A novel approach to triple-negative breast cancer molecular classification reveals a luminal immune-positive subgroup with good prognoses

Abstract

Triple-negative breast cancer is a heterogeneous disease characterized by a lack of hormonal receptors and HER2 overexpression. It is the only breast cancer subgroup that does not benefit from targeted therapies, and its prognosis is poor. Several studies have developed specific molecular classifications for triple-negative breast cancer. However, these molecular subtypes have had little impact in the clinical setting. Gene expression data and clinical information from 494 triple-negative breast tumors were obtained from public databases. First, a probabilistic graphical model approach to associate gene expression profiles was performed. Then, sparse k-means was used to establish a new molecular classification. Results were then verified in a second database including 153 triple-negative breast tumors treated with neoadjuvant chemotherapy. Clinical and gene expression data from 494 triple-negative breast tumors were analyzed. Tumors in the dataset were divided into four subgroups (luminal-androgen receptor expressing, basal, claudin-low and claudin-high), using the cancer stem cell hypothesis as reference. These four subgroups were defined and characterized through hierarchical clustering and probabilistic graphical models and compared with previously defined classifications. In addition, two subgroups related to immune activity were defined. This immune activity showed prognostic value in the whole cohort and in the luminal subgroup. The claudin-high subgroup showed poor response to neoadjuvant chemotherapy. Through a novel analytical approach we proved that there are at least two independent sources of biological information: cellular and immune. Thus, we developed two different and overlapping triple-negative breast cancer classifications and showed that the luminal immune-positive subgroup had better prognoses than the luminal immune-negative. Finally, this work paves the way for using the defined classifications as predictive features in the neoadjuvant scenario.

Molecular Classification and Future Therapeutic Challenges of Triple-negative Breast Cancer

“…The LAR type demonstrated less cellular adhesion, chemokine activity and disorders of G 1 /S transition cell cycle. The basal-like type had higher regulation of actin cytoskeleton and cell adhesion (76).…”

“…In 2019, Prado-Vázquez et al described two different molecular classifications which were based to cellular type and immune activity. The initial classification included 4 subgroups: 1) CLDN-low, 2) CLDN-high, 3) basal-like and 4) LAR group and was performed according to the stem cell cancer hypothesis (76,77). This classification is related to the differentiation process and especially the initiation of carcinogenesis.…”

Quadruple-Negative Breast Cancer: An Uneven Playing Field

“…The chief TNBC subtyping systems are briefly outlined in Figure 1. [2][3][4] Among these, the widely accepted Lehmann molecular classification categorizes TNBC into: basal-like (BL1 and BL2), immunomodulatory, luminal androgen receptor (LAR), mesenchymal, and mesenchymal stemlike. 3 The subtypes also respond differently to available therapies.…”

“…22 Despite conflicting reports on its merits as a prognostic marker, AR antagonists such as bicalutamide and enzalutamide have exhibited encouraging results, principally in the subset of patients with TNBC who belong to the LAR molecular subtype (that is partly dependent on AR signaling). [24][25][26][27][28][29][30] However, because only 20%-25% of TNBCs express AR, it leaves a vast majority of patients with TNBC who are in Triple-negative breast cancers (TNBCs) make up a highly heterogeneous group that can be classified variously, as outlined in the long columns (data adapted [2][3][4] ). Quadruple-negative breast cancer (QNBC) is clinically defined as an androgen receptor (AR)-negative TNBC and is briefly characterized in the lower half of the schematic.…”

Triple-negative pleomorphic lobular carcinoma and expression of androgen receptor: Personal case series and review of the literature

“…The LAR subtype is characterized by augmented androgen receptor (AR) signaling [10,11]. Several studies have developed specific molecular classifications of TNBC, including the LAR subtype [11][12][13]. One study reported that the pathologic complete response was worst in patients with LAR subtype of TNBC among all TNBC molecular subtypes [13].…”