Molecular classifications of breast carcinoma with similar terminology and different definitions: are they the same?

Summary

There are 4 major molecular classifications in the literature that divide breast carcinoma into basal and nonbasal subtypes, with basal subtypes associated with poor prognosis. Basal subtype is defined as positive for cytokeratin (CK) 5/6, CK14, and/or CK17 in CK classification; negative for ER, PR, and HER2 in triple negative (TN) classification; negative for ER and negative or positive for HER2 in ER/HER2 classification; and positive for CK5/6, CK14, CK17, and/or EGFR; and negative for ER, PR, and HER2 in CK/TN classification. These classifications use similar terminology but different definitions; it is critical to understand the precise relationship between them. We compared these 4 classifications in 195 breast carcinomas and found that (1) the rates of basal subtypes varied from 5% to 36% for ductal carcinoma in situ and 14% to 40% for invasive ductal carcinoma. (2) The rates of basal subtypes varied from 19% to 76% for HG carcinoma and 1% to 7% for NHG carcinoma. (3) The rates of basal subtypes were strongly associated with tumor grades (P < .001) in all classifications and associated with tumor types (in situ versus invasive ductal carcinomas) in TN (P < .001) and CK/TN classifications (P = .035). (4) These classifications were related but not interchangeable (κ ranges from 0.140 to 0.658 for HG carcinoma and from 0.098 to 0.654 for NHG carcinoma). In conclusion, although these classifications all divide breast carcinoma into basal and nonbasal subtypes, they are not interchangeable. More studies are needed to evaluate to their values in predicting prognosis and guiding individualized therapy.

Introduction

Breast cancer is a group of heterogeneous diseases, encompassing a number of distinct biological entities with specific pathologic features and biological behavior [1]. Currently, ER, PR, and HER2 expression, along with nodal status, tumor size, tumor type, tumor grade, and margin status, are used to determine a patient's treatment and predict prognosis. The pioneering works done by Perou et al [2] and Sorlie et al [3], [4] on global gene expression profiling for invasive breast carcinoma demonstrated that breast carcinomas can be subclassified into 5 subtypes: luminal A, luminal B, normal breast-like, HER2 overexpressing, and basal-like. These molecularly defined subtypes not only indicate the heterogeneity of breast carcinomas and the possible different cell lineage pathways in breast carcinogenesis, but also demonstrate the difference in clinical outcome, with basal subtype associated with poor prognosis. Using a double labeling technique, Boecker et al [5], [6] and Korsching et al [7] have demonstrated that both normal breast epithelium and breast cancer cells could be subclassified immunologically by cytokeratin (CK) markers into CK5/6-, CK14-, CK17-positive basal/stem cells, and CK8/18-positive luminal cells. Boecker et al [5] and we have observed that basal CK markers (CK5/6, CK14, CK17) show similar expression patterns in the ductal system, consistently positive in basal/myoepithelial cells, and occasionally positive in scattered luminal cells. It is not clear though whether the tumors of basal subtype arise from true basal/myoepithelial cells or from luminal cells with “switched on” basal cell markers.

In an effort to develop a molecular classification that is clinically significant and technically simple and readily available, investigators from different groups have proposed 4 major molecular classifications based on immunohistochemical (IHC) expression patterns of CK markers, ER, PR, HER2, and EGFR, which, to some degree, not only reflected the subtypes identified by gene expression profiling, but also correlated with clinical outcome (Fig. 1). Using CK markers, others and we have subclassified both ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) into basal/stem subtype and luminal subtype, with basal/stem subtype being positive for CK5/6, CK14, and CK17 [8], [9], [10], [11]. The basal/stem subtype is frequently ER/PR negative, EGFR positive, and associated with high nuclear grade [9], [10], [11], worse prognosis [12], [13], and less responsive to standard adjuvant chemotherapy [14]. Triple negative (TN) is commonly used as a clinical surrogate for basal-like tumors, which is consistent with basal-like subgroup defined by gene expression profiling and lacks the benefit of specific target therapy. These tumors are frequently larger grade 3 tumors, with pushing margins, poor Nottingham Prognostic Index, higher rates for recurrence and distant metastasis, and associated with basal CK markers, p-cadherin, p53, and EGFR expression [15]; tend to occur in patients under 40; have poor survival regardless of the stage at diagnosis [16]; and are more sensitive to anthracyclin-based neoadjuvant chemotherapy [17]. ER/HER2 classification was used by Matos et al [18] to divide invasive breast carcinomas into basal-type (ER−/HER2−, 7.6%), basal-like HER2 overexpression type (ER−/HER2+, 11.7%), luminal A (ER+/HER2−, 56.3%), and luminal B (ER+/HER2+, 16.5%). Both basal and basal-like types are mostly grade 3, frequently p-cadherin, p63, and CK5 positive. Nielsen et al [19] demonstrated that the most consistent IHC markers for basal subtype defined by gene expression profiling were CK5/6 and EGFR positive, and ER and HER2 negative. Livasy et al [20] also showed that basal subtype was consistently ER and HER2 negative, and with varying positivity for other markers (CK8/18-15/18, EGFR-13/18, CK5/6-11/18).

Although these classifications divide breast carcinoma into 2 major subtypes, basal and nonbasal, the precise relationship between these classifications is not clear. Here for the first time, we directly compared these classifications and studied their relationships in 195 cases of high-grade (HG) and non–high-grade (NHG) breast carcinoma, including 99 DCIS and 96 IDC.