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 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 percent of breast cancers.
These researchers and the many that 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.
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.
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, which gives doctors important information for making treatment decisions. Those with HER2 gene amplification or HER2 receptor overexpression are called HER2-positive breast cancer.
Currently, biopsy samples can undergo two tests to determine HER2 status: immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). IHC uses a chemical dye that attaches to HER2 proteins, allowing a pathologist to assign a value (0 to 3+) based on the amount of dye present. The less-widely available FISH test measures HER2 gene amplification. It is more sensitive than IHC and utilizes a fluorescent marker that binds to HER2 proteins, allowing pathologists to detect HER2 presence using a fluorescence microscope.
Once it’s been determined whether a breast cancer is HER2-positive or HER2-negative, doctors can choose an appropriate treatment strategy. Patients whose biopsies are HER2-positive would likely benefit greatly from a HER2-directed treatment regimen. Since the first targeted therapy for HER2-positive breast cancer was approved in the late 1990s (see the next section to learn more), several more therapies have been developed that specifically target HER2 on cancer cells, killing them with minimal harm to healthy cells. In contrast, HER2-negative breast cancers would not likely respond to HER2-targeted agents and would require an alternate treatment plan that doesn’t involve these therapies.
It is important to note that HER2-negative breast cancers that are IHC 1+ or 2+ without amplification, are not actually completely devoid of HER2—they simply don’t have enough receptor to respond to current HER2 targeted therapies. These breast cancers are now identified as a subset of breast cancers called HER2-low, following recent clinical trials that tested a new HER2-targeted therapy (see below section on treatments).
Patients with HER2-low breast cancer—which represents roughly 55 percent of breast cancers—may respond to certain HER2-targeted treatments. This illustrates the need for more sensitive testing to accurately define the minimum level of HER2 needed for a response so that more patients can benefit.
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 (1998) and for adjuvant (after surgery) HER2-positive breast cancer treatment (2006). Today it remains a standard of care worldwide.
In the decades that followed Herceptin® approval, researchers developed other HER2-targeted therapies.
These include other HER2-specific antibodies:
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:
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 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: damage:
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.
Breast cancer is the most common cancer in women in the U.S., and HER2-positive breast cancer accounts for about 20 percent of all breast cancer diagnoses (in 2023, that’s 297,790 women and 2,800 men who will be diagnosed). HER2-low breast cancers, which express low levels of HER2, represent an additional 55 percent 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, HER2-positive breast cancer is now a treatable disease and outcomes have dramatically improved for these patients.
Currently, survival rates exceed 90 percent 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.
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:
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:
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 a myriad of 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.
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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
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