Paolo Tarantino, Se-Eun Kim, Melissa E. Hughes, Ross J. Kusmick, Kalie Smith, Fara Brasó-Maristany, Nay Chan, Laia Paré Brunet, Laura Alder, Diana García-Cortés, Jorge Gomez Tejeda Zanudo, Alyssa Pereslete, Laura Noteware, Heather Moore, Amanda E.D. Van Swearingen, Tianyu Li, Hersh Gupta, Olivia D’Amico, Alba Martini, Stefania Morganti, Jennifer Spindel, Charmaine Cook, Christine McLaughlin, Kathrin Dvir, Ana C. Garrido-Castro, Sarah Sammons, Janet Files, Kerry Sendrick, Simone Buck, Deborah Dillon, Rinath Jeselsohn, Yvonne Y. Li, Andrew D. Cherniack, Patricia LoRusso, Maryam Lustberg, Rosario Vega- León, Francisco Pardo, Justin Davis, Claudius Mueller, Brian Corgiat, Giuseppe Curigliano, Carey K. Anders, Emanuel F. Petricoin, David L. Rimm, Aleix Prat, Nabihah Tayob, Nancy U. Lin, Sara M. Tolaney
Trastuzumab deruxtecan (T-DXd) is commonly used for treating metastatic breast cancer (MBC); however, traditional HER2 immunohistochemistry has largely failed to predict T-DXd activity. We reviewed survival outcomes and tested the reliability of multiple HER2 quantitative assays in predicting T-DXd's performance among 191 patients with MBC. We demonstrate that T-DXd's activity varies depending on the temporal evolution of HER2 immunohistochemical expression, with the longest activity observed among patients with HER2-positive disease or maintaining HER2-low disease across primary and metastatic settings. Quantitative HER2 assessment on pre-T-DXd samples showed that time-to-next treatment progressively increased by High Sensitivity-HER2 quartiles, Reverse Phase Protein Array HER2 quartiles, HER2DX ERBB2 mRNA scores and plasma-based DNADX HER2 signature tertiles (all with log-rank p < 0.05). Conversely, HER2 immunohistochemical subtypes showed limited predictive value for clinical outcomes. Additionally, elevated TOPO1 expression was associated with worse outcomes with T-DXd in HER2-negative breast cancer, suggesting potential relevance for payload-related markers in predicting T-DXd performance.