Genomic Alterations Associated with Recurrence and TNBC Subtype in High-risk Early Breast Cancers

The identification of early breast cancer (eBC) patients who may benefit from adjuvant chemotherapy has evolved to include assessment of clinicopathological features such as tumor size and nodal status, as well as several gene expression profiles for ER-positive, HER2-negative cancers. However, these tools do not reliably identify patients at the greatest risk of recurrence. The mutation and copy number landscape of triple-negative breast cancer (TNBC) subtypes defined by gene expression is also largely unknown, and elucidation of this landscape may shed light on novel therapeutic opportunities. The USO01062 Phase 3 clinical trial of standard chemotherapy (with or without capecitabine) enrolled a cohort of putatively high-risk patients based on clinical features, yet only observed a five-year disease-free survival event rate of 11.6%. In order to uncover genomic aberrations associated with recurrence a targeted next-generation sequencing (NGS) panel was used to compare tumor specimens from patients who had a recurrence event with a matched set who did not. The somatic mutation and copy number alteration landscapes of high-risk eBC patients were characterized and alterations associated with relapse were identified. Tumor mutational burden was evaluated but was not prognostic in this study, nor did it correlate with PDL1 or CD8 gene expression. However, TNBC subtypes had substantial genomic heterogeneity with a distinct pattern of genomic alterations and putative underlying driver mutations. Implications: The present study uncovers a compendium of genomic alterations with utility to more precisely identify high-risk patients for adjuvant trials of novel therapeutic agents.