1. 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)

2. Australian Ovarian Cancer Study  AOCS summary  Highlights of publications to date  Genome Wide Association Study for progression free survival  Ovarian Cancer Association Consortium

3. 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 Lifestyle and Diet questionnaire Blood sample Frozen tumour specimen Frozen tumour specimen Treatment and clinical details Treatment and clinical details Patient recruitment Control recruitment Epidemiology Core Brisbane Biospecimen Core Melbourne Clinical Follow-up Core Sydney www.aocstudy.org 2002 - 2006 PI: David Bowtell

4. AOCS: Clinical Follow-up Clinical follow-up at 6 month intervals (GCP guidelines) Date of relapse assigned according to GCIG criteria (CA125) Serum CA125 level Surgery Relapse PFS PI: Anna deFazio Jillian Hung

5. Bundaberg Cairns Gold Coast Hervey Bay Mackay Maryborough Rockhampton Sunshine Coast Toowoomba Townsville Armidale Bathurst Canberra Coffs Harbour Dubbo Grafton Goulburn Illawarra Lismore Moruya Orange Tamworth Tweed Heads Austin Bendigo Echuca Frankston Geelong Hamilton Mildura Mornington Taralgon Wodonga Launceston Whyalla Darwin Bunbury Mandura AOCS Centres Burnside War Memorial Flinders Medical Centre Royal Adelaide Hospital Freemason’s Mercy Women’s Monash Medical Centre Royal Women’s Mater Misericordiae Royal Brisbane Hospital Townsville Wesley Hospital Royal Hobart John Hunter Royal Hospital for Women Royal North Shore / Private Royal Prince Alfred Westmead Hospital King Edward Memorial St John of God

6. AOCS: an international resource  79 approved national and international projects  88 publications on ovarian cancer 2007 2008 2009 2010 2011 2012

7. PATHOGENESIS 2008

8. PATHOGENESIS 2010

9. 2011 PATIENT OUTCOMES

10. 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

11. 2012 PATHOGENESIS BRCA1 BRCA2 Wildtype BRCA1/2

12. Response to treatment at first progression

13. PATHOGENESIS 2010 2011

14. 2009 2010 PRIMARY TREATMENT RESISTANCE CCNE1 is now being investigated as a new clinical target…..

15. 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

16. 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/m 2 ) and carboplatin (AUC 5 or 6) Secondary analysis; also includes cases with > 4 cycles of unknown doses (Carboplatin IV AUC ? + Paclitaxel IV ? mg/m 2 ) Tertiary analysis: all invasive cases regardless of chemotherapy - to determine if particular genotypes are related to PFS or OS, independent of treatment

17. Secondary analysisTertiary analysis SNPHR95%CIPHR95%CIP PFS rs78740432.47[1.72,3.53]7.96x10 -7 1.48[1.14,1.91]3.35x10 -3 rs727006532.57[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 r 2 = 0.896

18. TTC39B rs7874043 with PFS for individual studies in Stages 1 and 2 combined Primary Secondary Tertiary

19. 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

21. 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

23. Summary of common variants associated with ovarian cancer risk LocusRisk allele frequency Per allele riskVarianceFraction variance explained (%) 9p22 (BNC2)0.681.220.0170.96 2q31 (HOXD1)0.311.110.0050.35 8q24 (CMYC)0.871.190.0070.48 17q21 (SKAP1)0.271.110.0040.30 19p13 (BABAM1)0.301.120.0050.30 3q25 (TIPARP)0.051.440.0120.76 5p15 (TERT)0.261.090.0030.16 8q21 (CHMP4C)0.071.180.0040.22 10p12 (MLLT10)0.331.100.0040.24 17q12 (HNF1B)0.381.050.0010.07 17q21 (PLEKH1M)0.171.130.0050.28 Total0.0674.1%

24. Subtype specific heterogeneity Serous Endometrioid Clear cellMucinous

25. © 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

26. © Queensland Institute of Medical Research | 26

27. © Queensland Institute of Medical Research | 27 Opportunities for drug ‘repositioning’

28. Summary of common variants associated with ovarian cancer risk LocusRisk allele frequency Per allele riskVarianceFraction variance explained (%) 9p22 (BNC2)0.681.220.0170.96 2q31 (HOXD1)0.311.110.0050.35 8q24 (CMYC)0.871.190.0070.48 17q21 (SKAP1)0.271.110.0040.30 19p13 (BABAM1)0.301.120.0050.30 3q25 (TIPARP)0.051.440.0120.76 5p15 (TERT)0.261.090.0030.16 8q21 (CHMP4C)0.071.180.0040.22 10p12 (MLLT10)0.331.100.0040.24 17q12 (HNF1B)0.381.050.0010.07 17q21 (PLEKH1M)0.171.130.0050.28 Total0.0674.1%