HER2‑Negative vs. HER2‑Positive Breast Cancer: What It Means for Diagnosis and Treatment

If you or a loved one has received a breast cancer diagnosis, you may have encountered the term HER2. Understanding whether your tumor is HER2‑negative or HER2‑positive can shape treatment decisions and prognosis.

HER2 stands for human epidermal growth factor receptor 2, a protein first identified in the 1980s that sits on the surface of breast cells and regulates normal growth. When overexpressed, it can drive rapid proliferation and metastasis.

In the United States, the National Cancer Institute reports that 81% of new female breast cancer cases between 2017 and 2021 were HER2‑negative, 14% were HER2‑positive, and the status was unknown in 6%.

A tumor that does not overexpress HER2 is classified as HER2‑negative. Even within this group, hormone receptor status—estrogen or progesterone positivity—plays a crucial role in determining treatment.

HER2‑positive cancers are less common but tend to grow and spread more aggressively because of the excess HER2 protein. Over the past three decades, targeted therapies have transformed the outlook for patients with HER2‑positive disease.

HER2‑low breast cancers are an emerging category that may respond to certain HER2‑targeted agents; ongoing studies are refining their definition and therapeutic options.

Accurate HER2 testing is essential. Two primary assays are used:

For both tests, a tissue sample is required.

1. Immunohistochemistry (IHC): a pathologist visually counts HER2 protein on cancer cells. Results are scored 0–3:

• 0–1: HER2‑negative
• 2: borderline; a follow‑up fluorescence in situ hybridization (FISH) test is recommended
• 3: HER2‑positive

2. FISH: a genetic test that evaluates HER2 gene amplification. It is more precise but less widely available. Both IHC and FISH assays approved by the FDA are available for clinical use.

HER2 status is now incorporated into the American Joint Committee on Cancer staging system, helping to gauge tumor aggressiveness alongside factors such as size, hormone receptor status, lymph node involvement, and distant spread.

Treatment Options for HER2‑Negative Breast Cancer

Therapies are tailored to hormone receptor status:

• Hormone‑negative tumors may receive chemotherapy, pembrolizumab (Keytruda) for node‑positive or large tumors, and PARP inhibitors like talazoparib (Talzenna).
• Hormone‑positive tumors are treated with hormone therapies—tamoxifen (Soltamox), abemaciclib (Verzenio), alpelisib (Piqray), olaparib (Lynparza), palbociclib (Ibrance), or ribociclib (Kisqali)—often combined with additional endocrine agents.

Treatment Options for HER2‑Positive Breast Cancer

Targeted therapy with trastuzumab (Herceptin) combined with chemotherapy remains the cornerstone of curative treatment, extending remission and improving survival. A typical curative course lasts up to 52 weeks, with cardiac monitoring continuing for at least two years after completion.

Additional HER2‑directed agents include:

Herceptin Biosimilars

Five biosimilars—such as trastuzumab‑dkst (Ogivri) and trastuzumab‑qyyp (Trazimera)—have FDA approval and provide cost‑effective alternatives to reference Herceptin.

Herceptin Hylecta (trastuzumab/hyaluronidase‑oysk)

Approved in 2019, this formulation allows faster intravenous administration while still requiring cardiac monitoring.

Pertuzumab (Perjeta)

Used with trastuzumab for high‑risk or node‑positive disease, particularly in stages II and above.

Neratinib (Nerlynx)

Often given after trastuzumab to reduce recurrence risk in patients with early‑stage disease.

Margetuximab‑cmkb (Margenza)

Indicated for metastatic or advanced HER2‑positive breast cancer following at least two prior HER2‑targeted therapies.

Fam‑trastuzumab deruxtecan (Enhertu)

Approved for second‑ or third‑line therapy in metastatic breast cancer and, as of August 2022, for certain HER2‑low metastatic cases.

Consultation with an experienced oncologist is vital to interpret HER2 testing and to design a personalized treatment plan that integrates these options.

Ongoing research continues to refine HER2‑targeted therapies, improving survival outcomes and offering new hope for patients diagnosed with this aggressive subtype.

Open dialogue with your healthcare team is essential—ask questions, review test results, and discuss the most appropriate therapies for your specific situation.