P11.37.B NOVEL PATIENT-DERIVED BREAST CANCER BRAIN METASTASES MODELS CHARACTERIZED BY LARGE-SCALE DRUG SCREENING AND INTEGRATIVE MULTI-OMICS PROFILING

Abstract BACKGROUND The development brain metastases is among the most critical predictive factors for breast cancer patient survival. At the same time, personalized selection of effective drugs against BCBM is particularly challenging due to various reasons, including tumor evolution and clonal selection throughout pre-treatments, and novelty and/or multiplicity of driver alterations at this prognostically leading metastatic site. MATERIAL AND METHODS To better understand individual BCBM biology and drug sensitivity, we generated novel patient-derived BCBM cell lines from three individuals with triple-negative and three with HER2-enriched breast cancer and tested their suitability as ex vivo and in vivo model systems. We performed a large-scale drug screening evaluating responses to 276 drugs and testing more than 10 dosage points. Both, the cell lines and their parental BCBM tissues, were further characterized by whole genome and RNA-sequencing. Integrative analyses of drug response and multi-omics data was performed together with the patients´ molecular tumor board as part of the Heidelberg CATCH study, a metastatic breast cancer precision oncology program, and clinical data. RESULTS Multi-omics analyses revealed that the novel cell lines maintained key molecular characteristics, including major predictive alterations, of the originating BCBM. Further, the cell lines proofed tumor growth in mice supporting their suitability for potential in vivo studies. Overall, the newly established BCBM cell lines exhibited drug responses that closely reflected the individual patient and breast cancer subtype. In addition to the validation of predicted drug sensitivities based on multi-omics data, functional drug response data exhibited the potential to further aid in target prioritization within therapeutic approaches. Of note, individual ex vivo drug responses and resistances overall broadly matched the retrospectively assessed real-life drug response and clinical courses. CONCLUSION Taken together, our findings emphasize the critical importance of personalized therapeutic strategies for BCBM patients and demonstrate the value of integrating functional drug screening with multi-omics data. Ultimately, the newly developed and characterized BCBM cell lines serve as a valuable resource for future research.