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

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. 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. 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. 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.