Trple-negative breast cancer molecular classification

Triple-negative breast cancer molecular classification, Gene expression assays have identified six different triple-negative breast cancer (TNBC) molecular subtypes (Lehman’s classification).

These are
  • basal-like 1 (BL1), 
  • basal-like 2 (BL2), 
  • mesenchymal-like (M),
  • mesenchymal/stem-like (MSL),
  • immunomodulatory (IM),
  • and luminal androgen receptor (LAR).
BL1 has a high TP53 mutation rate (92%), alterations in genes involved in DNA repair mechanisms (such as BRCA1, BRCA2, TP53 and RB1) and a cell-cycle gene signature.

BL2 has cell-cycle gene signatures, overexpression of growth factor signalling genes and overexpression of myoepithelial differentiation genes.

M and MSL subtypes are enriched for genes encoding regulators of cell motility, invasion and mesenchymal differentiation, but the MSL subtype is uniquely enriched for the genes that encode regulators of epithelial–mesenchymal transition and stemness.

The Claudin-low subtype from the intrinsic classification is mostly composed of the M and MSL subtypes312. MSL also shares numerous genes involved in the regulation of immune response with the IM subtype.

Finally, LAR is characterized by a higher mutational burden with overexpression of genes coding for mammary luminal differentiation, overexpression of the regulators of the androgen receptor (AR) signalling pathway and increased mutations in PI3KCA (55%), AKT1 (13%) and CDH1 (13%) genes.

This classification has been refined into four groups: 
  1. BL1 (immunoactivated),
  2. BL2 (immunosuppressed),
  3. M (including most of the MSL),
  4. and LAR, with implications for response to neoadjuvant chemotherapy.
Combining RNA and DNA profiling analyses, a similar classification of TNBC has been reported (Burstein’s classification), divided into four distinct subtypes.

These subtypes are: 
  • LAR,
  • mesenchymal (MES),
  • basal-like immunosuppressed (BLIS),
  • and basal-like immune-activated (BLIA).
Each subtype has specific therapeutic targets (for example, the LAR subtype can be targeted via the AR and the cell surface protein mucin) and different prognosis (for example, the BLIA subtype is associated with better prognosis than BLIS). Despite these multiple efforts, there is no established diagnostic assay yet for the classification of TNBC in routine practice.