Therapeutic opportunities for mucinous ovarian carcinoma

Kylie L Gorringe

Group Leader (Junior Faculty)

Peter MacCallum Cancer Centre

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March 30 - April 2, 2014

Sheraton Sonoma County

Petaluma, California

Off-Label Product Use

Will you be presenting or referencing off-label or investigational use of a therapeutic product?

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Mucinous ovarian tumours comprise a distinct subtype

• Respond poorly to conventional ovarian chemotherapies

• Prognosis when diagnosed at an advanced stage very poor

5 years

Borderline (BDL)

MOC Stage I

MOC Stage II

MOC Stage III-IV

EOM

100%

75%

50%

25%

0

Dis

ease

-specific

surv

ival

Genomic Analysis of Mucinous Tumours (GAMuT)

Contributing centres:

• Australian Ovarian Cancer Study

(AOCS)

• Peter MacCallum Cancer Centre

• Royal Womens Hospital (VIC)

• Hudson Institute of Medical Research

• Westmead GynBioBank

• Queensland Institute of Medical

Research

• Garvan Institute

• Mayo Clinic (USA)

• British Columbia Cancer Centre

(Canada)

• Canadian Ovarian Experimental

Unified Resource (COEUR)

• CRUK Edinburgh Centre (UK)

0

50

100

150

200

250

300

Exome WGS Targetedseq

RNAseq Copynumber

IHC (ER)

EOM

MOC

BDL

BEN

Treatment patterns – first line (79% of cases before 2011)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

I II III IV

Chemotherapy by FIGO stage

No Yes

Surgery only55%

Platinum only6%

Plat + taxane35%

Plat + tax + other2%

Plat + other1%

Other1%

Treatment patterns – recurrences, second and later lines (79% of cases before 2011)

- 21 patients with treatment data (19 with previous chemotherapy)

- 18 different combinations

- 14 different drugs

- Platinum-taxane still most common

- 10 patients, of which 9 had previous platinum-based therapy

Treatment complexity – how does the clinician choose?

0 500 1000 1500 2000

MOC,StageIII,G2

MOC,StageIII,G3

MOC,StageIII,G2

Signetringadenocarcinoma,T4N2M1,G3

Daysa erdiagnosis

FOLFO

X

Carb

opla

n/taxo

l

Carb

opla

n/taxo

l-2

Caelyx

Capecitab

ine

Carb

opla

n/taxo

l/gemcitab

ine

Pacltaxel

Doxorubicin

Oxalip

lan/cap

ecitabine

Etoposid

e

Topotecan

Capecitab

ine/Avas

n(B

evucizu

mab)

Panitu

mumab

Death

0

500

1000

1500

2000

MOC,StageIII,

G2

MOC,StageIII,

G3

MOC,StageIII,

G2

Signetring

adenocarcinoma,

T4N2M1,G

3

Daysa

erdiagnosis

FOLFOX

Carbopla n/taxol

Carbopla n/taxol-2

Caelyx

Capecitabine

Carbopla n/taxol/gemcitabine

Pacltaxel

Doxorubicin

Oxalipla n/capecitabine

Etoposide

Topotecan

Capecitabine/Avas n(Bevucizumab)

Panitumumab

Death

ERBB2 amplified

KRAS, ERBB3, FGFR2

mutations

Homologous recombination deficiency (n=195) Predicted

response to

platinum/PARPi:

Likely (0.5%)

Possible (3.6%)

Unlikely (96%)

HRD Score = telomeric imbalances (NtAI) + large scale transition (LST) + loss of heterozygosity (HRD-LOH)

BRCA-deficient median = 64, IQR 55-70 (Telli et al., 2016)

Marquard et al., 2015

HR

D S

core

Mismatch repair deficiency is rare in MOC (1/187)

Threshold of >40 mutations per Mb from: Nowak et al., J Mol Diagn. 2017 19(1): 84–91

MSH6 p.Arg1334SerfsTer7

MSH2 p.Leu376PhefsTer13 and p.Cys873ArgfsTer4

MSH2 p.Glu859Ter

ER status by immunohistochemistry

ER positive 10.9%

Are these a type of

sero-mucinous tumour?

OTTA study: 16% (Sieh et al. 2013)

ERBB2 amplification present in 26% of MOC

P=8x10-7

P=2x10-9

TP53 mutation is common – 64% in MOC

What are the targeted therapy options for MOC?

Things we could try now (but don’t know if they work in MOC):- Anti-HER2/HER3- BRAF inhibitors- CDK4/6 inhibitors (CDKN2A)

- Future possibilities (in trials):- RAS/RAF inhibitors- PI3K inhibition- Wnt inhibition (RNF43 mutation)- Mutant p53 reactivation: 48.6% with TP53 missense mutation

Benign Borderline Grade1 Grade2 Grade3

MOC

KRAS 64.6%

TP53 64.6%

CDKN2A 50.8%

ERBB2 26.5%

ERBB3 4.4%

RNF43 11.6%

ARID1A 9.9%

BRAF 8.8%

PIK3CA 8.3%

PTEN 2.2%

Truncating Essentialsplicesite Missense Amplification Homozygousdeletion

- 86% ≥2 possibilities

- 5.5% none of these

Summary

- MOC are genetically heterogeneous

- inter- and intra-tumoural heterogeneity

- testing targeted therapies will be challenging: MOC-specific trials will be difficult to recruit

- MOC should be included in basket trials based on molecular profiling

- Therapeutic options could include anti-HER2 therapies, BRAF inhibitors

- Therapies unlikely to be of use include PARP inhibitors, platinum

- Unknown if immunotherapies of use

- Future work – functional testing using organoids and PDX (DOD grant)

Carolina Salazar

AcknowledgementsCampbell/Gorringe Labs Pathology GAMuT - Australia

Ian Campbell Stephen Fox Westmead (NSW)

Dane Cheasley Prue Allan Anna deFazio

Simone Rowley Catherine Kennedy

Mei-Sim Lung GAMuT - Victoria Garvan (NSW)

Na Li WEHI Goli Samimi

Tanjina Kader Clare Scott Maret Boehm

Sakshi Mahale Matt Wakefield QIMR (QLD)

Hugo Saunders RMH/RWH Georgia Chenevix-Trench

Lisa Devereux Sumi Ananda

Georgina Bing Jan Pyman GAMuT - International

Abhimanyu Nigam Michael Christie Edinburgh (UK)

Carolina Salazar Alison Hadley Charlie Gourley

Former Orla McNally Michael Churchman

Sally Hunter Hudson Institute BCCA (Canada)

Georgie Ryland Andrew Stephens David Huntsman

David Choong Cabrini/Southern Jessica McAlpine

Michelle Torres Yoland Antill Blake Gilks

Tom Jobling University of Calgary (Canada)

Bioinformatics AOCS/CASCADE Martin Koebel

Jason Li David Bowtell Mayo Clinic (US) Scott Kaufmann

Richard Lupat Nadia Traficante Scott Kaufmann

Kaushalya Amarasinghe Sian Fereday COEUR tissue bank (Canada)

Niko Thio Joy Hendley

Magnus Zethoven Kathryn Alsop

Genomics Core Leanne Bowes

Gisela Mir-Arnau VCB Biobank

Tumour lymphocyte counting

- Small sample set (n=40 MOC)

- Intra-tumoural and stromal TIL counts generally low

- iTILs correlate with Grade, % FGA and ERBB2 amplification

- sTILs no significant correlations

p-value = 0.0035 p-value = 0.031 p-value = 0.048

p-value = 0.202 p-value = 0.44 p-value = 0.073

Endometrioid

Mucinous

Histological appearance

B-catenin mutation

MMR deficiency

KRAS, TP53 mutation

Genetic markers

ARID1A, PIK3CA

ER status

Endometriosis

0%

20%

40%

60%

80%

100%

Endometrioid "Seromucinous" ER+ mucinous ER- MucinousB catenin mutation PIK3CA mutation ARID1A mutation MMR deficiency KRAS mutation TP53

Comparison with other tumour types

Comparison with other tumour types

ERBB2/TP53 correlation

P=2x10-9

High copy number = worse survivalF

raction g

enom

e a

ltere

d b

y C

N

A

B C

Benign

Borderline

G1 MOC

G2 MOC

G3 MOC

Gain Loss

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 202122 X

BE

N

BD

L

G1

G2

G3

EO

M

EOM

G3

G2

G1

BDL

BEN

●●●

●

●

●

●

●

0.0

0.2

0.4

0.6

BEN BDL 1 2 3 EOM

Grade

FG

A

0 0.05 0.1 0.15 0.2

ValueP-value

Figure 2. CN analysis. A. Comparison of CN frequency across the genome, compar-

ing benign (BEN), borderline (BDL), MOC grade 1 (G1), grade 2 (G2) and grade 3

(G3) . B. Fraction of the genome altered (FGA) by group including extra-ovarian

(EOM) mucinous tumours (p<0.001). Tukey post-test comparison p-values shown at

right.C. Disease-specific survival by FGA. Score (logrank) test = 11.98 on 1 df,

p=0.002.

Dis

ease-s

pecific

surv

ival

BEN BDL G1 G2 G3

10%

Multivariate cox regression:

p=0.011, HR = 4.4, 95% CI 1.4-14(with stage, grade, ERBB2 amplification and 9p CN loss;

selected by AIC)

logrank P=4x10-5

How can we get evidence to support clinical use?- Grow patient cells in the lab to study

Tumour organoid cultures

Sachs & Clevers, Current Opinion in Genetics & Development (2014) 24:68-73

Carolina Salazar

(PhD student)

Dane Cheasley

(post-doc)