5. Baselga and Norton, 2002 updated
Evolution in Breast Cancer Classification
Classical Diagnosis
Ductal infiltrating
carcinoma of breast with
high grade of nuclear
atypia
Protein Expression
ErbB2 over expressing
breast tumour
Gene Expression Profiling
Partial two dimensional
cluster analysis of
17 breast tumours
Morphological
Diagnosis
Immunohistochemical
assessment
DNA microarray
analysis
CIRCOS Plot
Integrated Analysis
Chromosome, SNV,
LSV, indel, amplification
miRNA, RNA
6. AJCC 8th Edition: 1st January 2018
• Combining T/N/M with biology grade,proliferation, ER/PgR/HER2/GEP
• NB GEP only apply to LN negative disease; T1a-bN0M0
• OncotypeDx, Mammaprint, EndoPredict, PAM50, Breast Cancer Index
Giuliano Breast Feb 2018
12. Proliferation & Apoptosis
• MIB-1
• Antibody to Ki67
• Protein expressed variably through
cell cycle not G0
• Apoptosis
• One form of cell death
International Ki67 in Breast Cancer Working Group
26. DNA Classification
Tri NA Breast
Age 60%
APOBEC 14%
BRCA1/2 10%
?
APOBEC 2%
Point mutation SNV/SNA vs SNP; indel (30bp); amplif’n; LSV
Nik-Zainal
Nature
2016
27. TCGA: Molecular characteristics of TNBC
provides fuel for future therapeutics
Basal-like Breast Cancer
p53 mut 84% RB1 mut/loss 20%
PIK3CA mut 7% MYC focal gain 40%
PTEN loss 35% Global Hypomethylation
INPP4B loss 30% Aneuploidy and genomic instability
TCGA Nature 2012
28. Post-translational
Histones & tails
within the 25 genes most significantly
altered among all tumour types,
seven (28%) code for
chromatin-modifying enzymes—
KMT2C/MLL3, KMT2D/MLL2,
ARID1A, PBRM1, SETD2, CREBBP
and SMARCA4/BRG1
it is estimated that approximately 20% of all solid malignancies
harbor mutations in at least one SWI/SNF component
incl ~20% breast cancer
Morel Annals 2017
CpG island
37. Stratification of TNBC
TNBC
Luminal/AR Basal
Luminal A+B HER2-enriched Claudin-low/mesenchymal Basal-like
AR expression
Low – Immune – High
Gene expression or TILs
Chemo
sensitivity
Lapatinib
sensitivity
Chemo
sensitivity
Proliferation
20–30% 70–80%
Perou SABCS 2016.
38. PI3K/Akt/mTOR
inhibitors
Targeted RTK
inhibitors
DNA-repair
targeting agents
Cell cycle/mitotic
spindle inhibitors
RAF/MEK inhibitors
Clinically targetable pathways in TNBC
~90% of all patients had an
aberration in at least one of
these pathways
IMMUNOTHERAPEUTICS
Number
of
samples
with
aberrations
PI3K/Akt/mTOR DNA repair Ras/MAPK Cell cycle GFRs
0
10
20
30
40
TSC1
PIK3CA
PTEN
PIK3R1
RICTOR
RAPTOR
AKT1
AKT2
AKT3
BRCA1
BRCA2
ATM
RB1
AURKA
CDNK2A
CCNE1
CCND3
CCND2
CCND1
CDK6
CDK4
NF1
CRAF
BRAF
KRAS EGFR
MET
IGF1R
KIT
FGFR1
FGFR2
FGFR4
Balko Cancer Discov 2014.
39. Protein
• Ultimate effector
• capture the functional
state and dynamic
properties of a cell
• Kinome
• Phospho, other PTMs
• Membrane
• Cytoplasm
• Golgi etc
• Nuclear
40. TNBC – IHC; 133 biomarkers
• Stratify TNBC patients into high risk groups that showed over 5, 6, 7
and 8 times higher risk of developing metastasis to the bone, liver,
lung and brain, respectively, than low-risk subgroups
Klimov
BJC 2017
41.
42. Metabolome
• Metabolic reprogramming in
ER-positive breast cancer
• Super-SILAC mix to quantify
over 10,000 proteins
with high accuracy
Pozniak Cell 2016
44. Triple
Negative
Basal
Gluz et al, Ann Oncol 2009; Carey et al, Nat Rev Clin Oncol 2010;
Young et al, BMC Cancer 2009; Schneider et al, CCR 2008; Shah et al, Nature 2012
~75% of TNBC have
basal gene expression
• ~5% of breast cancers
• ~75-80% of BRCA1 mutation-associated BC are TN
• 50% BRCA1 carriers are basal-like
• Basal but not TN
(15-40%)
• Definition by gene
expression
• Express basal
cytokeratins
• Includes most
BRCA1 mutated
tumours
• Triple negative but
not basal (20-30%)
• Definition by IHC
• Includes non-IDC
histologies
• 10-30% can also
include “claudin-low”,
a subtype notable for
high expression of
stem cell markers
• 90% of TNBC do not
have BRCA mutations
BRCA1/2
mutated
TNBC; integrating clinical & molecular
