Transcript Australian Ovarian Cancer Study Georgia Chenevix

Australian Ovarian Cancer Study
Georgia Chenevix-Trench, David Bowtell, Anna deFazio and Penny Webb
Nadia Traficante, Sian Fereday, Jillian Hung, Kathryn Alsop and 105
clinical collaborators
Peter MacCallum Cancer Centre, Queensland Institute of Medical
Research, Westmead Hospital plus 57 hospitals
Clinical Collaborators:
ACT- R Stuart-Harris (Canberra Hospital); NSW- F Kirsten (Bankstown); J Rutovitz (Hornsby); P Clingan, A Glasgow (Illawarra Area
Health Services); A Proietto, S Braye, G Otton (John Hunter Hospital); J Shannon (Nepean Hospital); T Bonaventura, J Stewart
(Newcastle Mater Misericordiae); S Begbie (Port Macquarie Base Hospital); M Friedlander (Prince of Wales Hospital); D Bell, S
Baron-Hay, A Ferrier (dec.), G Gard, D Nevell, N Pavlakis, S Valmadre, B Young (until mid 2003) (Royal North Shore Hospital); C
Camaris, R Crouch, L Edwards, N Hacker, D Marsden, G Robertson (Royal Hospital for Women); P Beale, J Beith, J Carter, C
Dalrymple, R Houghton, P Russell, L Anderson (Royal Prince Alfred Hospital); M Links (St George Hospital); J Grygiel (St Vincent’s
Hospital); J Hill (Wagga Wagga Base Hospital); A Brand, K Byth, R Jaworski, P Harnett, R Sharma, G Wain (Westmead Hospital);
QLD- B Ward, D Papadimos (Mater Misericordiae Hospitals); A Crandon, M Cummings, K Horwood. A Obermair, L Perrin, D Wyld
(Royal Women’s Hospital); J Nicklin (Royal Women’s Hospital and Wesley Hospital); SA- M Davy, MK Oehler, C Hall, T Dodd, T
Healy, K Pittman (Royal Adelaide Hospital, Burnside Memorial Hospital); D Henderson (Flinders Medical Centre); J Miller, J Pierdes
(Queen Elizabeth Hospital); A Achan (ICPMR); TAS- P Blomfield, D Challis, R McIntosh, A Parker (Royal Hobart Hospital); VIC- B
Brown, R Rome (Freemasons Hospital); D Allen, P Grant, S Hyde, R Laurie M Robbie, (Mercy Hospital for Women), D Healy, T
Jobling, T Manolitsas, J McNealage, P Rogers, B Susil, E Sumithran, I Simpson, (Monash Medical Centre); K Phillips, D Rischin, S
Fox, D Johnson, P Waring, S Lade, M Loughrey, N O’Callaghan, W Murray, L Mileshkin, P Allan (Peter MacCallum Cancer Centre); V
Billson, J Pyman, D Neesham, M Quinn, A Hamilton (Royal Women’s Hospital); C Underhill (Border Medical Oncology); Prof R Bell
(Andrew Love Cancer Centre); LF Ng (Ballarat Base Hospital); R Blum (Bendigo Health Care Group); V Ganju (Peninsula Health);
WA- I Hammond, Y Leung (School for Women's and Infants' Health, University of Western Australia and the Western Australian
Gynaecologic Cancer Service); A McCartney (dec.), C Stewart (King Edward Memorial Hospital); M Buck (Mount Hospital)
Australian Ovarian Cancer Study
•
 AOCS summary
 Highlights of publications to date
 Genome Wide Association Study for
progression free survival
 Ovarian Cancer Association Consortium
PI: David Bowtell
2002 - 2006
Control recruitment Patient recruitment
Lifestyle and Diet
questionnaire
Epidemiology Core
Brisbane
Blood sample
Frozen tumour
specimen
Biospecimen Core
Melbourne
Treatment and
clinical details
Clinical Follow-up Core
Sydney
• 1,859 case women with ovarian, fallopian tube and primary peritoneal
cancer recruited through treatment centres & cancer registries across
Australia (1,097 frozen tissues), plus ascites at relapse
• 1,066 control women recruited, selected at random from Commonwealth
electoral roll
www.aocstudy.org
AOCS: Clinical Follow-up
2 5 L e v e l ( U/ m L )
level
SerumCA1CA125
100000
10000
SENSITIVE
His to lo gy :Ser ous adenoc ar c in oma,NOS
FIGOSta ge:IC( Sta ge Deta il:5)
Res id ualDis eas e:mac r os c opic dis eas e >2 c m
RESPONSE Pr imar y Tr eatment:Comple te CA125 r es pons e
Sec ond Lin e:Res pons e ( 50%)
Thir d Lin e:No Res pons e
Four ht Lin e:Res pons e ( 50%)
- O NG O I NG
PI: Anna60139
deFazio
Jillian Hung
1000
100
10
Relapse
Surgery
PFS
1
Fe b- M ayA
- u g - No v - F e b - M a y A
- u g - No v - F e b - M a y A
- u g - No v - F e b - M a y A
- u g - No v - F e b - M a y A
- u g - No v - F e b - M a y 03
03
03
03
04
04
04
04
05
05
05
05
06
06
06
06
07
07
07
07
08
08
Da t e
• Clinical follow-up at 6 month intervals (GCP guidelines)
• Date of relapse assigned according to GCIG criteria (CA125)
Upper Lim it of
CA125 Lev el
Car bopla t in
Pac lit ax el
Dox or ubic in
G em c it abin e
Sur ger y
Rela ps e
Nor m
AOCS Centres
Mater Misericordiae
Royal Brisbane Hospital
Townsville
Wesley Hospital
John Hunter
Royal Hospital for Women
Royal North Shore / Private
Royal Prince Alfred
Westmead Hospital
King Edward Memorial
St John of God
Bunbury
Mandura
Burnside War Memorial
Flinders Medical Centre
Royal Adelaide Hospital
Royal Hobart
Launceston
Whyalla
Darwin
Bundaberg
Cairns
Gold Coast
Hervey Bay
Mackay
Maryborough
Rockhampton
Sunshine Coast
Toowoomba
Townsville
Freemason’s
Mercy Women’s
Monash Medical Centre
Royal Women’s
Austin
Bendigo
Echuca
Frankston
Geelong
Hamilton
Mildura
Mornington
Taralgon
Wodonga
Armidale
Bathurst
Canberra
Coffs Harbour
Dubbo
Grafton
Goulburn
Illawarra
Lismore
Moruya
Orange
Tamworth
Tweed Heads
AOCS: an international resource
 79 approved national and international projects
 88 publications on ovarian cancer
2007 6
2008 5
2009 4
2010 3
2011
2
2012 1
0
5
10
15
20
25
30
PATHOGENESIS
2008
PATHOGENESIS
2010
PATIENT OUTCOMES
2011
PATHOGENESIS
2012
• 14.1% frequency (95% CI: 11.9-16.3%) of pathogenic mutations; increases to 16.6%
(95% CI: 13.9-19.3%) in serous tumours
• 44% (62/141) of the mutation carriers did not report a strong family history of breast
and/or ovarian cancer
• The overall frequency (14.1%) is high enough to suggest that genetic testing should be
offered to all women
• Can we show that mutation status also has an important prognostic and clinical role
to play in ovarian cancer management …?
PATHOGENESIS
2012
BRCA1
BRCA2
Wildtype
BRCA1/2
Response to treatment at first progression
PATHOGENESIS
2010
2011
PRIMARY TREATMENT RESISTANCE
2009
2010
CCNE1 is now being investigated as a new clinical target…..
Genome Wide Association Study (GWAS) of
progression free survival following treatment of
ovarian cancer with carboplatin and paclitaxel
Georgia Chenevix-Trench
Queensland Institute of Medical Research
Hypothesis
That Single Nucleotide Polymorphisms (SNPs) in
chemoresponse mediators are associated with progressionfree survival in women receiving paclitaxel and carboplatin for
advanced ovarian cancer
Primary: that chemoresponse SNPs are associated with ovarian
cancer progression in women receiving > 4 cycles of paclitaxel
(175 or 135 mg/m2) and carboplatin (AUC 5 or 6)
Secondary analysis; also includes cases with > 4 cycles of
unknown doses (Carboplatin IV AUC ? + Paclitaxel IV ? mg/m2)
Tertiary analysis: all invasive cases regardless of chemotherapy to determine if particular genotypes are related to PFS or OS,
independent of treatment
Association of two genotyped SNPs in
TTC39B with PFS
Secondary analysis
SNP
Tertiary analysis
HR
95%CI
P
HR
95%CI
P
rs7874043
2.47
[1.72,3.53]
7.96x10-7
1.48
[1.14,1.91] 3.35x10-3
rs72700653
2.57
[1.72,3.84]
4.14x10-6
1.38
[1.05,1.83] 2.23x10-2
PFS
r2 = 0.896
TTC39B rs7874043 with PFS for individual
studies in Stages 1 and 2 combined
Primary
Secondary
Tertiary
TTC39B and high density lipoprotein-cholesterol
• TTC39B (c9orf52) encodes tetratricopeptide repeat domain 39B, a
potential transmembrane protein
• two GWAS for lipid levels have identified common SNPs in this
locus associated with HDL-C levels (Teslovitch et al., 2010)
• knockdown of TTC39B in a mouse model results in elevated levels of
HDL-C
• genetic variant in TTC39B may affect response to statins
Collaborative Oncological Gene-Environment Study
Breast Cancer Association Consortium - BCAC
Ovarian Cancer Association Consortium - OCAC
Consortium of Investigators of Modifiers of BRCA1/2 - CIMBA
• Genotyped in
 103,991 breast cancer cases and controls
 39,774 ovarian cancer cases and controls (including AOCS)
 11,705 BRCA1 and BRCA2 carriers
• Telomere length was measured in 15,567 control subjects of two
BCAC studies
Summary of common variants
associated with ovarian cancer risk
Locus
Risk allele
frequency
Per allele risk
Variance
Fraction variance
explained (%)
9p22 (BNC2)
0.68
1.22
0.017
0.96
2q31 (HOXD1)
0.31
1.11
0.005
0.35
8q24 (CMYC)
0.87
1.19
0.007
0.48
17q21 (SKAP1)
0.27
1.11
0.004
0.30
19p13 (BABAM1)
0.30
1.12
0.005
0.30
3q25 (TIPARP)
0.05
1.44
0.012
0.76
5p15 (TERT)
0.26
1.09
0.003
0.16
8q21 (CHMP4C)
0.07
1.18
0.004
0.22
10p12 (MLLT10)
0.33
1.10
0.004
0.24
17q12 (HNF1B)
0.38
1.05
0.001
0.07
17q21 (PLEKH1M)
0.17
1.13
0.005
0.28
0.067
4.1%
Total
Subtype specific heterogeneity
Serous
Endometrioid
Clear cell
Mucinous
Sanseau et al, GlaxoSmithKline
• GWAS trait matched
drug indication for 63
genes
• GWAS trait was
different from drug
indication for 92 genes
– potential drug
repositioning
opportunities
© Queensland Institute
of Medical Research |
© Queensland Institute
of Medical Research |
Opportunities for drug ‘repositioning’
© Queensland Institute
of Medical Research |
Summary of common variants
associated with ovarian cancer risk
Locus
Risk allele
frequency
Per allele risk
Variance
Fraction variance
explained (%)
9p22 (BNC2)
0.68
1.22
0.017
0.96
2q31 (HOXD1)
0.31
1.11
0.005
0.35
8q24 (CMYC)
0.87
1.19
0.007
0.48
17q21 (SKAP1)
0.27
1.11
0.004
0.30
19p13 (BABAM1)
0.30
1.12
0.005
0.30
3q25 (TIPARP)
0.05
1.44
0.012
0.76
5p15 (TERT)
0.26
1.09
0.003
0.16
8q21 (CHMP4C)
0.07
1.18
0.004
0.22
10p12 (MLLT10)
0.33
1.10
0.004
0.24
17q12 (HNF1B)
0.38
1.05
0.001
0.07
17q21 (PLEKH1M)
0.17
1.13
0.005
0.28
0.067
4.1%
Total