Triple-Negative Breast Cancer: Distinguishing between Basal and Nonbasal Subtypes

Abstract

Purpose: Triple-negative (TN; estrogen receptor, progesterone receptor, and HER-2 negative) cancer and basal-like breast cancer (BLBC) are associated with poor outcome and lack the benefit of targeted therapy. It is widely perceived that BLBC and TN tumors are synonymous and BLBC can be defined using a TN definition without the need for the expression of basal markers. Experimental Design: We have used two well-defined cohorts of breast cancers with a large panel of biomarkers, BRCA1 mutation status, and follow-up data to compare the clinicopathologic and immunohistochemical features of TN tumors expressing one or more of the specific basal markers (CK5/6, CK17, CK14, and epidermal growth factor receptor; BLBC) with those TN tumors that express none of these markers (TN3BKE-).Results: Here, we show that although the morphologic features of BLBC are not significantly different from that of TN3BKE-tumors, BLBC showed distinct clinical and immunophenotypic differences. BLBC showed a statistically significant association with the expression of the hypoxia-associated factor (CA9), neuroendocrine markers, and other markers of poor prognosis such as p53. A difference in the expression of cell cycle-associated proteins and biomarkers involved in the immunologic portrait of tumors was seen. Compared with TN3BKE-tumors, BLBC was positively associated with BRCA1 mutation status and showed a unique pattern of distant metastasis, better response to chemotherapy, and shorter survival. Conclusion: TN breast cancers encompass a remarkably heterogeneous group of tumors. Expression of basal markers identifies a biologically and clinically distinct subgroup of TN tumors, justifying the use of basal markers (inTN tumors) to define BLBC.

Molecular insights on basal-like breast cancer

“…This subgroup present a greater genetic complexity compared with other BC subtypes, suggesting a greater degree of genetic instability [28,29]. Bergamaschi [30] found that BLBC show the highest frequency of DNA losses and gains compared with others subtypes and also reported that despite of the highest prevalence of genomic aberrations, BLBC show less genomic 8 amplifications than tumors pertaining to other molecular subgroups [10,28,30].…”

“…But some particular recurrent amplifications described in BLBC are approximately two to three times higher than the other subtypes [10,28] and it includes 7p11.2 involving the region of EGFR, 7q31 affecting caveolin 1, and 12p13 being the amplifications of 8p12 and 17q11.2 associated with poor outcomes [31].…”

“…There are several reported biomarkers associated with BLBC as well as putative candidates suitable for immunohistochemical screening (Table 1) [10,11,23], however, currently, there is no specific international consensus on complement biomarkers that can define BLBC.…”

“…They represent from 8% up to 37% of all BC cases, depending on the proportion of grade III cases included in the populations studied [10]. BLBC presents frequent mutations in the TP53 gene, evidence of genomic instability, and inactivation of the Rb pathway [11].…”

Markers of progression in early-stage invasive breast cancer: a predictive immunohistochemical panel algorithm for distant recurrence risk stratification

“…This study was based on a well-characterised cohort of early stage (I-III) primary operable invasive BC (n=1902) from patients enrolled into the Nottingham Tenovus Primary Breast Carcinoma Series between 1987 and 1998, and managed in accordance to a uniform protocol and has been comprehensively studied with a broad range of markers [9,10]. During the follow-up time within this series, distant recurrence had developed in 578/1902 cases (30 %).…”