Table of Contents
TNBC는 heterogeneous diseases이므로, subclassification이 제안되어 왔음. 최근에는 genome-wide approaches로 disease stratification 하고자 함
Such “molecular portraits” of breast cancer are envisioned to provide a rationale for breast cancer prognosis and prediction to therapy.
Search strategy and selection criteria #
Medline 검색으로 문헌 찾기
- "triple negative", "breast neoplasm"
- "classification", "gene expression profiling", "drug therapy"
Overlapping classifications of TNBC in whole-genome gene-expression profiling and identified 4 majors classifications
- Molecular subsets described by Burstein et al
- Lehmann et al
TNBC 치료 전략에 대한 consensus 부족으로 biomarker와 타겟 치료를 기준으로 제안
we tried to re-organize the classifcation into theranostic subgroups with clinical relevance: detectable targets/pathway aberrations and available/potential targeted therapy.
TNBC molecular subtypes with future clinical relevance and potential therapeutics #
5 molecular groups
- basal-like TNBC (BL-TNBC) - DNA repair deficiency, Growth factor pathway
- mesenchymal-like TNBC (ML-TNBC) - EMT and CSC
- immune-associated TNBC (I-TNBC)
- luminal/apocrine TNBC (LA-TNBC) - Androgen receptor overexpression
- HER2-enriched TNBC (HER2e-TNBC)
Basal-like TNBC #
- 25~80% of TNBC
- IHC characterization (CK5/6+; EGFR+; ER-; HER2-)
- high proliferative capacity and overexpression of BL cytokeratin genes
BL-TNBC can be seperated
- BL1 - Cell cycle, DNA repair genes
- BL2 - Growth factor signaling pathway EGF, MET pathway, IGF1R pathway
Chemotherapy에 가장 잘 반응함
Platinum-based chemotherapy #
Platinum-based regimens for BRCA-mutant TNBC, Combination with Caboplatin.
Poly-ADP ribose polymerase (PARP) inhibitor #
Mesenchymal-like TNBC #
재미있게도, 대부분의 mesenchymal stem-like (MSL) 샘플들은 일반적으로 normal-like로 구분되지만, 반면에 대부분의 mesenchymal (M) tumor들은 Basal-like로 구분된다. --> MSL 그룹 샘플들은 normal 조직이 많이 섞였을 수 있음.
Mesenchymal cells also harbor CSC-like features, the hallmarks of metastatic potential.
CSC regulators #
Notch signaling pathway도 CSC를 유지하는데 중요한 역할을 한다. -- Notch inhibitors such as γ-secretase inhibitors (GSIs) and delta-like ligand 4 monoclonal antibodies (mAbs)
Importantly, functional study suggested that PEST domain mutations of Notch receptors are frequent in TNBC and active Notch pathway conferring GSI sensitivity.
c-MET targeted therapy #
TGFβ inhibitors #
Immune modulatory/associated TNBC #
Immune cell process 관련 유전자 활성 관련, Cytokine signaling 등
Immune checkpoint blockade #
Tumor vaccines #
Luminal/apocrine TNBC #
ER, PR이 적음에도 호르몬 경로가 활성. high luminal gene expression, lack of basal-cytokeratin markers and low proliferation rate. -- 1/3 TNBC, good prognosis
AR inhibitors #
Histone deacetylase (HDAC) inhibitors #
HDAC regulates AR target genes
HDAC inhibitors cause cells with the TNBC phenotype to express ER and become sensitive to endocrine therapy.
HER2-enriched TNBC #
6~8% of TNBC, LA-TNBC와 유사. PI3KA 변이 비중이 높다.
Indeed, HER2e-TNBC shared characteristics with LA-TNBC including PI3KCA mutations and high levels of luminal-like genes such as AR.
HER2-targeted therapy #
HER2-directed vaccine #
HER2 peptide vaccine AE37
Overlapping pathways and potential therapeutics #
EGFR targeted therapy #
EGFR is overexpressed primarily in ML-, BL-, HER2e-TNBC.
Fibroblast growth factor receptor (FGFR) targeted therapy #
FGFR is highly expressed in ML- and BRCA associated tumors
IGFR-targeted therapy #
IGFR-related signaling genes are heavily enriched in ML-, BL-TNBC.
Excitingly, targeting this pathway in BL-TNBC may be highly effective as BRCA-defcient cells, unlike wild-type cells, cannot down-regulate IGFR expression.
PI3K/AKT/mTOR pathway targeted therapy #
PI3KCA mutations increase the sensitivity of cancer cells to PI3K/AKT/mTOR inhibitors.
PTEN loss as a predictor of treatment efficacy.
MAPK pathway targeted therapy #
MEK inhibitors for ML-TNBC.
An obvious feedback loop between the PI3K/AKT/mTOR and RAS/RAF/ MEK/ERK pathways has direct clinical implications, as MEK inhibition leads to PI3K activation and vice versa.
Angiogenesis inhibitors #
TP53 mutation targeting #
Therapeutic strategy and biomarker development #
Biologically driven combinatorial therapies shold be considered.
단독 타겟 약물시 활성화되는 보상 패스웨이나 임상시험에서 시너지가 있던 조합 활용
- EGFR- and MEK-inhibitors
- MEK-, MET- or PARP-inhibitors
- VEGF- and mTOR inhibitors
- PI3K- and AR-inhibitors (AR+에서 PI3K 변이가 많다)
본 리뷰는 4 predominant function/pathways를 확인함
- DNA-repair deficency
- EMT and CSC
- androgen receptor over expression