Chemotherapy drives genomic selection and shapes clonal architecture and therapeutic vulnerability of tumors in triple-negative breast cancer
Triple-negative breast cancer (TNBC) is highly aggressive, exhibits marked tumor heterogeneity, and has higher recurrence rates and earlier metastasis. We developed a pipeline for highly reliable genomic profiling and the identification of actionable mutations, paving the way for the implementation of precision therapies in TNBC. We performed whole-exome sequencing (WES) of pre- and post-chemotherapy tumors from 5 patients with TNBC. We developed an integrated bioinformatics pipeline, coupled with a machine learning tool, to identify high-confidence, clinically actionable tumor mutations. We identified high subclonal heterogeneity and ubiquitous (100%) penetrance of stem mutations in the TP53 gene in pre-chemotherapy tumors. Cytotoxic pressure reduced tumor mutational burden (TMB) and shifted allele frequencies of mutations in resistant subclones (median VAF shift from 0.51 to 0.18), thereby eradicating unstable dominant clones and foci of focal hypermutation (kataegis). This cytotoxic pressure reduced clonal diversity and reconfigured oncogenic pathways. Mutational signatures deconvolution demonstrates the fixation of the COSMIC 3 signature, associated with homologous recombination repair (HRD) deficiency in post-chemotherapy tumors. Comparative analysis of the mutational landscape demonstrates that chemotherapy selects for and restructures the tumor genomic architecture, providing evidence for the potential implementation of PARP inhibitors in residual disease in patients with TNBC.
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