Enhancing HER2 testing in breast cancer: predicting fluorescence in situ hybridization (FISH) scores from
Daniel O Macaulay1, Wenchao Han1, Mark D Zarella1
1Division of Computational Pathology and AI, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Abstract:
Breast cancer affects millions globally, necessitating precise biomarker testing for effective treatment. HER2 testing is crucial for guiding therapy, particularly with novel antibody-drug conjugates (ADCs) like trastuzumab deruxtecan, which shows promise for breast cancers with low HER2 expression. Current HER2 testing methods, including immunohistochemistry (IHC) and in situ hybridization (ISH), have limitations. IHC, a semi-quantitative assay, is prone to interobserver variability. While ISH provides higher precision than IHC, it remains more resource-intensive in terms of cost and workflow. However, turnaround time is typically faster than that of other advanced molecular methods such as next-generation sequencing. We adapted the clustering-constrained-attention multiple-instance deep learning model to improve IHC testing and reduce dependence on reflex fluorescence ISH (FISH) tests. Using 5,731 HER2 IHC images, including 592 cases with FISH testing, we trained two models: one for predicting HER2 scores from IHC images and another for predicting FISH scores from equivocal cases. The HER2 IHC score prediction model achieved 91% ± 0.01 overall accuracy and a receiver operating characteristic (ROC) area under the curve (AUC) of 0.98 ± 0.01. The FISH score prediction model had an ROC AUC of 0.84 ± 0.07, with sensitivity at 0.37 ± 0.13 and specificity at 0.96 ± 0.03. External validation on cases from 203 institutions showed similar performance. The HER2 IHC model maintained a 91% ± 0.01 accuracy and an ROC AUC of 0.98 ± 0.01, while the FISH model had an ROC AUC of 0.75 ± 0.03, with sensitivity at 0.28 ± 0.04 and specificity at 0.93 ± 0.01. Our model advances HER2 scoring by reducing subjectivity and variability in current scoring methods. Despite lower accuracy and sensitivity in the FISH prediction model, it may be a beneficial option for settings where reflex FISH testing is unavailable or prohibitive. With high specificity, our model can serve as an effective screening tool, enhancing breast cancer diagnosis and treatment selection.
