Posted on Jun 25, 2023
We look closer at the recent draft guidelines on HER2-testing in breast cancer, and examine alternatives to immunohistochemistry (IHC) for the task of identifying HER2-low tumours.
In June 2022, one conference presentation changed how we use HER2-directed treatments in breast cancer – and challenged the status quo in HER2 testing.
The results from the Destiny-Breast04 trial showed that trastuzumab-deruxtecan (Enhertu) could improve the progression-free survival and overall survival for patients with HER2-low/negative tumours. Dr Shanu Modi, presenting the results on behalf of the study team at the ASCO 2022 Annual Meeting, said “we anticipate these results to be practice changing.”
If the five-minute standing ovation was anything to go by, the Destiny-Breast04 results were enthusiastically welcomed by oncologists. They had been looking for new ways to treat HER2-low patients, who had historically experienced a poor prognosis.
But the Destiny-Breast04 results also raised a new question for pathologists – how to accurately determine which patients have this ‘HER2-low’ subtype.
How do we test for HER2-low status?
A year after the Destiny-Breast04 results, ASCO-CAP and ESMO have attempted to answer this question in their updated draft guidance on HER2 testing.
Both the ASCO-CAP and ESMO guidelines essentially say the same thing: it is very difficult to define a HER2-low subtype with immunohistochemistry (IHC), the ‘gold-standard’ test for the last 50 years. Nevertheless, ASCO-CAP guidelines have recommended that pathologists continue to use IHC as best they can, to try to identify the HER2-low population.
The response from experts has highlighted some of the challenges of doing so. In their commentary on the ASCO-CAP draft guidelines, Stuart Schnitt, Paolo Tarantino, and Laura Collins point out IHC assays to detect HER2 “do not have the sensitivity or dynamic range to reliably identify tumors with low levels of protein on the tumor cell surface and were not developed to be used for that purpose.”
The ASCO-CAP guidelines also admit that pre-analytical factors, such as the preparation of slides for staining and the antibodies used, will have even more influence when determining HER2-low status. Add to this the known inter-operator variability of IHC, and it’s clear that IHC may not be up to the job of identifying HER2-low patients. Given the Destiny-Breast04 results, this could have real consequences for the treatments patients receive, and their long-term survival.
Is RT-qPCR the alternative to IHC for HER2 testing?
Another well-established method could provide a better option for typing tumours – real time quantitative PCR. RT-qPCR can directly measure gene expression from tumours, with high concordance between laboratories and at low cost. And because of the proliferation of qPCR systems in pathology laboratories after the COVID pandemic, RT-qPCR-based tests would be relatively simple to implement, compared to more complex genetic sequencing tests.
MammaTyper® is the only RT-qPCR test on the market proven to be better than IHC at distinguishing low HER2 expression. Further evidence of this was presented at the recent ASCO Annual meeting in June 2023.
In a study of nearly 800 cases, MammaTyper® could distinguish between HER2-low and -negative tumours, showing a better long-term prognosis for patients with HER2-low cancers. However, when the same samples were tested using the classic IHC, the same survival benefit was not seen – indicating that IHC is unable to discriminate between tumours at the lower end of the HER2 expression scale.
“For HER2-low/neg tumours, it is clear that IHC just isn’t accurate enough anymore and new diagnostic tools are needed,” said Rich Hughes, Commercial Director at Cerca Biotech, in response to this latest study. “MammaTyper® can give pathologists the confidence to subtype breast cancer tissue accurately and quickly and provide a clear picture to clinicians and patients.”
There are increasing doubts about the ability of IHC to identify HER2-low patients. MammaTyper® is well-placed to help quantify HER2 expression in a consistent and reproducible manner. As advances in targeted treatments demand a more accurate and reliable diagnosis, the choice of assay will have a significant impact on the survival of many breast cancer patients.
Ready to discover how MammaTyper® could accurately define HER2-status in your patients? Get in touch to learn more and find out how you could test MammaTyper® for yourself.