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Determinants of long-term response to patritumab deruxtecan (HER3-DXd) in breast cancer patient-derived xenografts

ABSTRACT: Purpose: Novel antibody-drug conjugates (ADCs) have shown potent antitumor activity across multiple cancer types. Here, we aimed to identify potential determinants of response to patritumab deruxtecan (HER3-DXd), a HER3-directed ADC linked to a potent topoisomerase I inhibitor (TOP1i) payload, in breast cancer (BC) patient-derived xenograft (PDX) models. Experimental Design: The antitumor activity of HER3-DXd was assessed in 31 BC PDXs and classified according to tumor growth inhibition and duration of response. We analyzed the sensitivity to HER3-DXd according to the molecular characteristics of the PDX models, the sensitivity to the TOP1i irinotecan, and prior patient treatments. The biological effects following treatment with HER3- DXd were assessed and associated to treatment response. Results: Fourteen out of 31 (45%) PDXs exhibited a profound and sustained response to HER3-DXd. Basal-like PAM50 intrinsic subtype was associated with long-term response, across HER3/ERBB3 expression levels. We also observed a positive association between HER3-DXd and irinotecan sensitivity in the PDXs, as well as short-lasting antitumor response in models derived from patients with prior repeated exposure to chemotherapy. HER3-DXd showed sustained activity in BRCA1/BRCA2-mutated PARPi-resistant PDX models. Long-term responders exhibited persistent DNA damage and lacked early transcriptional activation of the G2/M cell cycle checkpoint to allow for DNA repair and R-loop resolution, in parallel resulting in immune pathways activation. Conclusions: HER3-DXd exhibited potent antitumor activity in breast cancer PDX models, including those with BRCA1/BRCA2 alterations and PARPi resistance. Notably, characteristics linked to long-term response were primarily associated with the TOP1i payload activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307574 | GEO | 2025/11/28

REPOSITORIES: GEO

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Project description:Osteosarcoma (OS) and Ewing’s sarcoma (EW) are the two most common pediatric solid tumors, after brain tumors. Multimodal treatments have significantly improved prognosis in localized disease but outcome is still poor in metastatic patients, for whom therapeutic options are often inadequate. Preclinical drug testing to identify promising treatment options that match the molecular make-up of these tumors is hampered by the lack of appropriate and molecularly well-characterized patient-derived models. To address this need, a panel of patient-derived xenografts (PDX) was established by subcutaneous implantation of fresh, surgically resected OS and EW tumors in NSG mice. Tumors were re-transplanted to next mice generations and fragments were collected for histopathological and molecular characterization. A model was considered established after observing stable histological and molecular features for at least three passages. To evaluate the similarity of the model with primary tumor, we performed a global gene expression profiling and tissue microarrays (TMA), to assess tumor specific biomarkers on tissues from OS/EW tumors and their PDXs (1st and 3rd passage). Moreover, we verified the feasibility of these models for preclinical drug testing. We implanted 61 OS and 29 EW samples: 14/38 (37%) primary OS and 9/23 (39%) OS lung metastases successfully engrafted; while among EW, 5/26 (19%) primary samples and 1/3 (33%) metastases were established. Comparison between patient samples and PDXs, highlighted that histology and genetic characteristics of PDXs were stable and maintained over passages. In particular, correlative analysis between OS and EW samples and their PDXs was extremely high (Pearson’s r range r=0.94-0.96), while patient-derived primary cultures displayed reduced correlation with human samples (r=0.90-0.93), indicating that in vitro adaptation superimpose molecular alterations that create genetic diversion from original tumors. No significant differentially expressed gene profile was observed from the comparison between EW samples and PDXs (fold change > 2, adjusted p <0.05 at paired t-test). In OS, the comparison between OS patient-derived tumors and PDX indicated differences in 397 genes, mostly belonging to immune system functional category. This is in line with the idea that human immune cells are gradually replaced by murine counterparts upon engraftment in the mouse. As proof-of concept, two EW PDX and one OS PDX have been treated with conventional and innovated drugs to test their value in terms of drug-sensitivity prediction. Overall, our study indicated that PDX models maintained the histological and genetic markers of the tumor samples and represent reliable models to test sensitivity to novel drug associations.

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Determinants of long-term response to patritumab deruxtecan (HER3-DXd) in breast cancer patient-derived xenografts

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