What Is HER2-Low Breast Cancer?
A classification allowing for targeted treatment options
FG Trade / Getty Images
Medically reviewed by Archana Sharma, DO, FAAP
HER2 (human epidermal growth factor receptor 2) is a protein that controls the growth and survival of normal, healthy cells. Some cancers, including breast, can make HER2 in higher-than-normal amounts.
Breast cancers that make higher-than-normal amounts of HER2 are considered HER2-positive, whereas breast cancers that make a tiny amount or no HER2 protein are HER2-negative.
HER2-low describes a novel subtype of breast cancer that makes some HER2 protein but not enough to be classified as HER2-positive.
This article highlights the symptoms, diagnosis, and targeted treatment of HER2-low breast cancer, which accounts for around 50% of all breast cancer cases.
What Does HER2-Low Mean?
When diagnosed with invasive or metastatic breast cancer, the HER2 status of the tumor (mass of rapidly dividing cells) will be determined, ultimately guiding treatment decisions.
Invasive breast cancer means the cancer cells have spread to surrounding tissue, whereas metastatic breast cancer has spread to distant parts of the body (e.g., the bones or brain).
HER2-low describes a breast cancer subtype "in between" HER2-positive and HER2-negative. The cancer cells have some HER2 protein on their surfaces but not enough to be considered HER2-positive.
In the past, HER2-low breast cancers were classified and treated as HER2-negative breast cancers because there was insufficient HER2 protein for HER2-targeting drugs to be effective.
However, a HER2-targeted therapy approved in 2022 is effective against HER2-low breast cancer. This offers hope and perhaps more time for people who have exhausted other treatment options.
Besides HER2 status, several other factors are considered when devising a personalized breast cancer treatment plan. Some of these factors include:
Cancer stage (spread and amount of cancer in the body)
Hormone receptor status (whether the tumor has proteins that the hormones estrogen and/or progesterone can attach to and stimulate growth, noted as ER+, ER-, PR+, PR-)
Presence of genetic mutations (e.g., BRCA1 and BRCA2)
Preference of the person treated and their menopausal status
Related: Genetic Testing for Breast Cancer
Symptoms of HER2-Low Breast Cancer
The symptoms of HER2-low breast cancer are the same as those of HER-2-positive and HER2-negative breast cancer.
The main distinction among the HER2 subtypes is that HER2-positive breast cancers tend to be the most aggressive. The excess HER2 protein on the cancer cells' surfaces makes the tumor rapidly grow and spread (metastasize). HER2-positive breast cancers are also more likely to recur.
HER2-low breast cancer symptoms include:
Breast cancer lump or mass (most common first symptom)
Partial or complete breast swelling
Breast or nipple pain or skin changes (e.g., dimpling, reddening, flaking, or thickening)
Nipple discharge that is clear or bloody
Nipple turning inward
Swollen lymph nodes in your armpit or near your collarbone
Related: When to Worry About a Breast Lump
At the time of diagnosis, between 5% and 8% of all people with breast cancer see a healthcare provider for symptoms of metastasis. The most common sites of breast cancer metastasis and their associated symptoms include:
Lungs: Trouble breathing, persistent cough, and hemoptysis (coughing up blood)
Liver: Right-sided abdominal discomfort or swelling, jaundice (yellowing of the skin and white part of the eyes), and diminished appetite
Brain: Significant headaches, weakness, numbness, and vision changes
Related: How Breast Cancer Spreads and Recurs
How Is HER2-Low Status Determined?
After a breast cancer tumor is detected, a tissue sample from the tumor is sent for special testing to determine if the cancer cells have high, low, or normal levels of HER2 protein.
The levels of HER2 protein classify a person's breast cancer subtype and, from there, inform a tailored treatment plan.
What Is Immunohistochemistry?
Immunohistochemistry involves a pathologist (a doctor specializing in analyzing body tissues) looking at a tissue sample under a microscope and measuring various proteins.
Immunohistochemistry (IHC) is the first laboratory test performed to identify HER2 status.
In detecting a person's HER2 status, immunohistochemistory entails measuring the number of HER2 protein receptors (docking sites) on the surface of breast cancer cells:
If the IHC score is 0 or 1+, the cancer is HER2-negative.
If the IHC score is 3+, the cancer is HER2-positive.
If the IHC score is 2+, fluorescence in situ hybridization (FISH) is performed.
FISH detects the gene that codes for the HER2 protein and sees how many copies are present. If FISH is positive (two copies of the gene are present), the cancer is HER2-positive; if negative, the tumor is HER2-low.
Learn More: HER2 Testing in Breast Cancer
HER2-Low Classification: Targeted Treatment
Breast cancer treatment, including the subtype HER2-low, aims to curb the growth and spread of breast cancer cells and prevent the disease from returning.
There are multiple treatment methods for breast cancer, including surgery, radiation, chemotherapy, hormone therapy, immunotherapy, and targeted therapy.
Related: How Breast Cancer Is Treated
Targeted therapies are drugs that "target" specific proteins on breast cancer cells to kill or slow their growth. They differ from chemotherapies because they are directed toward particular cells and not all healthy, fast-growing cells in the body.
HER2-low breast cancer was previously classified and treated as HER2-negative breast cancer. No targeted therapies were available until 2022.
In August 2022, the U.S. Food and Drug Administration approved the first targeted drug for HER2-low breast cancers, Enhertu (fam-trastuzumab deruxtecan).
Enhertu, also known as T-DXd, can be used in adults with unresectable (which refers to something that cannot be surgically removed) or metastatic HER2-low breast cancer who have:
Received one prior chemotherapy for metastatic breast cancer
Had their cancer return during or within six months of finishing chemotherapy administered after undergoing surgery
Enhertu is an intravenous (given through the vein) medication consisting of a monoclonal antibody (an artificial protein that binds to a specific target on cell surfaces) chemically connected to a chemo drug. In this case, the monoclonal antibody is trastuzumab, and the chemo drug is deruxtecan.
How Enhertu Works
The trastuzumb part of Enhertu attaches to HER2 on the surface of breast cancer cells and enters those cells. When inside the cell, the deruxtecan part of Enhertu is released, causing DNA damage and cell death.
Related: HER2-Low Breast Cancer Treatment
Is HER2 Low Good or Bad?
Breast cancer treatment is complex and requires a personalized approach. HER status, whether negative, positive, or low, is one considered factor, so it cannot be considered wholly "good" or "bad."
All said, HER2 is certainly a vital prognostic (measure of outcome) marker in breast cancer. Though HER2-positive cancer was historically associated with poor outcomes, the discovery of HER2-targeted therapies changed its outlook, resulting in better outcomes, including overall survival.
Regarding HER2-low breast cancer, experts are still learning more about this subtype. However, the fact that cancer responds to HER2-targeted therapies, like Enhertu, is promising.
In one trial, nearly 500 participants with previously treated HER2-low metastatic breast cancer were randomized to treatment with Enhertu or chemotherapy. The participants who received Enhertu had around a 50% lower risk of disease progression (worsening) and a 36% lower risk of death than those treated with chemotherapy.
Related: What Do Breast Cancer Statistics Mean?
Summary
HER2-low breast cancers contain HER2 proteins on their cell surfaces, but not enough to be classified as HER2-positive. HER2 status is determined by performing immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) on a breast cancer tissue sample.
Though there is still much to learn about HER2-low breast cancer, the discovery of a HER2-targeted therapy called Enhertu (trastuzumab deruxtecan), which is effective against unresectable or metastatic HER2-low breast cancer, offers much hope for current and future breast cancer care.
