Oncology


routinely obtained IHC and FISH data with the results of manual and semi-automated re- evaluation of the original IHC slides, and with RNA expression data from the same tissue block using MammaTyper. While RNA and IHC results showed strong overall correlation, discordant cases – often with low protein expression and RNA levels near the cut-off – highlighted the sensitivity of the RNA-based method for detecting weak biological signals. RNA testing clarified borderline HER2 classifications, including potential false positives missed by FISH. These findings demonstrate that RNA


assays offer a quantitative, reproducible and biologically continuous assessment, enabling more precise and standardised evaluation of key breast cancer biomarkers and resolving equivocal HER2 cases. Their use could therefore enhance endocrine responsiveness assessment and better guide treatment in patients with borderline results or biomarker expression close to established cut-off values.


Bridging the diagnostic gap with quantitative methods The recognition of HER2-low and HER2-ultralow as distinct breast cancers subtypes is reshaping diagnosis and treatment, expanding options for patients once deemed HER2-negative. However, these categories add complexity to testing, as current methods struggle to accurately distinguish subtle expression differences, particularly between IHC 0, 1+ and 2+ cases. Such variability can affect treatment decisions, highlighting the limitations of subjective, semi- quantitative approaches. Quantitative methods can improve accuracy,


reduce misclassification and better align patients with the most suitable therapies. RNA-based detection methods, such as RT-qPCR,


Figure 2: The MammaTyper workflow can be carried out in under six hours using FFPE tissue samples and a standard RT-qPCR machine.


show notable advantages over traditional techniques like IHC and ISH in refining breast cancer classification, addressing gaps in HER2 diagnostics. This is especially true in borderline HER2-low, HER2-ultralow or equivocal cases where IHC alone may lack precision. RT-qPCR assays like MammaTyper are designed to complement rather than replace IHC, and can be integrated into current workflows using widely available RT-qPCR platforms without specialised equipment, additional training or infrastructure, or prohibitive costs (Figure 2). Compared with FISH, MammaTyper is faster, less labour intensive and easier to scale across laboratories. It shows great promise for optimising healthcare resources by refining patient stratification, reducing the need for broader multigene testing, and enabling more patients to benefit from emerging targeted therapies.17


References 1. Tarantino P, Viale G, Press MF, Hu X, Penault-


Llorca F, Bardia A, et al. ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer. Annals of Oncology [Internet]. 2023 [cited 2025 Jul 25];34:645–59. Available from: https://doi.org/10.1016/j. annonc.2023.05.008


2. Burstein HJ. The Distinctive Nature of HER2- Positive Breast Cancers. New England Journal of Medicine [Internet]. 2005 Oct 20 [cited 2025 Jul 25];353(16):1652–4. Available from: https:// www.nejm.org/doi/full/10.1056/NEJMp058197


3. Loibl S, Gianni L. HER2-positive breast cancer. The Lancet [Internet]. 2017 Jun 17 [cited 2025 Jul 25];389(10087):2415–29. Available from: https://www.sciencedirect.com/science/ article/abs/pii/S0140673616324175


CSJ


4. Atallah N, Makhlouf S, Li X, Zhang Y, Mongan NP, Rakha E. Prediction of Response to Anti-HER2 Therapy Using A Multigene Assay. Modern Pathology. 2025 Apr;38(4):100713.


5. Bradley R, Braybrooke J, Gray R, Hills R, Liu Z, Peto R, et al. Trastuzumab for early-stage, HER2-positive breast cancer: a meta- analysis of 13 864 women in seven randomised trials. Lancet Oncol [Internet]. 2021 Aug 1;22(8):1139–50. Available from: https://doi.org/10.1016/S1470-2045(21)00288-6


6. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2- Positive Breast Cancer. New England Journal of Medicine. 2017 Jul 13;377(2):122–31.


7. von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. New England Journal of Medicine. 2019 Feb 14;380(7):617–28.


8. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. New England Journal of Medicine. 2022 Jul 7;387(1):9–20.


48 www.clinicalservicesjournal.com I November 2025


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