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.
Highlights
Triple-negative breast cancer (TNBC), which accounts for 10–20% of all breast cancers, does not express estrogen receptors (ERs) or progesterone receptors (PRs) and lacks human epidermal growth factor receptor-2 (HER2) amplification
50% of good pathologic response (Miller-Payne 3 to5) [14]. 48% of pCR when associated with standard CHT [15]. 68% and 33% of objective response rate (ORR) for carboplatin and docetaxel for BRCA mutant patients [19]. 37% of partial response when associated with weekly paclitaxel [99]
Published Results of Clinical trials No PFS improvement when added to CHT and bevacizumab [38]
Summary
Triple-negative breast cancer (TNBC), which accounts for 10–20% of all breast cancers, does not express estrogen receptors (ERs) or progesterone receptors (PRs) and lacks human epidermal growth factor receptor-2 (HER2) amplification. Recent papers highlighted the similarities and discrepancies of intrinsic PAM50 subtyping and Lehmann’s seven subtypes [6,7,8], our incomplete knowledge of TNBC - validated gene signature, biomarkers or targeted therapies - precludes our ability to provide a consensus on clinically achievable TNBC subgrouping. TNBC molecular subtypes with future clinical relevance and potential therapeutics We here provide five molecular groupings of TNBC that may have the greatest potential for clinical trial development using major previously published molecular classifications (PAM50 subtyping, claudinlow, Burstein’s four subtypes and Lehmann’s seven subtypes): 1) basal-like TNBC (BL-TNBC), characterized predominantly by DNA-repair deficiency and growth factor pathway expression; 2) mesenchymal-like TNBC (ML-TNBC), with epithelial to mesenchymal transition (EMT) and cancer stem cell (CSC) features; 3) immuneassociated TNBC (I-TNBC); 4) luminal/apocrine TNBC (LA-TNBC), with androgen receptor (AR) overexpression; and 5) HER2-enriched TNBC (HER2e-TNBC) (Figure 1). As a group, targeting DNA-repair deficiency appears to be a promising treatment for BL-TNBC with BRCAness characteristics or BRCA-mutations
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