ORIGINAL ARTICLE

Ovarian cancer among 8005 women from a breastcancer family history clinic: no increased risk ofinvasive ovarian cancer in families testing negativefor BRCA1 and BRCA2Sarah Louise Ingham,1,2,3 Jane Warwick,4 Iain Buchan,1 Sarah Sahin,3

Catherine O’Hara,5 Anthony Moran,5 Anthony Howell,3,6 D Gareth Evans2,3

1Centre for Health Informatics,Institute of Population Health,The University of Manchester,Manchester, UK2Department of GeneticMedicine, The University ofManchester, ManchesterAcademic Health ScienceCentre, St Mary’s Hospital,Central Manchester HospitalsFoundation Trust, Manchester,UK3Genesis Prevention Centre,University Hospital of SouthManchester, Manchester, UK4Imperial Clinical Trials Unit,Faculty of Medicine, School ofPublic Health, Imperial CollegeLondon, London, UK5NWCIS, The Palatine Centre,Christie Hospital, Manchester,UK6Department of MedicalOncology Manchester, ChristieHospital, Manchester, UK

Correspondence toProfessor D Gareth Evans,Department of GeneticMedicine, The University ofManchester, ManchesterAcademic Health ScienceCentre, St Mary’s Hospital,Oxford Road, ManchesterM13 9WL, UK;gareth.evans@cmft.nhs.uk

Received 15 February 2013Revised 5 March 2013Accepted 10 March 2013Published Online First28 March 2013

To cite: Ingham SL,Warwick J, Buchan I, et al. JMed Genet 2013;50:368–372.

ABSTRACTBackground Mutations in BRCA1/2 genes conferovarian, alongside breast, cancer risk. We examined therisk of developing ovarian cancer in BRCA1/2-positivefamilies and if this risk is extended to BRCA negativefamilies.Patients and Methods A prospective study involvingwomen seen at a single family history clinic inManchester, UK. Patients were excluded if they hadovarian cancer or oophorectomy prior to clinic. Follow-upwas censored at the latest date of: 31/12/2010; ovariancancer diagnosis; oophorectomy; or death. We usedperson-years at risk to assess ovarian cancer rates in thestudy population, subdivided by genetic status (BRCA1,BRCA2, BRCA negative, BRCA untested) compared withthe general population.Results We studied 8005 women from 895 families.Women from BRCA2 mutation families showed a 17-foldincreased risk of invasive ovarian cancer (relative risk(RR) 16.67; 95% CI 5.41 to 38.89). This risk increasedto 50-fold in women from families with BRCA1mutations (RR 50.00; 95% CI 26.62 to 85.50). Noassociation was found for women in families testednegative for BRCA1/2, where there was 1 observedinvasive ovarian cancer in 1613 women when 2.74 wereexpected (RR 0.37; 95% CI 0.01 to 2.03). There was noassociation with ovarian cancer in families untested forBRCA1/2 (RR 0.99; 95% CI 0.45 to 1.88).Discussion This study showed no increased risk ofovarian cancer in families that tested negative forBRCA1/2 or were untested. These data help counsellingwomen from BRCA1/2 negative families with breastcancer that their risk of invasive ovarian cancer is nothigher than the general population.

BACKGROUNDSince the identification of BRCA11 and BRCA22

speculation has continued regarding the breast andovarian cancer risk associated with mutations inthese genes,3 and whether these might account formost of the association between breast and ovariancancer. It is clear that cancer risk estimation isaffected by the method of ascertainment of the fam-ilies studied. Thus, breast cancer risks in large famil-ial breast cancer kindreds with BRCA1/BRCA2mutations are substantially higher4–9 than risksderived from population based studies.10–15 There isstill a wide range of ovarian cancer risk quoted for

BRCA1 (30–65%) and BRCA2 (10–35%).4–15

An important question, particularly for geneticcounselling, is whether women in breast cancer onlyfamilies have an increased risk of ovarian cancerafter negative testing for BRCA1/2 of an affectedfamily member. Only three studies that we couldfind addressed this issue.16–18 In 2534 women-yearsof follow-up in 165 BRCA1/2-negative families onecase of ovarian cancer was diagnosed, whereas only0.66 was expected (standard incidence ratios(SIR)=1.52, 95% CI 0.02 to 8.46). The variancearound this estimate and the recent identification oftwo further potential high risk genes in breast andovarian cancer kindreds19–21 prompted a reassess-ment of whether women can really be told theirrisks of ovarian cancer are not increased afterBRCA1/2-negative testing in their family. Here weassess the risk of invasive ovarian cancer in 8005women from a series of 895 families, including1613 women from families who tested negative forBRCA1/2 mutations, from time of referral (withoutovarian cancer) to our family history clinic.

METHODSPatientsThe Breast Cancer Family History Clinic (FHC) inSouth Manchester, established in 1987, collectsinformation (demographic, pedigree, screening anddisease symptomatology) on individuals and fam-ilies with a family history of breast and ovariancancer. Families within the north-west region ofEngland who have a family history of breast orovarian cancer are referred to the FHC by theirgeneral practitioners. Women who attend the FHChave a detailed family tree elicited including allfirst, second and if possible third degree relatives.The genetic status of all family members isrecorded (BRCA1, BRCA2 and negative results) iftesting has occurred. Details of all tested anduntested women and relatives are entered onto adatabase.Data on women in this prospective study were

verified against medical records, NHS summary carerecords and cancer registrations made by the NorthWest Cancer Intelligence Service (NWCIS). All casesof ovarian cancers were confirmed by means of hos-pital/pathology records, cancer registrations (from1960) or death certification. The date the patientfirst attended the FHC was considered the

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ascertainment date. Follow-up was censored at the latest datefrom 31 December 2010; ovarian cancer diagnosis; oophorec-tomy; or date of death (obtained from death certification eitherdirectly or via NWCIS). Women were excluded if they hadovarian cancer or oophorectomy prior to first referral to theFHC. All data on cancer incidence was collected prospectively.

Mutation testingFamilies with an available living family member with breast orovarian cancer were eligible for NHS testing if there was at leasta 20% likelihood of a mutation as per National Institute forHealth and Clinical Excellence (NICE) guidelines. Testing wascarried out by sequencing and multiple ligation dependentprobe amplification (MLPA), which we have shown has highsensitivity in detecting mutations.22 Testing was also availablethrough a research study (Familial Breast Cancer Study (FBCS))which had much looser criteria with only two affected relativeswith breast cancer usually being required. This study used acombination of conformation sensitive gel electrophoresis in 86fragments and MLPA. Through the FBCS study, 698/1140(61%) families were tested. These samples were also tested forthe 1100DelC mutation in CHEK2.

AnalysisWomen were grouped by genetic status and by ovarian cancertype (invasive epithelial or borderline). Person-years at risk werecalculated from the woman’s ascertainment date to date cen-sored. The expected numbers of ovarian cancer cases over thefollow-up period, for each family genetic status (BRCA1 posi-tive, BRCA2 positive, BRCA negative, BRCA untested), were cal-culated based on person-years at risk using population level datafor the north-west of England from NWCIS. Women testingnegative for a family BRCA1/2 mutation were excluded fromthis calculation as there were few in number and there wereno ovarian cancer events. The relative risk (RR) of developingovarian cancer was calculated as the number of observed casesdivided by the expected number of cases in the general popula-tion. Subgroups defined by their personal or family geneticstatus and ovarian cancer type (invasive epithelial or borderline)were analysed separately. Exact confidence limits for the relativerisk were calculated using the Poisson distribution.23 Statisticalresults are presented as the main effect with a 95% CI unlessotherwise stated. All calculations were performed with StataV.12 (http://www.stata.com).

RESULTSWe studied 8005 women from 895 families from time of refer-ral (without ovarian cancer) to our FHC. This excludes 319women who tested negative for their family mutation, althoughinterestingly one such case had previously developed a border-line mucinous ovarian tumour. Of these women who were eli-gible for follow-up with intact ovaries 70 women were alreadyreferred with a diagnosis of breast cancer and 406 developedbreast cancer in follow-up. There were 28 invasive epithelialovarian cancers, 5 borderline tumours and 2 germ cell tumoursin 81 704 women-years of follow-up. One thousand sixhundred and thirteen women from breast cancer families thathad tested negative for BRCA1/2 were followed for a total of17 589 years (range 0.04–25 years) and checked against cancerregistrations for a diagnosis of ovarian cancer. During follow-uponly one invasive epithelial ovarian cancer occurred, althoughtwo borderline tumours were diagnosed. The ovarian cancercase was the index case tested in her family as were the two bor-derline cases. Expected incidence for the general populationwas 2.99 cases (2.74 invasive and 0.25 borderline tumours)(table 1). The relative risk of developing invasive ovarian cancerin this group was 0.37 (95% CI 0.01 to 2.03) compared withthe general population. The relative risk of developing border-line tumours was 8.00 (95% CI 0.97 to 28.90). The 351women (218 positive, 133 untested) from BRCA2 breast cancerfamilies had a total follow-up of 3230.47 (0.02–23.72) years.During this time there were no occurrences of borderlinetumours, but five invasive epithelial tumours were recorded.The population expected number of ovarian cancers was 0.33(0.30 invasive cancers and 0.03 borderline tumours) (table 1).The RR of developing invasive disease in this group, comparedwith the general population, was 16.67 (95% CI 5.41 to 38.89)(table 1). There were 310 women (168 positive 132 untested)from families that had tested positive for BRCA1 and these had1981.60 years of follow-up (0.00–21.85 years), in which 13invasive epithelial ovarian cancers were detected. The incidenceof invasive tumours was expected to be 0.26 cases and of bor-derline tumours 0.03. The RR for the invasive cancers was50.00 although the CIs were wide (95% CI 26.62 to 85.50)(table 1).

Among families untested for BRCA1/2, 5731 women had58 904 years of follow-up and 14 ovarian tumours were diag-nosed (nine epithelial ovarian cancers, two malignant germ celltumours and three borderline tumours). Using the same averageinvasive ovarian tumour rates of 0.15 per 1000 as in theBRCA-negative cohort we would have expected 9.07 invasive

Table 1 Observed/expected ovarian cancers by BRCA status

BRCA Status n Observed cancers Expected cancers p Relative risk 95% CI

BRCA1 310 Invasive epithelial tumour 13 0.26 <0.001 50.00 26.62 85.50Borderline tumour 0 0.03 0.00 122.96Total 13 0.29 <0.001 44.83 23.87 76.66

BRCA2 351 Invasive epithelial tumour 5 0.30 0.001 16.67 5.41 38.89Borderline tumour 0 0.03 0.00 122.96Total 5 0.33 <0.001 15.15 4.92 35.36

BRCA-negative 1613 Invasive epithelial tumour 1 2.74 0.37 0.01 2.03Borderline tumour 2 0.25 8.00 0.97 28.90Total 3 2.99 1.00 0.21 2.93

BRCA untested 5731 Invasive epithelial tumour 9 9.07 0.99 0.45 1.88Borderline tumour 3 0.84 3.57 0.74 10.44Total 12 9.91 1.21 0.63 2.12

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ovarian cancers and, using a similar analysis, 0.84 borderlinetumours. The RR of developing invasive ovarian cancer in thisgroup was calculated to be 0.99 (95% CI 0.45 to 1.88) (table 1)and of borderline tumours was 3.57 (95% CI 0.74 to 10.44).The RR of developing borderline ovarian tumours in familiesnot known to have a BRCA1/2 mutation was significant (4.59,95% CI 1.49 to 10.70).

Lifetime breast cancer risk assessed by the Tyrer-Cuzickmodel,24 showed a significant difference between BRCA-negativeand BRCA-untested families (p<0.001, χ2 test). In BRCA-negative families 959/1613 (60%) were classified as high risk(lifetime breast cancer risk >1 in 4) before family testing whereasin untested families only 1968/5731 (34%) were classified assuch high risk. Of women with breast cancer, 212 were the indexcase in their families and so were tested fully for BRCA muta-tions; 45 (21%) tested BRCA1/2-positive and 167 BRCA1/2-negative. A further 72 tested positive for an already establishedfamily BRCA1/2 mutation and 4 were untested. Forty-threewomen developed breast cancer in families already tested nega-tive for BRCA1/2. In total this meant 121 women from BRCA1/2families with breast cancer were available for follow-up and 210from families tested negative. For ovarian cancer 12/15 (80%)tested positive as the index case, including 5 with breast cancer,the remaining 6 ovarian cancers in BRCA1/2 carriers were identi-fied after an index case including 1 with breast cancer. Of thethree testing negative for BRCA1/2, two had borderline tumours,one had developed this after developing breast cancer (table 2).Of 221 women with breast/ovarian tumours tested for 1100DelCin CHEK2 only three mutation carriers were identified all inbreast cancer only cases.

DISCUSSIONThe present study shows that in a large cohort of women frombreast cancer families who tested negative for BRCA1/2 therewas no clinically significant increased risk of invasive ovariancancer but there may be an increased risk of borderlinetumours. This study provides strong evidence to support thecounselling of women, whose family (with breast cancer andnot ovarian cancer) test negative for BRCA1/2, that they are notat increased risk of invasive ovarian cancer. Unsurprisinglyincreased ovarian cancer risk was found in women whose fam-ilies tested BRCA1/2-positive. In women from BRCA1 families,for invasive and borderline tumours combined, we estimatedthis risk to be at least 24 times the population average and inBRCA2 families at least 5 times the population average. Theabsence of a marked increased risk in untested families mayreflect some testing bias with regard to the prospective ovarian

cancers. Twelve of the 18 BRCA1/2 carriers with ovarian cancerwere the index case to identify the family mutation only afterthey were diagnosed. This may explain the absence of anyexcess risk of ovarian cancer in untested families as 21/33(64%) of the ovarian cancer cases came from tested familiescompared with only 28% of women without ovarian cancer.The untested families also contained less significant family his-tories. Given the potential testing bias the RRs for BRCA1 andBRCA2 for ovarian cancer are subject to error even includinguntested relatives which will contain a substantial number ofwomen who did not carry the family mutation. Testing biascould also exist for families testing negative for BRCA1/2,indeed, the two women with borderline tumours were testednegative as the index case which may have artificially raised theRR for borderline tumours in BRCA-negative families. Invasiveovarian cancer was deliberately separated from borderlinetumours as these are different entities and there is no evidencethat BRCA1/2 carriers are at increased risk of borderlinetumours.25 Nonetheless the overall increased risk of borderlinetumours in those women from untested families and BRCA1/2-negative families raises the question as to whether other genescould increase the risk of breast cancer and borderline ovariantumours. Previous work in Poland has suggested that theCHEK2 mutation I157T increases the risk of borderlinetumours although no such association was seen for 1100DelCin their study or in the two cases with testing in the presentstudy.26 The I157T is not a common UK mutation and formalassessment of whether non-truncating CHEK2 mutations couldaccount for some of the excess risk of borderline tumours isbeyond the scope of this manuscript. Nonetheless the data pre-sented here does raise the question as to whether CHEK2 orother genes may increase breast cancer and borderline ovariantumour risk.

Our study contained only 167 women who developed breastcancer who, as individuals, tested negative for BRCA1/2,although a further 53 are most likely also negative as an affectedrelative had already tested negative. Such women, however, maybe reassured by the findings of a large Swedish study,27 in whichfounder mutation, BRCA1 3171 ins5, explains the excess ofovarian cancer after breast cancer among 2600 women in theirregion. The Swedish team estimated that BRCA1 gene mutationswere associated with around 80–85% of the estimated 63 excesscases of ovarian cancer diagnosed after breast cancer in theircohort. This would leave only a small proportion of theincreased risk of ovarian cancer unexplained of which somecould be due to BRCA2. A further study showed that the excessrisk of breast and ovarian cancer in a Jewish cohort of 290

Table 2 Family mutation status by final affectation with cancer and breast cancer before clinic entry

BRCA1(tested)

BRCA2(tested)

Family tested negativefor BRCA1/2 (tested)

No familytesting

Negative for BRCA1/2mutation in family Total

Invasive ovarian cancer 13+ 5+ 1 9 0 28Borderline ovarian tumour 0 0 2* 3 0 5Breast cancer affected afterentry

46 (43) 45 (44) 183 (140) 122 10 (8 BRCA2) 416

Breast cancer affected atreferral

14 16 27 (17) 13 0 70

Unaffected 242 (113) 286 (154) 1401 5584 309 (160 BRCA2) 7668Total 310 351 1613 5731 319 8324

+Five BRCA1 carriers with ovarian cancer had previous breast cancer as did one BRCA2 carrier.*One individual testing negative also had previous breast cancer. Figures in columns 2–4 do not add precisely to totals because of these double counts.

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women tested for the common three Jewish BRCA1/2 mutationswas accounted for by the mutations, with only one of eightovarian type cancers occurring in non-carriers.16 AnotherCanadian study followed the 1492 first-degree relatives of breastcancer cases with negative BRCA1/2 testing for 9109 person-years of follow-up.17 Only two ovarian cancers were observedcompared with 2.34, expected RR 0.85 (95% CI 0.23 to 3.12).

The only other prospective study of ovarian cancer incidenceundertaken in New York, in women mainly unaffected frombreast cancer, showed that during 2534 women-years offollow-up one case of ovarian cancer was diagnosed, when 0.66were expected (SIR=1.52, 95% CI 0.02 to 8.46).18 This studyused questionnaires sent to families and did not verify diagnosesagainst a cancer registry as we have done. In addition, our studyhas over five times the amount of follow-up. Both studiesshowed no overall evidence of any increased risk. A prospectivestudy of ovarian cancer in Norway found that 46/47 (98%)cases of invasive epithelial ovarian cancer occurred in BRCA1/2carriers but no formal analysis of relative risk was carried out.19

Although data from the Breast Cancer Linkage Consortium(BCLC) estimated that close to 100% of families with two ormore ovarian cancers in addition to breast cancer (at least2<60 years) had mutations in BRCA1/2,5 recent results haveshown that three of eight (37.5%) of the mutations in RAD51Dwere in families with two or more ovarian cancers that fulfilledBCLC criteria.21 However, the frequency of RAD51C andRAD51D mutations was only 1.3%20 and 0.9%,21 respectivelyin breast and ovary kindreds negative for pathogenic mutationsin BRCA1 and BRCA2. Furthermore, although the initial studyon RAD51C20 suggested that mutations might be high risk forbreast and ovarian cancer, the RAD51D study estimated the riskwas only high for ovarian cancer, with a non-significantincreased breast cancer risk of less than twofold (1.37 (95% CI0.92 to 2.05, p=0.64)).21 Neither study found mutations inbreast cancer only kindreds (0/737), supporting the lack of astrong link with breast cancer.20 21

If BRCA1/2 mutations account for most of the inherited linkbetween breast and ovarian cancer then the main factor affectingthe ability to confidently exclude risk of ovarian cancer in fam-ilies testing negative is the sensitivity of testing. Tests on mostcancer predisposing genes are limited in that they do not screenthe intronic areas outside of the intron-exon boundaries nor dothey screen for positional effects of mutations in other genes thatcan affect genes at a distance such as EPCAM mutations andMSH2.28 There are relatively few papers that adequately assessthe sensitivity of BRCA1/2 mutation testing. Simply using a panelof found mutations and assessing different screening tests doesnot address the overall sensitivity.29 The tests can only be assessedagainst a gold standard such as gene sequencing which in anycase does not screen the introns. It is first necessary to identifyfamilies with a very high a priori probability of BRCA1/2 involve-ment such as breast/ovarian families fulfilling BCLC criteria orsuch families with a Manchester score30 of 40+. We have previ-ously shown that sequencing plus MLPA identified mutationsin 58/65 (89%) families with breast and ovarian cancer and aManchester score of 40+.31 Breast cancer phenocopies canreduce the sensitivity of tests because around 6% of tests ofbreast cancers in families with mutations are mutation negative;32

true sensitivity could be closer to 95%.22 Even taking the lowersensitivity estimate, this would reduce the excess risk of ovariancancer in a breast cancer only family by ninefold. The true likeli-hood of a missed mutation can be estimated from our testing of2009 breast cancer only families in which only 240 (11.9%; 100BRCA1; 140 BRCA2) had mutations identified by sequencing

plus MLPA. Allowing for a Bayesian calculation no more than1.5% of these breast cancer only families would have had amissed mutation.

There are some potential limitations to the present study. Notall participants remained in active follow-up and a small propor-tion may have moved out of the north-west of England and anovarian cancer could have been missed. Despite the largenumbers and long follow-up the number of cases of ovariancancer diagnosed is still quite small. Nevertheless this datashould reassure women from breast cancer only families thattest negative for BRCA1/2 that their risks of invasive ovariancancer are not increased.

In conclusion this, the largest prospective follow-up of aBRCA-negative cohort, has demonstrated that there is no clinic-ally significant increase in risk of invasive ovarian cancer in fam-ilies that have tested negative for BRCA1/2.

Acknowledgements We would like to thank The Genesis Breast CancerPrevention Appeal.

Contributors Conception: DGE, Data collection: DGE, SS, Data analysis: DGE, SLI,JW, CO’H, Manuscript writing: DGE, SLI, AH, IB, JW, Approval of final version: All.

Funding This article presents independent research partly funded by the NationalInstitute for Health Research (NIHR) under its Programme Grants for AppliedResearch programme (Reference Number RP-PG-0707–10031). The views expressedare those of the author(s) and not necessarily those of the NHS, the NIHR or theDepartment of Health.

Competing interests None.

Ethics approval North West—Greater Manchester Central ethics committee (aspart of the FHRisk study).

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement Anonymised data is available on request.

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372 Ingham SL, et al. J Med Genet 2013;50:368–372. doi:10.1136/jmedgenet-2013-101607

Cancer genetics

group.bmj.com on December 21, 2014 - Published by http://jmg.bmj.com/Downloaded from

BRCA2 and BRCA1families testing negative for

increased risk of invasive ovarian cancer inbreast cancer family history clinic: no Ovarian cancer among 8005 women from a

Catherine O'Hara, Anthony Moran, Anthony Howell and D Gareth EvansSarah Louise Ingham, Jane Warwick, Iain Buchan, Sarah Sahin,

doi: 10.1136/jmedgenet-2013-1016072013

2013 50: 368-372 originally published online March 28,J Med Genet 

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