Journal Article

Multimodal histopathologic models stratify hormone receptor-positive early breast cancer

Marra, Antonio, Schultz, Nikolaus, Cekan, Pavol, Razavi, Pedram, Curigliano, Giuseppe, Weigelt, Britta, Loeffler, Chiara M. L., Selenica, Pier, Mane, Eltjona, Munzone, Elisabetta, Waters, Michele, Shah, Sohrab P., Zagami, Paola, Frascarelli, Chiara, Fusco, Nicola, Kather, Jakob Nikolas, Reis-Filho, Jorge S., Guerini-Rocco, Elena, Erber, Ramona, Pareja, Fresia, El Nahhas, Omar S. M., Braunstein, Lior, Dellapasqua, Silvia, Paul, Evan D., Jee, Justin, Boehm, Kevin M., Chandarlapaty, Sarat, Wen, Hannah Y.

2025

Overview

The Oncotype DX® Recurrence Score (RS) is an assay for hormone receptor-positive early breast cancer with extensively validated predictive and prognostic value. However, its cost and lag time have limited global adoption, and previous attempts to estimate it using clinicopathologic variables have had limited success. To address this, we assembled 6172 cases across three institutions and developed Orpheus, a multimodal deep learning tool to infer the RS from H&E whole-slide images. Our model identifies TAILORx high-risk cases (RS > 25) with an area under the curve (AUC) of 0.89, compared to a leading clinicopathologic nomogram with 0.73. Furthermore, in patients with RS ≤ 25, Orpheus ascertains risk of metastatic recurrence more accurately than the RS itself (0.75 vs 0.49 mean time-dependent AUC). These findings have the potential to guide adjuvant therapy for high-risk cases and tailor surveillance for patients at elevated metastatic recurrence risk. The authors develop multimodal machine learning models to infer metastatic recurrence risk for early-stage, hormone receptor-positive breast cancer from H&E images using >6000 cases across three centers, outperforming a nomogram and unimodal methods.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/114/1564 / 631/114/2401 / 631/67/1347 / Adult / Aged / Breast cancer / Breast Neoplasms - diagnosis / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Deep Learning / Female / Humanities and Social Sciences / Humans / Lag time / Machine learning / Medical imaging / Metastases / Metastasis / Middle Aged / multidisciplinary / Neoplasm Recurrence, Local - pathology / Nomograms / Prognosis / Receptors / Receptors, Estrogen - metabolism / Receptors, Progesterone - metabolism / Risk / Science / Science (multidisciplinary) / Time dependence