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Study: A win for some patients with HER2-negative metastatic breast cancer

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At a glance Questions for your doctor
Study findings Clinical trials
Strengths and limitations Get support
What does this mean for me? Related resources


What is this study about?

This study reports on the DESTINY 04 clinical trial that looked at the drug trastuzumab deruxtecan (Enhertu or T-DXd) for people with breast cancer. Enhertu is a type of that was developed to treat breast cancer. Participants whose cancer was previously labeled as and who received Enhertu had better outcomes than people with breast cancer who received standard chemotherapy. These results challenge prior thinking that cancers are either or and reclassify the tumor marker into a third possible result called HER2-low that can guide treatment for breast cancer. These results offer a new treatment option for many people with hard-to-treat breast cancers.

Update: On 08/05/2022 the approved Enhertu to treat people with , HER2-low breast cancer who have received prior chemotherapy in the setting or who developed disease recurrence during or within six months of completing chemotherapy.

What is and how is it tested?

is a protein found on all breast cells. It controls how the cells grow and divide. When breast cells have too much , cells can multiply too quickly. Growth may then become uncontrolled and lead to cancer.

Pathologists use a to measure the amount of protein on the surface of tumor cells. scores range from 0 to 3+ (3 or higher). In the past, a tumor with a score of 0 to 1+ was called HER2-negative; a score of 2+ was considered borderline, while a score of 3+ was considered . Updated scores and associated results are shown in the table below.

Results of a test for status:

Score is 0 Tumor is
Score is 1+ or 2+ Tumor is HER2-low
Score is 3+ Tumor is

HER2 scores have long been used to guide treatment decisions. Treatment for people with breast cancer almost always includes drugs that target (often called “anti-HER2 therapy”). Several drugs specifically target breast cancer cells, including Herceptin (trastuzumab), Perjeta (pertuzumab), Tukysa (tucatinib) and Phesgo (pertuzumab, trastuzumab and hyaluronidase).

What is trastuzumab deruxtecan?

Trastuzumab deruxtecan (Enhertu or T-DXd) is related to the drug trastuzumab (Herceptin), which has been used to treat breast cancer since the late 1990s. Enhertu is an antibody-drug conjugate, a type of combination drug—trastuzumab combined with chemotherapy—for more powerful cancer-fighting action. Enhertu finds and directly delivers chemotherapy to cells with . Enhertu was first approved to treat metastatic breast cancer in 2019. Currently, it is one of three antibody-drug conjugates used to treat breast cancer.

Why is this study important?

The results of this study offer an immediate new treatment option for some people with metastatic breast cancers. Doctors look for the presence of the protein in breast cancer cells to guide treatment. In the past, people with breast cancer were considered if they had a “ score” of 3 or more. Cancers scored below 3 were called . This study demonstrates for the first time that an anti-HER2 drug can be effective against breast cancers with scores of 1 or 2.

These results will change standard practice regarding testing for breast cancer. They are relevant to both hormone receptor-positive (HR+) and hormone receptor-negative (HR-) breast cancers.

Study findings

The DESTINY-Breast04 phase 3 clinical trial tested the anti-HER2 drug trastuzumab deruxtecan (Enhertu or T-DXd) in people with previously treated HER2-low breast cancer. Doctors enrolled 557 people with breast cancer. Of these, 493 had hormone receptor-positive breast cancer and 63 had hormone receptor-negative breast cancer.

The participants had HER2-low cancers. HER2-low was defined as a score of 1+ or 2+ on a for levels. Everyone in the study had been previously treated with chemotherapy. The HR+ group had also tried at least one endocrine (hormone) therapy. Nearly 90 percent of participants had tried at least two lines of prior therapy. Most had tried three or more treatments.

Participants were placed into two groups. One group received the antibody conjugate anti-HER2 drug Enhertu. The other group received the chemotherapy chosen by their doctor—either capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel.

The study looked at the time during which cancer did not grow or spread (known as progression-free survival) and how long participants lived (known as overall survival). Enhertu was more effective than chemotherapy, improving both progression-free and overall survival. Across groups, people who took Enhertu did better, as shown by these data:

  Time Without Progression Overall Survival
Group Enhertu group Chemo group Enhertu group Chemo Group
All participants 9.9 months 5.1 months 23.4 months 16.8 months
People with HR+ Breast Cancer 10.1 months 5.4 months 23.9 months 17.5 months
People with HR-Negative Breast Cancer 8.5 months 2.9 months 18.2 months 8.3 months


The median time of treatment was 8.2 months for people in the Enhertu group and 3.5 months in the chemotherapy group. Nearly all participants in the trial experienced at least one side effect related to the therapies.

The most common side effects associated with Enhertu were nausea, fatigue and hair loss. They occurred more often in the Enhertu group than in the chemotherapy group. People taking Enhertu also experienced low blood cell counts, a common side effect of many cancer treatments.

Lung problems are a serious possible side effect of Enhertu; 12.1 percent of those in the Enhertu arm of the study developed lung disease. The median time to onset was around four months after starting treatment but ranged from 26 days to 710 days.

Strengths and limitations


  • The trial included people with hormone receptor-positive and hormone receptor-negative breast cancer.
  • All testing was done by the same lab to eliminate variations in testing.
  • The number of people with hormone receptor-negative breast cancer in the trial was small but still considered sufficient to yield results.
  • The study followed participants for progression-free survival and overall survival. The research team also gathered information on the side effects experienced by both groups.


  • The trial mostly included non-Hispanic white and Asian people with few Black or Latino participants. it is unclear whether Black or Latino people with breast cancer would similarly benefit.
  • The number of people with hormone receptor-negative breast cancer was small (see “Strengths”).


This study changes treatment guidelines for people with breast cancer. The results offer a new treatment option for many people who were previously told they have metastatic breast cancer and were not candidates for anti-HER2 targeted therapies.

What does this mean for me?

Enhertu is the first drug that effectively targets breast cancers with low scores. If you have previously been told you had or triple-negative breast cancer, this study may be immediately useful for you. It offers a new treatment option for some cancers that were previously identified as . The results apply to people with hormone receptor-positive or receptor-negative breast cancer, including those with .

As a next step, ask your doctor about the testing you had at diagnosis and whether Enhertu might be an option for you. Cancers with scores of 1+ or 2+ may respond to this drug. Depending on the kind of testing you previously had, you may need another test to confirm your score.


Modi S, Jacot W, Yamashita J, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. The New England Journal of Medicine 2022; 387: 9-20. Published online July 7, 2022.

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.


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posted 7/18/22

This article is relevant for:

People with HER2-low metastatic breast cancer

This article is also relevant for:

people with breast cancer

people with metastatic or advanced cancer

people with triple negative breast cancer

people with ER/PR + cancer

Be part of XRAY:

Expert Guidelines
Expert Guidelines

The National Comprehensive Cancer Network (NCCN) guidelines for treatment of advanced or HER2-low breast cancer list trastuzumab deruxtecan (Enhertu) as a preferred treatment for people who have tumors that are HER2-low ( 1+ or 2+), received chemotherapy in the setting and whose cancer no longer responds to hormonal therapy.

Updated: 07/21/2022

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • Was my tumor tested for using a test that measures HER2-low? If yes, what was the score? If not, can it be tested now?
  • Is Enhertu an option for me?
  • What are the risks and benefits associated with Enhertu?
  • Will my insurance cover the cost of additional testing and Enhertu?

Peer Support
Peer Support

The following organizations offer peer support services for people with, or at high risk for breast cancer:

Updated: 05/07/2024

Who covered this study?

U.S. News and World Report

New treatments battle advanced breast cancers This article rates 4.5 out of 5 stars

ABC News

Researchers: Breast cancer drug could help more patients This article rates 3.5 out of 5 stars

New York Times

Breast cancer drug trial results in “unheard-of” survival This article rates 3.0 out of 5 stars

How we rated the media

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