1. BRCA testing in women with ovarian cancer Dr Carole Brewer Peninsula Clinical Genetics Service 15 January 2016

2. Consultant clinics Genetic nurse or counsellor clinics Peninsula Clinical Genetics Service www.peninsulaclinicalgeneticsservice.co.uk/

4. Genetic mutations Genes that control cell growth- tumour suppressors, oncogenes etc. Germline mutations (vs somatic) Diagnostic- mutation searching Predictive- testing for known family mutation Referrals- tend to be unaffected people

5. Referrals to PCGS

6. Reasons for BRCA testing For the benefit of family: Predictive tests for relatives Management of future risks- patient and relatives

7. Reasons for BRCA testing For the benefit of family: Predictive tests for relatives Management of future risks- patient and relatives Influence current management

8. Ovca 63 brca 47 brca 35

9. Ovca 63 brca 47 brca 35 BRCA1 mutation

10. Ovca 63 brca 47 brca 35

11. Predictive genetic testing Unaffected, at-risk relatives Usually at 50% risk Mutation already identified in family Usually 2 counselling appointments, 4 weeks apart, blood taken at second Result 4 weeks later, given in person.

12. Ovca 63 brca 47 brca 35 Mutation positive Mutation negative

13. BRCA mutation carriers Ovarian cancer risks determined by –Gene –Family history BRCA1: 20-60% BRCA2: 10-20%

14. Age-related ovca risks BRCA1- –less than 2% before 40, –From 45, 1% per annum, rising to 2.5% at 65y BRCA2 –Later and lower –<1% per annum

15. Age-related ovca risks BRCA1- low before 40, ~1% pa 40-60 –0.6% by 40y –23% by 50y –30% by 60y –63% by 70y BRCA2-low before 50 –0.4% by 50y –7.4% by 60y –27% by 70y

16. Age-related ovca risks, (compared with breast cancer risks) BRCA1-breast cancer risk ~2% per annum 30’s onwards –0.6% by 40y (18%) –23% by 50y (49%) –30% by 60y (64%) –63% by 70y (70-80%) BRCA2- –0.4% by 50y (28%) –7.4% by 60y –27% by 70y (80%)

17. Ovarian cancer Ovca 54

18. Familial Ovarian cancer How to assess risk of ovarian ca?

21. 47y 38y63y Breast cancer Ovarian cancer 37y 42y 54y GillJo Marjorie, 70y PatShirley Rose Ivy 42y 63y

22. Ovca 63 brca 47

23. Manchester scoring system (Evans et al, 2004) CancerScore FBC <3011 FBC 30-398 FBC 40-496 FBC 50-594 FBC >592 MBC <6013 MBC>5910 Ovca <6013 Ovca >5910 Pancreatic cancer1 Prostate cancer <602 Prostate cancer >591

24. Manchester scoring system (Evans et al, 2004) CancerScore FBC <3011 FBC 30-398 FBC 40-496 FBC 50-594 FBC >592 MBC <6013 MBC>5910 Ovca <6013 Ovca >5910 Pancreatic cancer1 Prostate cancer <602 Prostate cancer >591

25. Manchester scoring system-revised, taking into account histology (Evans et al ) Tumour histology and biomarkers (in index case only) Score Her2+-4 Lobular-2 DCIS only LCIS only-4 Grade 1 IDC-2 Grade 2 IDC0 Grade 3 IDC+2 ER+ ER-+1 Grade 3, triple negative+4 Ovary: mucinous, borderline, germ cell (?except granulosa) No score given

26. Manchester scoring system-revised, taking into account histology (Evans et al ) Tumour histology and biomarkers (in index case only) Score Her2+-4 Lobular-2 DCIS only LCIS only-4 Grade 1 IDC-2 Grade 2 IDC0 Grade 3 IDC+2 ER+ ER-+1 Grade 3, triple negative+4 Ovary: mucinous, borderline, germ cell (?except granulosa) No score given

27. Score 15 =10% chance of finding a mutation Score of 20=20% chance Manchester scoring system

28. Genetic factors BRCA1/2 Other highly penetrant genes? Environmental factors Moderate family history, modest increased risk Genetic testing or surgery not usually indicated

29. Other potential ovarian cancer susceptilibity genes: RAD51B, RAD51C, RAD51D 28/3429 (0.82%) cases v 3/2000 controls (0.11%) Odds ratios 5.2 – 12 depending on gene =moderate risk, but rare Song et al 2015

30. Other potential ovarian cancer susceptilibity genes:BRIP1, BARD1,PALB2, NBN BRIP: 0.9% cases, 0.09% controls. –RR 11 EOC, 14 for HGS ovca BARD1, PALB2, NBN: No difference between cases and controls Ramus et al 2015

31. 47y 38y63y Breast cancer Ovarian cancer 37y 42y 54y GillJo Marjorie, 70y PatShirley Rose Ivy 42y 63y

32. 47y 38y63y Breast cancer Ovarian cancer 37y 42y 54y GillJo Marjorie, 70y PatShirley Rose Ivy 42y 63y Manchester score: 57!

33. 47y 38y63y 37y 42y 54y GillJo Marjorie, 70y PatShirley Rose Ivy 42y BRCA1 mutation

34. Ovca 63 Manchester sore: 10+6 =16 brca 47

35. Ovca 63 Manchester sore: 10+6 =16 ~10% chance of finding a mutation brca 47

36. Ovca 63 No surviving affected relative brca 47

37. Ovca 63 No surviving affected relative, So chance of mutation 5% (no testing) brca 47

39. Ovarian cancer Ovca 54 Why is important to know?

40. Double stranded DNA Normal cell

41. Double stranded DNA DS-DNA break Normal cell

42. Repaired by Homologous repair system – HR (BRCA1, BRCA2, RAD51 etc) Error-free Double stranded DNA Normal cell

43. Repaired by Homologous repair system – HR (BRCA1, BRCA2, RAD51 etc) Error-free Double stranded DNA Normal cell

44. Repaired by Homologous repair system – HR (BRCA1, BRCA2, RAD51 etc) Error-free BRCA-deficient cell

45. Repaired by Homologous repair system – HR (BRCA1, BRCA2, RAD51 etc) Error-free Repaired by non-HR system PARP -dependent Error prone BRCA-deficient cell

46. Repaired by Homologous repair system – HR (BRCA1, BRCA2, RAD51 etc) Error-free Repaired by non-HR system PARP -dependent Error prone BRCA-deficient cell

47. Repaired by Homologous repair system – HR (BRCA1, BRCA2, RAD51 etc) Error-free Repaired by non-HR system PARP -dependent Error prone BRCA-deficient cell

48. Repaired by Homologous repair system – HR (BRCA1, BRCA2, RAD51 etc) Error-free Repaired by non-HR system PARP -dependent Error prone BRCA-deficient cell

49. Repaired by Homologous repair system – HR (BRCA1, BRCA2, RAD51 etc) Error-free BRCA-deficient cell Repaired by non-HR system PARP -dependent Error prone

50. Repaired by Homologous repair system – HR (BRCA1, BRCA2, RAD51 etc) Error-free BRCA-deficient cell Repaired by non-HR system PARP -dependent Error prone

51. Repaired by Homologous repair system – HR (BRCA1, BRCA2, RAD51 etc) Error-free BRCA-deficient cell With PARP inhibition

52. Repaired by Homologous repair system – HR (BRCA1, BRCA2, RAD51 etc) Error-free BRCA-deficient cell With PARP inhibition

53. Repaired by Homologous repair system – HR (BRCA1, BRCA2, RAD51 etc) Error-free BRCA-deficient cell With PARP inhibition

55. Management of BRCA-related ovarian cancer Better prognosis Respond to platinum and non-platinum (even if early relapse) Olaparib treatment/ PARPi trials limiting testing may be denying some patients a useful therapeutic option?

56. Why not test everyone?

57. Cost –Genetic testing –Counselling

58. Why not test everyone? Cost –Genetic testing #500+ –Counselling

59. Why not test everyone? Cost –Genetic testing –Counselling Interpretation of results –(Cancer penetrance)

60. Why not test everyone? Cost –Genetic testing –Counselling Interpretation of results –(Cancer penetrance) –Variants of uncertain significance (VUSs)

61. Variants of uncertain significance (VUSs) Sequence change in gene that isn’t clearly pathogenic

62. Variants of uncertain significance (VUSs) Sequence change in gene that isn’t clearly pathogenic How common?

63. Variants of uncertain significance (VUSs) Sequence change in gene that isn’t clearly pathogenic How common?- 5-10%

64. Ovarian cancer Ovca 54 Chance of VUS =chance of pathogenec mutation

65. Ovarian cancer Ovca 54 BRCA2 VUS ?

66. Variants of uncertain significance (VUSs) Sequence change in gene that isn’t clearly pathogenic How common?- 5-10% Can we use these for predictive testing?

67. Variants of uncertain significance (VUSs) Sequence change in gene that isn’t clearly pathogenic How common?- 5-10% Can we use these for predictive testing?- NO!

68. Variants of uncertain significance (VUSs) Sequence change in gene that isn’t clearly pathogenic How common?- 5-10% Can we use these for predictive testing?- NO! Will these be resolved in foreseeable future?

69. Variants of uncertain significance (VUSs) Sequence change in gene that isn’t clearly pathogenic How common?- 5-10% Can we use these for predictive testing?- NO! Will these be resolved in foreseeable future? Unlikely

70. Ovarian cancer Will she benefit from PARPi?

71. Variants of uncertain significance (VUSs) Sequence change in gene that isn’t clearly pathogenic How common?- 5-10% Can we use these for predictive testing?- NO! Will these be resolved in foreseeable future? Unlikely Will this woman benefit from PARPi?

72. Ovarian cancer Ovca 54 How likely is a BRCA mutation? Is there any family history?

73. Australian ovarian cancer study group Alsop et al J clin oncol 2012 n=1001: non-mucinous, unselected for FH, any age Overall pick up 14% (n=141, with 83 VUS) –16.6% serous –22.6% HGS –8.3% >60 –8.2% with no, or unknown FH

74. Australian ovarian cancer study group Alsop et al J clin oncol 2012 n=1001: non-mucinous, unselected for FH, any age Overall pick up 14% (n=141, with 83 VUS) –16.6% serous –22.6% High Grage Serous –8.3% >60 –8.2% with no, or unknown FH

75. Australian ovarian cancer study group Alsop et al J clin oncol 2012 n=1001: non-mucinous, unselected for FH, any age Overall pick up 14% (n=141, with 83 VUS) –16.6% serous –22.6% HGS –8.3% >60 –8.2% with no, or unknown FH

76. Australian ovarian cancer study group Alsop et al J clin oncol 2012 n=1001: non-mucinous, unselected for FH, any age Overall pick up 14% (n=141, with 83 VUS-8.2% –16.6% serous –22.6% HGS –8.3% >60 –8.2% with no, or unknown FH

77. Typical BRCA patient Ovarian cancer Serous FIGO 3 Grade 3 Young (55 v 60.5) No PH brca, but often FH

78. …but, compared with overall cohort Fallopian tube and PPC FIGO 3 and 4 Age: 41-50 PH: 27% brca (8% cohort overall) FH: 53% (19% cohort overall)

79. BRCA mutations in unselected ovarian cancer Greek cohort- 6 founder mutations BRCA1 mutations in 27/592 (4.6%) sporadic cases 71% cases with mutation were HGS Stavropoulou et al 2013

80. Peninsula experience: BRCA testing in HGS ovca <60 40 referrals since Sept 2013 24 offered testing –2 declined –4 results awaited –12 negative –4 positive –2* Variant of uncertain significance (VUS)

81. BRCA testing in HGS ovca <60 of the 18 results

82. BRCA testing in HGS ovca <60 of the 17 results –4 (23.5%) positive

83. BRCA testing in HGS ovca <60 of the 18 results –3 (17.6%) positive –12 (67%) negative

84. BRCA testing in HGS ovca <60 of the 18 results –3 (17.6%) positive –12 (70%) negative –2 (11%) uncertain

85. 29317 HGS Ovca 42y Cancer (nos) 40 ‘Endometrial’ ca 70 726863 85 82 ‘womb’ 1901 54

86. HGS Ovca 46y Died young 72 Multiple myeloma 60 78 No cancers 86 No info Embolism 78 25691 G2 IDC 46 ?brca 60s BRCA neg

87. 28019 PPC 50y ‘spine’ cancer 79y Lung 70 82y ?breast cancer

88. 31889 PPC 65y 71 heart

89. BRCA testing threshold 10% chance of a pathogenic mutation –Manchester Score 15, eg 2 ovca any age 1 ovca <60 plus brca any age 1 ovca >60 age, plus 2 brca <60, High grade serous ovca <60y (MS13)

90. Genetic testing: BRCA1/2 searching for a mutation Manchester scoring system used to select families for testing. Threshold 10% chance of mutation Blood from affected relative 8 weeks

91. Consider Should we be testing more women with ovarian cancer? Should we be testing all women with ovarian cancer? High grade serous- how many women? Refer to genetics? ways to incorporate this in to routine care pathway? Future involvement of clinical genetics?

92. The future 1.Continue to refer all women for BRCA testing to clinical genetics? 2.If purpose is to determine management testing by oncology? 3.Collaborative approach? –Testing by oncol with input from CG

93. Pros and cons: status quo pros Patient: Detailed FH assessment, and thorough genetic counselling Gynaeoncol: One less thing… Clinical genetics:maintains control, gatekeeping etc cons Patient and oncol: Waiting time/delays CG: Workload

94. Pros and cons -full mainstreaming Pros Pt: seamless, (fewer delays) GO: control GC: workload, successful maintreaming Cons PT:Family issues GO: FUNDING, one more thing… CG: loss of gatekeeping etc

95. Pros and cons -collaborative approach Pros Best of both worlds Involvement in process, maintains control Successful collaboration- mainstreaming Cons None? Funding None (other than setting up) Cheaper overall

96. Consultant clinics Genetic nurse or counsellor clinics Peninsula clinical genetics service www.peninsulaclinicalgeneticsservice.co.uk/