Posted on Feb 26, 2024

What is HER2-low?

In breast cancer, HER2 status has traditionally been assessed using a combination of immunohistochemistry (IHC) to measure HER2 protein expression levels, and in-situ hybridization (ISH) to assess ERBB2 gene amplification status.

“HER2-positive” cancers are those that either scored 3+ with IHC, or 2+ with evidence of gene amplification from ISH. These HER2-positive cancers are eligible for HER2-directed therapies.

But there has always been a debate about the correct management of patients with intermediate-level HER2 expression (IHC 2+) with low levels of gene amplification. The ASCO-CAP guidelines of 2018 suggest this group is HER2-negative, whereas the UK NCCBP recommendations from 2022 say it should be counted as HER2-positive. Agreement on optimal management is needed.

However, the designation of the HER2-low group has been a breakthrough – in particular, the approval of trastuzumab deruxtecan (Enhertu) as a treatment for HER2-low advanced breast cancer, following the landmark results from the Destiny-Breast04 and DAISY phase 2 trials. Other antibody-drug conjugates (ADCs) targeting HER2 are also showing promising results for HER2-low group.

‘HER2-low’ represents as many as 55% of all breast cancers, and significantly expands the group of patients who might benefit from HER2-directed therapies.

IHC is not up to the task of defining HER2-low

Besides optimising the treatment algorithm for people with HER2-low breast tumours, the major challenge is accurately testing for HER2-low.

IHC falls short when it comes to distinguishing the HER2-low subtype. As others have pointed out, IHC was never designed to sensitively determine lower expression levels of HER2 protein. The current IHC/ISH paradigm of HER2 scoring is intrinsically subjective, depending on visual interpretation by pathologists.

As we have written before, the current guidelines on IHC testing of HER2 acknowledge that pre-analytical factors will have even more influence on IHC results at the lower end of the HER2 scale. And according to a recent UK study, inter-lab concordance on HER2-low scoring with IHC is poor, even among expert pathologists.

It’s clear that IHC-based testing is not suitable for stratifying patients on the lower end of the HER2 expression scale. More accurate and reproducible assays are needed.

Could MammaTyper® replace IHC in HER2-testing?

RT-qPCR-based methods like MammaTyper® hold significant advantages over IHC for determining HER2 status. RT-qPCR is fully quantifiable, objective, reproducible and not subject to the same level of inter-observer variability as IHC.

Studies have already shown that RT-qPCR has high concordance with IHC with respect to both individual biomarkers and to subtypes. MammaTyper® can already effectively distinguish between HER2-low and HER2-negative breast tumours.

Treatment sequencing algorithms for HER2-low are being proposed and refined, and new treatments on the horizon are showing promise for this group of patients. To make the most of this opportunity and improve treatment for this large group of breast cancer patients, a more reproducible test to assess HER2 status is a key priority.

Cerca Biotech is looking for collaborators on HER2 studies

Following extensive technical validation, we have already shown that MammaTyper® is a linear, quantitative, reproducible, and standardised test for HER2 and other key breast cancer markers: ER, PgR, and Ki67. Our mission for 2024 is to further demonstrate the clinical utility of the assay.

Specifically, for HER2, we want to demonstrate that MammaTyper® can define HER2-low and -ultralow tumours better than other assays.

To do this, we’re looking for collaborators with an interest in:

  1. HER2-low cohorts already treated with HER2-directed ADCs
  2. Serial testing of HER2
  3. Neoadjuvant HER2-directed therapy
  4. Defining HER2-ultralow tumours

Would you like to collaborate on studies to test MammaTyper®? Please get in touch with us at