Abstract Introduction: Breast cancer (BC) in women < 40 years old accounts for ~5% of BC diagnosed in the U.S. However, young women have more aggressive tumors and worse outcomes, including higher rates of recurrence and lower disease-free and overall survival, compared to older women. To better understand mechanisms for these disparities, an integrated proteogenomic study of tumors from young (< 40) and older (≥ 60) women was performed through the Applied Proteogenomics OrganizationaL Learning and Outcomes (APOLLO) program. Methods: 34 pairs of retrospectively collected, untreated primary breast tumors from young and older women, matched by immunohistochemistry (IHC) subtype and race, were selected from the Clinical Breast Care Project. Median patient follow-up was 7 years. Tumor cells were enriched by laser microdissection and analyzed using RNA sequencing, whole genome sequencing, global proteomics, phosphoproteomics, and reverse phase protein array (RPPA). Molecular and clinical data from tumors from young and old patients in the TCGA-BC and METABRIC studies, matched by IHC subtype and race, were used to corroborate findings from our cohort. Results are presented comparing young women and their tumors to their older counterparts. Results: Young women have worse clinical outcome measured by progression-free interval. Despite matching for IHC subtypes, tumors from young women are enriched for intrinsic basal-like subtype, BRCA1/2 germline mutations, and had fewer invasive lobular BCs. Differentially enriched molecules and pathways: A number of significantly differentially expressed genes (DEGs) and proteins were detected, which were able to separate luminal subtypes of BC by patient age. IRS1 and IRS2 were enriched at both transcript and protein levels; IRS1 has been reported to promote tamoxifen resistance. We observed limited overlap of DEGs between the APOLLO, TCGA, and METABRIC datasets. In contrast, 14 of the 28 significantly upregulated Cancer Hallmark pathways were also enriched in TCGA-BC and METABRIC datasets; suggesting targeting pathways, vs genes, may be more effective for therapeutic intervention. Integrated pathway/network analysis: Integrated pathway analysis of RNA and protein levels identified 5 Hallmark pathways upregulated in younger women, including ER response and proliferative pathways, and 6 downregulated immune-response pathways; 10 of the 11 were supported by the public datasets. Immune scores were also lower. Kinase substrate enrichment analysis identified 4 kinases with increased activity in tumors from young women. ESR1/ER: We identified for the first time a significant reduction of ER protein expression while confirming previously reported lower ESR1 gene expression and copy number variations. Surprisingly, integrated pathway analysis identified elevation of early and late estrogen responses in young women. ER activation, indicated by phosphorylated ER (pS118) normalized to total ER protein, was elevated in LumA tumors from young women. Conclusions: This first-ever integrated proteogenomic study shows that BC in young women is enriched for more aggressive molecular subtypes and for genes that promote tamoxifen resistance, exhibits lower immune pathways and immune scores, and shows enhanced ER responses despite lower gene and protein expression of ER. These findings may contribute to the understanding of the molecular mechanisms underlying worse outcomes of BC in young women, and offer new insight to therapeutic strategies. Disclaimer: The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions or policies of USUHS, HJF, the DoD or the Departments of the Army, Navy or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Citation Format: Praveen Kumar Raj Kumar, Jianfang Liu, Anthony Soltis, Nicholas Bateman, Qingrong Chen, Lori Sturtz, Brenda Deyarmin, Mariaelena Pierobon, Tamara Abulez, Anupama Praveen-Kumar, Xijun Zhang, Trinh Nguyen, Chunhua Yan, Ying Hu, Kate Guion, Jeffrey Hooke, Albert Kovatich, Leigh Fantacone-Campbell, Brad Mostoller, Leonid Kvecher, Stella Somiari, Patricia Steeg, Sheila Rajagopal, Kathleen Darcy, Jerry Lee, Clifton Dalgard, Thomas Conrads, Emanuel Petricoin, Daoud Meerzaman, Matthew Wilkerson, APOLLO Research Network, Xiaoying Lin, Craig Shriver, Stanley Lipkowitz, Hai Hu. Proteogenomic characterization of primary invasive breast tumors from young women compared to matched tumors from older women [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-13-10.
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