ArticleJournal of the National Cancer Institute2026
Postpartum breast cancer: evidence for a distinct phenotype.
Article in Journal of the National Cancer Institute, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundThe incidence of early onset breast cancers (BCs) has increased, paralleling rising trends in delayed childbearing. We hypothesize that a distinct postpartum BC (PPBC) subtype, identifiable by time since last birth (TSLB) and biomarker expression, contributes to this trend.
methodsWe applied GeoMx Digital Spatial Profiling (DSP) to measure associations between TSLB and 71 proteins in 640 BCs from women aged ≤40 years included in the Young Women's Breast Cancer Study. We analyzed data using univariable linear regression and multivariable sliced inverse regression to account for higher order interactions among biomarkers.
resultsIn keratin-rich segments, progesterone receptor (PR) (P = 1.00 × 10-4) and PTEN (P = 1.00 × 10-3) were associated with longer TSLB; multivariable analyses revealed positive associations for GZMB (P = 4.00 × 10-4), SMA (P = 1.00 × 10-4), and NF-1 (P = 1.00 × 10-3). In keratin-poor segments, univariable significant positive associations were found for PR (P = 2.00 × 10-4) and PTEN (P = 1.00 × 10-3), whereas CD20 (P = 3.00 × 10-4) and CTLA4 (P = 4.00 × 10-5) were negatively associated; multivariable significant associations were found for fibronectin (P = 3.00 × 10-5) and pan-Akt (P = 1.00 × 10-3). Associations persisted after adjustment for multiple comparisons and BC molecular subtypes. Associations including for PR, PTEN, and CD20 were strongest among women with the 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.
conclusionThese data support PPBC as a biologically coherent phenotype defined by TSLB and biomarker profile, with potential implications for prevention and therapy.
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