HISTOPATHOLOGY


additional training or infrastructure, and uses standard formalin-fixed, paraffin wax-embedded (FFPE) tissue samples. It supports more precise patient stratification and has the potential to optimise healthcare resources, helping to avoid unnecessary treatments, beter tailor therapeutic regimens and minimise the need for multigene testing.16


Conclusions The identification of HER2-low and HER2-ultralow as separate breast cancer subtypes is transforming the diagnosis and treatment for patients once deemed HER2-negative. However, these categories add complexity into existing testing workflows, exposing the limitations of subjective, semi-quantitative approaches, which often fail to support accurate patient stratification across the full range of expression. As discussed, variability in


interpretation can lead to inconsistent results, directly impacting treatment guidance, especially with the emergence of targeted therapies that rely on subtle distinctions in HER2 expression. Quantitative methods offer a practical way to enhance diagnostic accuracy, and can decrease the risk of misclassification and help to ensure patients receive the most appropriate treatment. RT-qPCR can support IHC and help to bridge the HER2 diagnostic gap, offering an additional technique where IHC alone may not provide sufficient clarity. This is especially true in borderline HER2-low, HER2-ultralow or equivocal cases, where these assays can increase confidence in classification to optimise new treatment regimens and improve patient outcomes.


PPi


References 1 Burstein HJ. The distinctive nature of


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Loibl S, Gianni L. HER2-positive breast cancer. Lancet. 2017;389(10087):2415-2429. doi:10.1016/S0140-6736(16)32417-5


3 Tarantino P, Viale G, Press MF, et al. ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer. Ann Oncol. 2023;34(8):645-659. doi:10.1016/j.annonc.2023.05.008


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5


von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant Pertuzumab and


Fig 2. Using FFPE tissue samples and a standard RT-qPCR machine, the workflow for MammaTyper can be carried out in under six hours.


Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med. 2017;377(2):122-131. doi:10.1056/NEJMoa1703643


6 von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017


7 Wolff AC, Hammond MEH, Allison KH, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/ College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol. 2018;36(20):2105-2122. doi:10.1200/ JCO.2018.77.8738


8 Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690


9 Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06). J Clin Oncol [Online]. 2024;42(17_ suppl):LBA1000.


10 Zaakouk M, Quinn C, Provenzano E, et al. Concordance of HER2-low scoring in breast carcinoma among expert pathologists in the United Kingdom and the Republic of Ireland - on behalf of the UK national coordinating commitee for breast pathology. Breast. 2023;70:82-91. doi:10.1016/j. breast.2023.06.005


11 Baez-Navarro X, van Bockstal MR, Nawawi D, et al. Interobserver Variation in the Assessment of Immunohistochemistry Expression Levels in HER2-Negative Breast Cancer: Can We Improve the Identification of Low Levels of HER2 Expression by Adjusting the Criteria? An International Interobserver Study. Mod


34 WWW.PATHOLOGYINPRACTICE.COM February 2026


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12 Robbins CJ, Fernandez AI, Han G, et al. Multi-institutional Assessment of Pathologist Scoring HER2 Immunohistochemistry. Mod Pathol. 2023;36(1):100032. doi:10.1016/j. modpat.2022.100032


13 Fernandez AI, Liu M, Bellizzi A, et al. Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue. JAMA Oncol. 2022;8(4):1-4. doi:10.1001/ jamaoncol.2021.7239


14 Varga Z, Lebeau A, Bu H, et al. An international reproducibility study validating quantitative determination of ERBB2, ESR1, PGR, and MKI67 mRNA in breast cancer using MammaTyper®. Breast Cancer Res. 2017;19(1):55. doi:10.1186/s13058-017-0848-z


15 Atallah N, Makhlouf S, Li X, Zhang Y, Mongan NP, Rakha E. Prediction of Response to Anti-HER2 Therapy Using A Multigene Assay. Mod Pathol. 2025;38(4):100713. doi:10.1016/j. modpat.2025.100713


16 National Institute for Health and Care Excellence. MammaTyper in vitro diagnostic test for determining breast cancer subtypes. (NICE, 2018) www.nice.org. uk/advice/mib135/chapter/The-technology


Vinicio Tassani has been the Scientific Advisor at Cerca Biotech since 2021, and has over 25 years of international experience across clinical and commercial roles. A biomarkers specialist, he led clinical support and marketing for ACS, heart failure and stroke POC tests at Biosite (later Inverness/Alere/Abbot). He also contributed to the introduction of BNP as a routine biomarker in Europe, supported the rollout of ST2 with Critical Diagnostics, and led the EMEA launch of EndoPredict at Myriad Genetics, deepening his expertise in breast cancer biomarkers.


Vinicio@Cercabiotech.com www.Cercabiotech.com


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