Patient-derived organoid models of malignant phyllodes tumors for drug sensitivity testing and identification of targeted therapeutic strategies.

Background: Malignant phyllodes tumors (MPT) of the breast are rare fibroepithelial neoplasms. It exhibits rapid growth, large size, and a high local recurrence rate.

Methods: In this study, we established novel patient-derived organoid (PDO) models from two primary MPT samples and conducted comprehensive genetic profiling and drug screening.

Results: The PDO models faithfully recapped the histopathological and molecular features of the primary tumors, including stromal overgrowth, leaf-like projections, and the expression of key diagnostic markers. Drug testing revealed significant heterogeneity in response profiles to chemotherapeutic reagents between the two MPT-derived organoids, implying the importance of personalized drug testing. Next-generation sequencing analysis identified recurrent mutations in TP53, RB1, EGFR, ATM, and RECQL4, which correlated with the drug sensitivity profiles observed in the organoid models. Targeted therapeutic drugs, such as Abemaciclib (targeting the RB1 pathway) with an IC50 value of 1.744 µM, and Alflutinib Mesylate (targeting the EGFR pathway) with an IC50 value of 0.9150 µM, exhibited significant cytotoxic effects in the MPT2 organoid models.

Conclusions: This study highlights the novel application of PDOs for studying the molecular landscape of MPTs and identifying effective therapeutic targets, offering a promising platform for guiding personalized treatment strategies for this rare and challenging cancer.