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A population-based analysis of germline BRCA1 and BRCA2 testing among ovarian cancer patients in an era… Hanley, Gillian E; McAlpine, Jessica N; Miller, Dianne; Huntsman, David; Schrader, Kasmintan A; Blake Gilks, C.; Mitchell, Gillian Mar 5, 2018

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RESEARCH ARTICLE Open AccessA population-based analysis of germlineBRCA1 and BRCA2 testing among ovariancancer patients in an era of histotype-specific approaches to ovarian cancerpreventionGillian E. Hanley1* , Jessica N. McAlpine1, Dianne Miller1, David Huntsman2, Kasmintan A. Schrader3,C. Blake Gilks2 and Gillian Mitchell3AbstractBackground: Identifying female carriers of BRCA1 and BRCA2 mutations is imperative for prevention of ovariancancer and breast cancer. There are five major histologic subtypes of ovarian cancer and high grade serous cancer(the most common) is reported in 75–100% of BRCA1 and BRCA2 mutation carriers. We examined histology-basedreferral to the Hereditary Cancer Program following an educational prevention campaign recommending BRCA1and BRCA2 mutation screening for all high-grade serous cancer patients.Methods: We conducted a population-based retrospective study in the province of British Columbia, Canada thatincluded all patients visiting the Hereditary Cancer Program for genetic counselling for BRCA1 and BRCA2 mutationbetween 2001 and 2014. We examined the difference in rates of BRCA1 and BRCA2 testing between serous cancerpatients and endometrioid and clear cell cancer patients using a differences in differences analysis. We alsocalculated the mean number of family members tested for every BRCA1 and BRCA2 identified ovarian cancer patientbefore and after the educational campaign.Results: There were 5712 women tested for a BRCA1 and BRCA2 mutation at the HCP between 2001 and 2014, 887of which had previously received a diagnosis of ovarian cancer. By 2013, 43% of serous cancer patients were beingtested for BRCA1 and BRCA2 mutations compared with 20% of endometrioid and clear cell patients (p < 0.001). Themean number of family members tested for each BRCA1 and BRCA2 positive ovarian cancer patient increased afterthe educational campaign from 2.54 to 3.27 (p = 0.071), and the number of family members identified as BRCApositive also increased significantly.Conclusions: Recommendations for histology-based referral significantly increased the likelihood of serous cancerpatients being tested for BRCA mutations. There was also an increase in the number of carrier tests performed foreach BRCA1 and BRCA2 index ovarian cancer patient.Keywords: BRCA, Ovarian cancer, Risk reduction, Histology-based referral* Correspondence: Gillian.hanley@vch.ca1Department of Obstetrics & Gynaecology, University of British Columbia,Vancouver, BC, CanadaFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Hanley et al. BMC Cancer  (2018) 18:254 https://doi.org/10.1186/s12885-018-4153-8BackgroundOvarian cancer is the leading cause of death due togynecologic malignancy and the fifth most commoncause of cancer deaths in developed countries. While thegeneral population lifetime risk of ovarian cancer is lowat 1.4% [1], women at high-risk of developing the diseasedue to their inheritance of a germline BRCA1 andBRCA2 mutation have an average cumulative risk ofbetween 40% to 75% and 11% to 34%, respectively [2–5].Inherited germline mutations of BRCA1 and BRCA2have been reported in 11% to as high as 25% of all inva-sive ovarian carcinomas [6–10]. Women with germlinemutations in BRCA1 and BRCA2 are also predisposed toautosomal dominant hereditary breast cancer.Identifying female carriers of BRCA1 and BRCA2mutations is imperative for prevention of ovarian cancerand breast cancer. While screening for ovarian cancerhas not been demonstrated to be of benefit [11] riskreducing interventions can be undertaken. Use of oralcontraceptive pills has been shown to decrease risk ofovarian cancer in BRCA1 and BRCA2 mutation carrierswithout significantly increasing the risk of breast cancer[12] and risk-reducing bilateral salpingo-oophorectomyis highly protective reducing ovarian cancer and overallmortality by 80% and 60% respectively following surgery[13–15]. Enhanced screening for breast cancer can alsobe undertaken.Histomorphologic classification of epithelial ovariancancer, often aided by immunohistochemistry, is highlyreproducible and delineates five major histologic sub-types of ovarian cancer: high-grade serous (HGSC), clearcell, endometrioid, mucinous and low-grade serous. [16]HGSC is the most common, accounting for approxi-mately 70% of invasive ovarian carcinomas and respon-sible for 90% of mortality in this disease. [17, 18] HGSCis the histotype reported in 75–100% of BRCA1 andBRCA2 mutation carriers who develop ovarian carcin-oma. [6, 8, 10, 19–21] Our previous research has illus-trated that BRCA1 and BRCA2 germline mutations werepresent in over 20% of women who underwent surgicalstaging in British Columbia with pathology confirmedHGSC. Notably, 19% of BRCA1 or BRCA2 mutation car-riers identified did not have a family history suggestiveof hereditary breast and ovarian cancer syndrome andthus would not have been referred for, nor qualified forhereditary cancer testing [10].Due to concerns of missed opportunities for referral,in September of 2010, our gynecologic tumor group inBritish Columbia initiated a province-wide ovarian can-cer prevention initiative, which strongly emphasized theimportance of referring HGSC patients for hereditarycancer counselling and index BRCA1 and BRCA2 gen-etic testing at BC’s coordinated site for publicly fundedhereditary cancer genetic testing, the sole site of BRCA1and BRCA 2 mutation testing in the province. In theearly years of this recommendation the hereditary cancerprogram in fact accepted any non-mucinous ovariancarcinoma for referral, as histotype assignment was notas reliable. However, the principal focus was increasedcapture of HGSC carcinomas and in November 2011our pathology department generated a reflex statementwith their reports stating “high-grade serous carcinomaof the ovary/fallopian tube/peritoneum is associated witha BRCA1 or BRCA2 mutation in over 20% of patients.We recommend this patient be referred to the BCCAHereditary Cancer Program.” The emphasis on HGSCpatients resulted from the fact that studies done withcentral expert pathology review report that 95–100% ofovarian cancer patients with germline BRCA1 or BRCA2mutations had invasive serous ovarian carcinomas, instudies where there was central pathology review usingcurrent diagnostic criteria [10, 20, 21].Herein we present the provincial statistics on uptakeof index BRCA1 and BRCA2 genetic testing in BC beforeand after the 2010 campaign comparing rates of testingbetween serous cancer patients and endometrioid andclear cell ovarian cancer patients. We also examinenumbers of carrier tests performed for family membersof each BRCA1 and BRCA2 mutation positive identifiedovarian cancer patient, as prevention efforts rely on up-take of carrier testing in family members who have yetto be diagnosed with ovarian cancer.MethodsWe conducted a population-based retrospective study ofall women who visited the HCP between 2001 and 2014in the Canadian province of British Columbia (popula-tion of 4.6 million) for index BRCA1 and BRCA2 muta-tion testing. This is the sole source of BRCA mutationtesting in British Columbia, and thus is a population-based dataset for all patients tested during this studyperiod. We were unable to capture women who werereferred to the HCP but chose not to visit the HCP inour dataset. With approval of all data stewards, we usedPopulation Data BC to access the BC Cancer Registrydata for 1985 to 2013, linked with vital statistics deathdata [22, 23]. Thus we have one more year of data onindex BRCA1 and BRCA2 genetic testing allowing for alag time between diagnosis and testing and more im-portantly for having family members carrier tested oncean index patient is identified. All inferences, opinions,and conclusions drawn are those of the authors and donot reflect the opinions or policies of the Data Stewards.Out of concern for women’s privacy and according toour agreement with the relevant data stewards we donot report cell sizes smaller than 5. In these cases, wereport approximate percentages.Hanley et al. BMC Cancer  (2018) 18:254 Page 2 of 8In BC cancer is a reportable disease and all cases areentered into the provincial Cancer Registry. The registrysources include hematology and pathology reports, deathcertificates, hospital reports, and cancer treatments. Thedata available include details about the type of cancerdiagnosed and the date of diagnosis. These data werelinked with data from BC’s Hereditary Cancer Program.Ethics approval was obtained from the University ofBritish Columbia Behavioural Research Ethics Board.We accessed data from the HCP including informationon the gene tested, the results of the test, the date of thefirst visit to the HCP, whether the patient was an indexor carrier patient, as well as data on family memberswho were also tested at the HCP, including the degree ofrelation, gender and the number of first, second, thirdand fourth degree relatives. We classified patients ashaving BRCA1 and BRCA2 mutation testing if they hadeither BRCA1 or BRCA2 mutation testing or both.The data from the BC Cancer Registry was accessedfor all patients who visited the HCP. We classifiedpatients as having ovarian cancer if they were in theregistry with an International Classifications of Disease(ICD-10-CA) code of C56.x or C48.x or a cancer sitedescription of “Ovary” or “Fallopian tube”. We used theInternational Classification of Diseases for Oncology(ICD-O-3) morphology codes to assign histologic sub-type (see Additional file 1 for details on morphologycodes). The codes are unable to distinguish betweenhigh grade and low-grade serous cancers, and thus wehave classified them as serous cancers. There are alsoovarian cancers with morphology codes that are notdetailed enough to classify into histologic subtypes andwere considered “unknown” histologic subtype. Thesecancers were excluded from all subtype-specific analyses.Statistical analysisTo clearly assess the effects of the educational campaignwe examined differences rates of testing between serouscancer patients and endometrioid and clear cell cancerpatients. Since the educational campaign only made rec-ommendations around referral of HGSC, we did not ex-pect rates of testing to change among endometrioid andclear cell cancer patients. We examined the characteristicsof the women who visited the HCP following a diagnosisof serous ovarian cancers compared to women with adiagnosis of either clear cell or endometrioid ovarian can-cer. We used t-tests to test for statistically significant dif-ferences between the groups for continuous variables andchi-squared tests for categorical variables.We examined the difference in rates of BRCA1 andBRCA2 testing between serous cancer patients and endo-metrioid and clear cell cancer patients and the differencein this difference before and after the educational cam-paign (a differences in differences analysis). We alsocalculated odds ratios indicating the odds of BRCA1 andBRCA2 testing in serous patients compared to clear cellor endometrioid patients both before and after the educa-tional campaign. Finally we examined the number ofcarrier tests in families and the mean number of familymembers tested for every BRCA1 and BRCA2 identifiedovarian cancer patient and serous ovarian cancer beforeand after the campaign and tested whether this changedsignificantly using two-sided t-tests. We did the same forthe number of family members identified as BRCA posi-tive before and after the educational campaign.ResultsThere were 5712 women tested for a BRCA1 andBRCA2 mutation at the HCP between 2001 and 2014.Of these women, 887 were identified as having receiveda diagnosis of ovarian cancer between 1985 and 2013;however most of these cancers (811, 91.5%) were diag-nosed between 2001 and 2013. This represents 21.1% ofall ovarian cancers diagnosed in BC during this timeperiod (n = 4201).Table 1 outlines the histologic subtype breakdown forthe 887 ovarian cancer patients who visited the HCPalong with the rates of BRCA germline mutations byhistologic subtype. This is broken down before and afterthe educational campaign. Due to the inclusion of codeswithout significant detail to classify into histologic sub-types, 18.7% of ovarian cancers among women visitingthe HCP were of unknown subtype. Of the women whovisited the HCP 65.5% were classified as having serouscancer, 10% were classified as endometrioid. 5.2% clearcell and 0.6% mucinous (mucinous cancer was excludedfrom Table 1 due to privacy concerns around small cellsizes). There were significantly more serous cancer pa-tients tested after the campaign (increasing from 59.0%to 72.5%) and significantly fewer endometrioid, clear celland unknown histologic subtypes. The majority of BRCApositive patients with ovarian carcinoma had serous car-cinoma (75.6%) and rate of BRCA positivity increasedamong serous cancer patients before and after the cam-paign (73.8% to 79.7%); however, this difference was notstatistically significant. Ovarian carcinomas in mutationcarriers were uncommonly reported to be of endome-trioid (N = 5), clear cell (absolute number not reporteddue to privacy restrictions, approximate percentage <5%) or mucinous (N = 0) histotypes (Table 1).Table 2 outlines characteristics of women with serouscancer and clear cell or endometrioid cancer. Amongthose who were tested for BRCA1 and BRCA2 muta-tions, serous cancer patients were significantly older anddiagnosed at a later year, were of older age at the time oftheir first visit to the HCP, and visited the HCP in a lateryear. There were no significant differences betweenindex or carrier patient status, proband status or number ofHanley et al. BMC Cancer  (2018) 18:254 Page 3 of 8Table 1 Histologic subtype of ovarian cancer patients who visited the HCP for BRCA mutation testing before and after theeducational campaignBRCA mutation tested (n = 887) BRCA positive (n = 163)Histologic subtype, n (%) Before the campaign After the campaign Total Before the campaign After the campaign TotalSerous 270 (59.0) 311 (72.5) 581 (65.5) 76 (73.8) 48 (79.7) 124 (75.6)Endometrioid 60 (13.1) 29 (6.8) 89 (10.0) 5 (4.9) < 3% a < 5%aClear cell 31 (6.8) 15 (3.5) 46 (5.2) < 4%a < 3%a < 5%aUnknown 95 (20.7) 71 (16.6) 166 (18.7) 19 (18.5) 10 (16.4) 29 (17.7)p-value < 0.001 0.519aSuppressed due to small cell sizes so approximate percentages have been reported Mucinous cancer was excluded from this table due to privacy concernsaround small cell sizesTable 2 Characteristics of ovarian cancer patients visiting HCP for BRCA1 or BRCA2 testing in British Columbia by serous status,2001–2013Serous ovarian cancerN = 581Endometrioid or clear cell ovarian cancersN = 134p-valueAge at diagnosis 60.0 ± 11.1 51.3 ± 11.0 < 0.001Year of diagnosis 2007.9 ± 4.3 2005.3 ± 5.2 < 0.001Age at time of first visit to HCP 62.3 ± 11.4 55.1 ± 11.3 < 0.001Year of first visit to HCP 2009.6 ± 3.4 2008.4 ± 3.3 < 0.001Index testIndex 564 (97.1) 129 (96.3)Carrier 17 (2.9) 5 (3.7) 0.237Proband statusYes 527 (90.7) 116 (86.6)No 54 (9.3) 18 (13.4) 0.151Number of first degree relative0–3 423 (72.8) 97 (72.4)4–6 122 (21.0) 32 (23.9)7+ 36 (6.2) 5 (3.7) 0.455Number of second degree relatives0–3 257 (44.2) 58 (43.3)4–6 189 (32.5) 53 (40.0)7+ 135 (23.2) 23 (17.1) 0.180Number of third degree relatives0–3 303 (52.2) 62 (46.3)4–6 164 (28.2) 38 (28.4)7+ 114 (19.6) 34 (25.4) 0.290Number of fourth degree relatives0–3 545 (93.8) 122 (91.0)4–6 14 (2.4) a < 5%7+ 22 (3.8) a < 5% 0.323BRCA1 or BRCA2 positive 124 (21.3) 10 (7.5) < 0.001aSuppressed due to small cell sizes so approximate percentages have been reportedHanley et al. BMC Cancer  (2018) 18:254 Page 4 of 8first, second, third or fourth degree relatives between thegroups. Serous cancer patients were significantly more likelyto be BRCA1 and BRCA2 mutation positive with 21.3%testing positive for either BRCA1 or BRCA2 mutationscompared to 7.5% of endometrioid or clear cell patients.Figure 1 outlines the percentage of all BC serouscancer patients and endometrioid or clear cell ovariancancer patients who were tested for BRCA1 and BRCA2mutation status over time. The educational campaign ismarked with a dotted line. Figure 1 clearly illustratesthat rates of index BRCA1 and BRCA2 genetic testingwere similar between serous cancer and endometrioid orclear cell cancer patients before 2010. After 2010 ahigher proportion of serous cancer patients were beingtested for BRCA1 and BRCA2 mutations. By 2013, 43%of serous cancer patients were being tested for BRCA1and BRCA2 mutations compared with 20% of endome-trioid and clear cell patients. Differences in differencesanalysis reveals that the difference in testing rates be-tween serous cancer patients and endometroid and clearcell patients before and after the campaign was signifi-cant (p < 0.0001). Table 3 also reports odds ratios ofreceiving BRCA1 and BRCA2 testing before and afterthe educational campaign with endometrioid and clearcell cancer patients acting as the reference category. Ser-ous patients were not significantly more likely to receivetesting before the September 2010 educational cam-paign, but nearly 5 times (OR = 4.70; 95% CI 2.89–7.62)more likely to receive BRCA1 and BRCA2 testing afterthe educational campaign.With respect to carrier testing, Table 4 outlines themean number of family members tested per BRCA1 andBRCA2 positive ovarian cancer and serous cancerpatient before and after the educational campaign. Themean number of family members tested per BRCA positiveovarian cancer patient and serous ovarian cancer patientincreased after the campaign from 2.54 to 3.27 and from2.60 to 3.36 respectively; however, neither increase was sta-tistically significant at the 95% confidence level. Therewere significantly more family members identified for eachBRCA positive ovarian cancer patient (1.62 vs. 2.18, p =0.009) and serous ovarian cancer patient (1.64 vs. 2.30, p =0.019) after the educational campaign. We were unable totest the differences for BRCA positive endometrioid andclear cell cancer patients because of small numbers.DiscussionFollowing the 2010 educational campaign recommend-ing that all HGSC patients be referred to the HCP forgermline BRCA1 and BRCA2 testing, rates of testing didsignificantly increase compared to rates prior to therecommendation and compared to endometrioid andclear cell cancer patients. This suggests that physicians(including family practitioners, general obstetriciangynecologists and medical and gynecologic oncologists)responded to the recommendations made in 2010. ThisFig. 1 Percentage of serous cancer patients and endometrial and clear cell patients seen at HCP annuallyHanley et al. BMC Cancer  (2018) 18:254 Page 5 of 8is consistent with the observed high uptake of surgicalremoval of fallopian tubes at the time of routine gyneco-logic surgery, which was also recommended in theSeptember 2010 ovarian cancer prevention educationalcampaign [24]. The educational campaign was supportedby the pathology department initiating a reflex commentin all pathology reports with the diagnosis of HGS fallo-pian tube, ovarian, and primary peritoneal carcinoma inorder to prompt referral to the HCP for these women.The finding in our manuscript that 21.3% of serousovarian cancer patients were germline BRCA1 or BRCA2mutation carriers is consistent with previous researchreporting a 20% and 23% germline mutation rate inHGSC patients [9, 10, 25]. However, our findings dif-fer in that Schrader et al. [10] previously reportedthat germline BRCA mutation were exclusively associ-ated with high-grade serous histology. The Schraderseries (n = 131) had undergone extensive pathologyreview with additional immunohistochemistry per-formed to aid in histologic subtype assignment. Casesthat could not be assigned histotype with confidencewere excluded. Although there have been considerableadvances in categorization of epithelial ovarian cancersubtypes with high interobserver agreement in histo-type assignment [26] for this disease, our large seriesof included cases (n = 887) include cancers subtypedprior to these publications, and most cases did nothave the benefit of additional immunohistochemicaltests to help characterize challenging cases. Thus weexpect that many cases reported as clear cell, endo-metrioid carcinomas, or of unspecified type, from his-torical cohorts found to have BRCA mutations, wereactually HGSC. Consistent with this Alsop et al. indicatedthat in their Australian cohort 8 of the 10 designated endo-metrioid cancer patients and 3 of 4 clear cell cancerpatients identified with BRCA1 or BRCA2 mutations werereclassified as HGSC following immunohistopathologyreview, so that considerably less than 5% of patients witheither endometrioid or clear cell carcinoma were found tohave a germline BRCA mutation [9]. In this manuscript, wereport a small number (n = 10, 7.5%) of germline BRCA1and BRCA2 mutations found in women diagnosed withendometrioid and clear cell cancer on their initial pathologyreports. The vast majority of these mutation carriers werediagnosed before 2005 prior to the changes in epithelialovarian carcinoma histotyping. We hypothesize that manyof these cancers also were high-grade serous histology.We are encouraged by the significant increase in ratesof BRCA1 and BRCA2 mutation testing following theeducational campaign, however, it remains that only 43%of serous cancer patients were ultimately tested by theend of our study period. There is also substantial roomfor improvement in carrier testing family members whena mutation has been identified. While the number offamily members tested for each BRCA1 or BRCA2 posi-tive ovarian cancer patient increased following the edu-cational campaign, the mean number of family memberstested was 3.27 following the campaign. Given the highfrequency of germline BRCA1 and BRCA2 mutations inwomen with HGSC and the high penetrance of thesegenes, it is imperative that every effort is made to iden-tify women and their family members. For the womanwith HGSC there are immediate predictive and prognos-tic implications as patients carrying germline BRCA1and BRCA2 mutations have been shown to have im-proved rates of progression-free and overall survival andmore frequently respond to platinum and non-platinum-based regimens than mutation-negative patients [9].Germline mutation status is also increasingly relevant inguiding treatment with oral poly (ADP-ribose) polymer-ase inhibitors, with highly favorable response ratesdemonstrated, even in heavily pretreated individuals, inwomen with BRCA1 or BRCA2 mutations [27–29].Finally, additional screening for breast cancer and risk-reducing interventions through chemoprevention andsurgical procedures can be undertaken by the individualand family members who are known BRCA1 or BRCA2germline mutation carriers to prevent future cancers.The population-based nature of this study and itsinclusion of all women seen at the HCP in BritishColumbia between 2001 and 2014 is an importantTable 4 Average number of carrier tests per BRCA identified patients before and after the educational campaignIndex patient Before campaign After campaign p-valueCarrier tests per BRCA positive ovarian cancer patient 2.54 (2.48) 3.27 (2.60) 0.071Family members identified as BRCA positive 1.62 (1.10) 2.18 (1.63) 0.009Carrier tests per BRCA positive serous cancer patient 2.60 (2.3) 3.36 (2.7) 0.098Family members identified as BRCA positive 1.64 (1.10) 2.29 (1.75) 0.012Table 3 Odds ratio of likelihood of being seen at HCP beforeand after the educational campaignOdds of BRCA1 or BRCA2 testingBefore the educational campaignEndometroid or clear cell 1.00 (ref)Serous cancer 1.27 (0.96–1.68)After the educational campaignEndometrioid or clear cell 1.00 (ref)Serous cancer 4.70 (2.89–7.62)Hanley et al. BMC Cancer  (2018) 18:254 Page 6 of 8strength of this study; however, the study is not withoutlimitations. Our reliance on the ICD morphologic codesto classify tumours into histologic subtypes likely intro-duced some misclassification, as previously described. Inaddition, we were unable to examine referral patterns tothe HCP to discern who was referred but did not followup and why (patient decision vs. physician team). Weexpect that rates of referral were higher than the numberof women visiting the HCP, but we are unable to quan-tify this difference. Finally, there were other eventsaffecting the rate of BRCA1 and BRCA2 mutation testingduring our study period, most notably Angelina Jolie’s an-nouncement regarding her BRCA1 status in May of 2013,which increased demand for genetic counselling consider-ably. However, because there was a considerable length oftime between the educational campaign and AngelinaJolie’s announcement, we can conclude that rates of test-ing among HGSC patients increased following the educa-tional campaign and not as a result of Angelina’s Jolie’sannouncement (95% confidence level).ConclusionsOur research suggests that the 2010 educational cam-paign followed by the change in the pathology reportsdid increase BRCA1 and BRCA2 mutation testing ratesamong serous cancer patients in BC. There was also anincrease in the number of carrier tests performed foreach positive BRCA1 and BRCA2 ovarian cancer patient.We anticipate that the rate of identification of germlineBRCA1 and BRCA2 mutation carriers will rapidly in-crease as we move towards new models of genetic test-ing in BC designed to accelerate the time to geneticdiagnosis. We expect that testing will soon be initiatedby the treating physician (near time of diagnosis) [30,31]. Other jurisdictions are trialing methods to improvetheir genetic assessment rates such as the introductionof “opt-out” genetics referrals, which have dramaticallyimproved assessment rates within a relatively shortperiod of time [32]. Importantly, with the more rapididentification of new families, it will be critical to ensurethere is translation of the preventative benefit in identi-fying germline mutation carriers through optimized roleout of cascade carrier testing in the family. Futureresearch should investigate whether the women identi-fied as BRCA1 and BRCA2 positive through carrier test-ing are undergoing effective risk-reducing interventions.Additional fileAdditional file 1: ICD-O morphology codes for histologic subtyping.(DOCX 13 kb)AbbreviationsHCP: Hereditary Cancer Program; HGSC: High grade serous ovarian cancerAcknowledgmentsWe would like to thank SzeWing Mung for her work compiling the datafrom the Hereditary Cancer Program.FundingThis study was supported by the Canadian Cancer Society Research Instituteand the Canadian Institutes for Health Research. Gillian Hanley is supportedby the Canadian Cancer Society (grant #702786) and by a CIHR NewInvestigator Award: Drug Safety Effectiveness Network. The funding bodyhad no role in the design of the study and collection, analysis, andinterpretation of data and in writing the manuscript.Availability of data and materialsThe data used herein are available from Population Data BC, The BC CancerAgency, and the BC Hereditary Cancer Program but restrictions apply to theavailability of these data, which were used under a data sharing agreementfor the current study, and so are not publicly available. Data are howeveravailable from Population Data BC, The BC Cancer Agency, and the BCHereditary Cancer Program following completion of a data access requestand with permission of the data stewards.Authors’ contributionsAll authors contributed to the conception and design of the study, GEH andGM participated in acquisition of the data, GEH conducted analysis and allauthors participated in the interpretation of the data. GEH drafted the articleand all authors participated in editing and finalizing the article. All authorsapproved the final version.Ethics approval and consent to participateEthics approval for this study was obtained from the University of BritishColumbia’s Behavioural Research Ethics Board (H14–02280). Patient consentwas not required.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Obstetrics & Gynaecology, University of British Columbia,Vancouver, BC, Canada. 2Pathology & Laboratory Medicine, University ofBritish Columbia, Vancouver, BC, Canada. 3Department of Medical Genetics,University of British Columbia, Vancouver, BC, Canada.Received: 11 July 2017 Accepted: 20 February 2018References1. Canadian Cancer Society. Canadian cancer statistics 2014. Toronto, Canada;2014. http://www.cancer.ca/en/cancer-information/cancer-101/canadian-cancer-statistics-publication/?region=sk. Accessed 27 Feb 2018.2. Mavaddat N, Peock S, Frost D, Ellis S, Platte R, Fineberg E, et al. Cancer risksfor BRCA1 and BRCA2 mutation carriers: results from prospective analysis ofEMBRACE. J Natl Cancer Inst. 2013;105(11):812–22.3. Boyd J. Specific keynote: hereditary ovarian cancer: what we know.Gynecologic oncology. 2003;88(1 Pt 2):S8–10. discussion S1–34. King MC, Marks JH, Mandell JB. New York breast cancer study G. Breast andovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.Science. 2003;302(5645):643–6.5. Prat J, Ribe A, Gallardo A. Hereditary ovarian cancer. Hum Pathol.2005;36(8):861–70.6. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, et al. PopulationBRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst. 2006;98(23):1694–706.Hanley et al. BMC Cancer  (2018) 18:254 Page 7 of 87. Pal T, Permuth-Wey J, Betts JA, Krischer JP, Fiorica J, Arango H, et al. BRCA1and BRCA2 mutations account for a large proportion of ovarian carcinomacases. Cancer. 2005;104(12):2807–16.8. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, et al.Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in apopulation series of 649 women with ovarian cancer. Am J Hum Genet.2001;68(3):700–10.9. Alsop K, Fereday S, Meldrum C, de Fazio A, Emmanuel C, George J, et al.BRCA mutation frequency and patterns of treatment response in BRCAmutation-positive women with ovarian cancer: a report from the Australianovarian cancer study group. [erratum appears in J Clin Oncol. 2012Nov 20;30(33):4180]. J Clin Oncol. 2012;30(21):2654–63.10. Schrader KA, Hurlburt J, Kalloger SE, Hansford S, Young S, Huntsman DG,et al. Germline BRCA1 and BRCA2 mutations in ovarian cancer: utility of ahistology-based referral strategy. Obstet Gynecol. 2012;120(2 Pt 1):235–40.11. Rosenthal AN, Fraser L, Manchanda R, Badman P, Philpott S, Mozersky J,et al. Results of annual screening in phase I of the United Kingdom familialovarian cancer screening study highlight the need for strict adherence toscreening schedule. J Clin Oncol. 2013;31(1):49–57.12. Moorman PG, Havrilesky LJ, Gierisch JM, Coeytaux RR, Lowery WJ, PeragalloUrrutia R, et al. Oral contraceptives and risk of ovarian cancer and breastcancer among high-risk women: a systematic review and meta-analysis.J Clin Oncol. 2013;31(33):4188–98.13. Finch A, Beiner M, Lubinski J, Lynch HT, Moller P, Rosen B, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritonealcancers in women with a BRCA1 or BRCA2 mutation. JAMA.2006;296(2):185–92.14. Kauff ND, Domchek SM, Friebel TM, Robson ME, Lee J, Garber JE, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study.J Clin Oncol. 2008;26(8):1331–7.15. Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, et al.Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carrierswith cancer risk and mortality. JAMA. 2010;304(9):967–75.16. Gilks CB. Molecular abnormalities in ovarian cancer subtypes other thanhigh-grade serous carcinoma. J Oncol. 2010;2010:740968.17. Kobel M, Kalloger SE, Huntsman DG, Santos JL, Swenerton KD, Seidman JD,et al. Differences in tumor type in low-stage versus high-stage ovariancarcinomas. Int J Gynecol Path. 2010;29(3):203–11.18. Singh N, McCluggage WG, Gilks CB. High grade serous carcinoma (HGSC) oftubo-ovarian origin: recent developments. Histopathol. 2017;https://doi.org/10.1111/his.13248.19. Zhang S, Royer R, Li S, McLaughlin JR, Rosen B, Risch HA, et al. Frequenciesof BRCA1 and BRCA2 mutations among 1,342 unselected patients withinvasive ovarian cancer. Gynecol Oncol. 2011;121(2):353–7.20. Shaw PA, McLaughlin JR, Zweemer RP, Narod SA, Risch H, Verheijen RH,et al. Histopathologic features of genetically determined ovarian cancer.Int J Gynecol Path. 2002;21(4):407–11.21. Wang YK, Bashashati A, Anglesio MS, Cochrane DR, Grewal DS, Ha G, et al.Genomic consequences of aberrant DNA repair mechanisms stratify ovariancancer histotypes. Nat Genet. 2017;49(6):856–65.22. BC Cancer Agency Registry Data (2015). V2. Population Data BC .DataExtract. BC Cancer Agency. www.popdata.bc.ca.23. BC Vital Statistics Agency (2015): Vital Statistics Deaths. V2. BC Vital StatisticsAgency. 2015 www.popdata.bc.ca.24. McAlpine JN, Hanley GE, Woo MM, Tone AA, Rozenberg N, Swenerton KD,et al. Opportunistic salpingectomy: uptake, risks, and complications of aregional initiative for ovarian cancer prevention. Am J Obstet Gynecol.2014;210(5):471 e1–11.25. Hennessy BT, Timms KM, Carey MS, Gutin A, Meyer LA, Flake DD 2nd, et al.Somatic mutations in BRCA1 and BRCA2 could expand the number ofpatients that benefit from poly (ADP ribose) polymerase inhibitors inovarian cancer. J Clin Onc. 2010;28(22):3570–6.26. Kobel M, Bak J, Bertelsen BI, Carpen O, Grove A, Hansen ES, et al. Ovariancarcinoma histotype determination is highly reproducible, and is improvedthrough the use of immunohistochemistry. Histopathol. 64(7):1004–13.27. Domchek SM, Aghajanian C, Shapira-Frommer R, Schmutzler RK, Audeh MW,Friedlander M, et al. Efficacy and safety of olaparib monotherapy ingermline BRCA1/2 mutation carriers with advanced ovarian cancer andthree or more lines of prior therapy. Gynecol Oncol. 2016;140(2):199–203.28. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al.Olaparib maintenance therapy in patients with platinum-sensitive relapsedserous ovarian cancer: a preplanned retrospective analysis of outcomes byBRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15(8):852–61.29. Kummar S, Oza AM, Fleming GF, Sullivan DM, Gandara DR, Naughton MJ,et al. Randomized trial of oral cyclophosphamide and Veliparib in high-grade serous ovarian, primary peritoneal, or fallopian tube cancers, orBRCA-mutant ovarian cancer. Clin Cancer Res. 2015;21(7):1574–82.30. Kentwell M, Dow E, Antill Y, Wrede CD, McNally O, Higgs E, et al.Mainstreaming cancer genetics: a model integrating germline BRCA testinginto routine ovarian cancer clinics. Gynecol Oncol. 2017;145(1):130–6.31. Percival N, George A, Gyertson J, Hamill M, Fernandes A, Davies E, et al.The integration of BRCA testing into oncology clinics. Br J Nursing.2016;25(12):690–4.32. Kanchi KL, Johnson KJ, Lu C, McLellan MD, Leiserson MD, Wendl MC, et al.Integrated analysis of germline and somatic variants in ovarian cancer.Nat Commun. 2014;5:3156.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Hanley et al. BMC Cancer  (2018) 18:254 Page 8 of 8


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