A Simple Method for Robust and Accurate Intrinsic Subtyping of Breast Cancer

Abstract

Motivation: The PAM50 signature/method is widely used for intrinsic subtyping of breast cancer samples. However, depending on the number and composition of the samples included in a cohort, the method may assign different subtypes to the same sample. This lack of robustness is mainly due to the fact that PAM50 subtracts a reference profile, which is computed using all samples in the cohort, from each sample before classification. In this paper we propose modifications to PAM50 to develop a simple and robust single-sample classifier, called MPAM50, for intrinsic subtyping of breast cancer. Like PAM50, the modified method uses a nearest centroid approach for classification, but the centroids are computed differently, and the distances to the centroids are determined using an alternative method. Additionally, MPAM50 uses unnormalized expression values for classification and does not subtract a reference profile from the samples. In other words, MPAM50 classifies each sample independently, and so avoids the previously mentioned robustness issue. Results: A training set was employed to find the new MPAM50 centroids. MPAM50 was then tested on 19 independent datasets (obtained using various expression profiling technologies) containing 9637 samples. Overall good agreement was observed between the PAM50- and MPAM50-assigned subtypes with a median accuracy of 0.792, which (we show) is comparable with the median concordance between various implementations of PAM50. Additionally, MPAM50- and PAM50-assigned intrinsic subtypes were found to agree comparably with the reported clinical subtypes. Also, survival analyses indicated that MPAM50 preserves the prognostic value of the intrinsic subtypes. These observations demonstrate that MPAM50 can replace PAM50 without loss of performance. On the other hand, MPAM50 was compared with 2 previously published single-sample classifiers, and with 3 alternative modified PAM50 approaches. The results indicated a superior performance by MPAM50. Conclusions: MPAM50 is a robust, simple, and accurate single-sample classifier of intrinsic subtypes of breast cancer.