Purpose: Gene signatures and Ki67 stratify the same breast tumour into opposing good/poor prognosis groups in approximately 20% of patients. Given this discrepancy, we hypothesized that the combination of a clinically relevant signature and immunohistochemical (IHC) markers may provide more prognostic information than either classifier alone. Experimental design: We assessed Ki67 alone or combined with ER, PR and HER2 (forming IHC subtypes), and the research versions of the Genomic Grade Index (GGI), 70-gene, cell-cycle score (CCS), Recurrence Score (RS) and PAM50 signatures on matching TMA/whole tumour sections and microarray data in two Swedish breast cancer cohorts of 379 and 209 patients, with median follow-up of 12.4 and 12.5 years, respectively. Firstly, we fit cox proportional hazard models and used the change in likelihood-ratio ( LR) to determine the additional prognostic information provided by signatures beyond that of 1) Ki67 and 2) IHC subtypes. Secondly and uniquely, we then assessed whether signatures could compete well with pathology-based immunohistochemical classifiers by calculating the additional prognostic information of Ki67/IHC subtypes beyond signatures. Results: In cohort 1 only RS and PAM50 provided additional prognostic information beyond Ki67 and IHC subtypes ( LR-2 Ki67: RS= 12.8, PAM50 = 20.7, IHC subtypes: RS= 12.9, PAM50 = 11.7). Conversely, IHC subtypes added prognostic information beyond all signatures except PAM50. Similar results were observed in cohort 2. Conclusion(s): RS and PAM50 provided more prognostic information than the IHC subtypes in all breast cancer patients, however the IHC subtypes did not add any prognostic information to PAM50.
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