ESPWA: a deep learning-enabled tool for precision-based use of endocrine therapy in resource-limited settings.

Background: Cancer morbidity disproportionately affects patients in low- and middle-income countries (LMICs), where timely and accurate tumor profiling is often nonexistent. Immunohistochemistry-based assessment of estrogen receptor (ER) status, a critical step to guide use of endocrine therapy (ET) in breast cancer, is often delayed or unavailable. As a result, ET is often prescribed empirically, leading to ineffective and toxic treatment for ER-negative patients. To address this unmet need, we developed Methods: We curated two cohorts of H&E WSIs with tissue-matched ER status: The Cancer Genome Atlas (TCGA, n = 1085) and Zanmi Lasante (ZL, n = 3448) from Haiti. We trained two models using weakly supervised attention-based multiple instance learning: a "TCGA" model, trained on TCGA data, and ESPWA, trained on the ZL dataset. Model performance was evaluated using 10-fold cross validation. Results: Performance of the "TCGA" model was sensitive to the domain shift between the TCGA and ZL datasets, with a performance of an area under receiver operating characteristic (AUROC) of 0.846 on the TCGA test sets and 0.671 on the ZL test sets. Compared to the "TCGA" model, ESPWA demonstrated improved performance on the ZL cohort (AUROC=0.790; p=0.005). Subgroup analyses revealed clinically relevant populations in which ESPWA demonstrated improved performance relative to the overall cohort. Finally, ESPWA outperformed an academic breast pathologist (accuracy: 0.726 vs 0.639 respectively; p <0.001) in determining ER status from H&E WSIs. Conclusion: ESPWA ("Hope" in Haitian Creole) offers an accessible framework to identify individualized therapeutic insights from H&E WSIs in LMICs. We have initiated clinical trials, using ESPWA, in ZL and sub-Saharan African countries to inform precision-based use of ET for prospective patients.