作者与单位 Authors & Affiliations
Stefan J. Hutten1, Xue Chao1, Madelon Badoux1, Timo Eijkman1, Michael Sheinman2, Roebi de Bruijn1, Andrea Herencia-Ropero3, Alba Llop-Guevara3, Catrin Lutz1, Jelle Wesseling1, Violeta Serra3, Jacco Van Rheenen1, Colinda LGJ Scheele4, Jos Jonkers1
1Netherlands Cancer Institute, Amsterdam, Netherlands,2Weizmann Institute of Science, Tel Aviv, Israel,3Vall D'Hebron Institute of Oncology, Barcelona, Spain,4VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
摘要 Abstract
Targeted therapies are important for invasive breast cancer (IBC) treatment but are generally not standard-of-care in the neoadjuvant setting. To identify therapies with the potential to improve neoadjuvant treatment response, it is essential to develop patient-derived preclinical models that faithfully reflect the diversity of primary IBC subtypes in patients. Here, we collected data of all breast cancer patients (N=1675) diagnosed in the Antoni van Leeuwenhoek hospital (AVL) for a period of three years, while simultaneously receiving tissue samples of 314 patients to establish a collection of mouse-intraductal patient-derived xenograft (MIND-PDX) models fully recapitulating the heterogeneity of primary IBC. Serial transplantation of lesions resulted in the first large-scale cohort of 60 transplantable IBC-MIND models, comprising 31 luminal (i.e., ER+/HER-), 5 HER2+ and 24 TN models, as well as 7 matching PDX organoid (PDXO) models. We show that our IBC-MIND cohort can serve as a platform for preclinical evaluation of experimental neoadjuvant treatments. For triple-negative IBC, we demonstrate that neoadjuvant treatment does not benefit from addition of a PARP inhibitor, while for estrogen receptor (ER) positive IBC the combination of a CDK4/6 inhibitor and fulvestrant improves neoadjuvant treatment response. Our work provides a valuable resource of primary IBC models to study breast cancer biology and develop novel neoadjuvant treatments.