Mapping a personalized chemo-resistome in breast cancer patients by longitudinal transcriptomics

Understanding resistance mechanisms to chemotherapy is key to improving therapeutic outcomes. Despite the considerable importance of resistance to cancer morbidity and mortality, the actual response of an individual patient remains a ‘black box’. Recent studies demonstrate that tumors acquire resistance by rewiring transcriptional program; however, our comprehension of the emerging resistance mechanisms in each patient is limited.

To dissect the individualized emergence of resistance in breast cancer patients we applied longitudinal transcriptomics combined with temporal dynamics analysis. Matched triplets of archived tumor biopsies from pre-treatment, post-treatment and adjacent normal epithelium were collected from 33 breast cancer patients that underwent neo-adjuvant chemotherapy. We performed full transcriptome analysis by mRNA sequencing. Longitudinal pattern analysis algorithm was developed to follow dynamic expression fluctuations in individual patients. Enrichment analysis was used to map the rewired resistant pathways. We found multiple pathways directly related to the mechanism of action of the administered chemotherapies. Other emerged pathways involve multi-drug resistance pathways. Finally, we created personal chemo-resistome maps to illustrate emergence of individual resistance-related pathways. The maps exemplify the co-existence of several such pathways in each patient. Importantly, some categories exhibited patient-specific or subtype-specific occurrence, emphasizing the individual emergence of transcription rewiring upon treatment.

Mapping the complexity of the various resistance pathways in individual patients can provide important insights on the underlying mechanisms. Depicting an individual road map to resistance by analyzing expression rewiring can offer personalized therapeutic strategies in the future.