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Cancer genetics

ORIGINAL ARTICLE

Ovarian cancer among 8005 women from a breast cancer family history clinic: no increased risk of invasive ovarian cancer in families testing negative for BRCA1 and BRCA2
Sarah Louise Ingham,1,2,3 Jane Warwick,4 Iain Buchan,1 Sarah Sahin,3 Catherine OHara,5 Anthony Moran,5 Anthony Howell,3,6 D Gareth Evans2,3
1

Centre for Health Informatics, Institute of Population Health, The University of Manchester, Manchester, UK 2 Department of Genetic Medicine, The University of Manchester, Manchester Academic Health Science Centre, St Marys Hospital, Central Manchester Hospitals Foundation Trust, Manchester, UK 3 Genesis Prevention Centre, University Hospital of South Manchester, Manchester, UK 4 Imperial Clinical Trials Unit, Faculty of Medicine, School of Public Health, Imperial College London, London, UK 5 NWCIS, The Palatine Centre, Christie Hospital, Manchester, UK 6 Department of Medical Oncology Manchester, Christie Hospital, Manchester, UK Correspondence to Professor D Gareth Evans, Department of Genetic Medicine, The University of Manchester, Manchester Academic Health Science Centre, St Marys Hospital, Oxford Road, Manchester M13 9WL, UK; gareth.evans@cmft.nhs.uk Received 15 February 2013 Revised 5 March 2013 Accepted 10 March 2013 Published Online First 28 March 2013

ABSTRACT Background Mutations in BRCA1/2 genes confer ovarian, alongside breast, cancer risk. We examined the risk of developing ovarian cancer in BRCA1/2-positive families and if this risk is extended to BRCA negative families. Patients and Methods A prospective study involving women seen at a single family history clinic in Manchester, UK. Patients were excluded if they had ovarian cancer or oophorectomy prior to clinic. Follow-up was censored at the latest date of: 31/12/2010; ovarian cancer diagnosis; oophorectomy; or death. We used person-years at risk to assess ovarian cancer rates in the study population, subdivided by genetic status (BRCA1, BRCA2, BRCA negative, BRCA untested) compared with the general population. Results We studied 8005 women from 895 families. Women from BRCA2 mutation families showed a 17-fold increased risk of invasive ovarian cancer (relative risk (RR) 16.67; 95% CI 5.41 to 38.89). This risk increased to 50-fold in women from families with BRCA1 mutations (RR 50.00; 95% CI 26.62 to 85.50). No association was found for women in families tested negative for BRCA1/2, where there was 1 observed invasive ovarian cancer in 1613 women when 2.74 were expected (RR 0.37; 95% CI 0.01 to 2.03). There was no association with ovarian cancer in families untested for BRCA1/2 (RR 0.99; 95% CI 0.45 to 1.88). Discussion This study showed no increased risk of ovarian cancer in families that tested negative for BRCA1/2 or were untested. These data help counselling women from BRCA1/2 negative families with breast cancer that their risk of invasive ovarian cancer is not higher than the general population.

BRCA1 (3065%) and BRCA2 (1035%).415 An important question, particularly for genetic counselling, is whether women in breast cancer only families have an increased risk of ovarian cancer after negative testing for BRCA1/2 of an affected family member. Only three studies that we could nd addressed this issue.1618 In 2534 women-years of follow-up in 165 BRCA1/2-negative families one case of ovarian cancer was diagnosed, whereas only 0.66 was expected (standard incidence ratios (SIR)=1.52, 95% CI 0.02 to 8.46). The variance around this estimate and the recent identication of two further potential high risk genes in breast and ovarian cancer kindreds1921 prompted a reassessment of whether women can really be told their risks of ovarian cancer are not increased after BRCA1/2-negative testing in their family. Here we assess the risk of invasive ovarian cancer in 8005 women from a series of 895 families, including 1613 women from families who tested negative for BRCA1/2 mutations, from time of referral (without ovarian cancer) to our family history clinic.

METHODS Patients
The Breast Cancer Family History Clinic (FHC) in South Manchester, established in 1987, collects information (demographic, pedigree, screening and disease symptomatology) on individuals and families with a family history of breast and ovarian cancer. Families within the north-west region of England who have a family history of breast or ovarian cancer are referred to the FHC by their general practitioners. Women who attend the FHC have a detailed family tree elicited including all rst, second and if possible third degree relatives. The genetic status of all family members is recorded (BRCA1, BRCA2 and negative results) if testing has occurred. Details of all tested and untested women and relatives are entered onto a database. Data on women in this prospective study were veried against medical records, NHS summary care records and cancer registrations made by the North West Cancer Intelligence Service (NWCIS). All cases of ovarian cancers were conrmed by means of hospital/pathology records, cancer registrations (from 1960) or death certication. The date the patient rst attended the FHC was considered the

BACKGROUND
Since the identication of BRCA11 and BRCA22 speculation has continued regarding the breast and ovarian cancer risk associated with mutations in these genes,3 and whether these might account for most of the association between breast and ovarian cancer. It is clear that cancer risk estimation is affected by the method of ascertainment of the families studied. Thus, breast cancer risks in large familial breast cancer kindreds with BRCA1/BRCA2 mutations are substantially higher49 than risks derived from population based studies.1015 There is still a wide range of ovarian cancer risk quoted for

To cite: Ingham SL, Warwick J, Buchan I, et al. J Med Genet 2013;50: 368372. 368

Ingham SL, et al. J Med Genet 2013;50:368372. doi:10.1136/jmedgenet-2013-101607

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Cancer genetics
ascertainment date. Follow-up was censored at the latest date from 31 December 2010; ovarian cancer diagnosis; oophorectomy; or date of death (obtained from death certication either directly or via NWCIS). Women were excluded if they had ovarian cancer or oophorectomy prior to rst referral to the FHC. All data on cancer incidence was collected prospectively.

RESULTS
We studied 8005 women from 895 families from time of referral (without ovarian cancer) to our FHC. This excludes 319 women who tested negative for their family mutation, although interestingly one such case had previously developed a borderline mucinous ovarian tumour. Of these women who were eligible for follow-up with intact ovaries 70 women were already referred with a diagnosis of breast cancer and 406 developed breast cancer in follow-up. There were 28 invasive epithelial ovarian cancers, 5 borderline tumours and 2 germ cell tumours in 81 704 women-years of follow-up. One thousand six hundred and thirteen women from breast cancer families that had tested negative for BRCA1/2 were followed for a total of 17 589 years (range 0.0425 years) and checked against cancer registrations for a diagnosis of ovarian cancer. During follow-up only one invasive epithelial ovarian cancer occurred, although two borderline tumours were diagnosed. The ovarian cancer case was the index case tested in her family as were the two borderline cases. Expected incidence for the general population was 2.99 cases (2.74 invasive and 0.25 borderline tumours) (table 1). The relative risk of developing invasive ovarian cancer in this group was 0.37 (95% CI 0.01 to 2.03) compared with the general population. The relative risk of developing borderline tumours was 8.00 (95% CI 0.97 to 28.90). The 351 women (218 positive, 133 untested) from BRCA2 breast cancer families had a total follow-up of 3230.47 (0.0223.72) years. During this time there were no occurrences of borderline tumours, but ve 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, compared with 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 had 1981.60 years of follow-up (0.0021.85 years), in which 13 invasive epithelial ovarian cancers were detected. The incidence of invasive tumours was expected to be 0.26 cases and of borderline tumours 0.03. The RR for the invasive cancers was 50.00 although the CIs were wide (95% CI 26.62 to 85.50) (table 1). Among families untested for BRCA1/2, 5731 women had 58 904 years of follow-up and 14 ovarian tumours were diagnosed (nine epithelial ovarian cancers, two malignant germ cell tumours and three borderline tumours). Using the same average invasive ovarian tumour rates of 0.15 per 1000 as in the BRCA-negative cohort we would have expected 9.07 invasive

Mutation testing
Families with an available living family member with breast or ovarian cancer were eligible for NHS testing if there was at least a 20% likelihood of a mutation as per National Institute for Health and Clinical Excellence (NICE) guidelines. Testing was carried out by sequencing and multiple ligation dependent probe amplication (MLPA), which we have shown has high sensitivity in detecting mutations.22 Testing was also available through a research study (Familial Breast Cancer Study (FBCS)) which had much looser criteria with only two affected relatives with breast cancer usually being required. This study used a combination of conformation sensitive gel electrophoresis in 86 fragments and MLPA. Through the FBCS study, 698/1140 (61%) families were tested. These samples were also tested for the 1100DelC mutation in CHEK2.

Analysis
Women were grouped by genetic status and by ovarian cancer type (invasive epithelial or borderline). Person-years at risk were calculated from the womans ascertainment date to date censored. The expected numbers of ovarian cancer cases over the follow-up period, for each family genetic status (BRCA1 positive, BRCA2 positive, BRCA negative, BRCA untested), were calculated based on person-years at risk using population level data for the north-west of England from NWCIS. Women testing negative for a family BRCA1/2 mutation were excluded from this calculation as there were few in number and there were no ovarian cancer events. The relative risk (RR) of developing ovarian cancer was calculated as the number of observed cases divided by the expected number of cases in the general population. Subgroups dened by their personal or family genetic status and ovarian cancer type (invasive epithelial or borderline) were analysed separately. Exact condence limits for the relative risk were calculated using the Poisson distribution.23 Statistical results are presented as the main effect with a 95% CI unless otherwise stated. All calculations were performed with Stata V .12 (http://www.stata.com).

Table 1 Observed/expected ovarian cancers by BRCA status

BRCA Status BRCA1 n 310 Invasive epithelial tumour Borderline tumour Total Invasive epithelial tumour Borderline tumour Total Invasive epithelial tumour Borderline tumour Total Invasive epithelial tumour Borderline tumour Total Observed cancers 13 0 13 5 0 5 1 2 3 9 3 12 Expected cancers 0.26 0.03 0.29 0.30 0.03 0.33 2.74 0.25 2.99 9.07 0.84 9.91 p <0.001 <0.001 0.001 <0.001 Relative risk 50.00 0.00 44.83 16.67 0.00 15.15 0.37 8.00 1.00 0.99 3.57 1.21 95% CI 26.62 23.87 5.41 4.92 0.01 0.97 0.21 0.45 0.74 0.63 85.50 122.96 76.66 38.89 122.96 35.36 2.03 28.90 2.93 1.88 10.44 2.12

BRCA2

351

BRCA-negative

1613

BRCA untested

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ovarian cancers and, using a similar analysis, 0.84 borderline tumours. The RR of developing invasive ovarian cancer in this group 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 families not known to have a BRCA1/2 mutation was signicant (4.59, 95% CI 1.49 to 10.70). Lifetime breast cancer risk assessed by the Tyrer-Cuzick model,24 showed a signicant difference between BRCA-negative and BRCA-untested families ( p<0.001, 2 test). In BRCAnegative families 959/1613 (60%) were classied as high risk (lifetime breast cancer risk >1 in 4) before family testing whereas in untested families only 1968/5731 (34%) were classied as such high risk. Of women with breast cancer, 212 were the index case in their families and so were tested fully for BRCA mutations; 45 (21%) tested BRCA1/2-positive and 167 BRCA1/ 2-negative. A further 72 tested positive for an already established family BRCA1/2 mutation and 4 were untested. Forty-three women developed breast cancer in families already tested negative for BRCA1/2. In total this meant 121 women from BRCA1/2 families with breast cancer were available for follow-up and 210 from 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 identied after an index case including 1 with breast cancer. Of the three 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 1100DelC in CHEK2 only three mutation carriers were identied all in breast cancer only cases. cancers. Twelve of the 18 BRCA1/2 carriers with ovarian cancer were the index case to identify the family mutation only after they were diagnosed. This may explain the absence of any excess risk of ovarian cancer in untested families as 21/33 (64%) of the ovarian cancer cases came from tested families compared with only 28% of women without ovarian cancer. The untested families also contained less signicant family histories. Given the potential testing bias the RRs for BRCA1 and BRCA2 for ovarian cancer are subject to error even including untested relatives which will contain a substantial number of women who did not carry the family mutation. Testing bias could also exist for families testing negative for BRCA1/2, indeed, the two women with borderline tumours were tested negative as the index case which may have articially raised the RR for borderline tumours in BRCA-negative families. Invasive ovarian cancer was deliberately separated from borderline tumours as these are different entities and there is no evidence that BRCA1/2 carriers are at increased risk of borderline tumours.25 Nonetheless the overall increased risk of borderline tumours in those women from untested families and BRCA1/ 2-negative families raises the question as to whether other genes could increase the risk of breast cancer and borderline ovarian tumours. Previous work in Poland has suggested that the CHEK2 mutation I157T increases the risk of borderline tumours although no such association was seen for 1100DelC in their study or in the two cases with testing in the present study.26 The I157T is not a common UK mutation and formal assessment of whether non-truncating CHEK2 mutations could account for some of the excess risk of borderline tumours is beyond the scope of this manuscript. Nonetheless the data presented here does raise the question as to whether CHEK2 or other genes may increase breast cancer and borderline ovarian tumour risk. Our study contained only 167 women who developed breast cancer who, as individuals, tested negative for BRCA1/2, although a further 53 are most likely also negative as an affected relative had already tested negative. Such women, however, may be reassured by the ndings of a large Swedish study,27 in which founder mutation, BRCA1 3171 ins5, explains the excess of ovarian cancer after breast cancer among 2600 women in their region. The Swedish team estimated that BRCA1 gene mutations were associated with around 8085% of the estimated 63 excess cases of ovarian cancer diagnosed after breast cancer in their cohort. This would leave only a small proportion of the increased risk of ovarian cancer unexplained of which some could be due to BRCA2. A further study showed that the excess risk of breast and ovarian cancer in a Jewish cohort of 290

DISCUSSION
The present study shows that in a large cohort of women from breast cancer families who tested negative for BRCA1/2 there was no clinically signicant increased risk of invasive ovarian cancer but there may be an increased risk of borderline tumours. This study provides strong evidence to support the counselling of women, whose family (with breast cancer and not ovarian cancer) test negative for BRCA1/2, that they are not at increased risk of invasive ovarian cancer. Unsurprisingly increased ovarian cancer risk was found in women whose families tested BRCA1/2-positive. In women from BRCA1 families, for invasive and borderline tumours combined, we estimated this risk to be at least 24 times the population average and in BRCA2 families at least 5 times the population average. The absence of a marked increased risk in untested families may reect some testing bias with regard to the prospective ovarian

Table 2 Family mutation status by final affectation with cancer and breast cancer before clinic entry
BRCA1 (tested) Invasive ovarian cancer Borderline ovarian tumour Breast cancer affected after entry Breast cancer affected at referral Unaffected Total 13+ 0 46 (43) 14 242 (113) 310 BRCA2 (tested) 5+ 0 45 (44) 16 286 (154) 351 Family tested negative for BRCA1/2 (tested) 1 2* 183 (140) 27 (17) 1401 1613 No family testing 9 3 122 13 5584 5731 Negative for BRCA1/2 mutation in family 0 0 10 (8 BRCA2) 0 309 (160 BRCA2) 319 Total 28 5 416 70 7668 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 24 do not add precisely to totals because of these double counts.

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women tested for the common three Jewish BRCA1/2 mutations was accounted for by the mutations, with only one of eight ovarian type cancers occurring in non-carriers.16 Another Canadian study followed the 1492 rst-degree relatives of breast cancer cases with negative BRCA1/2 testing for 9109 personyears of follow-up.17 Only two ovarian cancers were observed compared with 2.34, expected RR 0.85 (95% CI 0.23 to 3.12). The only other prospective study of ovarian cancer incidence undertaken in New York, in women mainly unaffected from breast cancer, showed that during 2534 women-years of follow-up one case of ovarian cancer was diagnosed, when 0.66 were expected (SIR=1.52, 95% CI 0.02 to 8.46).18 This study used questionnaires sent to families and did not verify diagnoses against a cancer registry as we have done. In addition, our study has over ve times the amount of follow-up. Both studies showed no overall evidence of any increased risk. A prospective study of ovarian cancer in Norway found that 46/47 (98%) cases of invasive epithelial ovarian cancer occurred in BRCA1/2 carriers 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 or more ovarian cancers in addition to breast cancer (at least 2<60 years) had mutations in BRCA1/2,5 recent results have shown that three of eight (37.5%) of the mutations in RAD51D were in families with two or more ovarian cancers that fullled BCLC criteria.21 However, the frequency of RAD51C and RAD51D mutations was only 1.3%20 and 0.9%,21 respectively in breast and ovary kindreds negative for pathogenic mutations in BRCA1 and BRCA2. Furthermore, although the initial study on RAD51C20 suggested that mutations might be high risk for breast and ovarian cancer, the RAD51D study estimated the risk was only high for ovarian cancer, with a non-signicant increased breast cancer risk of less than twofold (1.37 (95% CI 0.92 to 2.05, p=0.64)).21 Neither study found mutations in breast cancer only kindreds (0/737), supporting the lack of a strong link with breast cancer.20 21 If BRCA1/2 mutations account for most of the inherited link between breast and ovarian cancer then the main factor affecting the ability to condently exclude risk of ovarian cancer in families testing negative is the sensitivity of testing. Tests on most cancer predisposing genes are limited in that they do not screen the intronic areas outside of the intron-exon boundaries nor do they screen for positional effects of mutations in other genes that can affect genes at a distance such as EPCAM mutations and MSH2.28 There are relatively few papers that adequately assess the sensitivity of BRCA1/2 mutation testing. Simply using a panel of found mutations and assessing different screening tests does not address the overall sensitivity.29 The tests can only be assessed against a gold standard such as gene sequencing which in any case does not screen the introns. It is rst necessary to identify families with a very high a priori probability of BRCA1/2 involvement such as breast/ovarian families fullling BCLC criteria or such families with a Manchester score30 of 40+. We have previously shown that sequencing plus MLPA identied mutations in 58/65 (89%) families with breast and ovarian cancer and a Manchester score of 40+.31 Breast cancer phenocopies can reduce the sensitivity of tests because around 6% of tests of breast cancers in families with mutations are mutation negative;32 true sensitivity could be closer to 95%.22 Even taking the lower sensitivity estimate, this would reduce the excess risk of ovarian cancer in a breast cancer only family by ninefold. The true likelihood of a missed mutation can be estimated from our testing of 2009 breast cancer only families in which only 240 (11.9%; 100 BRCA1; 140 BRCA2) had mutations identied by sequencing
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plus MLPA. Allowing for a Bayesian calculation no more than 1.5% of these breast cancer only families would have had a missed mutation. There are some potential limitations to the present study. Not all participants remained in active follow-up and a small proportion may have moved out of the north-west of England and an ovarian cancer could have been missed. Despite the large numbers and long follow-up the number of cases of ovarian cancer diagnosed is still quite small. Nevertheless this data should reassure women from breast cancer only families that test negative for BRCA1/2 that their risks of invasive ovarian cancer are not increased. In conclusion this, the largest prospective follow-up of a BRCA-negative cohort, has demonstrated that there is no clinically signicant increase in risk of invasive ovarian cancer in families that have tested negative for BRCA1/2.
Acknowledgements We would like to thank The Genesis Breast Cancer Prevention Appeal. Contributors Conception: DGE, Data collection: DGE, SS, Data analysis: DGE, SLI, JW, COH, Manuscript writing: DGE, SLI, AH, IB, JW, Approval of nal version: All. Funding This article presents independent research partly funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research programme (Reference Number RP-PG-070710031). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Competing interests None. Ethics approval North WestGreater Manchester Central ethics committee (as part 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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The trouble with phenocopies: are those testing negative for a family BRCA1/2 mutation really at population risk? J Med Genet 2007;44:105.

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Ovarian cancer among 8005 women from a breast cancer family history clinic: no increased risk of invasive ovarian cancer in families testing negative for BRCA1 and BRCA2
Sarah Louise Ingham, Jane Warwick, Iain Buchan, et al. J Med Genet 2013 50: 368-372 originally published online March 28, 2013

doi: 10.1136/jmedgenet-2013-101607

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