Deep learning identifies morphological patterns of homologous recombination deficiency in luminal breast cancers from whole slide images

Homologous recombination DNA-repair deficiency (HRD) is becoming a well-recognized marker of platinum salt and polyADP-ribose polymerase inhibitor chemotherapies in ovarian and breast cancers. While large-scale screening for HRD using genomic markers is logistically and economically challenging, stained tissue slides are routinely acquired in clinical practice. With the objectives of providing a robust deep-learning method for HRD prediction from tissue slides and identifying related morphological phenotypes, we first show that digital pathology workflows are sensitive to potential biases in the training set, then we propose a method to overcome the influence of these biases, and we develop an interpretation method capable of identifying complex phenotypes. Application to our carefully curated in-house dataset allows us to predict HRD with high accuracy (area under the receiver-operator characteristics curve 0.86) and to identify morpho-logical phenotypes related to HRD. In particular, the presence of laminated fibrosis and clear tumor cells associated with HRD open new hypotheses regarding its phenotypic impact.