Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype?

Abstract

Significant research has been conducted to better understand the extensive, heterogeneous molecular features of triple-negative breast cancer (TNBC). We reviewed published TNBC molecular classifications to identify major groupings that have potential for clinical trial development. With the ultimate aim to streamline translational medicine, we linked these categories of TNBC according to their gene-expression signatures, biological function, and clinical outcome. To this end, we define five potential clinically actionable groupings of TNBC: 1) basal-like TNBC with DNA-repair deficiency or growth factor pathways; 2) mesenchymal-like TNBC with epithelial-to-mesenchymal transition and cancer stem cell features; 3) immune-associated TNBC; 4) luminal/apocrine TNBC with androgen-receptor overexpression; and 5) HER2-enriched TNBC. For each defined subtype, we highlight the major biological pathways and discuss potential targeted therapies in TNBC that might abrogate disease progression. However, many of these potential targets need clinical validation by clinical trials. We have yet to know how we can enrich the targets by molecular classifications.

Keywords: epithelial-mesenchymal transition; gene expression profiling; immunotherapy; targeted therapy; triple-negative breast cancer.

Figure 1. TNBC classifications

Lehmann's (yellow), PAM50/claudin-low (blue) classifications and their potent overlaps (green) are shown in this figure. Abbreviations: AR, androgen receptor; BL, basal-like; EGF, epidermal growth factor; HER2, human epidermal growth factor receptor 2; IGF, insulin growth factor; IM, immunomodulary; LAR, luminal androgen receptor; M, mesenchymal; MSL mesenchymal stem-like; TGFβ, transforming growth factor β.

Figure 2. Basal-like TNBC

Drug classes previously evaluated or currently being investigated in breast cancer clinical trials are shown. *More than 100 studies of anti-IGFR1 therapy (anti-receptor Abs, anti-ligand Abs, receptor-TKIs, and metformin) have been conducted. **Many combination drugs are currently being investigated: EGFR and HER2-TKIs (e.g., lapatinib and BIBW2992), c-MET and VEGFR-TKIs (e.g., cabozantinib) or FGFR and VEGFR-TKIs (e.g., lucitanib, dovitinib, BIBF1120). Abbreviations: BER, base-excision repair; CDK, cyclin-dependent kinase; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; IGFR, insulin growth factor receptor; HR, homologous recombination; mAb, monoclonal antibody; TKI, tyrosine-kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.

Figure 3. Mesenchymal TNBC

Drug classes previously evaluated or currently being investigated in breast cancer clinical trials are shown. *Many combination drugs are currently being investigated: EGFR and HER2-TKIs; c-MET and VEGFR-TKIs or FGFR and VEGFR-TKIs. **Not yet in clinical trials. ***PI3K/AKT/mTOR inhibitors are detailed in luminal/apocrine-TNBC part (Figure 4). # PDGFR and IGFR are also overexpressed in ML-TNBC and are targetable. However, current therapies targeting PDGFR have a large overlap with those that target VEGF. Imatinib, an anti-PDGF agent, had potential immunosuppressive effects and no antitumor activity in metastatic breast cancer overexpressing PDGFβ. Abbreviations: DKK1, Dickkopf-homolog-1; DLL, delta-like ligand; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; FRZ, Frizzle receptor; GSI, γ-secretase inhibitor; HGF, hepatocyte growth factor; HH, Hedgehog ligand; mAb, monoclonal antibody; NF-κB, nuclear factor κ-beta; NSAID, non-steroidal anti-inflammatory drug; PTCH, patched receptor; SMO, smoothened; TGFβ, transforming growth factor β; TKI, tyrosine-kinase inhibitor; VDR, vitamin D receptor; VEGFR, vascular endothelial growth factor receptor.

Figure 4. Immune-associated TNBC

Drug classes previously evaluated or currently being investigated in breast cancer clinical trials are shown. Abbreviations: AMP, adenosine monophosphate; APC, antigen-presenting cell; CSF-1R, colony stimulating factor-1; CTLA-4, cytotoxic-T-lymphocyte-antigen-4; LT lymphocyte T; LTreg, lymphocyte T regulator; mAb, monoclonal antibody; MAGE-A3, melanoma-associated-antige3; MHC, major histocompatibility complex; MUC1, mucin-1; PD-1, program-death-1; PDL-1, program-death-ligand-1; TCR, T-cell receptor.

Figure 5. Luminal/apocrine TNBC and HER2-enriched TNBC

Drug classes previously evaluated or currently being investigated in breast cancer clinical trials are shown. *Dual PI3K/AKT/mTOR inhibitors are on the way. **Current mechanistic-driven combination drugs use MEK inhibitors with: AR inhibitors, PI3K inhibitors, AKT inhibitors, and dual PI3K/mTOR inhibitors. ***Inhibition of HSP90, a molecular chaperone essential for the stability and integrity of various “client” proteins such as AR, is an attractive therapeutic target for cancer. # Anti-HER2, anti-EGFR, and anti-VEGF treatments are more specific for HER2-enriched TNBC. ## AR signaling has an important role in the molecular apocrine subgroup, which mainly overlaps the luminal-TNBC subgroup but could also overlap the HER2e-TNBC subgroup because of the high frequency of HER2 amplification. Abbreviations: AR, androgen receptor; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; HDAC, histone deacetylase; HSP90, heat-shock protein 90; mAb, monoclonal antibody; MDM2, mouse double minute 2; TKI, tyrosine-kinase inhibitor; VEGFA, vascular endothelial growth factor A; VEGFR, vascular endothelial growth factor receptor.

Figure 6. Flow chart of potent new TNBC clinical trial

Potent new design on TNBC clinical trial based on the classification we detailed and the new targeted drugs currently in development in TNBC. Abbreviations: AR, androgen receptor; ARi, androgen receptor inhibitor; BL, basal-like; EGFR, epidermal growth factor receptor; EGFRi, epidermal growth factor receptor inhibitor; I, immunomodulary; LA, luminal/apocrine; ML, mesenchymal-like; mTORi, mTOR inhibitor; PDL-1i, PDL-1 inhibitor.