Abstract P4-10-24: Extracellular matrix remodelling is a targetable feature of invasive lobular carcinoma (ILC)

Abstract Background: Invasive lobular carcinoma (ILC) has previously been identified as overexpressing collagens and elastin as well as LOXL1, a collagen cross-linking enzyme belonging to the lysly oxidase (LOX) family. Abberant LOX activity can promote breast cancer invasion and metastasis through remodelling of the extracellular matrix (ECM). The clinical stage pan-LOX inhibitor PXS-5505 has demonstrated anti-tumour potential through the disruption of the collagen matrix in models of pancreatic and myeloid cancer, and exhibits an excellent safety profile. Given that ILCs are enriched for ECM remodelling, we propose that inhibition of LOX be investigated as a therapeutic strategy in the treatment of ILC. Methods: We xenograft ILC cells into the milk ducts of mice (MIND) to faithfully recapitulate ILC disease progression including ECM remodelling processes. We used cell line and PDX MIND models of ILC to examine their response to LOX inhibition (LOXi) alone and combination with ovariectomy (OVX) to mimic aromatase inhibition (AI). Results: Treatment with LOXi alone significantly decreased primary tumour growth compared to vehicle in cell line and patient derived xenograft models of ILC. This was accompanied by changes in the “matrix structure” and downmodulation of proliferative markers, and a transcriptional level MYC and ER signalling pathways. The magnitude of response to LOXi differed across ER+ ILC models, either being sufficient to reduce primary tumour growth alone (SUM44, p=0.000410), or in combination with OVX (MM134, p=0.032). In the metastatic ER- IPH-926 model LOXi significantly reduced metastatic dissemination to the lungs (p=0.013). Histologically, combination treatment decreased collagen matrix density and alignment as well as the Ki67 index. Proteomic profiling revealed LOXi alone and in combination with OVX downmodulated matrix-associated proteins, as well as MYC transcription factor targets. Functional pathway and keyword enrichment analysis identified down modulation of cell adhesion, cell cycle and apoptosis-related pathways. Conclusion: These data demonstrate that ECM remodelling is a targetable feature of ILC and suggest that the LOXi PXS-5505, a well tolerated drug provides additional benefit to standard of care endocrine therapy. Changes in fibrillar collagen and matrix-associated proteins result in decreased MYC activity, which may serve as an endpoint in a prospective window trial. Citation Format: Renee Flaherty, Flavia Hughes, George Sflomos, Carlos Ronchi, Hazel Quinn, Solene Pezot, Samuel Jouny, Harveena Padda, Theo Roumeliotis, Giovanna Ambrosini, Beatrice Howard, Cathrin Brisken. Extracellular matrix remodelling is a targetable feature of invasive lobular carcinoma (ILC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-10-24.