therapeutic opportunities for mucinous ovarian carcinoma
TRANSCRIPT
Therapeutic opportunities for mucinous ovarian carcinoma
Kylie L Gorringe
Group Leader (Junior Faculty)
Peter MacCallum Cancer Centre
Faculty Disclosure
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Position
EmployeeOther
(please specify)
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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x No, nothing to disclose
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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)