HER2-Positive Breast Cancer: Testing, Treatment, and Research

Learn more about HER2-positive breast cancer treatment, survival rates, and research advancements funded by the Breast Cancer Research Foundation

Breast cancer is not a single disease but a group of diseases. Understanding the subtypes of breast cancer is essential for making effective treatment decisions—and for accelerating research.

Scientists discovered human epidermal growth factor receptor 2 (HER2)-positive breast cancer when searching for genes that cause cancer. On the most basic level, cancer is the result of normal cells growing unchecked, an observation that led researchers to speculate that specific genes or gene mutations enable this to occur. In the 1980s, they identified a link between the HER2 gene and cancer formation, specifically demonstrating that a mutation in the HER2 gene stimulated cells to grow and divide excessively. So, they wondered if this particular gene could cause cancer.

Two independent teams led by Dr. Dennis J. Slamon and former Breast Cancer Research Foundation (BCRF) investigator Dr. Stuart Aaronson showed that the HER2 gene and its protein product (HER2 protein) could cause normal cells to grow uncontrollably like cancer cells. And Dr. Slamon and his colleagues estimated that HER2 protein is overexpressed in 25 to 30% of breast cancers.

These researchers and the many who followed realized that identifying drivers of breast cancer growth could lead to targeted therapies for patients. Their foundational studies helped define HER2-positive breast cancer as a distinct type of breast cancer and opened the door for years of research to find effective, precise therapies to treat it. Without these advances, HER2-positive breast cancer would have remained an aggressive breast cancer with very poor patient outcomes. Instead, our success treating this form today is seen as a crowning achievement in breast cancer research.

What is the HER2 protein?

To understand what HER2-positive breast cancer is, it’s important to first know what HER2 is and how it functions. Genes are portions of DNA with instructions for a cell to make specific proteins. The HER2 gene tells the cells to make HER2 protein, a receptor that sits on the cell surface and relays signals to the internal cellular machinery.

In the case of breast cells, the HER2 protein facilitates their normal growth and repair. But in some cases, the HER2 gene doesn’t function properly and signals to breast cells to keep growing. This uncontrollable growth leads to tumor formation. The gene’s normal function may be altered if it produces too many copies of itself (a process known as gene amplification) or too many copies of HER2 receptors (overexpression). A mutation in the HER2 gene can also cause its amplification and subsequent overexpression of HER2 receptors. HER2 gene amplification, protein overexpression, or both may cause breast cells to form HER2-positive breast cancer.

What does HER2-positive breast cancer mean?

HER2-positive breast cancer means the cancer cells have too much HER2 protein or extra copies of the HER2 gene, which can cause the cancer to grow more quickly but may make it responsive to treatments that target HER2 specifically.

During a diagnostic workup, doctors use a series of tests on biopsy samples to screen for gene abnormalities or the presence of certain proteins. For example, biopsy samples are tested for the presence of targetable hormone receptors (estrogen or progesterone) and the HER2 protein. From these tests, they can determine what subtype of breast cancer a person has; in this case, HER2-positive breast cancer when HER2 amplification or overexpression is present.

This classification helps guide treatment decisions based on how the cancer behaves biologically.

What’s the difference between HER2-negative and HER2-positive?

HER2-positive breast cancer has high levels of the HER2 protein or extra copies of the HER2 gene, which can drive faster tumor growth. HER2-negative breast cancer does not have high levels of the HER2 protein or extra copies of the HER2 gene.

Doctors determine HER2 status using tests on a biopsy sample. Immunohistochemistry (IHC) uses a dye that attaches to HER2 proteins, allowing a pathologist to assign a value (0 to 3+) based on the amount of dye/HER2 is present.  Fluorescence in situ hybridization (FISH) uses a more sensitive fluorescent dye to indicate gene amplification or the presence of extra copies of HER2.

This distinction matters because it helps guide treatment. HER2-positive cancers are often treated with therapies designed to block the HER2 protein and slow cancer growth. HER2-negative cancers are less likely to respond to these therapies, so doctors rely on other targeted therapies or treatment combinations depending on the tumor’s other features.

There’s also an important middle category: HER2-low or -ultralow breast cancer. These tumors don’t have enough HER2 to be considered HER2-positive, but they aren’t completely negative either. Newer treatments have shown that some people with HER2-low or -ultralow disease may still benefit from HER2-targeted therapies. This group makes up a significant portion of breast cancer cases—roughly 55%—which is changing how researchers think about testing and treatment.

HER2-positive breast cancer treatment

As investigators began the search for ways to target HER2-positive breast cancer, HER2 proved to be a highly sensitive target—leading to major breakthroughs to effectively treat this aggressive subtype. Since HER2-positive breast cancer is dependent on HER2 gene amplification or overexpression, researchers wanted a way to stop the HER2 protein from exerting its effect on the breast cancer cells. They developed and tested monoclonal antibodies that could recognize and bind to the HER2 protein and hinder its effect on cell growth.

Researchers, including several BCRF investigators, conducted clinical trials to test the monoclonal antibody trastuzumab (Herceptin^®) for HER2-positive breast cancer. Herceptin was FDA approved in combination with chemotherapy for HER2-positive metastatic breast cancer treatment in 1998 and for adjuvant (after surgery) HER2-positive breast cancer treatment in 2006. Today it remains a standard of care worldwide.

In the decades that followed Herceptin approval, researchers developed other HER2-targeted therapies.

HER2-targeted antibodies

These include other HER2-specific antibodies:

• Pertuzumab (Perjeta^®) was FDA approved in 2012 (in the metastatic setting) and 2017 (for adjuvant therapy) in combination with Herceptin and docetaxel.
• Margetuximab (Margenza^®) in combination with chemotherapy was approved in 2020 for use in patients with metastatic HER2-positive breast cancer who have received prior treatments with other HER2-targeted therapies.

Tyrosine kinase inhibitors (TKIs)

Drugs to target HER2 were also developed for HER2-positive breast cancer treatment. Called tyrosine kinase inhibitors (TKIs), these agents bind to HER2 receptors on the cancer cell surface, thereby blocking the receptor signals that tell breast cancer cells to keep growing:

• Lapatinib (Tykerb^®) received FDA approval in 2007 for HER2-positive breast cancer treatment in patients already treated with capecitabine (chemotherapy). Additional accelerated approval was granted in 2010 for post-menopausal women with HR-positive/HER2-positive metastatic breast cancer.
• Neratinib (Nerlynx^®) was approved in 2017 for extended adjuvant treatment of adults with early-stage HER2-positive breast cancer following Herceptin-based therapy. In late 2020, it was also FDA-approved for metastatic HER2-positive breast cancer treatment.
• Tucatinib (Tukysa^®) received FDA approval in 2020 in combination with Herceptin and chemotherapy (capecitabine) for treating HER2-positive metastatic breast cancer that can’t be removed with surgery (unresectable), or that has spread to other parts of the body. Patients also had to have received one or more prior treatments. This was based on a clinical trial led by BCRF investigator Dr. Nancy Lin. Importantly, tucatinib was the first small-molecule inhibitor shown to be effective in patients with brain metastases, which are unfortunately difficult to treat.

Antibody-drug conjugates and emerging HER2-directed treatments

As technology improved, researchers found ways to engineer antibody-drug conjugates (ADCs) that are composed of a HER2-specific antibody linked to a potent drug. These ADCs leverage the recognition power of antibodies that can bind to the HER2 protein on breast cancer cells. Once bound, the antibody and the linked drug are both pulled into the cell, delivering a toxic payload that maximizes the damage to cancer cells while sparing healthy normal cells:

• Ado-trastuzumab emtansine (T-DM1/Kadcyla^®) was FDA approved in 2013 for the treatment of adults with HER2-positive metastatic breast cancer who previously received Herceptin and a taxane, separately or in combination. In 2019, it was further approved for adjuvant treatment in those patients who have residual disease after neoadjuvant taxane and Herceptin-based treatment.
• Trastuzumab deruxtecan (T-DXd/Enhertu^®) received FDA approval in 2019 for treating adults with HER2-positive breast cancer that is metastatic or unresectable and who have received two or more prior HER2-targeted therapies. In 2022, further approval was granted to include patients who received prior HER2-therapies either in the metastatic, neoadjuvant, or adjuvant setting and have recurrences within six months of completing therapy. Notably, T-DXd demonstrated efficacy in patients with HER2-low and -ultralow breast cancer, helping to characterize a subset of patients that could benefit from this and potentially other HER2-targeted therapies.

Researchers have shown that the PI3K/AKT/PTEN cell signaling pathway is important for regulating multiple processes. And some breast cancers harbor alterations in this pathway that allow them to grow uncontrollably. Building on these findings, they developed therapies to inhibit this pathway. The drug capivasertib (Trupaq^®) emerged from these investigations and, in 2023, was FDA-approved as the first-in-class AKT inhibitor for treating HER2-low breast cancers. This was based on the CAPItello-291 clinical trial involving several BCRF investigators.

Although significant progress has been made in HER2-positive breast cancer treatment, resistance to therapies can develop over time, and tumors may recur. Extensive research continues to refine and improve existing HER2-targeted therapies, explore ways to prevent recurrence, and devise new ways to target the sensitive HER2 protein.

Currently, there are over 10 ADCs and more than four TKIs in development. ADCs that can stimulate a patient’s immune system to attack HER2-positive breast cancer cells are another avenue being exploited to increase the arsenal of treatments for HER2-positive breast cancer.

Other technologies are also being tested as possible strategies for preventing or treating HER2-positive breast cancer, including 19 agents called bispecific antibodies, constructs called engineered toxin bodies, and 13 HER2-targeting vaccines.

Today, advances in targeted therapy have transformed HER2-positive breast cancer into one of the most precisely treatable subtypes despite its biological aggressiveness. A combination of targeted therapies, chemotherapy, and newer antibody-drug conjugates has dramatically improved outcomes, with ongoing research continuing to refine how and when these treatments are used to achieve the best possible results for patients.

HER2-positive breast cancer survival rates and statistics

Breast cancer is the most common cancer in women in the U.S., and HER2-positive breast cancer accounts for about 20% of all breast cancer diagnoses (in 2026, that’s 321,910 women and 2,670 men who will be diagnosed). HER2-low breast cancers, which express low levels of HER2, represent an additional 55% of all breast cancer cases.

HER2-positive breast cancer is aggressive and fast-growing and was previously associated with poor outcomes and higher mortality rates than other breast cancer subtypes. With the development of HER2-targeted agents, though, HER2-positive breast cancer is now a treatable disease—and outcomes have dramatically improved for these patients.

Currently, survival rates exceed 90% in HER2-positive breast cancer that is diagnosed early and treated with chemotherapy and dual antibody therapy. However, five-year survival rates vary by hormone receptor (HR) status and differ based on the location of the cancer at diagnosis, with better outcomes observed for localized (confined to the breast) compared to regional (near the breast) or distant (metastatic) HER2-positive breast cancer.

HER2-positive	Localized	Regional	Distant
HR-positive	100	90	32
HR-negative	77	66	12

BCRF’s HER2-positive breast cancer research

BCRF funds the best and brightest minds in the breast cancer research field, including those advancing our understanding of HER2-positive breast cancer. BCRF-supported research covers a range of topics regarding this subtype:

• Developing ways to better predict prognosis and improve outcomes for patients with HER2-positive breast cancer
• Refining current biomarkers used to define HER2-positive breast cancer and assessing how they vary between patients, during tumor progression and metastasis within a single tumor, and throughout therapy
• Developing a more precise test to measure HER2-low levels so that more patients can benefit from HER2-targeted therapies
• Improving HER2-targeted therapies with a particular focus on how immune cells in the HER2-positive breast tumor microenvironment influence a tumor’s response to treatment
• Testing the clinical and immunologic activity of a novel anti-HER2 antibody therapy in early-stage, HER2-positive breast cancer
• Understanding what drives treatment response and resistance in patients with HER2-positive breast cancer

BCRF researchers are also seeking to gain a better understanding of the metastatic process, including in HER2-positive breast cancer. While studies have already revealed that in patients with HER2-positive breast cancer, some metastases can be prevented with existing HER2-targeted treatments, many areas of investigation remain:

• Identifying and treating drivers of resistance in advanced HR-positive/HER2-positive breast cancers
• Focusing on how the tumor interacts with nearby immune cells to influence HER2-positive metastatic breast cancer formation
• Developing complex HER2-positive metastatic breast cancer models to test the next generation of cancer immunotherapies and predict tumor response to therapy
• Conducting a clinical trial in patients with HR-positive/HER2-enriched metastatic breast cancer to see if androgen receptor-inhibiting drugs can improve treatment response in these patients. HER2-enriched is molecular subtype of breast cancer and not the same as HER2-positive.

We have come a long way from those foundational studies that first revealed how the HER2 gene and protein play a role in breast cancer development. Long considered aggressive breast cancer with poor prognosis, thanks to research, HER2-positive breast cancer is now treatable with myriad different agents. Research has already helped countless patients with HER2-positive breast cancer have better outcomes, but investigators are still striving to improve survival outcomes and treatments for all of these patients.

Advancing hope through HER2-positive breast cancer research

Every advance in HER2-positive breast cancer treatment—from targeted therapies to next-generation antibody-drug conjugates—has been made possible through sustained scientific discovery and research funding. What was once considered one of the most aggressive breast cancer subtypes is now highly treatable for many patients, and outcomes continue to improve.

This progress is not accidental. It comes from decades of dedicated research supported by organizations like BCRF, and from continued investment in understanding how HER2-driven cancers grow, spread, and respond to treatment.

If you want to help accelerate the next breakthroughs in HER2-positive breast cancer research, you can support this work by donating, starting a fundraiser, or exploring more ways to give today.

Frequently Asked Questions

What does a HER2-positive diagnosis mean for treatment decisions?

A HER2-positive diagnosis means the cancer is driven in part by excess HER2 protein or gene amplification, which makes it more likely to respond to HER2-targeted therapies. In practice, HER2-positivity directly guides treatment planning, as doctors typically include HER2-targeted drugs alongside other treatments. It also helps determine the combination and sequencing of therapies used for each patient.

What is the difference between HER2-positive and HER2-low breast cancer?

HER2-positive breast cancer has high levels of HER2 protein or clear gene amplification, which makes it responsive to established HER2-targeted therapies. HER2-low breast cancer has lower levels of HER2 expression that were historically not considered actionable, but newer treatments—such as antibody-drug conjugates—have shown benefit in some patients with this subtype. This distinction is an evolving area of breast cancer research.

What are the side effects of HER2-targeted therapies?

Side effects vary depending on the specific drug used, but may include fatigue, nausea, diarrhea, and lowered blood counts, especially when combined with chemotherapy. Some HER2-targeted treatments can also affect heart function, so cardiac monitoring is often part of care. Most side effects are manageable, and treatment plans are adjusted to balance effectiveness with quality of life.

Can HER2-positive breast cancer become HER2-negative over time?

Yes, in some cases, HER2 status can change as the disease evolves or after treatment, meaning a tumor may later test as HER2-negative or show reduced HER2 expression. This can occur due to tumor heterogeneity or selective pressure from therapy. Because of this, doctors may re-test metastatic or recurrent disease to ensure treatment decisions remain appropriate.

Selected References

1.  HER2 Genetic Link to Breast Cancer. (2018, April 11). National Cancer Institute. https://www.cancer.gov/research/progress/discovery/her2

2.  Di Fiore, P. P., Pierce, J. R., Kraus, M. H., Segatto, O., King, C. R., & Aaronson, S. A. (1987, July 10). erb B-2 Is a Potent Oncogene When Overexpressed in NIH/3T3 Cells. Science; American Association for the Advancement of Science. https://doi.org/10.1126/science.2885917

3.  Female Breast Cancer Subtypes – Cancer Stat Facts. (n.d.). SEER. https://seer.cancer.gov/statfacts/html/breast-subtypes.html

4. Moutafi, M., Robbins, C. T., Yaghoobi, V., Fernandez, A., Martinez-Morilla, S., Xirou, V., Bai, Y., Song, Y., Gaule, P., Krueger, J. S., Bloom, K., Hill, S., Liebler, D. C., Fulton, R., & Rimm, D. L. (2022). Quantitative measurement of HER2 expression to subclassify ERBB2 unamplified breast cancer. Laboratory Investigation, 102(10), 1101–1108.

5.  Swain, S. M., Shastry, M., & Hamilton, E. (2022, November 7). Targeting HER2-positive breast cancer: advances and future directions. Nature Reviews Drug Discovery; Nature Portfolio. https://doi.org/10.1038/s41573-022-00579-0