Proteogenomic characterization of invasive breast tumors in young women.

Breast cancer in women <40, accounting for ~5% of all breast cancer cases diagnosed in the U.S., is more aggressive and associated with worse outcomes compared to breast cancer in older women. We performed a first-ever integrated proteogenomic study from a matched cohort of laser-microdissected tumors of 34 young (<40 years) and 34 older (≥60 years) women to identify molecular features that may underlie the worse outcomes in young women. Progression-free interval was shorter in young women, and their tumors were enriched for more aggressive molecular subtypes. Our multi-omic analysis identified distinct clusters between age groups in luminal but not basal-like cancers. Notably, GATA3 mutations were enriched in luminal tumors from young women while TP53 and PIK3CA mutations were more common in luminal tumors from older women. Young women's tumors exhibited lower estrogen receptor (ER) expression yet paradoxically enhanced ER response pathways and increased expression of tamoxifen-resistance-associated genes (IRS1, FERMT1). Immune pathway activity and immune scores were lower in tumors from young women, whereas proliferative and MYC pathways were notably elevated, identifying potential therapeutic targets. Transcriptomic data from TCGA and METABRIC confirmed our findings, with 10 of 11 observed pathways corroborated. Finally, differential expression of four immune-related surface proteins also suggested the potential of age-specific responses to immune-based therapies. Together, these findings may contribute to the understanding of the molecular mechanisms underlying worse outcomes in young women and offer new insight to therapeutic strategies.