results and impact

Patients with previously treated HER2-low metastatic breast cancer who were treated with T-DXd had significant improvements in survival compared to those treated with chemotherapy. Among the study’s 494 participants, the risk of disease progression was approximately 50 percent lower, and the risk of death was 36 percent lower with T-DXd compared to chemotherapy.

For people living with advanced, metastatic breast cancer, particularly where their cancers have become resistant and all treatment avenues have been exhausted, this provides a significant benefit and offers hope for more time.

What’s to come for HER2-low research

BCRF investigators are steadily working to expand breast cancer treatments to more of the patient population. DESTINY-Breast04’s results provide a new option for patients with HER2-low breast cancer, but are the current methods of quantifying HER2-low accurate enough?

Dr. David Rimm has significant expertise in developing and standardizing tests that can precisely define the molecular features of a person’s breast cancer so that they receive the most personalized treatment possible.

Recognizing the need to refine how HER2 levels are determined and maximize the utility of T-DXd, his team developed a new, more sensitive assay to detect and measure low levels of HER2—those scored 0 and 1+ as well as 2+ that require added precision. This test has the potential to better distinguish those patients with sufficient levels of HER2 who will be responsive to T-DXd.

 “The current IHC assay is missing many women that have HER2 target present in their tumors,” he said. “We believe that a more sensitive assay will reveal even more women that can benefit from this new drug”

Dr. Ian Krop is currently conducting a clinical trial testing the effectiveness of HER2-targeted treatments in combination with immunotherapy for patients with advanced HER2-positive breast cancer. Dr. Krop serves as chief scientific officer for the Translational Breast Cancer Research Consortium (TBCRC), which conducts innovative and high-impact clinical trials for breast cancer over 18 clinical sites. TBCRC, continuously supported by BCRF since its founding in 2005, has conducted numerous, specialized translational studies to identify targeted therapies against breast cancer.

He noted that about a third of triple-negative breast cancers, which currently have few targeted therapies, are also HER2-low and those patients in the DESTINY-Breast04 trial benefitted from T-DXd.

“These ADCs are just getting better and there is no reason why we can’t keep tweaking these drugs to continue to improve,” Dr. Krop said. “We don’t just have them targeting HER2, we have an ADC targeting a protein called Trop2 that is approved for the treatment of triple-negative breast cancers, providing one of the first targeted therapies for this type of breast cancer, and there are more to come. It’s really exciting.”

The DESTINY-Breast04 trial represents a new era of targeted therapies and has opened up treatment to a new HER2-low subset of breast cancer patients. The benefit shown in DESTINY-Breast04 was significant for those patients with advanced breast cancers that have become resistant to other treatments—patients who have very few options.

Next, T-DXd will be tested in patients with earlier stage HER2-positive and HER2-low breast cancer whose disease has not yet become resistant to therapy.

“I think it’s very likely that as we use this drug in women whose cancers aren’t so resistant, we are going to see a much bigger benefit,” Dr. Krop said. “Getting underway now are trials where we’re using Enhertu to prevent metastatic disease in the first place. I think we’re going to be using these [types of targeted therapies] more and more widely going forward.”