Abstract: Methods and systems for generating a predictive HER2 score using machine learning models are disclosed. An example method generally includes identifying a plurality of nuclei and membrane segments in regions of interest in an input image using a first machine learning model. For the plurality of nuclei and membrane segments identified in the input image, a plurality of features are extracted and classified into one of a plurality of feature categories. Using a second machine learning model, a predictive HER2 score indicating the likelihood of whether a stained tissue sample captured in the input image is HER2 positive or HER2 negative is generated based on the classification assigned to the plurality of extracted features associated with the plurality of segments.