Breast cancer classification relies on identifying specific proteins on the surface of tumor cells. The Human Epidermal Growth Factor Receptor 2 (HER2) is a protein that sits on the surface of all breast cells and is involved in controlling cell growth and division. When a breast cancer is classified as HER2-negative, it means the cancer cells do not have an excess amount of this protein, a characteristic present in approximately 80% of all breast cancers. This absence of HER2 overexpression signifies that the cancer is not driven by this particular growth pathway.
Defining HER2 Negative Status
HER2-negative status is determined through a precise diagnostic process performed on a tumor tissue sample. Pathologists use laboratory tests to measure the amount of HER2 protein present on the cancer cells’ surface and the number of HER2 genes within the cells. The primary method used is Immunohistochemistry (IHC), which uses a dye to stain the HER2 protein, with results reported on a scoring scale from 0 to 3+.
A score of 0 or 1+ definitively classifies the cancer as HER2-negative, indicating a low or normal level of the protein. If the IHC test returns an equivocal score of 2+, the pathologist must perform a second test called Fluorescence In Situ Hybridization (FISH). The FISH test measures the number of copies of the HER2 gene inside the cell nuclei. A negative result from the FISH test confirms that the tumor is HER2-negative.
The Major Subtypes of HER2 Negative Cancer
HER2-negative breast cancer is further categorized based on the presence or absence of Hormone Receptors (HRs), specifically the Estrogen Receptor (ER) and Progesterone Receptor (PR). Hormone receptor status defines the cancer’s biology and its susceptibility to targeted therapies. The most common subtype is Hormone Receptor-Positive/HER2-Negative, which accounts for about 70% of all breast cancer cases.
This HR+/HER2- group is often referred to as Luminal A or B and relies on estrogen and/or progesterone to fuel its growth. Because these tumors express hormone receptors, they are generally considered less aggressive and often respond well to therapies that block hormonal signaling.
The second major subtype is Hormone Receptor-Negative/HER2-Negative, which is known as Triple-Negative Breast Cancer (TNBC). TNBC is defined by the absence of all three common receptors—Estrogen Receptor, Progesterone Receptor, and HER2. This subtype accounts for approximately 10% to 15% of all breast cancers and is typically more aggressive with a higher rate of recurrence compared to HR+/HER2- disease. The lack of targeted receptors means that treatment must rely on other systemic methods to manage the disease.
Treatment Strategies Based on Subtype
For the HR-Positive/HER2-Negative subtype, the primary systemic treatment involves Endocrine Therapy (ET). These therapies, such as Tamoxifen or Aromatase Inhibitors, work by either blocking the effects of estrogen on the cancer cells or by lowering the body’s overall estrogen production.
In many cases, Endocrine Therapy is combined with newer targeted drugs known as Cyclin-Dependent Kinase 4/6 (CDK4/6) inhibitors. CDK4/6 inhibitors interfere with the cell division cycle, stopping cancer cells from multiplying. This combination of hormone therapy and CDK4/6 inhibitors is a standard approach for both advanced and high-risk early-stage HR+/HER2- disease.
Triple-Negative Breast Cancer (TNBC) relies mainly on Chemotherapy as the foundational systemic treatment. Chemotherapy is often given before surgery to shrink the tumor, a strategy known as neoadjuvant therapy, or after surgery to eliminate any remaining cancer cells. Newer treatments are now available that exploit other characteristics of TNBC, such as the use of PARP inhibitors for tumors with specific DNA repair gene mutations like \(BRCA1\) or \(BRCA2\). Immunotherapy agents, like PD-L1 inhibitors, are also increasingly used in combination with chemotherapy for certain TNBC tumors, as they help the patient’s own immune system recognize and attack the cancer cells.
Monitoring and Long-Term Prognosis
Patients with HER2-negative breast cancer enter a long-term surveillance phase involving regular check-ups and imaging. The goal of this monitoring is to detect any signs of recurrence early, as prompt intervention can significantly improve outcomes. The prognosis varies considerably between the two major HER2-negative subtypes.
The prognosis for HR-Positive/HER2-Negative cancer is generally favorable, given the effectiveness of endocrine therapy. The slow-growing nature of these tumors and the long duration of hormone therapy contribute to high long-term survival rates. Conversely, Triple-Negative Breast Cancer is associated with a more challenging prognosis due to its aggressive nature and higher likelihood of recurrence in the initial years after diagnosis. Despite this, the introduction of immunotherapy and PARP inhibitors has improved outcomes for TNBC patients.