Study: Enhertu shows promising results for HER2-low and HER2-ultralow metastatic breast cancer

RELEVANCE

Most relevant for: People with HR-positive metastatic breast cancer.

It may also be relevant for:

• people with breast cancer

Relevance: High

Strength of Science: High

Relevance rating details

What is this study about?

The main goal of this study was to see if treatment with Enhertu, a new targeted therapy, helped patients live longer without their cancer growing (progression-free survival). Findings from this study build on previous research suggesting a new way to classify breast cancers that were previously labeled as HER-negative. Some breast cancers in these new categories, called “HER2-low” and “HER2-ultralow,” may respond to a type of targeted therapy called anti-HER2 therapy.

Why is this study important?

This study provides new guidance for treating metastatic hormone receptor-positive (HR-positive) breast cancer. It also confirms the importance of categorizing cancers as HER2-low and HER2-ultralow to guide treatment.

HER2 is a protein that is sometimes found on the surface of breast cancer cells. Some breast cancer drugs work by targeting HER2 to block or slow cancer growth. Doctors decide whether to use these drugs based on lab tests that look at the level of HER2 on the surface of cancer cells—test results range from 0 to 3+. Breast cancers with high levels of HER2 (a score of 3+) were previously considered HER2-positive and could be treated with HER2-targeted treatments. Breast cancers with lower levels of HER2 (a score below 3) were considered to be HER2-negative and were not treated with HER2-targeted drugs.

In 2022, the DESTINY-04 study changed this understanding by demonstrating that study participants with HER2-low cancers (HER2 scores of 1+ or 2+) responded to the anti-HER2 drug Enhertu (trastuzumab deruxtecan, covered in previous XRAYs on DESTINY-04 and later FDA approval).

Researchers in the DESTINY-06 study wanted to see if Enhertu can treat cancers with even lower levels of HER2: HER2-ultralow cancers that have a HER2 score above zero but below one This study compared Enhertu to chemotherapy as a treatment for hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer in those who had already tried hormone therapy.

Results of a test for HER2 status:

Study findings

The DESTINY-06 study included 866 people with metastatic, HR+ breast cancer. Of these, 713 had HER2-low breast cancer and 153 had HER2-ultralow breast cancer. None had received prior chemotherapy, but most had already received at least two lines of hormone therapy for metastatic disease, including a CDK4/6 inhibitor.

Participants from 324 hospitals and cancer centers were randomly assigned to receive either Enhertu or one of three chemotherapy options: capecitabine, nab-paclitaxel or paclitaxel.

Overall, the researchers found that Enhertu is more effective than chemotherapy for both HER2-low and HER2-ultralow breast cancers.

Specifically, the researchers found that:

• Enhertu delayed cancer growth more effectively than chemotherapy: People with HER2-low breast cancer who were treated with Enhertu went 13.2 months without cancer growth compared to 8.1 months for people who received chemotherapy. The results for people with HER2-ultralow breast cancer were similar, although the test group was smaller.
• More people responded to Enhertu than chemotherapy: 57% of people with HER2-low cancers who took Enhertu had cancers that shrank or stopped growing, compared to 32% of people who received chemotherapy.
• Participants in both study groups experienced some side effects:
  • People in the Enhertu group were more likely to have moderate-to-severe side effects. Slightly more than half (53%) of people who took Enhertu experienced a moderate or more serious side effect, compared to 44% in the chemotherapy group.
  • The three most common side effects of Enhertu were nausea, fatigue and hair loss. In rare instances, the drug caused serious lung disease.
  • The most common side effects reported by people in the chemotherapy group were fatigue, risk of infection (due to low white blood cell count) and painful swelling or pain in the hands and feet (hand-foot syndrome).

The research team continues to follow participants and will provide more information in the future on whether Enhertu helps participants live longer (improves overall survival).

What does this mean for me?

If you have metastatic HR-positive breast cancer, these results may affect your treatment plan. If you are currently taking a hormone therapy that is working, this study is unlikely to affect your current treatment plan. If hormone therapies stop working, HER2 testing may guide your treatment options. If your cancer has detectable HER2 levels, even if levels are low or ultralow, Enhertu instead of chemotherapy might be an option. 

Although this study did not include people with triple-negative breast cancer (TNBC), previous studies have shown that some people with TNBC who have low HER2 expression may benefit from Enhertu. Additional studies are needed to explore this further.

If your last HER2 test was negative, particularly if it was not done recently, ask your doctor whether another HER2 test might be helpful. Additionally, HER2 test results sometimes change, especially if testing was done before the cancer returned or spread. Ask your medical team if a new test is needed or if Enhertu may be right for you.

Reference

Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. New England Journal of Medicine. 2024; 391(22):2110-2122.

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

Share your thoughts on this XRAY review by taking our brief survey.  

posted 5/15/25