Australian Ovarian Cancer StudyGeorgia Chenevix-Trench, David Bowtell, Anna deFazio and Penny

WebbNadia Traficante, Sian Fereday, Jillian Hung, Kathryn Alsop and 105

clinical collaboratorsPeter 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

• 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

Lifestyle and Diet questionnaire

Blood sample Frozen tumour specimen

Treatment and clinical details

Patient recruitmentControl recruitment

Epidemiology Core Brisbane

Biospecimen Core Melbourne

Clinical Follow-up Core Sydney

www.aocstudy.org

2002 - 2006

PI: David Bowtell

AOCS: Clinical Follow-up

60139 - O NG O I NG

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Upper Lim it of Nor m alCA125 LevelCar boplat inPac lit ax elDoxor ubic inG em c it abineSur ger yRelapse

SENSITIVE His tology : Ser ous adenocar c inoma, NOSFIGO Stage: IIIC ( Stage Detail: 5)Res idual Dis ease: mac r osc opic disease >2 cm RESPONSE Pr imar y Tr eatment: Complete CA125 r esponse Second Line: Res ponse ( 50%) Thir d Line: No Res ponse Four th Line: Respons e ( 50%)

• Clinical follow-up at 6 month intervals (GCP guidelines)

• Date of relapse assigned according to GCIG criteria (CA125)

Ser

um C

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Surgery Relapse

PFS

PI: Anna deFazioJillian Hung

BundabergCairnsGold CoastHervey BayMackayMaryboroughRockhamptonSunshine CoastToowoombaTownsville

ArmidaleBathurstCanberraCoffs HarbourDubboGraftonGoulburnIllawarraLismoreMoruyaOrangeTamworthTweed HeadsAustin

BendigoEchucaFrankstonGeelongHamiltonMilduraMorningtonTaralgonWodonga

Launceston

WhyallaDarwin

BunburyMandura

AOCS Centres

Burnside War MemorialFlinders Medical CentreRoyal Adelaide Hospital

Freemason’s

Mercy Women’sMonash Medical CentreRoyal Women’s

Mater Misericordiae Royal Brisbane HospitalTownsvilleWesley Hospital

Royal Hobart

John HunterRoyal Hospital for WomenRoyal North Shore / PrivateRoyal Prince AlfredWestmead Hospital

King Edward MemorialSt John of God

AOCS: an international resource

79 approved national and international projects

88 publications on ovarian cancer

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PATHOGENESIS 2008

PATHOGENESIS 2010

2011PATIENT OUTCOMES

• 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 …?

2012

PATHOGENESIS

2012

PATHOGENESIS

BRCA1 BRCA2 Wildtype BRCA1/2

Response to treatment at first progression

PATHOGENESIS

2010

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2009

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PRIMARY TREATMENT RESISTANCE

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-TrenchQueensland Institute of Medical Research

Hypothesis

That Single Nucleotide Polymorphisms (SNPs) in chemoresponse mediators are associated with progression-

free 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

Secondary analysis Tertiary analysis

SNP HR 95%CI P HR 95%CI P

PFS

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

Association of two genotyped SNPs in TTC39B with 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 - OCACConsortium 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

Total 0.067 4.1%

Subtype specific heterogeneity

Serous Endometrioid Clear cell Mucinous

© Queensland Institute of Medical Research | 25

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 | 26

© Queensland Institute of Medical Research | 27

Opportunities for drug ‘repositioning’

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

Total 0.067 4.1%