Abstract PS4-02: Patient-derived Xenografts (PDX) Allow Deconvolution of Combination Chemotherapy Response

Abstract Introduction: Triple-negative breast cancer (TNBC) patients frequently receive combination chemotherapy treatment, including most recently taxane/platinum combinations. However, treatment is not biomarker-guided. As such, it is not known which patient will respond to one or the other agent, or indeed which patients actually require the combination for the most effective treatment. We hypothesized that optimization of chemotherapy may be possible if molecular mechanisms and biomarkers underlying response to individual treatments can be identified. We evaluated this hypothesis in a preclinical trial using a cohort of 50 patient-derived xenograft (PDX) models of TNBC treated with either single-agent docetaxel or carboplatin, or their combination. Methods: 50 TNBC PDXs were evaluated for response to four weekly treatments with either single agent docetaxel (20 mg/kg), or carboplatin (50 mg/kg); 42 of these were also treated with their combination. Multi-omics profiling (genomics, transcriptomics, proteomics) was conducted before treatment. Gene level associations by treatment type were used to construct consensus gene sets by integrating our data with external TNBC PDX and patient cohorts which were then used to build XGBoost models to predict treatment-specific responses. Pathway analysis was performed using signed -log10 p-values from gene level results as input for Gene Set Enrichment Analysis. Results: Direct comparison of responses to carboplatin, docetaxel, and their combination showed that combination treatment was largely ineffective at generating enhanced responses over the best single agent. Only 13% of the 42 PDX showed enhanced responses in combination, with a comparable percentage (12%) showing antagonism between docetaxel and carboplatin, a phenomenon observed previously in vitro. Proteogenomic profiles revealed distinct genes associated with responses to each agent and their combination, suggesting different molecular mechanisms underlying each treatment response. A substantial number of genes linked to single-agent and combination treatments were validated in multiple independent PDX and patient cohorts receiving platinum and taxane-containing neoadjuvant therapy, confirming the clinical relevance of our PDX panel. Chemotherapy-specific predictors for pathological complete response (pCR)/CR achieved AUROCs of 0.79, 0.67, and 0.70 for platinum, taxane, and combination treatments, respectively. The single-agent platinum model was the most effective in predicting platinum response, with a similar trend for taxane and platinum+taxane predictors. These findings reinforce the observation that distinct gene sets are linked to responses to different chemotherapy treatments. Since the predictors used treatment-associated genes found in both PDX and clinical samples, these results suggest biomarker combinations for translation and clinical development to select TNBC tumors that may respond to specific regimens. In PDXs responsive to any treatment, several basal cytokeratins were among the top upregulated proteins compared to PDXs resistant to all treatments. KRT5 was validated by IHC in PDX tumors, achieving an AUROC of 0.83 for predicting responsiveness, indicating its potential as a future chemoresponse marker in TNBC. PDXs refractory to all treatment arms had higher levels of mitochondrial and cancer stem-cell-related pathways. Treatment with romidepsin, an HDAC inhibitor that targets these pathways and increases DNA damage, enhanced carboplatin response in a chemoresistant PDX model with high abundance of HDAC proteins. Conclusion: Proteogenomic characterization identifies molecular mechanisms and putative biomarkers for stratifying TNBC tumors for single or combination chemotherapy treatments, suggests targeted therapies to augment chemotherapy response, and provides a valuable resource for researchers and clinicians. Citation Format: Jonathan Lei, Lacey E. Dobrolecki, Chen Huang, Ramakrishnan R. Srinivasan, Suhas Vasaikar, Alaina N. Lewis, Christina Sallas, John D. Landua, Chang In Moon, Yuxing Liao, Na Zhao, Jin Cao, Susan G. Hilsenbeck, C. Kent Osborne, Mothaffar F. Rimawi, Matthew J. Ellis, Varduhi Petrosyan, Bo Wen, Kai Li, Alexander B. Saltzman, Antrix Jain, Anna Malovannaya, Gerburg Wulf, Shunqiang Li, Daniel C. Kraushaar, Elisabetta Marangoni, Tao Wang, Senthil Damodaran, Xiaofeng Zheng, Funda Meric-Bernstam, Bryan E. Welm, Alana L. Welm, Xi Chen, Gloria V. Echeverria, Meenakshi Anurag, Bing Zhang, Michael T. Lewis. Patient-derived Xenografts (PDX) Allow Deconvolution of Combination Chemotherapy Response [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 PS4-02.