Diagnostic plasma protein signatures in sporadic and BRCA1/2 breast cancer patients via targeted proteomics

BACKGROUND: Early breast cancer diagnosis is critical, particularly for individuals at hereditary risk. The aim of this study was to identify blood-derived protein biomarkers for breast cancer diagnosis to improve current screening strategies. METHODS: Absolute quantification of 98 plasma proteins was performed via a UPLC-MRM-MS assay on plasma samples from 135 breast cancer patients and paired controls, one-third of which were of hereditary BRCA1/2 origin, and from women diagnosed within 5 years from blood collection. Plasma protein concentration profiles were compared between patients and paired controls across breast cancer subgroups. RESULTS: Proteomic analysis revealed four plasma proteins with elevated abundance and four other proteins with reduced abundance across different breast cancer subgroups. Haptoglobin (HP) was elevated in sporadic cases (n = 88) and cases with grade 3 tumors (n = 44), adipocyte plasma membrane-associated protein was elevated in cases with large tumors (n = 60) and grade 3 tumors (n = 44), lipopolysaccharide-binding protein (LBP) was elevated in node-positive (n = 58) and HER2 (n = 9) cases, and secreted protein acidic and cysteine rich was elevated in luminal B (n = 45) cases. Transthyretin was reduced in luminal B patients, and apolipoprotein A4 was reduced in HER2 patients. Immunoglobulin heavy constant mu (IGHM) and CD5 antigen-like (CD5L) were lower in BRCA1/2 (n = 47) and triple-negative (n = 17) patients than in paired controls. IGHM and CD5L were also lower in BRCA1/2 patients than in paired sporadic patients. Additionally, IGHM in plasma was lower among BRCA2 mutation carriers (n = 7) diagnosed with breast cancer within 5 years of blood collection than among paired controls and CD5L was also lower than among paired controls and sporadic patients diagnosed within 5 years of blood collection. The plasma proteins associated with breast cancer specific survival were LBP, HP, and IGHM. CONCLUSIONS: These findings indicate that plasma protein concentrations may have diagnostic and prognostic value for breast cancer screening and could provide valuable insights for biomarker discovery.