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HER2-Low, A Separate Entity?

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Given the success of Trastuzumab Deruxtecan (T-DXd or Enhertu) in breast cancer in HER2-low patients, there were a number of presentations and an interesting “debate” on this topic at the San Antonio Breast Cancer Symposium (SABCS).  On Wednesday morning 3 presentations were given updating or reporting trials of T-DXd.  This was followed by a debate on whether or not HER2-low is a separate entity. HER2-low is defined as HER2 read by pathologists as IHC score according to ASCO/CAP guidelines of HER2 = 1+ or 2+ without gene amplification.  Between 20 and 40% of cases are read as HER2 IHC = 0.  The question for the debate was “Are the HER2=0 cases a different entity than HER2-low cases”.  All agree that HER2 amplified is a different entity.  I was allowed to “set the stage” for the debate by giving a presentation called “HER2 low: A pathologist's perspective” followed by Giuseppe Curigliano, MD, PhD of the European Institute of Oncology in Milano, Italy arguing that HER2-Low is a separate entity and then followed by Sara Tolaney, MD, MPH of the Dana-Farber Cancer Institute in Boston, MA arguing that HER2 low is not a separate entity.  

In my presentation I first reviewed three abstracts/posters that were presented, each suggesting that pathologists reading IHC could accurately classify HER2-low with about 80% accuracy (pathologist concordance).  Ruschoff et al noted that this was in contrast to work published by our group (Fernandez et al, JAMA Oncology 2022) where we showed a concordance of 60% or less.  The difference was that all of the SABCS abstracts compared only 2 or 3 pathologists per group, which is not representative of the real world where there are 21,000 pathologists in the US alone.  I then showed an ONEST (observers needed for evaluation of a subjective test) analysis which suggests that the pathologists have great concordance when assessing IHC = 3+ VS NOT 3+, (>85% at 6 readers) but do much worse for IHC=0 vs Not 0 (<25% at 10 readers).   This suggests that the current FDA approved assay for low HER2 which was designed for high HER2 is not likely to be accurate or reproducible for selection of patients with low HER2.  Baez-Navarro (Eu J Cancer, 2022) suggested that the current assay is like “weighing mice on a scale made for elephants.”  Then I the showed data from a fully quantitative assay called HS-HER2 (high sensitivity-HER2) that provides a measurement of HER2 in the low range in attomols/mm2 that shows that many case called IHC=0 have detectable level of HER2 protein above the limit of detection of the assay.  This assay is published (Moutafi et al, Lab Invest 2022) and offered in a CLIA lab, but only at Yale so far.  There are plans to broadly commercialize this test and there are rumors that other low HER2 tests will also soon be available.

My presentation was followed by Dr. Curigliano who made a strong case for HER2-low being a separate entity.  He mostly supported his argument with data related to prognosis.  In contrast, Sara Tolaney made an even stronger case for HER2-low NOT being a separate entity, but her data was largely supported by IHC classification that is most likely flawed and thus not accurate.  In the end, she, and all of us, concluded that HER2 low is an important biomarker, but that a new assay is needed to optimally determine the levels of HER2 proteins in breast tissue slides.   In summary, this new drug, T-DXd, is a very promising new therapy that will really make a difference for patients in the advanced breast cancer setting.  However, due to its pulmonary toxicity in about 10% of patients, the drug really needs an accurate biomarker.  Unfortunately, the current biomarker is not up to the task and we are all hopeful that new biomarker test(s) will soon be available that accurately match patients to the new drug.

Dr. Rimm has Sponsored Research Agreements from Amgen, Cepheid, Navigate Biopharm, Konica/Minolta, Akoya, BCRF and NIH. He has also received honorariums from Astra Zeneca, Cell Signaling Technology, Cepheid, Danaher, NextCure, Paige.AI, Regeneron, Sanofi, and Verily.

Illustration by Jennifer Bogartz

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