HER2-Low and HER2-Ultralow: What Do They Mean in IDC?

If you are reading your pathology report and see terms like HER2-low or HER2-ultralow, you may wonder if this means you have a rare or entirely different type of invasive ductal carcinoma. The short answer is no. HER2-low and HER2-ultralow are not separate types, stages, or conventional subtypes of breast cancer, and these terms alone do not determine how aggressive your cancer is or your overall prognosis ^[1][2]. Instead, they describe the very low amount of HER2 protein found on the surface of your tumor cells ^[3].

Historically, breast cancers were divided into two strict categories: “HER2-positive” (high levels of the protein) or “HER2-negative” (little to no protein) ^[2]. However, scientists realized that the “HER2-negative” category actually includes tumors with trace amounts of HER2 protein ^[4]. Recognizing these trace amounts has become important because of highly sensitive new treatments that can seek out even very small amounts of HER2 ^[5].

What the Scores Mean

Pathologists measure HER2 using a test called Immunohistochemistry (IHC), which stains the cells and assigns a score from 0 to 3+ ^[3]. If the score is borderline (2+), they use a second test called ISH (in-situ hybridization) to look for extra copies of the HER2 gene inside the cells.

• HER2-Positive: A score of 3+, or a score of 2+ with a positive ISH test.
• HER2-Low: A score of 1+, or a score of 2+ with a negative ISH test ^[3][2].
• IHC 0 (Traditionally HER2-Negative): Standard reporting often just labels a score of 0 as HER2-negative. However, within this score, there can either be absolutely no staining, or there can be incomplete, faint staining in 10% or fewer of the tumor cells. Clinical trials use the term HER2-Ultralow to describe tumors with that faint, incomplete staining ^[3][5]. Many pathology labs do not formally write “ultralow” on the report; they simply report an IHC 0 ^[4].

Distinguishing between “low,” “ultralow,” and “no staining” requires evaluating extremely faint stains, which can be difficult and lead to disagreement among pathologists ^[6][7]. Additionally, the amount of HER2 protein can change over time or differ between the original breast tumor and cancer that has spread to other parts of the body ^[8]. For this reason, if breast cancer returns or spreads, doctors may recommend a new biopsy to re-test the HER2 levels, provided a biopsy is safe, feasible, and likely to change your treatment ^[9].

Does It Change Your Treatment?

Whether a HER2-low or HER2-ultralow result changes your treatment plan depends on the stage of your cancer, what treatments you have already had, your hormone receptor status, and the guidelines in your country ^[5][10].

Breast cancers are also classified by whether they are fueled by hormones like estrogen or progesterone (hormone-receptor-positive) or if they lack those receptors and HER2 (triple-negative).

For Localized or Early-Stage Breast Cancer:
If you have early-stage invasive ductal carcinoma (cancer that has not spread beyond the breast and nearby lymph nodes), having a HER2-low or HER2-ultralow tumor does not currently change your standard treatment outside of clinical trials ^[5][11]. Your care is guided by your hormone receptor status, tumor size, grade, and lymph node involvement ^[12][11].

For Unresectable or Metastatic Breast Cancer:
The biggest impact of these new categories is for patients with metastatic breast cancer (cancer that has spread to distant organs) or advanced cancer that cannot be safely removed by surgery ^[5][13].

For these patients, specific drugs known as antibody-drug conjugates (ADCs) have been developed. An ADC is a targeted antibody linked to a chemotherapy drug; it circulates in the body and preferentially binds to cells with HER2 protein to deliver the chemotherapy ^[13].

Clinical trials (such as DESTINY-Breast04 and DESTINY-Breast06) showed that the ADC trastuzumab deruxtecan can significantly improve outcomes for specific patients ^[13][14]:

• HER2-Low: Approved in many regions for metastatic patients who have previously received chemotherapy, or for hormone-receptor-positive patients who have progressed after endocrine (hormone) therapy ^[13][10].
• HER2-Ultralow: Specifically shown to benefit hormone-receptor-positive metastatic patients after endocrine therapy and before starting metastatic chemotherapy ^[14][10].

Important Safety Note: Because ADCs circulate throughout the body, they can affect healthy cells and carry serious risks. A notable, potentially life-threatening risk of trastuzumab deruxtecan is interstitial lung disease (ILD) or pneumonitis (severe lung inflammation) ^[13][14]. Patients must immediately report any new cough, shortness of breath, or fever to their care team. Other common side effects include nausea, fatigue, low blood counts, and potential cardiac effects ^[13].

Always discuss your specific pathology report with your oncologist to understand what your HER2 status means for your immediate and future treatment options.