HER2-Low Expression: What to Know

  • A high level of HER2 overexpression — as determined by either 3+ staining by immunohistochemistry (IHC) for the HER2 protein or evidence of HER2 gene amplification by fluorescence in situ hybridization — is a strong predictive factor for sensitivity to HER2-targeted agents.
  • The treatment landscape for HER2-low breast cancer is expanding, and the importance of detecting low expression levels of HER2 is becoming increasingly relevant.
  • Trastuzumab deruxtecan is not only directly effective in strongly HER2-positive tumor cells, but also exerts its effect in tumor cells with HER2-low expression.

Precise oncology has allowed us to categorize patients with breast cancer into different subgroups according to their distinct risk profiles. Currently, modern drug development paradigm has shifted to focusing on treatment strategies tailored toward these subtypes.

As most who work in the breast cancer space know, HER2 amplification is linked to a poor prognosis, with an increased risk of recurrence and mortality — and it serves as a predictor of response to anthracycline-based chemotherapy in breast cancer patients. Most notably, it is the only marker that predicts the therapeutic benefits of HER2-targeted treatments like trastuzumab, lapatinib, and pertuzumab. Since these therapies are only effective in breast cancers with HER2 overexpression or amplification, accurate assessment of HER2 status is crucial for optimal treatment planning.

HER2-Scoring Analysis 

Currently, immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and chromogenic in situ hybridization (CISH), including silver in situ hybridization (SISH) are regarded as standard methods for determination of HER2 status in breast cancer.

IHC is the most widely utilized method to determine whether a tumor exhibits overexpression of the HER2 receptor protein on the surface of cancer cells. 

To ensure consistency and reliability in HER2 testing for breast cancer, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) jointly issued guidelines and recommendations in 2007, updated in 2013 and 2018. These guidelines address a comprehensive range of pre-analytic, analytic, and post-analytic variables to standardize HER2 assessment and improve diagnostic accuracy.

Score System:

  • Positive (3+): Circumferential membrane staining that is complete, intense, and in >10% of tumor cells
  • Equivocal (2+): Weak to moderate complete membrane staining observed in >10% of tumor cells
  • Negative (1+): Incomplete membrane staining that is faint or barely perceptible and within >10% of the invasive tumor cells
  • Negative (0): No staining observed. Incomplete membrane staining that is faint or barely perceptible and within ≤10% of the invasive tumor cells

“HER2 can be scored by immunohistochemistry (IHC) or in situ hybridization (ISH). Immunohistochemistry is 0 1, 2, or three. A score of three is positive, a score of two needs additional testing, a score of 0 and 1 are historically what we would’ve called negative,” Dr. Stephanie Graff, Director of Breast Oncology at Lifespan Cancer Institute at Brown University, tells SurvivorNet Connect.

In cases with HER2 IHC 2+, an additional observer blinded to previous results recounts ISH.

“The additional testing that we do for a 2+ result is the ISH… We see that patients that are HER2 2+ and ISH negative or HER2 1+, actually get some level of response to Trastuzumab Deruxtecan,” Dr. Graff adds.

Customizing Treatment According to HER2 Score

The success of clinical trials evaluating the HER2-directed antibody-drug conjugate T-DXd in breast cancers with lower HER2 expression — classified as IHC 1+ and IHC 2+ with a negative fluorescence in situ hybridization (FISH) test, previously considered “HER2-negative” — has led to the adoption of a new terminology, now referring to these tumors as “HER2-low.” 

“We know even from the very beginning that some of those patients in the HER2 zero group are drug-responders. And so we coined the phrase ‘HER2 low’ to talk about them because as it turns out, the HER2 zero can either be really, really a zero HER2, no staining at all, or it can be HER2 zero where it’s less than 5% staining, but a little bit of dye that has filtered onto that slide and all of that messy gray scale is to say it’s not actually black and white,
Dr. Graff explains.

“It is truly a gray scale when it comes to trastuzumab deruxtecan, which seems to be a unique drug. This is not true for medicines like Trastuzumab or Herceptin. It’s not true for medicines like TDM one or Capela.”

However, it remains uncertain whether HER2 oncogenic signaling contributes to the progression of HER2-low breast cancer or if the anti-tumor effects of trastuzumab deruxtecan in this subgroup are due to interference with HER2 signaling or simply improved delivery of the cytotoxic agent.

“And so I think the group from Yale has shown that if you do enough biopsies, you’re eventually going to find that HER2 low expression in a metastatic tumor. And so I think that in the metastatic space there is a high likelihood that as we test a tumor over time we’ll see variability across that HER2 staining and targeting that HER2 low expression is likely a treatment plan for most patients with breast cancer that has metastasized,” Dr. Graff explains.