PAM50MET: A prognostic model based on PAM50 and clinical variables in metastatic hormone receptor (HR)-positive/HER2 negative breast cancer

Abstract

Background: Predicting prognosis in metastatic HR+/HER2-negative disease might be of clinical value. Here, we developed and validated a prognostic biomarker in 765 patients (pts) recruited in 2 phase III trials evaluating endocrine-based therapies. Method(s): PAM50 and clinical data were available from 821 pts treated with letrozole+placebo/ lapatinib in the first-line setting (EGF3008). Among them, 484 pts were selected based on HER2-negative disease and no prior endocrine therapy or relapse >=6 months since tamoxifen discontinuation. To derive a prognostic model, the following variables were evaluated: 1) PAM50 subtypes, signatures and genes 2) ECOG, 4) visceral disease, 5) num. metastasis, 6) biopsy-type and 7) age. Using the variables, a progression-free survival (PFS) cox model was evaluated in 2/3 pts using Elastic Net (Monte Carlo CV). C-index of each model was estimated in 1/3 pts. The final model was tested in 261 pts treated with exemestane+placebo/everolimus (BOLERO2). PAM50 was performed in FFPE tumors (>=80% primary). Result(s): In EGF3008, prognostic models that integrated PAM50 and clinical variables yielded superior C-index values compared to models with PAM50-only or clinical variables-only. The final model (PAM50MET) combined 21 variables, including 2 PAM50 subtypes, the Basal signature, 14 genes and 4 clinical variables. In EGF3008, the optimized cutpoint was associated with PFS (hazard ratio=0.41; p<0.0001) and overall survival (OS; hazard ratio=0.41; p<0.0001). In BOLERO2, PAM50MET score was associated with PFS (p=0.004) and OS (p<0.0001). Using the same cutpoint, PAM50MET-low was associated with better PFS (hazard ratio=0.72; p=0.028) and OS (hazard ratio=0.51; p<0.0001). The median PFS and OS in PAM50MET-low was 6.9 and 36.5 months compared to 5.2 and 23.4 months in PAM50MET-high. Conclusion(s): PAM50MET could help identify pts with HR+/HER2-negative metastatic disease candidates, especially in the first-line setting, for endocrine therapy-only vs. endocrine therapy + CDK4/6 inhibitor vs. new treatment strategies. Further validation of PAM50MET in pivotal clinical trials that have evaluated endocrine-based therapies is justified.