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The Cell Cycle Cancer Test
1
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Shaping the Future of Personalised Healthcare
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G2 G1
M
S
Cdc45 Cdc6 MCM Replisome
Cdt1 Geminin
Cdc7 CDK
ASK Cyclin
P P
ORC
License to Replicate
The DNA Replication Initiation Machinery
Cell Cycle
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Three Ways Out of Cycle
quiescence
senescence
differentiation
Cdc6
ORC MCM
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DNA replication
initiation proteins in
tissue maintenance and cancer
Introduction
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DNA replication
initiation proteins in
tissue maintenance and cancer
From bench
to bedside – new tests
for cancer detection and prognosis
Introduction
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From bench
to bedside – new tests
for cancer detection and prognosis
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Requirement for Prognostic and
Predictive Markers in Breast cancer
50% of patients who
receive loco-regional treatment
will never relapse, whereas
the remainder will die of
metastatic disease
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Requirement for Prognostic and
Predictive Markers in Breast cancer
50% of patients who
receive loco-regional treatment
will never relapse, whereas
the remainder will die of
metastatic disease
50%
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Requirement for Prognostic and
Predictive Markers in Breast cancer
1/3 of patients who are node-
negative will experience relapse
1/3
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Requirement for Prognostic and
Predictive Markers in Breast cancer
1/3 of node-positive patients not
receiving adjuvant therapy will be
disease-free after 10 years
1/3
1/3
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Cell Cycle Phase Progression
in Breast Cancer
G2 G1
M
S
H3
MCM
P
Geminin
MCM2 Ki67 Geminin
Aurora A
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Tumour biopsy material
Multiparameter analysis:
Mcm2, geminin and H3S10ph
Mcm2 high (>30%)? No
No
Geminin or
H3S10ph high?
Good Prognosis
Phenotype I
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Tumour biopsy material
Multiparameter analysis:
Mcm2, geminin and H3S10ph
Mcm2 high (>30%)? No
No No
Yes
Geminin or
H3S10ph high? Geminin or
H3S10ph high?
Good Prognosis Good Prognosis
Phenotype II
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Shaping the Future of Personalised Healthcare
Tumour biopsy material
Multiparameter analysis:
Mcm2, geminin and H3S10ph
Mcm2 high (>30%)? No
No No
Yes
Geminin or
H3S10ph high? Geminin or
H3S10ph high?
Good Prognosis Good Prognosis
Yes
Poor Prognosis
Phenotype III
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Cell Cycle State Predicts the Outcome
of Breast Cancer after Surgery
Days from diagnosis to death, recurrence or last follow up
Pro
po
rtio
n r
em
ain
ing
fre
e f
rom
recu
rren
ce
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Clone generation
Clonal stability and Isotype homogeneity
12
Accelerated antibody stability study
7
0
0.5
1
1.5
2
2.5
3
TP0 TP1 TP2 TP3 TP4
Intensity scores of 37°C stability study
Negative
1 1/10
2 1/10
3 1/10
4 1/10
5 1/10
6 1/10
7 1/10
Immunisation
Clone pre-selection (ELISA)
many clones
3
Development
IHC titration and reproducibility
11
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IHC titration curve Mcm2 antibodies
Mcm2 BD Ab
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Validation in tissues with varying expression levels
Placenta Colon Fallopian tube
High Medium Low
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Stability testing of Ab clones
Select stable clones at a minimum of 18 months equivalent real time
37°C Stability Study day 80
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Over and under treatment for patients
with breast cancer?
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Over and undertreatment for patients
with breast cancer?
Chemotherapy No Chemotherapy
29% (n=9)
71% (n=22)
Phenotype I
24% (18/76) of patients
received adjuvant
chemotherapy with
minimal benefit
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Over and undertreatment for patients
with breast cancer?
Chemotherapy No Chemotherapy
20% (n=9)
80% (n=36)
Phenotype II
24% (18/76) of patients
received adjuvant
chemotherapy with
minimal benefit
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Over and under treatment for patients
with breast cancer?
Chemotherapy No Chemotherapy
54% (n=57)
46% (n=49)
Phenotype III
46% (49/106) of patients
did not receive treatment
with adjuvant
chemotherapy
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Failed trials? Let FGL find out why…
Plasma Membrane
Receptor Protein
Growth Factor
Signal
Transduction Cascade
Out-of-cycle Phenotype I
Cell Cycle
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Failed trials? Let FGL find out why…
Plasma Membrane
Receptor Protein
Growth Factor
Signal
Transduction Cascade
G1 Arrest Phenotype II
G1
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Failed Clinical trials? Let FGL find out why…
Plasma Membrane
Receptor Protein
Growth Factor
Signal
Transduction Cascade
Actively Cycling Phenotype III
G2 G1
M
S
G1
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Shaping the Future of Personalised Healthcare
Advantages
• Can be used for all forms of breast cancer
• Simple, inexpensive IHC based test
• Identification of CT sensitive and insensitive tumours for breast cancers
• Enables patient stratification for clinical oncology trials
• Applicable to FFPE samples
Thank You www.fglabs.com
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