Summary #

Introduction #

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"
• ClinicalTrials.gov

Overlapping classifications of TNBC in whole-genome gene-expression profiling and identified 4 majors classifications

1. Claudin-low
2. Intrinsic-PAM50
3. Molecular subsets described by Burstein et al
4. 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

1. basal-like TNBC (BL-TNBC) - DNA repair deficiency, Growth factor pathway
2. mesenchymal-like TNBC (ML-TNBC) - EMT and CSC
3. immune-associated TNBC (I-TNBC)
4. luminal/apocrine TNBC (LA-TNBC) - Androgen receptor overexpression
5. HER2-enriched TNBC (HER2e-TNBC)

Basal-like TNBC #

Features

• 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

1. BL1 - Cell cycle, DNA repair genes
2. 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 #

HR dysfunction has been shown to sensitize breast cancer cell to PARP inhibition, resulting in Cell cycle arrest and Apoptosis.

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.

EMT 중 epithelial-realated gene들은 발현이 줄어듬. elevated vimentin and decreased E-cadherin

EGFR 종종 과발현됨 - EMT 연관.

Mesenchymal cells also harbor CSC-like features, the hallmarks of metastatic potential.

CSC, EMT 관련 발현 증가는 chemotherapy 저항과 관련됨.

CSC regulators #

Wnt signaling pathway, beta-catenin signaling의 활성은 CD44+/CD24-와 상관관계가 있다. -- Wnt inhibitors such as vitamin D3, non-steroidal anti-inflammatory drug, some antibiotics (Salinomycin).

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 #

c-MET signaling은 EMT와 CSC를 조절할 수 있다.

Appropriately, co-inhibition of EGFR and c-MET suppressed tumor growth in preclinical models

TGFβ inhibitors #

TGFβ Tyrosine-kinase inhibitor induced a tremendous MET reversing EMT in CD44+ breast cancer cells, which justifed its further development. -- Trabedersen

Immune modulatory/associated TNBC #

Immune cell process 관련 유전자 활성 관련, Cytokine signaling 등

Immune checkpoint blockade #

Immune checkpoint pathway는 정교한 일련의 과정으로 T-cell의 과도한 활성으로부터 자신을 보호한다. 이들 checkpoint를 저해함으로 치료함.

CTLA-4의 활성을 통해 T-cell 활성을 강화한다. -- Ipilimumab, Tremelimmumab.

PTEN을 저해하는 것은 PD-L1을 up-regulate한다. -- PI3K pathway를 타겟하는 것이 이 타입의 TNBC에 효과적일 수 있음

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 #

Bicalutamide, Enzalutamide

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- 임에도 Trastuzumab 효과

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 #

VEGF inhibitors

TP53 mutation targeting #

MDM2 inhibitors

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)

MDA-MB-231 세포주

Conclusions #

본 리뷰는 4 predominant function/pathways를 확인함

1. DNA-repair deficency
2. EMT and CSC
3. immune-associated
4. androgen receptor over expression

Incoming Links #

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