CorePAM: a 24-gene PAM50-derived expression score with cross-platform external validation for breast cancer prognosis.

BACKGROUND

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.

METHODS

Cox elastic-net regression ([Formula: see text]) 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 (ΔC-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 ΔC-index. Secondary analyses evaluated pathologic complete response (pCR) prediction in four neoadjuvant cohorts (N = 697) plus I-SPY2 (N = 986).

RESULTS

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 [Formula: see text]. Random-effects meta-analysis (K = 4) yielded pooled HR = 1.37 (95% CI 1.24-1.52; [Formula: see text] = 38.2%; [Formula: see text]). 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; [Formula: see text] = 0%; [Formula: see text]).

CONCLUSIONS

CorePAM-a 24-gene PAM50-derived score-met the pre-specified ΔC-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.