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APOLLO-BRCA-1: Proteogenomic Analysis of Invasive Breast Tumors in Young (less than 40 years old) vs Older Patients (greater than or equal to 60 years old)

Breast cancer in women under the age of 40, accounting for ~5% of breast cancer diagnosed in the U.S., is more aggressive with worse outcomes than breast cancer in older women. The aim of this study is to to identify molecular features that may underlie the worse outcomes in young women with breast cancer. We performed a first-ever integrated proteogenomic study from a matched cohort of laser-microdissected tumors of 34 young (age < 40) and 34 older (age ≥ 60) women. In this cohort, we have demonstrated that the progression-free interval is shorter in young women, and their tumors are enriched for more aggressive molecular subtypes. Genomic, transcriptomic, proteomic, phosphoproteomic, and pathway differences between these age groups were identified. Tumors in young women, despite having lower estrogen receptor (ER) gene and protein expression, had enhanced ER response pathways and were enriched with genes that promote tamoxifen resistance, and exhibited lower immune pathways and immune scores. Overall, these findings may contribute to the understanding of the molecular mechanisms underlying worse outcomes in young women and offer new insight to therapeutic strategies. Whole genome sequencing and RNA-sequencing data are available through dbGaP. Proteomics data are available from the Proteomic Data Commons at the National Cancer Institute.