CA125 serum levels in BRCA1/BRCA2 pathogenic sequence variant carriers as an ovarian cancer screening tool– a longitudinal study

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The value of longitudinal CA125 measurements in BRCA1/BRCA2 carriers as a tool for ovarian cancer detection is reported herein. Asymptomatic BRCA1/BRCA2 PSV carriers attending the Meirav high risk clinic for > 3 years were eligible. Data on specific PSV, risk reducing surgeries, and cancer diagnoses were obtained from participants' records. Statistical analyses employed χ 2 and Wilcoxon-Rank tests. Overall, 739 (399 BRCA1 , 336 BRCA2 , 4 BRCA1 + BRCA2 ) PSV carriers were included. Mean age at the start of follow up was 38.96 ± 11.13 years, mean follow up time was 7.93 ± 2.34 years, (5860.80 women/years). Most participants (490/739 − 66.3%) had stable CA125 levels ( ± 5 U/µl). Of participants, 61 had CA125 levels > 35 U/µl at least twice (n = 42) or at least doubling of marker levels to a minimum of 20 U/µl (n = 19), results that have led to further cancer defining investigations. Of these, 14 and 4 were diagnosed with breast and ovarian cancer, respectively. In conclusion, longitudinally stable CA125 levels were noted in most BRCA1/BRCA2 PSV carriers, elevated levels were a poor marker for ovarian cancer development. . BRCA1/BRCA2 PSV carriers ovarian cancer risk early detection Longitudinal CA125 levels risk reducing surgery Introduction Female carriers of germline BRCA1 or BRCA2 Pathogenic Sequence Variants (PSVs) are at a substantially high lifetime risk of for developing breast cancer (BC) and ovarian cancer (OvC) estimated to be more than 60% for BC (for both genes) and 40–60% ( BRCA1 ) and 15–30% (for BRCA2 ) for OvC [ 1 ]. Additionally, even higher OvC risk rates were reported in Ashkenazi Jewish (AJ) BRCA2 carriers [ 2 ]. Given the lack of an established screening scheme for early detection of OvC, these high-risk women are offered risk reducing salpingo-oophorectomy (RRSO) at age 35–40 years (for BRCA1 PSV carriers) and 40–45 years (for BRCA2 PSV carriers), after completing childbearing and family planning [ 3 ]. Since BRCA1/BRCA2 genotyping is offered at an earlier age (25–30 years) to assess BC risk and offer BC surveillance and/or risk reducing surgery of the breasts [ 4 ], in some, but not all, high risk clinics, a surveillance scheme is also offered for early detection of OvC for female BRCA1/BRCA2 carriers, prior to and up to the time of RRSO. Such a scheme is offered, while clearly stressing its lack of proven effectiveness in providing bona fide “early OvC detection”. To that end, in Israel BRCA1/BRCA2 PSV carriers are offered a semiannual pelvic exam, transvaginal ultrasound, and serum level measurements of CA125 [ 5 ]. The low efficacy of this combined approach has been stated in the past both by researchers 6 and echoed by the NCCN guidelines [ 4 ]. Yet, the value of longitudinal CA 125 measurements and the effect of RRSO on these levels specifically in BRCA1/BRCA2 PSVs carriers has been reported infrequently [ 7 , 8 ] and never reported in AJ BRCA1/BRCA2 PSV carriers. Since cancer risk may, in part, be determined by the exact position of the PSV along these genes 9, the fact that most AJ carry one of three predominant mutations in both genes [ 10 ] makes focusing on AJ BRCA1/BRCA2 PSV carriers a less confounder-prone analysis. Thus, the current study aimed to evaluate the role, if any, that semiannual measurements of CA125 in Israeli, mostly AJ, BRCA1/BRCA2 PSV carriers play in OvC detection at an early, potentially curable, stage. The secondary aim was to evaluate if these levels change in relation to RRBSO, an infrequently reported outcome in previous studies. Patients and Methods Patients - Israeli women, who were genotyped in the context of genetic counseling, and found to harbor a PSV in the BRCA1 and/or BRCA2 gene, attending the Meirav high risk clinic, Sheba Medical Center, Tel-Hashomer, for at least 3 years who have had ≥ 2 CA125 determinations, who were cancer free at joining the clinic (i.e., asymptomatic carriers) were eligible. The routine surveillance scheme offered at the Meirav Center for female BRCA carriers from age 25 years includes: a semiannual physician guided breast exam and breast imaging (mammography alternating with breast MRI), and semiannual gynecological exam, transvaginal ultrasound, and serum level determination of CA125 as previously outlined [ 5 ]. The physician who conducted the clinical exams were experts in Surgery and Gynecological Oncology. Data on specific PSV, risk reducing surgeries, and cancer diagnoses during follow up were obtained from participants' records (including pathology reports), by one of the medical team professionals involved in maintaining the high-risk clinic clinical routine. The study was approved by the Sheba Medical Center Ethics Committee (IRB approval number SMC- 1492-014). All participants sign an informed consent at the time of joining the clinic that enables prospective/retrospective analyses of clinical outcomes and correlation with imaging and laboratory results. Data were collected from the time each participant joined the high-risk clinic until 12/2023. Statistical analyses - For demographic characteristics, descriptive statistics were used. Data analyses were performed using SPSS 12.0.2 software (SPSS, Chicago, IL). Differences between characteristics were tested two-sided with the χ2- test, and continuous variables were compared using the Wilcoxon-Rank test. p-values < 0.05 were significant. Results Participant characteristics and clinical follow up – Overall, the study encompassed 739 asymptomatic BRCA1/BRCA2 PSV carriers (399 BRCA1 , 336 BRCA2 ,4 BRCA1 and BRCA2 ). Mean age at the start of follow up was 38.96 ± 11.13 years (range 25–58 years), mean follow up time was 7.93 + 2.34 (range 3-11.6 years) – a total of 5860.8 women/years. The most common PSVs in BRCA1 were c.68_69del (p.Glu23fs; rs80357914; aka 185delAG) (n = 299) and c.5266dup (p.Gln1756fs; rs80357906- AKA 5382insC) (n = 66) and for BRCA2 c.5946del (p.Ser1982fs; rs80359550- aka 6174delT) (n = 308). During follow up, 14.1% (n = 104) [ BRCA1 (69) / BRCA2 (35)] PSV carriers developed cancer: 93 breast [n = 69 (74.2%) BRCA1 ], 6 - ovarian (all BRCA1 ), 5 pancreatic, 4 endometrial, and one colon. Of women diagnosed with OvC, stage at diagnosis was 3B-C in 4/6; of women diagnosed with pancreatic cancer stage at diagnosis was 5/6 1a-b Of participants, 360 underwent RRSO during follow up (mean age at surgery 53.86 ± 9.83 years) CA125 levels –The majority of participants (490/739 − 66.3%) had CA125 levels that were stable (± 5 U/µl): mean 9.03 ± 3.05 U/µl (range 1.54–29.6) over the entire study period. Of participants, 42 (5.7%) had CA125 levels that were < 35 U/µl cutoff at least twice and 19 had a doubling of CA125 levels to a minimum of 20 U/µl, both levels leading to additional studies to detect possible cancer (E.G., breast MRI, PET CT). Of these, 14 were diagnosed with BC, 4 with OvC, and 7 with other cancer types (endometrial, pancreatic, colon). Thus, only 4/61 (6.5%) of those who had a “serological alert” for the possibility of OvC were actually diagnosed with OvC. In 140/360 carriers who remained asymptomatic throughout the study period and underwent RRSO, comparison between pre and post RRSO levels up to 20 months after surgery was possible. The mean pre- and post-surgery CA 125 levels for the entire group were 14.7 ± 12.9 U/µl and 9.1 ± 6.9 U/µl, respectively (P 30% change in pre- and post-surgery levels: in 73/140 (52.14%) levels were reduced from 18.37 ± 16.42 U/µl to 8.51 ± 7.89 U/µl (p < 0.0001) and 3 (2.14%) had levels 30% higher after RRSO- from 9.82 ± 8.36 U/µl to 21.57 ± 16.58 U/µl (p = 0.3346). All others (64/140–45.7%) showed no significant change in CA125 levels pre and post-surgery – 10.69 ± 5.19 U/µl to 9.23 ± 4.16 U/µl (p = 0.0815). Discussion In the current study, serial semiannual measurements of CA125 levels in Israeli BRCA1/BRCA2 PSV carriers showed that these levels were stable in most cancer free cases (66.3%) for a mean follow up period of 7.93 years spanning 5860.80 women/years. Level range for the most part are well below the established 35 U/µl cutoff, generally accepted to be the reference value in the general, average risk population at age 35 years [ 11 ]. Of participants, 6 were diagnosed with OvC of whom 4 were diagnosed at an advanced stage. Only 4/61 (6.5%) of those who had a “serological alert” for the possibility of OvC were diagnosed with OvC. Lastly, no consistent effect of RRSO on CA125 levels was noted in ~ 50% of women who underwent the procedure where comparison between pre- and post-surgery CA125 values was available. Normal values for CA125 vary, depending on a host of factors: menstrual cycle, menopausal status, race, smoking, and caffeine consumption to mention some [ 12 , 13 , 14 ]. Serum CA125 levels are elevated in 50% of early-stage ovarian cancers, and 92% of advanced-stage tumors [ 13 ]. However, due to the low incidence of OvC, screening of average-risk women with CA125 results in a considerable number of false positives 15 and is not recommended. Given the substantially increased risk for developing OvC for BRCA1/BRCA2 PSV carriers, risk-reducing salpingo-oophorectomy (RRSO) by age 40 years for BRCA1 and by age 45 years for BRCA2 PSVs carriers is universally recommended [ 4 ]. Prior to risk reducing surgery, some (but not all) high risk clinics offering surveillance scheme implementation to female BRCA1/BRCA2 PSV carriers [ 5 ], offer these high-risk women semiannual - annual screening with transvaginal ultrasound (TVUS) and CA125 level determination starting at age 35, or 5–10 years earlier than the earliest age of OvC diagnosis in the family. The effectiveness of this scheme for early detection of OvC in high-risk women, has not been proven. In fact, such a scheme has been advocated against by several groups [ 6 , 16 – 20 ], and is not recommended by the NCCN. Notably, some of those studies had a limited number of cases and a short follow up period. For example, Woodward et al [ 17 ] concluded that OvC screening by annual TVUS and CA125 is inefficient for detecting early-stage OvC in BRCA1/BRCA2 PSV carriers based on analysis of 20 and 11 BRCA1 and BRCA2 PSV carriers, respectively, with a mean follow-up time of 29.4 months. Nobbenhuis et. al., [ 21 ] reported that annual serum CA125 and TVUS screening revealed advanced stage OVC in 2/58 BRCA1 gene PSV carriers and none in 45 women had a BRCA2 gene PSV, with a high rate of re-calls for a single elevated CA125. Similarly, Oei et. al., [ 22 ] who concluded that annual CA125 surveillance is ineffective in early detection of OvC based on analysis of 265 BRCA1/BRCA2 PSV carriers followed up for a median of 2.07 years, who underwent 1278 CA125 determinations. Yet, there are some reports supporting the use of serial CA125 measurements with the rate of change (rather than a single fixed level) as an indicator of the need to further pursue the possibility of OvC by additional analyses and imaging. Reports from large trials of high-risk women in the UK and USA (20% of whom were BRCA1/BRCA2 PSV carriers) showed promise with significant increases in the fraction of women with early stage OvC detected [ 23 , 24 ]. Both trials utilized the Risk of Ovarian Cancer Algorithm (ROCA) using CA125 as a single biomarker, performed every 3–4 months followed by TVUS for women with abnormal results. Cortesi et al [ 25 ] reported that CA125 determination in 127 BRCA PSV carriers, for a total of 1,094 follow-up years reached a sensitivity rate in cancer detection of 73%. In contrast, Olivier and coworkers [ 6 ] reported a combined sensitivity of 40%, specificity of 99%, positive predictive value (PPV) of 40% and negative predictive value (NPV) of 99%, with CA125 level determinations performing better than TVUS on separate analyses from a study that encompassed 132 BRCA1 , 20 BRCA2 PSV carriers who were recruited from 1996–2002. Noteworthy, van der Velde et. al. [ 19 ] who concluded that annual gynecological screening of female BRCA carriers to prevent advanced stage OvC is not effective, based that conclusion on 87 BRCA1/BRCA2 carriers who were followed up for 3 and 2.7 years, respectively. Yet, in that study, the NPV for CA125 estimation alone was 99.4% meaning that a negative test almost always excluded ovarian cancer. Regarding the effect of RRSO on CA125 levels, Grandi et al [ 8 ] reported that of 116 BRCA PSV carriers, a 6-month decrease in CA125 (median from 10.3 to 9.5 U/ml, − 7.8%, P = 0.003), after RRSO which was significantly linked only to endometriosis history and only partially accounted for by risk reducing surgery. Chen et. al. [ 26 ] reported statistically significant reductions in CA125 levels 6 months after RRSO in 48 BRCA1 carriers (mean 15.1 → 12.4 U/µl p = 0.04), but no significant differences in 40 BRCA2 carriers (mean 12.8 → 14.6 U/µl ; p = 0.5). These differences were not affected by the diagnosis of BC. van Altena et. al. [ 27 ] reported that CA125 levels in BRCA1 (n = 48) or BRCA2 (n = 12) were 10.15 U/mL before RRSO and 8.36 U/µl (18% decrease) at a median of 12 months after RRSO (p = 0.004), with significance maintained only for premenopausal women. The limitations of the study should be enumerated. This is a single institution experience that may not reflect the situation in all of Israel and in other ethnically diverse and geographically disperse populations, some cancer cases may have been unreported (as they have not been treated at the same medical center), and the total number of newly diagnosed cancers during the study period was limited. In conclusion, longitudinally stable CA125 levels are noted in most asymptomatic BRCA PSV carriers, serially increased levels rarely indicate breast and/or ovarian cancer, and no consistent effect on these levels can be attributed to RRSO in a sizable portion of BRCA carriers undergoing this procedure. Clearly the use of CA125 in BRCA1/BRCA2 PSV carriers should be discouraged and its lack of efficacy should be emphasized when surveillance options are discussed with asymptomatic BRCA1/BRCA2 PSV carriers. This study in the context of the previous work that has been published should promote a search for alternative means for early detection of OvC in high-risk women that are beyond the traditional serological biomarker paradigm: epigenetic signatures in serum, microbiome composition in vaginal fluids, novel modes of imaging, to name a few. Declarations Competing interests - all authors declare no competing interests Declarations This study involves human participants, was performed in accordance with the Declaration of Helsinki, and was approved by the Sheba Medical center IRB - IRB approval number SMC- 1492-014. Participants gave informed consent to participate in the study before taking part. Funding information- The authors received no specific funding for this work Author Contribution JK and EF conceived, planned, and summarized the project. Cases (with clinical data and outcomes) were contributed by DMF and JK. Dataset assembly/organization by YL and DA, who also provided intellectual contribution and edits. YL and DA performed the statistical analyses. All authors contributed to manuscript writing and editing. DMF and EF were responsible for the overall content as guarantors. Acknowledgement The authors are grateful to the team of health care professionals and administrative personnel at the Meirav High risk Clinic, Sheba Medical Center, Tel-Hashomer for their ongoing assistance with patient care. Data availability statement - All data relevant to the study are included in the article. References Kuchenbaecker KB, Hopper JL, Barnes DR et al (2017) Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA 317:2402–2416. 10.1001/jama.2017.7112 Simchoni S, Friedman E, Kaufman B et al (2006) Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population. Proc Natl Acad Sci U S A 103(10):3770–3774. 10.1073/pnas.0511301103 Eleje GU, Eke AC, Ezebialu IU, Ikechebelu JI, Ugwu EO, Okonkwo OO (2018) Risk-reducing bilateral salpingo-oophorectomy in women with BRCA1 or BRCA2 mutations. Cochrane Database Syst Rev 8(8):CD012464. 10.1002/14651858.CD012464.pub2) National Comprehensive Cancer Network guidelines (( https://www.nccn.org/guidelines/category_2 version 3.2024)) Madorsky-Feldman D, Sklair-Levy M, Perri T et al (2016) An international survey of surveillance schemes for unaffected BRCA1 and BRCA2 mutation carriers. Br Can Res Treat 157(2):319–327. 10.1007/s10549-016-3805-0 Olivier RI, Lubsen-Brandsma MA, Verhoef S, van Beurden M (2006) CA125 and transvaginal ultrasound monitoring in high-risk women cannot prevent the diagnosis of advanced ovarian cancer. 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Br J Cancer 94(6):814–819. 10.1038/sj.bjc.6603015 Skates SJ, Greene MH, Buys SS et al (2017) Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk - Combined Results from Two Screening Trials. Clin Cancer Res 23(14):3628–3637. 10.1158/1078-0432.CCR-15-2750 Rosenthal AN, Fraser LSM, Philpott S, et al and the United Kingdom Familial Ovarian Cancer Screening Study collaborators et al (2017) Evidence of Stage Shift in Women Diagnosed With Ovarian Cancer During Phase II of the United Kingdom Familial Ovarian Cancer Screening Study. J Clin Oncol 35(13):1411–1420. doi: 10.1200/JCO.2016.69.9330. Erratum in: J Clin Oncol 2017;35(23):2722 Cortesi L, De Matteis E, Toss A et al (2017) Evaluation of Transvaginal Ultrasound plus CA-125 Measurement and Prophylactic Salpingo-Oophorectomy in Women at Different Risk Levels of Ovarian Cancer: The Modena Study Group Cohort Study. Oncology 93(6):377–386. 10.1159/000479155 Chen Y, Bancroft E, Ashley S et al (2014) Baseline and post prophylactic tubal-ovarian surgery CA125 levels in BRCA1 and BRCA2 mutation carriers. Fam Cancer 13(2):197–203. 10.1007/s10689-013-9697-9 van Altena AM, Holtsema H, Hendriks JC, Massuger LF, de Hullu JA (2011) Cancer antigen 125 level after a bilateral salpingo-oophorectomy: what is the contribution of the ovary to the cancer antigen 125. level? Menopause 18(2):133–137. 10.1097/gme.0b013e3181ecfb51 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4440317","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":307748350,"identity":"ae35a4e1-b2ae-4f1e-b5e5-3c18405a1f4d","order_by":0,"name":"Dana Mdorsky Feldman","email":"","orcid":"","institution":"The Meirav high risk clinic 1, Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Dana","middleName":"Mdorsky","lastName":"Feldman","suffix":""},{"id":307748351,"identity":"13e2b754-7366-403f-84a5-69a0f0858652","order_by":1,"name":"Yael Laitman","email":"","orcid":"","institution":"The Meirav high risk clinic 1, Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yael","middleName":"","lastName":"Laitman","suffix":""},{"id":307748352,"identity":"b733981f-4292-4ef1-8159-f9b8f809eb58","order_by":2,"name":"Dana Albagli","email":"","orcid":"","institution":"The Meirav high risk clinic 1, Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Dana","middleName":"","lastName":"Albagli","suffix":""},{"id":307748353,"identity":"70f51fc7-35e3-40d1-bddd-35271c128645","order_by":3,"name":"Jacob Korach","email":"","orcid":"","institution":"The Meirav high risk clinic 1, Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jacob","middleName":"","lastName":"Korach","suffix":""},{"id":307748354,"identity":"3e960e79-192d-47cd-8474-c35bca5e457f","order_by":4,"name":"Eitan Friedman","email":"data:image/png;base64,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","orcid":"","institution":"The Meirav high risk clinic 1, Sheba Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Eitan","middleName":"","lastName":"Friedman","suffix":""}],"badges":[],"createdAt":"2024-05-18 09:08:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4440317/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4440317/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62785156,"identity":"e8847d81-c5bf-4082-9110-91c172b10bb9","added_by":"auto","created_at":"2024-08-19 13:00:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":335177,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4440317/v1/25f5422f-9ce5-4647-a341-b23d65047d75.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"CA125 serum levels in BRCA1/BRCA2 pathogenic sequence variant carriers as an ovarian cancer screening tool– a longitudinal study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFemale carriers of germline \u003cem\u003eBRCA1\u003c/em\u003e or \u003cem\u003eBRCA2\u003c/em\u003e Pathogenic Sequence Variants (PSVs) are at a substantially high lifetime risk of for developing breast cancer (BC) and ovarian cancer (OvC) estimated to be more than 60% for BC (for both genes) and 40\u0026ndash;60% (\u003cem\u003eBRCA1\u003c/em\u003e) and 15\u0026ndash;30% (for \u003cem\u003eBRCA2\u003c/em\u003e) for OvC [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Additionally, even higher OvC risk rates were reported in Ashkenazi Jewish (AJ) \u003cem\u003eBRCA2\u003c/em\u003e carriers [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Given the lack of an established screening scheme for early detection of OvC, these high-risk women are offered risk reducing salpingo-oophorectomy (RRSO) at age 35\u0026ndash;40 years (for \u003cem\u003eBRCA1\u003c/em\u003e PSV carriers) and 40\u0026ndash;45 years (for \u003cem\u003eBRCA2\u003c/em\u003e PSV carriers), after completing childbearing and family planning [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Since \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e genotyping is offered at an earlier age (25\u0026ndash;30 years) to assess BC risk and offer BC surveillance and/or risk reducing surgery of the breasts [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], in some, but not all, high risk clinics, a surveillance scheme is also offered for early detection of OvC for female \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e carriers, prior to and up to the time of RRSO. Such a scheme is offered, while clearly stressing its lack of proven effectiveness in providing \u003cem\u003ebona fide\u003c/em\u003e \u0026ldquo;early OvC detection\u0026rdquo;. To that end, in Israel \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers are offered a semiannual pelvic exam, transvaginal ultrasound, and serum level measurements of CA125 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The low efficacy of this combined approach has been stated in the past both by researchers 6 and echoed by the NCCN guidelines [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Yet, the value of longitudinal CA 125 measurements and the effect of RRSO on these levels specifically in \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSVs carriers has been reported infrequently [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and never reported in AJ \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers. Since cancer risk may, in part, be determined by the exact position of the PSV along these genes 9, the fact that most AJ carry one of three predominant mutations in both genes [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] makes focusing on AJ \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers a less confounder-prone analysis. Thus, the current study aimed to evaluate the role, if any, that semiannual measurements of CA125 in Israeli, mostly AJ, \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers play in OvC detection at an early, potentially curable, stage. The secondary aim was to evaluate if these levels change in relation to RRBSO, an infrequently reported outcome in previous studies.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003e\u003cb\u003ePatients\u003c/b\u003e- Israeli women, who were genotyped in the context of genetic counseling, and found to harbor a PSV in the \u003cem\u003eBRCA1\u003c/em\u003e and/or \u003cem\u003eBRCA2\u003c/em\u003e gene, attending the Meirav high risk clinic, Sheba Medical Center, Tel-Hashomer, for at least 3 years who have had\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;2 CA125 determinations, who were cancer free at joining the clinic (i.e., asymptomatic carriers) were eligible. The routine surveillance scheme offered at the Meirav Center for female \u003cem\u003eBRCA\u003c/em\u003e carriers from age 25 years includes: a semiannual physician guided breast exam and breast imaging (mammography alternating with breast MRI), and semiannual gynecological exam, transvaginal ultrasound, and serum level determination of CA125 as previously outlined [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The physician who conducted the clinical exams were experts in Surgery and Gynecological Oncology. Data on specific PSV, risk reducing surgeries, and cancer diagnoses during follow up were obtained from participants' records (including pathology reports), by one of the medical team professionals involved in maintaining the high-risk clinic clinical routine. The study was approved by the Sheba Medical Center Ethics Committee (IRB approval number SMC- 1492-014). All participants sign an informed consent at the time of joining the clinic that enables prospective/retrospective analyses of clinical outcomes and correlation with imaging and laboratory results. Data were collected from the time each participant joined the high-risk clinic until 12/2023.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical analyses\u003c/b\u003e- For demographic characteristics, descriptive statistics were used. Data analyses were performed using SPSS 12.0.2 software (SPSS, Chicago, IL). Differences between characteristics were tested two-sided with the χ2- test, and continuous variables were compared using the Wilcoxon-Rank test. p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eParticipant characteristics and clinical follow up\u003c/span\u003e \u0026ndash; Overall, the study encompassed 739 asymptomatic \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers (399 \u003cem\u003eBRCA1\u003c/em\u003e, 336 \u003cem\u003eBRCA2\u003c/em\u003e,4 \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e). Mean age at the start of follow up was 38.96\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;11.13 years (range 25\u0026ndash;58 years), mean follow up time was 7.93\u0026thinsp;+\u0026thinsp;2.34 (range 3-11.6 years) \u0026ndash; a total of 5860.8 women/years. The most common PSVs in \u003cem\u003eBRCA1\u003c/em\u003e were c.68_69del (p.Glu23fs; rs80357914; aka 185delAG) (n\u0026thinsp;=\u0026thinsp;299) and c.5266dup (p.Gln1756fs; rs80357906- AKA 5382insC) (n\u0026thinsp;=\u0026thinsp;66) and for \u003cem\u003eBRCA2\u003c/em\u003e c.5946del (p.Ser1982fs; rs80359550- aka 6174delT) (n\u0026thinsp;=\u0026thinsp;308).\u003c/p\u003e \u003cp\u003eDuring follow up, 14.1% (n\u0026thinsp;=\u0026thinsp;104) [\u003cem\u003eBRCA1\u003c/em\u003e (69) /\u003cem\u003eBRCA2\u003c/em\u003e (35)] PSV carriers developed cancer: 93 breast [n\u0026thinsp;=\u0026thinsp;69 (74.2%) \u003cem\u003eBRCA1\u003c/em\u003e], 6 - ovarian (all \u003cem\u003eBRCA1\u003c/em\u003e), 5 pancreatic, 4 endometrial, and one colon. Of women diagnosed with OvC, stage at diagnosis was 3B-C in 4/6; of women diagnosed with pancreatic cancer stage at diagnosis was 5/6 1a-b\u003c/p\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eOf participants, 360 underwent RRSO during follow up (mean age at surgery 53.86\u0026thinsp;\u0026plusmn;\u0026thinsp;9.83 years)\u003c/h2\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eCA125 levels\u003c/span\u003e \u0026ndash;The majority of participants (490/739\u0026thinsp;\u0026minus;\u0026thinsp;66.3%) had CA125 levels that were stable (\u0026plusmn;\u0026thinsp;5 U/\u0026micro;l): mean 9.03\u0026thinsp;\u0026plusmn;\u0026thinsp;3.05 U/\u0026micro;l (range 1.54\u0026ndash;29.6) over the entire study period.\u003c/p\u003e \u003cp\u003eOf participants, 42 (5.7%) had CA125 levels that were \u0026lt;\u0026thinsp;35 U/\u0026micro;l cutoff at least twice and 19 had a doubling of CA125 levels to a minimum of 20 U/\u0026micro;l, both levels leading to additional studies to detect possible cancer (E.G., breast MRI, PET CT). Of these, 14 were diagnosed with BC, 4 with OvC, and 7 with other cancer types (endometrial, pancreatic, colon). Thus, only 4/61 (6.5%) of those who had a \u0026ldquo;serological alert\u0026rdquo; for the possibility of OvC were actually diagnosed with OvC.\u003c/p\u003e \u003cp\u003eIn 140/360 carriers who remained asymptomatic throughout the study period and underwent RRSO, comparison between pre and post RRSO levels up to 20 months after surgery was possible. The mean pre- and post-surgery CA 125 levels for the entire group were 14.7\u0026thinsp;\u0026plusmn;\u0026thinsp;12.9 U/\u0026micro;l and 9.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9 U/\u0026micro;l, respectively (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Of these, 76 (54.2%) had a\u0026thinsp;\u0026gt;\u0026thinsp;30% change in pre- and post-surgery levels: in 73/140 (52.14%) levels were reduced from 18.37\u0026thinsp;\u0026plusmn;\u0026thinsp;16.42 U/\u0026micro;l to 8.51\u0026thinsp;\u0026plusmn;\u0026thinsp;7.89 U/\u0026micro;l (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and 3 (2.14%) had levels 30% higher after RRSO- from 9.82\u0026thinsp;\u0026plusmn;\u0026thinsp;8.36 U/\u0026micro;l to 21.57\u0026thinsp;\u0026plusmn;\u0026thinsp;16.58 U/\u0026micro;l (p\u0026thinsp;=\u0026thinsp;0.3346). All others (64/140\u0026ndash;45.7%) showed no significant change in CA125 levels pre and post-surgery \u0026ndash; 10.69\u0026thinsp;\u0026plusmn;\u0026thinsp;5.19 U/\u0026micro;l to 9.23\u0026thinsp;\u0026plusmn;\u0026thinsp;4.16 U/\u0026micro;l (p\u0026thinsp;=\u0026thinsp;0.0815).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the current study, serial semiannual measurements of CA125 levels in Israeli \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers showed that these levels were stable in most cancer free cases (66.3%) for a mean follow up period of 7.93 years spanning 5860.80 women/years. Level range for the most part are well below the established 35 U/\u0026micro;l cutoff, generally accepted to be the reference value in the general, average risk population at age 35 years [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Of participants, 6 were diagnosed with OvC of whom 4 were diagnosed at an advanced stage. Only 4/61 (6.5%) of those who had a \u0026ldquo;serological alert\u0026rdquo; for the possibility of OvC were diagnosed with OvC. Lastly, no consistent effect of RRSO on CA125 levels was noted in ~\u0026thinsp;50% of women who underwent the procedure where comparison between pre- and post-surgery CA125 values was available.\u003c/p\u003e \u003cp\u003eNormal values for CA125 vary, depending on a host of factors: menstrual cycle, menopausal status, race, smoking, and caffeine consumption to mention some [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Serum CA125 levels are elevated in 50% of early-stage ovarian cancers, and 92% of advanced-stage tumors [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, due to the low incidence of OvC, screening of average-risk women with CA125 results in a considerable number of false positives 15 and is not recommended. Given the substantially increased risk for developing OvC for \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers, risk-reducing salpingo-oophorectomy (RRSO) by age 40 years for \u003cem\u003eBRCA1\u003c/em\u003e and by age 45 years for \u003cem\u003eBRCA2\u003c/em\u003e PSVs carriers is universally recommended [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Prior to risk reducing surgery, some (but not all) high risk clinics offering surveillance scheme implementation to female \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], offer these high-risk women semiannual - annual screening with transvaginal ultrasound (TVUS) and CA125 level determination starting at age 35, or 5\u0026ndash;10 years earlier than the earliest age of OvC diagnosis in the family. The effectiveness of this scheme for early detection of OvC in high-risk women, has not been proven. In fact, such a scheme has been advocated against by several groups [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and is not recommended by the NCCN. Notably, some of those studies had a limited number of cases and a short follow up period. For example, Woodward et al [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] concluded that OvC screening by annual TVUS and CA125 is inefficient for detecting early-stage OvC in \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers based on analysis of 20 and 11 \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e PSV carriers, respectively, with a mean follow-up time of 29.4 months. Nobbenhuis et. al., [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] reported that annual serum CA125 and TVUS screening revealed advanced stage OVC in 2/58 \u003cem\u003eBRCA1\u003c/em\u003e gene PSV carriers and none in 45 women had a \u003cem\u003eBRCA2\u003c/em\u003e gene PSV, with a high rate of re-calls for a single elevated CA125. Similarly, Oei et. al., [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] who concluded that annual CA125 surveillance is ineffective in early detection of OvC based on analysis of 265 \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers followed up for a median of 2.07 years, who underwent 1278 CA125 determinations.\u003c/p\u003e \u003cp\u003eYet, there are some reports supporting the use of serial CA125 measurements with the rate of change (rather than a single fixed level) as an indicator of the need to further pursue the possibility of OvC by additional analyses and imaging. Reports from large trials of high-risk women in the UK and USA (20% of whom were \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers) showed promise with significant increases in the fraction of women with early stage OvC detected [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Both trials utilized the Risk of Ovarian Cancer Algorithm (ROCA) using CA125 as a single biomarker, performed every 3\u0026ndash;4 months followed by TVUS for women with abnormal results. Cortesi et al [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] reported that CA125 determination in 127 \u003cem\u003eBRCA\u003c/em\u003e PSV carriers, for a total of 1,094 follow-up years reached a sensitivity rate in cancer detection of 73%. In contrast, Olivier and coworkers [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] reported a combined sensitivity of 40%, specificity of 99%, positive predictive value (PPV) of 40% and negative predictive value (NPV) of 99%, with CA125 level determinations performing better than TVUS on separate analyses from a study that encompassed 132 \u003cem\u003eBRCA1\u003c/em\u003e, 20 \u003cem\u003eBRCA2\u003c/em\u003e PSV carriers who were recruited from 1996\u0026ndash;2002. Noteworthy, van der Velde et. al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] who concluded that annual gynecological screening of female \u003cem\u003eBRCA\u003c/em\u003e carriers to prevent advanced stage OvC is not effective, based that conclusion on 87 \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e carriers who were followed up for 3 and 2.7 years, respectively. Yet, in that study, the NPV for CA125 estimation alone was 99.4% meaning that a negative test almost always excluded ovarian cancer.\u003c/p\u003e \u003cp\u003eRegarding the effect of RRSO on CA125 levels, Grandi et al [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] reported that of 116 \u003cem\u003eBRCA\u003c/em\u003e PSV carriers, a 6-month decrease in CA125 (median from 10.3 to 9.5 U/ml, \u0026minus;\u0026thinsp;7.8%, P\u0026thinsp;=\u0026thinsp;0.003), after RRSO which was significantly linked only to endometriosis history and only partially accounted for by risk reducing surgery. Chen et. al. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] reported statistically significant reductions in CA125 levels 6 months after RRSO in 48 \u003cem\u003eBRCA1\u003c/em\u003e carriers (mean 15.1 \u0026rarr; 12.4 U/\u0026micro;l p\u0026thinsp;=\u0026thinsp;0.04), but no significant differences in 40 \u003cem\u003eBRCA2\u003c/em\u003e carriers (mean 12.8 \u0026rarr; 14.6 U/\u0026micro;l ; p\u0026thinsp;=\u0026thinsp;0.5). These differences were not affected by the diagnosis of BC. van Altena et. al. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] reported that CA125 levels in \u003cem\u003eBRCA1\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;48) or \u003cem\u003eBRCA2\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;12) were 10.15 U/mL before RRSO and 8.36 U/\u0026micro;l (18% decrease) at a median of 12 months after RRSO (p\u0026thinsp;=\u0026thinsp;0.004), with significance maintained only for premenopausal women.\u003c/p\u003e \u003cp\u003eThe limitations of the study should be enumerated. This is a single institution experience that may not reflect the situation in all of Israel and in other ethnically diverse and geographically disperse populations, some cancer cases may have been unreported (as they have not been treated at the same medical center), and the total number of newly diagnosed cancers during the study period was limited.\u003c/p\u003e \u003cp\u003eIn conclusion, longitudinally stable CA125 levels are noted in most asymptomatic \u003cem\u003eBRCA\u003c/em\u003e PSV carriers, serially increased levels rarely indicate breast and/or ovarian cancer, and no consistent effect on these levels can be attributed to RRSO in a sizable portion of BRCA carriers undergoing this procedure. Clearly the use of CA125 in \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers should be discouraged and its lack of efficacy should be emphasized when surveillance options are discussed with asymptomatic \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers. This study in the context of the previous work that has been published should promote a search for alternative means for early detection of OvC in high-risk women that are beyond the traditional serological biomarker paradigm: epigenetic signatures in serum, microbiome composition in vaginal fluids, novel modes of imaging, to name a few.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003e \u003cb\u003eCompeting interests\u003c/b\u003e-\u003c/strong\u003e \u003cp\u003eall authors declare no competing interests\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eDeclarations\u003c/h2\u003e \u003cp\u003e This study involves human participants, was performed in accordance with the Declaration of Helsinki, and was approved by the Sheba Medical center IRB - IRB approval number SMC- 1492-014. Participants gave informed consent to participate in the study before taking part.\u003c/p\u003e\u003ch2\u003eFunding information-\u003c/h2\u003e \u003cp\u003eThe authors received no specific funding for this work\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJK and EF conceived, planned, and summarized the project. Cases (with clinical data and outcomes) were contributed by DMF and JK. Dataset assembly/organization by YL and DA, who also provided intellectual contribution and edits. YL and DA performed the statistical analyses. All authors contributed to manuscript writing and editing. DMF and EF were responsible for the overall content as guarantors.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors are grateful to the team of health care professionals and administrative personnel at the Meirav High risk Clinic, Sheba Medical Center, Tel-Hashomer for their ongoing assistance with patient care.\u003c/p\u003e\u003ch2\u003eData availability statement -\u003c/h2\u003e \u003cp\u003eAll data relevant to the study are included in the article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKuchenbaecker KB, Hopper JL, Barnes DR et al (2017) Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. 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Menopause 18(2):133\u0026ndash;137. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/gme.0b013e3181ecfb51\u003c/span\u003e\u003cspan address=\"10.1097/gme.0b013e3181ecfb51\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"BRCA1/BRCA2 PSV carriers, ovarian cancer risk, early detection, Longitudinal CA125 levels, risk reducing surgery","lastPublishedDoi":"10.21203/rs.3.rs-4440317/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4440317/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e female pathogenic sequence variant (PSV) carriers in Israel are offered semiannual CA125 serum level determination and transvaginal ultrasound, until risk reducing salpingooophorectomy (RRSO). The value of longitudinal CA125 measurements in \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e carriers as a tool for ovarian cancer detection is reported herein. Asymptomatic \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers attending the Meirav high risk clinic for \u0026gt;\u0026thinsp;3 years were eligible. Data on specific PSV, risk reducing surgeries, and cancer diagnoses were obtained from participants' records. Statistical analyses employed χ\u003csup\u003e2\u003c/sup\u003e and Wilcoxon-Rank tests. Overall, 739 (399 \u003cem\u003eBRCA1\u003c/em\u003e, 336 \u003cem\u003eBRCA2\u003c/em\u003e, 4 \u003cem\u003eBRCA1\u0026thinsp;+\u0026thinsp;BRCA2\u003c/em\u003e) PSV carriers were included. Mean age at the start of follow up was 38.96\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;11.13 years, mean follow up time was 7.93\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;2.34 years, (5860.80 women/years). Most participants (490/739\u0026thinsp;\u0026minus;\u0026thinsp;66.3%) had stable CA125 levels (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;5 U/\u0026micro;l). Of participants, 61 had CA125 levels\u0026thinsp;\u0026gt;\u0026thinsp;35 U/\u0026micro;l at least twice (n\u0026thinsp;=\u0026thinsp;42) or at least doubling of marker levels to a minimum of 20 U/\u0026micro;l (n\u0026thinsp;=\u0026thinsp;19), results that have led to further cancer defining investigations. Of these, 14 and 4 were diagnosed with breast and ovarian cancer, respectively. In conclusion, longitudinally stable CA125 levels were noted in most \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e PSV carriers, elevated levels were a poor marker for ovarian cancer development.\u003c/p\u003e \u003cp\u003e.\u003c/p\u003e","manuscriptTitle":"CA125 serum levels in BRCA1/BRCA2 pathogenic sequence variant carriers as an ovarian cancer screening tool– a longitudinal study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-31 12:04:22","doi":"10.21203/rs.3.rs-4440317/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f647de36-aa52-4f7e-ac78-8210ee3c3f31","owner":[],"postedDate":"May 31st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-19T12:52:47+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-31 12:04:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4440317","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4440317","identity":"rs-4440317","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}