Postpartum breast cancer: evidence for a distinct phenotype.

The incidence of early onset breast cancers (BCs) has increased, paralleling rising trends in delayed childbearing. We hypothesize that a distinct postpartum BC subtype (PPBC), identifiable by time since last birth (TSLB) and biomarker expression, contributes to this trend. We applied GeoMx Digital Spatial Profiling (DSP) to measure associations between TSLB and 71 proteins in 640 BCs from women ages ≤40 years included in the Young Women's BC Study. We analyzed data using univariable linear regression and multivariable Sliced Inverse Regression to account for higher order interactions among biomarkers. In keratin-rich segments, PR (p = 1.00x10-4) and PTEN (p = 1.00x10-3) were associated with longer TSLB; multivariable analyses revealed positive associations for GZMB (p = 4.00X10-4), SMA (1.00X10-4) and NF-1 (p = 1.00X10-3). In keratin-poor segments, univariable significant positive associations were found for PR (p = 2.00x10-4) and PTEN (p = 1.00x10-3), whereas CD20 (p = 3.00x10-4) and CTLA4 (p = 4.00x10-5) were negatively associated; multivariable significant associations were found for fibronectin (p = 3.00x10-5) and pan-Akt (p = 1.00x10-3). Associations persisted after adjustment for multiple comparisons and BC molecular subtypes. Associations including for PR, PTEN and CD20 were strongest among women with shortest TSLB. OPAL multiplex immunofluorescence assays for PR, PTEN, CD20, SMA and CTLA4, replicated several DSP findings, particularly when stratified by subtype and with compartment matching. In TCGA, RNA species linked to proteins associated with TSLB correlated strongly with a T cell exhaustion signature previously linked to poor prognosis among premenopausal women. These data support PPBC as a biologically coherent phenotype defined by TSLB and biomarker profile, with potential implications for prevention and therapy.