Feasibility of Classification of Triple Negative Breast Cancer by Immunohistochemical Surrogate Markers

Abstract

Using the 7 immunohistochemical surrogate markers, we tried to classify 200 TNBCs into 4 molecular subtypes; luminal androgen receptor, mesenchymal, basal-like immune-activated, and basal-like immune-suppressive types. Our results showed that each subtype had significant differences in clinicopathological characteristics and prognosis. Introduction: Recently, Burstein et al identified 4 stable molecular subtypes of triple negative breast cancer (TNBC) by mRNA profiling: luminal androgen receptor (LAR), mesenchymal (MES), basal-like immune-activated (BLIA), and basallike immune-suppressive (BLIS) types. The purpose of this study was to assess the feasibility of immunohistochemistry (IHC) surrogate panel in classifying the TNBC molecular subtypes using a large cohort of TNBC retrieved from a single institution. Materials and Methods: IHC for androgen receptor [AR], claudin-3, E-cadherin, cytokeratin 5/6 [CK5/6], epidermal growth factor receptor [EGFR], indoleamine 2,3-dioxygenase 1 [IDO1], and Forkhead box C1 [FOXC1] were performed using the tissue microarray constructed from 200 TNBC samples. Results: The 200 TNBCs were classified as LAR (AR(+), n = 22; 11.0%), MES (claudin 3(-) and/or E-cadherin(-), n = 23; 11.5%), basal-like (CK5/6(+) and/or EGFR(+), n = 85; 42.5%), mixed (n = 60; 30%), and unclassifiable type (n = 10; 5%). LAR type was associated with older patient age, apocrine histologic features, low density of stromal tumor-infiltrating lymphocytes (TIL), and low Ki-67 labeling index. MES type was associated with tumor cell discohesiveness and metaplastic features. Basal-like type was associated with younger patient age, high histologic grade, high stromal TIL density, and high Ki-67 labeling index. Basal-like TNBCs were further classified as BLIA (IDO1(+) and FOXC1(+), n = 27) or BLIS type (IDO1-and FOXC1(+), n = 11). BLIS type was associated with large tumor size and low stromal TIL density, which had the worst prognostic outcome among 4 subtypes. Conclusion: The IHC surrogate panel may define TNBC subtypes with distinct clinicopathologic characteristics and prognostic significance.