A Prognostic Model Based on PAM50 and Clinical Variables (PAM50MET) for Metastatic Hormone Receptor-positive HER2-negative Breast Cancer

Abstract

Purpose: Predicting prognosis in HR⁺/HER2^- metastatic breast cancer (MBC) might be clinically useful; however, no validated prognostic biomarkers exist in this setting to date.

Patients and methods: In phase III, EGF30008 trial, 484 patients with HER2^- MBC who received letrozole and placebo or lapatinib were selected. PAM50 data, ECOG performance status, visceral disease, number of metastasis, biopsy type, and age were evaluated. A progression-free survival (PFS) Cox model was evaluated. The final model (PAM50MET) with a prespecified cutoff was validated in patients (n = 261) with HR⁺/HER2^- advanced breast cancer (aBC) from BOLERO-2 (phase III trial that evaluated exemestane and placebo or everolimus).

Results: In EGF30008, prognostic models with PAM50 plus clinical variables yielded higher C-index values versus models with only PAM50 or clinical variables. The PAM50MET model combined 21 variables: 2 PAM50 subtypes, basal signature, 14 genes, and 4 clinical variables. In EGF30008, the optimized cutoff was associated with PFS [HR = 0.37; 95% confidence interval (CI), 0.29-0.47; P < 0.0001] and overall survival (OS; HR = 0.37; 95% CI, 0.27-0.51; P < 0.0001). The median (months; 95% CI) PFS and OS were 22.24 (19.0-24.9) and not reached in PAM50MET-low versus 9.13 (8.15-11.0) and 33.0 (28.0-40.0) in PAM50MET-high groups, respectively. In BOLERO-2, the PAM50MET-low was associated with better PFS (HR = 0.72; 95% CI, 0.53-0.96; P = 0.028) and OS (HR = 0.51; 95% CI, 0.35-0.69; P < 0.0001). The median (months) (95% CI) PFS and OS were 6.93 (5.57-11.0) and 36.9 (33.4-NA) in PAM50MET-low versus 5.23 (4.2-6.8) and 23.5 (20.2-28.3) in PAM50MET-high groups, respectively.

Conclusions: PAM50MET is prognostic in HR⁺/HER2^- MBC, and further evaluation might help identify candidates for endocrine therapy only or novel therapies.