Comparison of Basal-like Triple-Negative Breast Cancer Defined by Morphology, Immunohistochemistry and Transcriptional Profiles

Patrycja Gazinska; Anita Grigoriadis; John P Brown; Rosemary R Millis; Anca Mera; Cheryl E Gillett; Lars H Holmberg; Andrew N Tutt; Sarah E Pinder

Disclosures

Mod Pathol. 2013;26(7):955-966. 

In This Article

Abstract and Introduction

Abstract

Basal-like invasive breast cancer is an important clinical group because of its association with a triple-negative phenotype defined by the lack of expression of estrogen, progesterone and human epidermal growth factor receptors 2, relative lack of therapeutic options and poor prognosis. However, depending on the method used to define these lesions, morphological assessment, immunohistochemical markers or gene expression, a different set of tumors is captured. The aim of this study was to investigate the consequences of using different methodological approaches to define basal-like lesions among triple-negative breast carcinomas with regard to their clinicopathological features and patient outcome. The cohort consisted of 142 invasive breast cancers with a triple-negative receptor status. First, each was reviewed histologically and those with morphological basal-like features were characterized as 'Path-Basal'. Second, the 'Core Basal' immunohistochemical lesions, defined as cytokeratin 5/6 and/or epidermal growth factor receptor 1 positive, within the triple-negative breast cancers were identified, and third their classification based on gene expression profiling was retrieved and those in the molecular 'PAM50 basal-like' subtype recorded. A total of 116 basal-like breast cancers were identified among the 142 triple-negative breast cancers by at least one of these three classifications (80%), but only 13 samples were defined as basal-like with all three methods. None of these 13 tumors were associated with lymphovascular invasion. The 34 morphological 'Path-Basal' lesions were significantly associated with a lack of nodal metastases. Comparing the estimates of death in the three classifications, the highest risk of death was seen for the 'Core Basal' group. In this study, we highlight that the definition of basal-like breast cancer based on different methodologies varies significantly and does not identify the same lesions. This incomplete overlap of cases emphasizes the need for consistent or new approaches to improve precise identification.

Introduction

Breast cancer is a heterogeneous disease, which can be classified into biologically, morphologically and clinically meaningful entities. Approximately 12 to 17% are triple-negative breast cancers lacking expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2).[1] These lesions are also characterized by a high incidence of TP53 mutations, as well as low levels of RB and high levels of p16 proteins.[2,3] Triple-negative breast cancers are more prevalent in patients below the age of 50 years[4] who are of African-American ethnicity[5] and who have a more aggressive clinical behavior[6–8] as well as a distinctive metastatic pattern.[9] In particular, triple-negative breast cancers are clinically problematic as there is no approved targeted systemic therapy for these lesions; in some series, patients with triple-negative breast cancers have an increased risk of recurrence between the first and third years after diagnosis and an increased mortality in the first 5 years after treatment. Currently, chemotherapy is the only systemic therapy available for triple-negative breast cancers and is curative in a subset of patients with chemotherapy-sensitive disease.[10]

Genomic studies such as the PAM50 gene expression assay have demonstrated that breast cancers can be classified into at least five intrinsic subtypes (luminal A, luminal B, HER2-enriched, basal-like and normal breast-like).[11] Triple-negative breast cancers overlap with the molecular entity of 'basal-like' breast cancers,[12] but these are not the same entity and equating them is misleading.[13–15] Many current studies make use of microarray-based expression profiling to define basal-like breast cancers; however, continuous efforts are being made to define these lesions with standard pathological techniques, for example, using immunohistochemical markers as surrogates.[7,16,17] With the latter approach, it has been reported that ~50% of triple-negative breast cancers are either positive for epidermal growth factor receptor 1 (EGFR) and/or basal cytokeratin (CK) 5/6 and have been referred to as 'Core Basal'.[16] Among triple-negative breast cancers treated with adjuvant anthracycline-based chemotherapy, the 'Core Basal' phenotype has been reported to be associated with a significantly worse outcome.[16]

Classically, they are high-grade lesions of ductal/no-special type, mostly having a high mitotic index, lack of tubule formation and marked cellular pleomorphism.[14,18] The nuclear chromatin pattern ranges from coarse to vesicular, and prominent nucleoli are commonly present.[19] A pushing, or partially pushing, margin and a peritumoral lymphocytic infiltrate are frequently described.[18,20] In particular, large zones of geographic necrosis, frequent apoptotic cells, stromal lymphocytic infiltrates and scanty stromal content are characteristic.[21] Occasionally, these tumors also contain areas of spindle cell and squamous metaplasia.[14,22] From a morphologic point of view, basal-like breast carcinomas are clearly a heterogeneous group of cancers, including medullary, metaplastic and spindle cell, myoepithelial and adenoid cystic tumors.[14]

As there is presently no consensus regarding the optimal definition of basal-like triple-negative breast cancers, our aim was to explore the clinicopathological features of basal-like breast cancers when defined by molecular, immunohistochemical and morphological approaches. A cohort of consecutive triple-negative breast cancer patients with extensive clinical information was reviewed histopathologically and subjected to a panel of immunohistochemical biomarkers characterizing 'Core Basal' lesions. In addition, assignment to the molecular basal-like PAM50 subtype on the basis of their expression profiles was retrieved and comparison between these three classifications was made.

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