Early temporal transcriptional and cytokine responses distinguish chemotherapy sensitivity in patient-derived xenograft models of triple-negative breast cancer

Chemotherapy remains the backbone of neoadjuvant treatment for triple-negative breast cancer (TNBC), and response to chemotherapy strongly correlates with patient prognosis. However, predicting chemoresistance remains a major clinical challenge. To address this obstacle, we performed serial fine needle aspirations followed by RNA-sequencing on patient-derived xenograft (PDX) models of TNBC that were either chemoresponsive or chemoresistant. We found that these two classes of PDX models exhibited distinct transcriptional trajectories that diverged within one week of chemotherapy initiation, preceding measurable changes in tumor volume. At early time points, chemoresponsive tumors showed activation of apoptotic and cytokine-related pathways, while these changes were absent in chemoresistant models. Notably, cytokine upregulation in chemoresponsive tumors coincided with infiltration of myeloid-derived immune cells into the tumor bed within seven days of chemotherapy, indicating active microenvironment remodeling, even in mice lacking a fully intact immune system. Analysis of paired biopsies from patients with TNBC collected before treatment and within four days of the first chemotherapy dose revealed a consistent pattern: chemoresponsive tumors upregulated inflammatory pathways, whereas chemoresistant tumors showed diminished activation of these pathways. These results underscore the potential clinical value of early on-treatment tumor sampling to detect chemoresistance and guide therapeutic intervention.