171119 - oncosignal - flyer brochure...

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


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)


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



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

n p

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


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

n d

ise

ase

fre

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urv

iva

l 1.00

0.75

0.50

0.25

0

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

© 2017 Koninklijke Philips N.V. All rights reserved. Specifi cations are subject to change without notice. Trademarks are the property of Koninklijke Philips N.V. (Royal Philips) or their respective owners.

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.

1 2 3 4 5 6 7 8 9 10 11 12

ABCDEFGH

RefNotchFOXOHHTGF-ß WntERAR

OncoSignal: Test procedure

Please [email protected]; [email protected]; [email protected].

171119 - oncosignal - flyer brochure...

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