The PAM50 classifier predicts breast cancer prognosis but requires 50 genes and specialised platforms. We derived CorePAM, the smallest data-driven PAM50 subset maintaining non-inferior prognostic performance relative to a full 50-gene Cox elastic-net model, without pre-specifying gene count.

Cox elastic-net regression ((alpha = 0.5)) with deterministic 10-fold cross-validation was applied in the SCAN-B cohort (N = 3069; GSE96058). Gene selection followed a pre-specified non-inferiority margin ((Delta )C-index = 0.010). External validation used four independent cohorts: TCGA-BRCA (N = 1072; RNA-seq), METABRIC (N = 1978; microarray; disease-specific survival), GSE20685 (N = 327; microarray), and GSE1456 (N = 159; microarray). Incremental value over a clinical model (CORE-A: age and ER status) was assessed by bootstrap (Delta )C-index. Secondary analyses evaluated pathologic complete response (pCR) prediction in four neoadjuvant cohorts (N = 697) plus I-SPY2 (N = 986).

CorePAM comprises 24 genes with an out-of-fold C-index of 0.670 (gap vs 50-gene maximum: 0.009). The score was independently associated with survival in all validation cohorts: TCGA-BRCA (HR = 1.20), METABRIC DSS (HR = 1.41), GSE20685 (HR = 1.40), GSE1456 (HR = 1.71); all (p < 0.02). Random-effects meta-analysis (K = 4) yielded pooled HR = 1.37 (95% CI 1.24−1.52; (I^2) = 38.2%; (p = 1.6 times 10^{-9})). CorePAM provided incremental value beyond CORE-A and remained significant after adjustment for T-stage and nodal status. For pCR, pooled OR 1.69 (95% CI 1.39−2.05; (I^2) = 0%; (p = 1.9 times 10^{-7})).

CorePAM—a 24-gene PAM50-derived score—met the pre-specified (Delta )C-index non-inferiority criterion relative to a 50-gene Cox elastic-net comparator in derivation and retained prognostic discrimination across four external RNA-seq and microarray cohorts, remained significant after anatomical staging adjustment, and was associated with pCR in secondary neoadjuvant analyses. This reduction from 50 to 24 genes may simplify future assay development, although platform-specific analytical validation is required before clinical deployment.