Biomarkers in triple negative breast cancer: A review #
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Structured data

About: Triple-negative breast cancer
Date Published: 2015-12-10
Publisher: World Journal of Clinical Oncology
URL: http://www.ncbi.nlm.nih.gov/pubmed/26677438

Summary #

Introduction #

유방암의 예후나 치료 반응을 알아보는 pathological feature에는,

Patient age
Tumour stage
Axillary lymphnode involvement
Lymphovascular invasion
histologic grade
hormonal and HER2 status

Sorlie et al has diversified 5 subgroups by DNA microarray

Luminal A
Luminal B
HER-2/neu
basal like
normal like

TNBC #

TNBC features

Young age
Advanced stage at presentation
Unfavourable histopathology
Grade 3
Higher proliferative index
Lack of tubule formation
Higher rate of metastases
Higher rate of local recurrence during 3 year after treatment and 5 year death rate

TNBC subtypes #

6 groups based upon Gene expression

BL-1 and BL-2 #

BL-1: rapidely dividing cells, increased proliferation and Cell cycle checkpoint loss with increased expression of DNA damage response genes. Ki67 high. - Cell cycle을 타겟하는 antimitotic agents 반응이 좋음
BL-2: EGFR, TP63, MET high. glycolysis, gluconeogenesis high

Immunomodulatory subtype #

Immune cell and Cytokine signalling, antigen presentation and processing and signalling of immune transduction pathways

Mesenchymal and mesenchymal stem like subtype #

EMT and growth factor pathway

Angiogenesis including VEGFR2 and high response to Dasatinib (RTK inhibitor) and mTOR inhibitor

Luminal androgen receptor subtype #

Androgen receptor signalling.

AR antagonist eg Biclutamide

Basal cell and TNBC #

In BLBC overexpression of ID4 leads to the deregulation of BRCA1

BLBC are also known to have either TP53 over expression or mutation.

BLBC show a highly agressive GEP with low Bcl-2 but high TP53 and Ki67.

BRCA and TNBC #

BRCA1 결함은 TNBC와 관련됨

BRCA1 plays vital role in DNA repair by Homologous recombination. Inactivation of this gene due to BRCA mutation should trigger Cell cycle arrest but this too is inhibited by p53 mutations in TNBC

germline BRCA1 변이가 있는 유방암 환자의 80%는 TNBC이며, TNBC의 10%는 BRCA1 변이를 갖고 있음.

Biomarkers in TNBC #

EGFR #

tumor cell survival에 관여하는 3개의 수용체

ERBB1 (EGFR)
ERBB2 (HER2)
ERBB3 (HER3)
ERBB4 (HER4)

EGFR signal cascade is important for

cell proliferation
angiogenesis
metastatic spread
and the inhibition of apoptosis

유방암의 40~50%에서 EGFR amplification 확인, TNBC에서 80%.

In a study the authors found that 60% of patients with grade III and 3 lymph nodes showed EGFR expression, indicating that EGFR expression is related to aggressiveness of the disease.

EGFR expression in TNBC is associated with poor response to chemotherapy

So EGFR is a biomarker in TNBC and a target for Cetuximab, a RTK inhibitor

VEGF #

지름 2mm 이상의 tumor에서 Angiogenesis가 중요함

The angiogenesis is initiated by VEGF binding to VEGFR-2 which triggers the specific activation of RTKs followed by multiple signalling cascades resulting in the endothelial cells survival, proliferation, migration, adhesion, actin remodelling and vessels permeability

In TNBC higher VEGF levels are associated with shorter DFS, OS, and DDFS. And size of tumor, grade and metastatic sites.

VEGF is a target for Bevacizumab in TNBC patients.

C-kit and basal cytokeratins #

C-kit is a cytokine receptor present on the surface of hematopoietic stem cell.

C-kit binds to Stem cell factor.

Expression of CK-5, CK-14, CK-17 was related to poor prognosis, high grade tumours, ER negativity, short DFS and OS.

TP53 #

p53 is activated in response to cellular stress by many pathways that are dependent on distinct upstream regulatory kinases.

An ataxia-telangectasia mutated proteins released in response to DSB
A pathway dependent on INK4 gene product, p14ARF activated by oncogenes
A pathway induced by chemotherapy drugs and UV light

유방암의 18~25%에서 p53 변이가 있다.

Tumours with p53 mutation are highly invasive, poorly differentiated and high grade tumours.

p63/p73 expression is seen in one-third of patients with TNBC

TOP-2A #

This gene encodes topoisomerase II α and plays a crucial role in DNA transcription. - DNA double strand break를 임시로 만들고, 다시 엮는 역할 - 변이가 있으면 상황이 악화됨 - Anthracycline therapy target it.

higher expression of 2.7~8.8% of TNBC. 이 발현이 많으면 Anthracycline 치료 반응이 좋지 않음.

Ki67 #

Cellular marker for proliferation. Ki67 antigen is present inside the cell nucleus during interphase and during mitosis it is relocated to the surface of the chromosomes.

Ki67 expression is less in normal breast tissue (< 3%).

Ki67 was over expressed particularly in ER-negative cells and its expression in carcinoma cells was much higher.

In breast cancer high Ki67 is associated with of poor outcome although these tumours show very good clinical response to combination chemotherapy.

In TNBC, it was found that Ki67 levels were significantly increased in ductal TNBC compared to other histologic types (80% in TNBC vs 10%-30% in other types).

PARP #

Main function of PARP1 is as DNA damage nick sensor.

PARP1의 활성은 중요한 역할을 한다. 다음과 같은 흥미로운 생물학적 이유때문에,

Base excision repair에서 중요한 역할
Necrosis에 이르게 함
Proinflammatory 유전자들의 전사를 촉진함

PARP enzymes are involved in cellular response in inflammation, ischemia and oxidative stress.

PARP1은 carcinogenesis의 거의 전 과정에 관여함.

Inhibition of PARP1 leads to cell death through Apoptosis.

BRCA mutation과 PARP inhibitor는 Synthetic lethality 관계.

PARP1 has been targeted as therapeutic option in TNBC with drugs like Iniparib, Olaparib.

Heat shock protein 90 #

It is a cellular Chaperone protein that mediates the post-translational modification and stabilization of a number of conformationally labile proteins, steroid receptors, CDK4, RAF-1, AKT and other proteins that are useful for sending proliferative signals.

Its’ over expression is associated with neoplastic changes in mammary acini, increases cell migration and invasion in vitro.

Geldanamicyn and Tanespimycin both are antibiotics and inhibitors of HSP.

The PU-H71 another HSP blocker has shown complete response in TNBC models

Cox-2 #

Cox is a conversion enzyme of arachidonic acid and prostaglandin.

It is expressed by stimuli such as inflammatory response and tumor promoters.

Approximately 40% of patient with breast cancer over expresses Cox-2. Cox-2 can also be used as a biomarker to assess response to neoadjuvant chemotherapy in breast cancer.

Cox-2 expression is associated with positive lymph node involvement.

Cox-2 expression is also related to MDR-1, a multidrug resistance gene.

RTK #

Other TKs over-expressed in carcinoma of the breast are BRK, c-Src, and EGFR.

TK over-expression in women with breast cancer is have high risk of metastasis.

TK inhibitors such as Imatinib, Erlotinib, Gefitinib and Lapatinib are used for treatment of many solid tumours.

mTOR #

One of the pathway is commonly dysregulated in breast cancer is phosphatidylinositol 3-kinase/mammalian target of Rapamycin (PI3K/mTOR).

Over expression of the PI3K/mTOR is associated with poor response to treatment with hormones and Trastuzumab.