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OncoSignalSignalingpathway activity.Supporting therapy selection.
Determining the functional activity of tumor-driving signal transduction pathways.Essential knowledge has been acquired on the role of signal transduction pathways in cancer growth, providing input for development of drugs targeting signaling pathways. Identifi cation of the tumor-driving pathway and its causative defect is crucial for selecting the most eff ective therapy.
Philips OncoSignal Molecular Pathway Diagnostics determines the activity of tumor-driving signal transduction pathways by measuring mRNA transcribed from target genes of the pathway transcription factors and data interpretation with computational pathway models. (W Verhaegh et al, Cancer Research 2014 74(11): 2936-45).
Trastuzumab
Lapatinib
TamoxifenWnt inhibitors
Bevacizumab
Sunitinib
Estrogen Wnt
VEGF
VEGFR
Cancer cellproliferation
Chemotherapy
Androgen AR
ERRAS
HER2
EGFR
NFκBNotch
TGFβ Hedgehog
Al
LR
S SS
F
T T T T T
Trastuzumab
Lapatinib
TamoxifenWnt inhibitors
Bevacizumab
Sunitinib
Estrogen Wnt
VEGF
VEGFR
Cancer cellproliferation
Chemotherapy
Androgen AR
ERRAS
HER2
EGFR
NFκBNotch
TGFβ Hedgehog
Al
LR
S SS
F
T T T T T
10-15 Signal transduction pathways are known to drive cancer growth; Targeted drugs target the following pathways: Estrogen receptor (ER) and Androgen receptor (AR), Wnt, Notch, Hedgehog, TGF-ß, NF-κB and the growth factor stimulated signaling pathways: phosphoinositide 3-kinase/AKT/FOXO, RAS/MAPK/ERK, and JAK/STAT.
OncoSignal enables functional assessment of pathway activity in tumor samples. The expression levels of selected target genes of these pathways are measured using our qPCR test kit; our sophisticated computational models interpret the data and indicate the activity scores of the diff erent pathways. OncoSignal is applicable across a broad range of cancer types.
Philips OncoSignal qPCR kits are in development, not available for sale. OncoSignal pathway analysis is already available through our dedicated service lab for Research Purposes Only. Not for use in diagnostic procedures.
Testing “down-stream” for mRNA transcriptionof the target genes of pathways
ER pathway in breast cancer
High ER pathway activity in MCF7 breast cancer cell lines upon addition of estradiol (E2) in duplicate. Pathway activity inhibited by fulvestrant (left) and tamoxifen (right). Ref: EJ Blok et al, SABCS 2015
Cell line
ER
act
ivit
y sc
ore
(re
lati
ve s
cale
)
Control 1nM E2 10nM E2 E2+Fulves.
ER
act
ivit
y sc
ore
(re
lati
ve s
cale
)
Control 100nMtamoxifen 1nM E2 E2+100nM
tamoxifen
Adjuvant primaryER stain positive breast cancer patients with active ER pathway show better response to adjuvant tamoxifen treatment. Ref: W Verhaegh et al, Cancer Research 2014 74(11): 2936-45
Advanced ER positive breast cancer patients with an active ER pathway in the primary tumor show longer progression free survival of later-developed metastases on first line tamoxifen treatment. Ref: AM Siewerts et al, AACR 2016
Metastatic cancer
Fra
ctio
n d
ise
ase
fre
e s
urv
iva
l 1.00
0.75
0.50
0.25
0
0 1 2 3 4 5
Time (years)
ER active n=91ER inactive n=69p=0.0033
Fra
ctio
n p
rog
ress
ion
fre
e s
urv
iva
l
0.2
0
0 10 20 30 40 50 60
0.4
0.6
0.8
1.0
Time (months)
n=36 ER activen=94 ER inactivep=0.0021
Philips OncoSignal qPCR kits are in development, not available for sale. OncoSignal pathway analysis is already available through our dedicated service lab for Research Purposes Only. Not for use in diagnostic procedures.
TEAM IIA study: Neo-adjuvant hormonal treatment of ER receptor positive patients. Ref: EJ Blok et al, SABCS 2015
Progressive disease (PD) (assessed by palpation) is associated with low baseline ER pathway activity.
Response to hormonal therapy is correlated to decrease in pathway activity.
Neo-adjuvant primary
CR PR SD PD
CR PR SD PD
n=6 n=7 n=8 n=2
p=0.003
Baseline
Dierence resection vs. baseline
n=11
p=0.03
n=12 n=12
n=3
CR (complete response)PR (partial response)SD (stable disease)PD (progressive disease)
CR (complete response)PR (partial response)SD (stable disease)PD (progressive disease)
Pa
thw
ay a
ctiv
ity
ind
ex
Δ P
ath
way
act
ivit
y in
de
x
CR PR SD PD
CR PR SD PD
n=6 n=7 n=8 n=2
p=0.003
Baseline
Dierence resection vs. baseline
n=11
p=0.03
n=12 n=12
n=3
CR (complete response)PR (partial response)SD (stable disease)PD (progressive disease)
CR (complete response)PR (partial response)SD (stable disease)PD (progressive disease)
Pa
thw
ay a
ctiv
ity
ind
ex
Δ P
ath
way
act
ivit
y in
de
x
Other pathways in breast cancer
Active pathways in breast cancerDominant pathway activity varies across breast cancer subtypes. Pathway analysis in individual patients may guide therapy choice. In 13% of patients combinations of active pathways were observed. Ref: H van Ooijen, AACR 2015
TGF-ß induces TGF-ß pathway activity in an ER negative breast cancer cell line (MDA-MB-231).
TGF-ß pathway / cell line
ResponseNon-PD, n=11PD, n=9
HH
act
ivit
y s
core
(re
lati
ve s
cale
)
ER, 215
ER, 112 ER, 31
ER&PI3K
HH&PI3K
ER&TGFbER&HH
HH&TGFb
PI3K&TGFb
Wnt&HH
AR&TGFbWnt&TGFb
ER&WntAR&PI3K
ER&AR Wnt&PI3K HH&AR
Wnt, 15
HH, 44
AR, 12
Wnt, 14
Wnt, 35TGFb, 32TGFb
P13K, 25P13K, 24
AR, 1AR, 15
Wnt, 4
Wnt, 2HH, 34
HH, 22
HH, 24
HH, 18
AR, 2
AR, 4
P13K, 59
P13K, 118
P13K, 4
TGFb, 34 TGFb, 18
ER, 0ER, 0
TGFb, 9
Luminal A (n=511) Luminal B (n=360)
HER2 (n=143) Basal (n=171)
Normal-like (n=109)
Combination of pathways
p=0.0097T
GF
-ß a
ctiv
ity
sco
re (
rela
tive
sca
le)
0.029
n = 4
n = 4
TreatmentControlTGF-ß
Higher Hedgehog pathway activity in patients with progressive disease (PD).
High Hedgehog pathway activity in metastasized breast cancer patients is indicative of more aggressive tumor progression.
HH active n=6HH inactive n=14p=0.0036
Fra
ctio
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rog
ress
ion
fre
e s
urv
iva
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1.00
0.75
0.50
0.25
0
0 5 10 15 20 25 30 35
Time (months)
20 M1 ER positive patients with first line tamoxifen.Ref: AM Siewerts et al, AACR 2016
Hedgehog pathway / metastatic cancer
ResponseNon-PD, n=11PD, n=9
HH
act
ivit
y s
core
(re
lati
ve s
cale
)
ER, 215
ER, 112 ER, 31
ER&PI3K
HH&PI3K
ER&TGFbER&HH
HH&TGFb
PI3K&TGFb
Wnt&HH
AR&TGFbWnt&TGFb
ER&WntAR&PI3K
ER&AR Wnt&PI3K HH&AR
Wnt, 15
HH, 44
AR, 12
Wnt, 14
Wnt, 35TGFb, 32TGFb
P13K, 25P13K, 24
AR, 1AR, 15
Wnt, 4
Wnt, 2HH, 34
HH, 22
HH, 24
HH, 18
AR, 2
AR, 4
P13K, 59
P13K, 118
P13K, 4
TGFb, 34 TGFb, 18
ER, 0ER, 0
TGFb, 9
Luminal A (n=511) Luminal B (n=360)
HER2 (n=143) Basal (n=171)
Normal-like (n=109)
Combination of pathways
p=0.0097
Philips OncoSignal qPCR kits are in development, not available for sale. OncoSignal pathway analysis is already available through our dedicated service lab for Research Purposes Only. Not for use in diagnostic procedures.
An active PI3K pathway* is associated with increased risk of recurrence in adjuvant tamoxifen treated breast cancer patients. Ref: W Verhaegh et al, Cancer Research 2014 74(11): 2936-45
Fra
ctio
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ise
ase
fre
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0.75
0.50
0.25
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0 1 2 3 4 5
Time (years)
FOXO active n=113FOXO inactive n=47p=0.037
EGFR inhibitor, erlotinib, inhibits PI3K pathway activity* in different breast cancer cell lines. Ref: H van Ooijen, SABCS 2017
*FOXO activity score is inversely related to PI3K pathway activity.
PI3K pathway / cell line PI3K pathway / adjuvant primary
FO
XO
act
ivit
y sc
ore
(re
lati
ve s
cale
)
0.057 0.2 0.33
Treatment
BT20 Control
BT20 erlotinib 0.5h
BT20 erlotinib 6h
BT20 erlotinib 24h
MDA-MB-453 control
MDA-MB-453 erlotinib 24h
MCF7 control
MCF7 erlotinib 24h
Triple negative(BT20)
ER positive(MCF7)
HER2 positive(MDA-MB-453)
n = 4
n = 3
n = 3
n = 3
n = 3
n = 2
n = 2
n = 2
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www.philips.com
www.philips.com/oncosignal
OncoSignal qPCR tests and services to determine the tumor-driving pathway activity can be carried out using standard lab equipment in combination with cloud-based OncoSignal computational models for data interpretation. The test procedure should be performed in a laboratory suited for molecular diagnostics.
Studies to evaluate prediction of targeted therapy response in di� erent cancer types are ongoing. Not yet available for sale.
RNA extraction OncoSignal qPCR kit OncoSignal data analysis software
qPCR kit runs on standard Lab Equipment
Purifi ed RNA Tumor tissue (FFPE)
Features• Applicable to multiple cancer types.• RNA extracted from FFPE or FF tissue sample or cells can be used as test input. • Standard procedures and equipment for RNA extraction & qPCR (96-well plate).• Currently available pathways: ER, AR, FOXO/PI3K, HH, Wnt, TGF-ß, Notch.• Pathways in development: AP1, PR, JAK/STAT, NF-κB.• Short turnaround time of qPCR procedure and data analysis (within 1 day).• Data analytics through stand alone web-based software or as module in Philips IntelliSpace Genomics.
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ABCDEFGH
RefNotchFOXOHHTGF-ß WntERAR
OncoSignal: Test procedure
Please contactjos.rijntjes@philips.com; paul.van.de.wiel@philips.com; sieglinde.neerken@philips.com.