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

Consultant clinics Genetic nurse or counsellor clinics Peninsula Clinical Genetics Service

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

Referrals to PCGS

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

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

Ovca 63 brca 47 brca 35

Ovca 63 brca 47 brca 35 BRCA1 mutation

Ovca 63 brca 47 brca 35

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.

Ovca 63 brca 47 brca 35 Mutation positive Mutation negative

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

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

Age-related ovca risks BRCA1- low before 40, ~1% pa –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

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%)

Ovarian cancer Ovca 54

Familial Ovarian cancer How to assess risk of ovarian ca?

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

Ovca 63 brca 47

Manchester scoring system (Evans et al, 2004) CancerScore FBC <3011 FBC FBC FBC FBC >592 MBC <6013 MBC>5910 Ovca <6013 Ovca >5910 Pancreatic cancer1 Prostate cancer <602 Prostate cancer >591

Manchester scoring system (Evans et al, 2004) CancerScore FBC <3011 FBC FBC FBC FBC >592 MBC <6013 MBC>5910 Ovca <6013 Ovca >5910 Pancreatic cancer1 Prostate cancer <602 Prostate cancer >591

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

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

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

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

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

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

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

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

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

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

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

Ovca 63 No surviving affected relative brca 47

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

Ovarian cancer Ovca 54 Why is important to know?

Double stranded DNA Normal cell

Double stranded DNA DS-DNA break Normal cell

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

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

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

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

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

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

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

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

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

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

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

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

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?

Why not test everyone?

Cost –Genetic testing –Counselling

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

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

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

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

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

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

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

Ovarian cancer Ovca 54 BRCA2 VUS ?

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?

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!

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?

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

Ovarian cancer Will she benefit from PARPi?

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?

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

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

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

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

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

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

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

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

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

BRCA testing in HGS ovca <60 of the 18 results

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

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

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

29317 HGS Ovca 42y Cancer (nos) 40 ‘Endometrial’ ca ‘womb’

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

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

31889 PPC 65y 71 heart

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)

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

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?

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

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

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

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

Consultant clinics Genetic nurse or counsellor clinics Peninsula clinical genetics service