Breast cancer is a complex disease classified by various molecular characteristics. One of the primary identifiers is the status of the human epidermal growth factor receptor 2, or HER2. For many years, tumors were categorized as either HER2-positive or HER2-negative, a distinction that directed the course of treatment. Recently, a more nuanced classification known as HER2-low has been recognized, reshaping how oncologists approach therapy for a large group of patients.
Understanding the HER2 Spectrum
The HER2 protein is a receptor found on the surface of cells that helps regulate cell growth and division. In some breast cancers, these receptors are overexpressed, meaning there are far more of them than usual, which can fuel the rapid and uncontrolled growth of cancer cells. This understanding led to a binary classification system based on the quantity of HER2 protein on a tumor’s cells.
This system defines a spectrum of HER2 expression. HER2-positive breast cancer is characterized by a high density of HER2 receptors, while HER2-negative has little to no detectable HER2 protein. Between these two lies HER2-low, a classification for tumors that have some HER2 proteins, but not enough to be considered HER2-positive.
Until recently, HER2-low tumors were managed the same as HER2-negative tumors, so treatments targeting the HER2 protein were not considered an option. The recognition of HER2-low as a distinct subtype, representing an estimated 50-60% of all breast cancers, has been a major development.
Diagnosing HER2-Low Status
Determining a tumor’s HER2 status begins after a biopsy, when a tissue sample is sent to a pathology lab for analysis. The primary method used is a test called immunohistochemistry, or IHC. This technique uses antibodies that bind to the HER2 protein on cancer cells, and a chemical dye makes them visible under a microscope.
Pathologists evaluate the results of the IHC test using a scoring system that quantifies the amount of HER2 protein present. A score of 0 indicates that no HER2 protein was detected, and these tumors are classified as HER2-negative. Scores of 1+ or 2+ signify some HER2 protein, while a score of 3+ indicates a high level of HER2 protein, confirming a HER2-positive diagnosis.
Tumors that return an IHC score of 1+ are categorized as HER2-low. A score of 2+ is considered equivocal or borderline, requiring further testing for a final determination. This follow-up test, known as fluorescence in situ hybridization (FISH), provides a more precise measurement.
The FISH test works at the genetic level, counting the HER2 genes inside the cancer cells. If the FISH test shows extra copies of the gene, the cancer is classified as HER2-positive. If the gene count is normal despite the IHC 2+ protein score, the tumor is designated as HER2-low.
Targeted Therapies for HER2-Low Tumors
The distinction of HER2-low status is meaningful due to the development of drugs known as antibody-drug conjugates (ADCs). These medications function like a biological “smart bomb,” delivering chemotherapy directly to cancer cells while largely sparing healthy tissues. This targeted approach is possible because the ADC has two main components: an antibody and a chemotherapy payload.
The antibody component is engineered to bind to the HER2 protein on the surface of the tumor cell. Even the small number of HER2 receptors present on HER2-low cells is sufficient for the antibody to latch onto. Once attached, the cancer cell absorbs the ADC, bringing the chemotherapy agent inside. The drug is then released, killing the cancer cell from within.
A drug that has changed the treatment for this patient group is trastuzumab deruxtecan. This ADC links trastuzumab, an antibody that targets the HER2 receptor, to deruxtecan, a chemotherapy drug. Clinical trials have shown this drug to be effective in patients with metastatic HER2-low breast cancer that has progressed after other treatments.
This targeted delivery system makes the HER2-low classification important. It allows oncologists to use an anti-cancer drug in a population that was previously ineligible for HER2-targeted treatments. For patients whose cancer is also hormone receptor-positive, other therapies like endocrine therapy may still be part of the overall treatment plan, but the ADC represents a new tool for their tumor type.
Patient Prognosis and Outlook
Historically, the prognosis for patients with HER2-low breast cancer was similar to that for patients with HER2-negative disease, as they received the same treatments. The outlook was largely dependent on other factors, such as the cancer’s stage and hormone receptor status.
The arrival of ADCs has altered this landscape, particularly for patients with metastatic disease. Clinical trial data has demonstrated that treatments like trastuzumab deruxtecan can lead to improvements in progression-free survival, meaning patients live longer without their cancer growing or spreading. The risk of disease progression was found to be about 50% lower in patients treated with the ADC compared to standard chemotherapy.
This has created new avenues of treatment for a large patient population that previously had fewer options once their disease became resistant to initial therapies. The ability to now specifically target the low levels of HER2 protein has turned what was once a simple negative classification into an opportunity for personalized therapy. This shift offers a new strategy in the management of advanced breast cancer.