Concordance of immunohistochemistry based and gene expression-based subtyping in breast cancer

Background Use of immunohistochemistry (IHC) based surrogates of molecular breast cancer subtypes is common in research and clinical practice, but information on their comparative validity and prognostic capacity is scarce. Methods Data from two PAM50-subtyped Swedish breast cancer cohorts were used; STO-3 with 561 patients diagnosed 1976-1990, and Clinseq with 237 patients diagnosed 2005-2012. We evaluated three surrogate classifications; the IHC3 surrogate classifier based on ER/PR/HER2, and the StGallen and Prolif surrogate classifiers also including Ki-67. Accuracy, kappa, sensitivity and specificity were computed as compared to PAM50. Alluvial diagrams of misclassification patterns were plotted. Distant recurrence-free survival was assessed using Kaplan-Meier plots, and tamoxifen treatment benefit for luminal subtypes was modeled using flexible parametric survival models. Results The concordance with PAM50 ranged from poor to moderate (kappa = 0.36–0.57, accuracy = 0.54-0.75), with best performance for the Prolif surrogate classification in both cohorts. Good concordance was only achieved when luminal subgroups were collapsed (kappa = 0.71- 0.69, accuracy = 0.90-0.91). The StGallen surrogate classification misclassified luminal A into luminal B, the reverse pattern was seen with the others. In distant recurrence-free survival, surrogates were more similar to each other than PAM50. The difference in tamoxifen treatment benefit between luminal A and B for PAM50 was not replicated with any surrogate classifier. Conclusions All surrogate classifiers had limited ability to distinguish between PAM50 luminal A and B, but patterns of misclassifications differed. PAM50 subtyping appeared to yield larger separation of survival between luminal subtypes than any of the surrogate classifications.