Wonkyung Jung, Taebum Lee, Sangwon SHIN, Biagio Brattoli, Mohammad Mostafavi, Gahee Park, Sukjun Kim, Hyunwoo Lee, Yoon Ah Cho, Eun Yoon Cho, So-Woon Kim, Sergio Pereira, Chang Ho Ahn, Siraj Mahamed Ali, Douglas E Mirsky, Chan-Young Ock<\/p>\n
ASCO, 2024<\/strong><\/p>\n Background:<\/strong> Methods:<\/strong> Results:<\/strong>
\nHER2-targeted antibody-drug conjugates (ADCs) can effectively target tumor cells even in HER2-low breast cancers (1+ and 2+\/no amp). We developed an AI-based whole-slide image (WSI) analyzer for immunohistochemistry (IHC)-stained slides, exploring a cutoff differentiating between true HER2 negative versus HER2 ultra-low.<\/p>\n
\nAn AI-based IHC WSI analyzer was developed using 6,188 WSIs stained by 19 types of IHC including HER2 and from various cancers, annotated by 153 pathologists. The model predicts cells as tumor cells or non-tumor cells and generates HER2 expression continuous score (HER2ecs, 0-100%), quantifying IHC staining intensity of membrane, nucleus, cytoplasm, and membrane+cytoplasm separately for each cell. A total of 401 HER2 IHC WSIs were acquired from Samsung Medical Center (n=275), Kyung Hee University Hospital (n=78), and Commercial Biobank (n=48), scored as 0 (n=347) and 1+ (n=54) by pathologists.<\/p>\n
\nIn total, 67,169,114 tumor cells and 119,113,886 non-tumor cells from 401 WSIs were successfully evaluated. Comparing HER2 score 0 versus 1+ by pathologists, mean HER2ecs of nucleus (1.7% vs 4.1%), cytoplasm (6.5% vs 12.9%), and membrane (3.6% vs 8.2%) were comparable. In HER2 score 0 WSIs, membrane HER2ecs of tumor cell was 3.6 \u00b1 7.8% (mean \u00b1 standard deviation), while that of non-tumor cell was 0.9 \u00b1 2.9% (p <0.001 vs. tumor cell), suggesting, even in HER2 score 0 cases, tumor cell exhibits HER2 expression beyond non-specific HER2 staining intensity. Based on our internal validation dataset, membrane-specific HER2ecs of 6.0% was the optimal threshold discriminating HER2 no-staining cells versus HER2 incomplete and faint\/barely perceptible cells (AI-HER2-weak) per ASCO\/CAP guideline. Among HER2 score 0 by pathologists, when applying this cutoff, the proportion of WSIs showing AI-HER2-weak or higher membrane-specific HER2ecs in over 10% of all tumor cells was 23.6% (82\/347). Interestingly, that of WSIs among HER2 score 1+ by pathologists was 51.9% (28\/54), which is comparable to 52.3%, objective response rate of trastuzumab deruxtecan in HER2-low patients in DESTINY-Breast04.<\/p>\n