Breast cancer is a complex and varied disease, which is why it’s classified into different subtypes based on specific characteristics of the cancer cells. One of the most important factors used to classify breast cancer is the HER2 status (Human Epidermal Growth Factor Receptor 2), which plays a significant role in determining the aggressiveness of the cancer and guiding treatment decisions. Traditionally, breast cancer has been divided into two HER2 categories: HER2-positive and HER2-negative. However, advancements in research have introduced a third category: HER2-low, which changes the way we think about HER2-negative breast cancer.

What Is HER2 and Why Is It Important?

HER2 is a protein found on the surface of breast cells that promotes cell growth. In some breast cancers, there is an overexpression of the HER2 protein due to the amplification of the HER2 gene. When this happens, the cancer cells grow and divide more rapidly, leading to a more aggressive form of cancer known as HER2-positive breast cancer.

HER2 status is critical because it guides treatment. Historically, people with HER2-positive breast cancer are treated with targeted therapies such as trastuzumab (Herceptin), pertuzumab (Perjeta), and others, which specifically attack HER2 receptors, improving outcomes significantly.

But what about those classified as HER2-negative? The landscape has shifted in recent years.

HER2-Positive vs. HER2-Negative: The Traditional Classification

For a long time, HER2 status was binary:

• HER2-positive breast cancer: These cancers have a large number of HER2 receptors on their cells. This makes them more aggressive but also more responsive to HER2-targeted therapies.
• HER2-negative breast cancer: These cancers have little to no HER2 protein on the surface of their cells and therefore do not benefit from HER2-targeted therapies.

However, this simplistic classification left a gap for those patients whose cancers fell between these two extremes. New research has led to the discovery of the HER2-low category, a middle ground that represents a significant portion of what was once considered HER2-negative.

What Is HER2-Low Breast Cancer?

HER2-low breast cancer refers to cases where the cancer cells express low levels of HER2 protein, but not enough to be classified as HER2-positive. This new classification typically includes patients with immunohistochemistry (IHC) scores of 1+ or 2+ (with no amplification on further testing). To put it simply:

• HER2-positive: IHC score of 3+ or confirmed HER2 gene amplification.
• HER2-low: IHC score of 1+ or 2+ (without amplification).
• HER2-negative: IHC score of 0.

About 60% of breast cancers previously classified as HER2-negative now fall into the HER2-low category. This reclassification opens up new treatment possibilities for a significant group of patients who were previously ineligible for HER2-targeted therapies.

Why Is HER2-Low Significant?

The recognition of HER2-low breast cancer is important for several reasons:

1. More Refined Diagnosis: By dividing HER2-negative into two groups (HER2-low and true HER2-negative), oncologists can now offer a more precise diagnosis and treatment plan tailored to the patient’s specific cancer subtype.

2. New Treatment Options: Recent advancements in targeted therapies, such as the drug trastuzumab deruxtecan (Enhertu), have shown promise in treating HER2-low breast cancer. Enhertu, an antibody-drug conjugate, delivers chemotherapy directly to cancer cells expressing low levels of HER2. This is a breakthrough for HER2-low patients, who previously had limited targeted treatment options.

3. Impact on Hormone Receptor-Positive and Triple-Negative Breast Cancers: Many HER2-low breast cancers are also hormone receptor-positive (HR-positive), meaning they rely on hormones like estrogen or progesterone to grow. These cancers may respond to both hormone therapies and new HER2-low treatments. Additionally, some triple-negative breast cancers (TNBC)—which are notoriously difficult to treat—fall into the HER2-low category, offering new avenues for treatment that weren’t available before.

Who Is Affected by HER2-Low Breast Cancer?

HER2-low breast cancer affects a wide range of patients, but it is more commonly found in people with:

• Hormone receptor-positive (HR-positive) breast cancer: Many of these tumors express low levels of HER2, even though they were previously considered HER2-negative.
• Older patients: As research continues, it’s becoming clear that HER2-low breast cancer is more prevalent in certain age groups and may respond differently to treatment than other subtypes.
• Triple-negative breast cancer (TNBC): Although TNBC is usually aggressive and doesn’t express HER2 or hormone receptors, a small percentage of TNBC cases are now reclassified as HER2-low.

Treatment Options for HER2-Low Breast Cancer

For people diagnosed with HER2-low breast cancer, the discovery of their status can significantly influence their treatment options. Traditionally, they would not have been eligible for HER2-targeted therapies. However, with new therapies being developed, particularly antibody-drug conjugates (ADCs) like Enhertu, treatment strategies are evolving.

Here’s a breakdown of potential treatments for HER2-low breast cancer:

1. Hormone Therapy: For those who are also hormone receptor-positive, treatments like tamoxifen or aromatase inhibitors are still widely used. However, combining these with HER2-low-targeted therapies may yield better outcomes.

2. Chemotherapy: Many patients with HER2-low breast cancer will still require chemotherapy, particularly those with higher-stage or more aggressive tumors.

3. Targeted Therapies: New targeted therapies, especially antibody-drug conjugates (ADCs), offer hope for HER2-low patients. These drugs are designed to target the HER2 protein on cancer cells, even at lower levels, while delivering chemotherapy directly to the cancer cells.

4. Immunotherapy: For certain HER2-low patients, particularly those with triple-negative breast cancer, immunotherapy may be an option in combination with chemotherapy.

The classification of HER2-low breast cancer is still relatively new, and ongoing research will likely continue to refine our understanding of this subtype. Clinical trials are underway to evaluate the efficacy of additional HER2-targeted therapies for HER2-low patients, as well as the role of combination therapies involving hormone therapy, chemotherapy, and immunotherapy.

Additionally, the evolving landscape of breast cancer treatment emphasizes the importance of precision medicine—an approach that tailors treatment to the specific characteristics of an individual’s cancer.

The discovery and recognition of HER2-low breast cancer represents a major step forward in the personalization of breast cancer treatment. This new classification offers hope for thousands of patients who may benefit from emerging therapies that target HER2 at lower levels. As the science progresses, it’s important for patients to be aware of their HER2 status and discuss all available treatment options with their healthcare team.

HER2-low breast cancer shows us that even as we make advances in understanding cancer, there is still so much more to uncover. Every new discovery brings us closer to more effective, tailored treatments that can improve outcomes for patients around the world.