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Small Methods, Sep 06 2025, | https://doi.org/10.1002/smtd.202500599 Improving HER2 Diagnostics with Digital Real-Time PCR for Ultrafast, Precise Prediction of Anti-HER2 Therapy Response in Patients with Breast Cancer

Hee-Joo Choi ^1,2,3, Soo Young Park^4,5, Minsik Song⁶, Jinhyuk Chang ¹, YoonSik Kim ¹, Hosub Park ⁷, Chihwan David Cha ⁸, Sohyeon Yang ^4,9, Nam Hun Heo ¹⁰, Min Ji Song ^4,9, Da Sol Kim ^4,9, Hayeon Kim ^4,9, Minuk Kim¹, Jae Eun Park ¹, Yesung Lee ¹, EunChae Ji ¹, Heekyoung Chung ¹, Ilecheon Jeong ¹¹, Mineui Hong¹², Jin-Wu Nam ^2,13,14, Mee-Hye Oh ¹⁵, Ji-Hye Lee ¹⁵, Jinwoo Seol ⁶, Hee-Young Won ⁶, Hyun-Woo Song ⁶, Jaewon Eom⁶, Do Young Lee ⁶, Han Suk Ryu ^4,9,16, Si-Hyong Jang ¹⁵, Jeong-Yeon Lee ^1,2

¹Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
²Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, Republic of Korea.
³Hanyang Biomedical Research Institute (HBRI), Hanyang University, Seoul, Republic of Korea.
⁴Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁵Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
⁶OPTOLANE Technologies Inc., Jagok-ro, Gangnam-gu, Seoul, Republic of Korea.
⁷Department of Pathology, Hanyang University Hospital, Seoul, Republic of Korea.
⁸Department of Surgery, Hanyang University College of Medicine, Seoul, Republic of Korea.
⁹Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea.
¹⁰Clinical Trial Center, Soonchunhyang University Cheonan Hospital, Cheonan-si, Chungcheongnam-do, Republic of Korea.
¹¹Genome Insight Technology Inc., Yuseong-gu, Daejeon, Republic of Korea.
¹²Department of Pathology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
¹³Hanyang Institute of Advanced BioConvergence, Hanyang University, Seoul, Republic of Korea.
¹⁴Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Republic of Korea.
¹⁵Department of Pathology, Soonchunhyang University Cheonan Hospital, Cheonan-si, Chungcheongnam-do, Republic of Korea.
¹⁶Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.

H.-J.C., S.Y.P., M.S., J.C., and Y.K. contributed equally to this work.
Corresponding Authors: Do Young Lee, Han Suk Ryu, Si-Hyong Jang, Jeong-Yeon Lee

Abstract

While human epidermal growth factor receptor (HER2) has emerged as a tumor-agnostic biomarker, standard HER2 testing for anti-HER2 therapies using immunohistochemistry (IHC) and in situ hybridization (ISH) assays remains subjective, time-consuming, and often inaccurate. To address these limitations, an ultrafast and precise HER2 testing method is developed using Lab-On-An-Array (LOAA) digital real-time PCR (drPCR), a fully automated digital PCR enabling real-time absolute quantification. A multicenter study involving four independent breast cancer cohorts cross-validates the high diagnostic accuracy of drPCR-based HER2 assessment. Comparative analyses with artificial intelligence algorithms, next-generation sequencing, and droplet digital PCR demonstrate that drPCR is faster, simpler, and more accurate than conventional assays for assessing HER2 status, while IHC/ISH frequently yields false positives. Importantly, in patients initially diagnosed as HER2-positive and treated with neoadjuvant anti-HER2 therapy, the HER2 drPCR(+)/IHC-ISH(+) group achieves high pathological complete response rates, while HER2 drPCR(-)/IHC-ISH(+) cases exhibit poor treatment responses, highlighting the superior predictive accuracy of drPCR for anti-HER2 therapy response. Additionally, drPCR identifies patients with chromosome 17 centromere abnormalities, HER2-zero/ERBB2 hemizygous deletion, and ERBB2 hyperamplification who respond favorably to anti-HER2 therapy. Collectively, these findings establish drPCR as a clinically feasible, standardized, and ultrafast HER2 testing method for improved prediction of anti-HER2 therapy response in patients with cancer.

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