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Trends and timing of risk-reducing mastectomy uptake in unaffected BRCA1 and BRCA2 carriers in Slovenia

Open AccessPublished:March 26, 2021DOI:https://doi.org/10.1016/j.ejso.2021.03.248

      Abstract

      Objectives

      Risk-reducing mastectomy (RRM) is one of key prevention strategies in female carriers of germline BRCA pathogenic/likely pathogenic variants (PV/LPV). We retrospectively investigated the rate, timing and longitudinal trends of bilateral RRM uptake and the incidence and types of cancers among unaffected BRCA carriers who underwent genetic counseling at the Institute of Oncology Ljubljana in Slovenia.

      Materials and methods

      Female BRCA carriers without personal history of cancer were included in the study. Clinical data on PV/LPV type, date of RRM, type of reconstructive procedure, occult carcinoma and histopathology results was collected and analyzed.

      Results

      Of the 346 unaffected BRCA carriers (median age 43 years, 70% BRCA1, 30% BRCA2, median follow-up 46 months) who underwent genetic testing between October 1999 and December 2019, 25.1% had a RRM (range 35–50 years, median age at surgery 38 years). A significant difference in time to prophylactic surgery between women undergoing RRM only vs. women undergoing RRM combined with risk-reducing salpingo-oophorectomy was observed (22.6 vs 8.7 months, p = 0.0009). We observed an upward trend in the annual uptake in line with the previously observed Angelina Jolie effect. In 5.7% of cases, occult breast cancer was detected. No women developed breast cancer after RRM. Women who did not opt for surgical prevention developed BRCA1/2-related cancers (9.3%).

      Conclusion

      The uptake of RRM among unaffected BRCA carriers is 25.1% and is similar to our neighboring countries. No women developed breast cancer after RRM while women who did not opt for surgical prevention developed BRCA1/2 related cancers in 9.3% of cases. The reported data may provide meaningful aid for carriers when deciding on an optimal prevention strategy.

      Keywords

      Introduction

      Germline pathogenic/likely pathogenic variants (PV/LPV) in BRCA1 and BRCA2 genes are the leading genetic cause of breast and ovarian cancer. The estimated lifetime risk of breast cancer in BRCA PV/LPV carriers ranges from 45 to 72%. In BRCA1 carriers, the estimated lifetime risk of breast cancer is 60–65% by age 70 years, and 72% by age 80 years. In BRCA2 carriers, the estimated risk of breast cancer is 45–55% by age 70 years, and 69% by age 80 years. The estimated lifetime risk of ovarian cancer ranges from 44 to 59% in BRCA1, and 11–17% in BRCA2 carriers [
      • Kuchenbaecker K.B.
      • Hopper J.L.
      • Barnes D.R.
      • Phillips K.A.
      • Mooij T.M.
      • Roos-Blom M.J.
      • et al.
      Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
      ,
      • Mavaddat N.
      • Peock S.
      • Frost D.
      • Ellis S.
      • Platte R.
      • Fineberg E.
      • et al.
      Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE.
      ,
      • Antoniou A.
      • Pharoah P.D.P.
      • Narod S.
      • Risch H.A.
      • Eyfjord J.E.
      • Hopper J.L.
      • et al.
      Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies.
      ]. In Slovenia, all female BRCA PV/LPV carriers are encouraged to adhere to one of the two prevention strategies for breast cancer: i) intensive screening using yearly magnetic resonance imaging (MRI) of the breast combined with mammography or tomosynthesis, or ii) risk-reducing mastectomy (RRM). Risk-reducing salpingo-oophorectomy (RRSO) is also recommended for carriers between 35 and 40 years of age and upon completion of child bearing [
      ]. While radiological screening is less invasive and enables early cancer detection, prophylactic surgery is the only risk reducing strategy with a beneficial impact on cancer incidence and mortality. Several studies have demonstrated that RRM is effective in reducing the incidence of breast cancer [
      • Hartmann L.C.
      • Schaid D.J.
      • Woods J.E.
      • Crotty T.P.
      • Myers J.L.
      • Arnold P.G.
      • et al.
      Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer.
      ,
      • Hartmann L.C.
      • Sellers T.A.
      • Schaid D.J.
      • Frank T.S.
      • Soderberg C.L.
      • Sitta D.L.
      • et al.
      Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers.
      ,
      • Rebbeck T.R.
      • Friebel T.
      • Lynch H.T.
      • Neuhausen S.L.
      • Van’t Veer L.
      • Garber J.E.
      • et al.
      Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE study group.
      ,
      • Domchek S.M.
      • Friebel T.M.
      • Singer C.F.
      • Gareth Evans D.
      • Lynch H.T.
      • Isaacs C.
      • et al.
      Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.
      ]. RRSO has been associated with a decrease in ovarian cancer incidence and mortality [
      • Finch A.P.M.
      • Lubinski J.
      • Møller P.
      • Singer C.F.
      • Karlan B.
      • Senter L.
      • et al.
      Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation.
      ] and a decrease in fallopian tube and primary peritoneal serous cancer incidence [
      • Domchek S.M.
      • Friebel T.M.
      • Singer C.F.
      • Gareth Evans D.
      • Lynch H.T.
      • Isaacs C.
      • et al.
      Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.
      ].
      Several studies worldwide have investigated the uptake of RRM in BRCA PV/LPV carriers, which appears to be highly variable [
      • Meijers-Heijboer E.J.
      • Verhoog L.C.
      • Brekelmans C.T.M.
      • Seynaeve C.
      • Tilanus-Linthorst M.M.A.
      • Wagner A.
      • et al.
      Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation.
      ,
      • Bradbury A.R.
      • Ibe C.N.
      • Dignam J.J.
      • Cummings S.A.
      • Verp M.
      • White M.A.
      • et al.
      Uptake and timing of bilateral prophylactic salpingo-oophorectomy among BRCA1 and BRCA2 mutation carriers.
      ,
      • Metcalfe K.A.
      • Birenbaum-Carmeli D.
      • Lubinski J.
      • Gronwald J.
      • Lynch H.
      • Moller P.
      • et al.
      International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers.
      ,
      • Beattie M.S.
      • Crawford B.
      • Lin F.
      • Vittinghoff E.
      • Ziegler J.
      Uptake, time course, and predictors of risk-reducing surgeries in BRCA carriers.
      ,
      • Evans D.G.R.
      • Lalloo F.
      • Ashcroft L.
      • Shenton A.
      • Clancy T.
      • Baildam A.D.
      • et al.
      Uptake of risk-reducing surgery in unaffected women at high risk of breast and ovarian cancer is risk, age, and time dependent.
      ,
      • Skytte A.B.
      • Gerdes A.M.
      • Andersen M.K.
      • Sunde L.
      • Brøndum-Nielsen K.
      • Waldstrøm M.
      • et al.
      Risk-reducing mastectomy and salpingo-oophorectomy in unaffected BRCA mutation carriers: uptake and timing.
      ,
      • Manchanda R.
      • Burnell M.
      • Abdelraheim A.
      • Johnson M.
      • Sharma A.
      • Benjamin E.
      • et al.
      Factors influencing uptake and timing of risk reducing salpingo- oophorectomy in women at risk of familial ovarian cancer: a competing risk time to event analysis.
      ,
      • This P.
      • De La Rochefordière A.
      • Savignoni A.
      • Falcou M.C.
      • Tardivon A.
      • Thibault F.
      • et al.
      Breast and ovarian cancer risk management in a French cohort of 158 women carrying a BRCA1 or BRCA2 germline mutation: patient choices and outcome.
      ,
      • Collins I.M.
      • Milne R.L.
      • Weideman P.C.
      • McLachlan S.A.
      • Friedlander M.L.
      • Cuningham K.
      • et al.
      Preventing breast and ovarian cancers in high-risk BRCA1 and BRCA2 mutation carriers.
      ,
      • Singh K.
      • Lester J.
      • Karlan B.
      • Bresee C.
      • Geva T.
      • Gordon O.
      Impact of family history on choosing risk-reducing surgery among BRCA mutation carriers.
      ,
      • Metcalfe K.
      • Eisen A.
      • Senter L.
      • Armel S.
      • Bordeleau L.
      • Meschino W.S.
      • et al.
      International trends in the uptake of cancer risk reduction strategies in women with a BRCA1 or BRCA2 mutation.
      ]. A recently published analysis by Metcalfe et al. noted an increase in the uptake of RRM in 2009–2017 compared to 1995–2008 [
      • Metcalfe K.
      • Eisen A.
      • Senter L.
      • Armel S.
      • Bordeleau L.
      • Meschino W.S.
      • et al.
      International trends in the uptake of cancer risk reduction strategies in women with a BRCA1 or BRCA2 mutation.
      ]. Similarly, an increase in RRM rates following Angelina Jolie's public announcement on having undergone RRM in 2013 has been observed [
      • Evans D.G.
      • Wisely J.
      • Clancy T.
      • Lalloo F.
      • Wilson M.
      • Johnson R.
      • et al.
      Longer term effects of the Angelina Jolie effect: increased risk-reducing mastectomy rates in BRCA carriers and other high-risk women.
      ,
      • Evans D.G.R.
      • Barwell J.
      • Eccles D.M.
      • Collins A.
      • Izatt L.
      • Jacobs C.
      • et al.
      The Angelina Jolie effect: how high celebrity profile can have a major impact on provision of cancer related services.
      ,
      • Lee J.
      • Kim S.
      • Kang E.
      • Park S.
      • Kim Z.
      • Lee M.H.
      Influence of the Angelina Jolie announcement and insurance reimbursement on practice patterns for hereditary breast cancer.
      ]. There is currently no available data on the rate, timing and longitudinal trends of bilateral RRM uptake in BRCA carriers in Slovenia. The present study aimed to assess the rate, timing and dynamics of RRM uptake among unaffected BRCA PV/LPV carriers in Slovenia.

      Materials and methods

       Study setting

      The Cancer Genetics Clinic and the Department of Molecular Diagnostics at the Institute of Oncology Ljubljana are the central cancer genetic counseling and testing facilities in Slovenia. Since 1999, genetic counseling and testing is offered to women with personal and family history of ovarian and breast cancer. Women with confirmed BRCA PV/LPV and BRCA negative women with high breast cancer risk are assessed in a multidisciplinary setting by an onco–genetic team. In accordance with Slovenian and international guidelines, high risk women are offered risk-reducing procedures [
      ,
      ]. In Slovenia, all BRCA PV/LPV carriers may opt for prophylactic surgery as part of public health care service. Prophylactic surgical procedures including breast reconstruction are fully covered by the Health Insurance Institute of Slovenia and are therefore performed without additional costs for the patient. In consultation with the surgical team, patients wishing to undergo both RRM and RRSO may be offered a combined procedure.
      This study was designed as a retrospective study. The rate and timing of RRM were our primary endpoints. Women who had undergone RRM and RRSO in a single (combined) procedure were also included in the analysis of the timing of RRM.

       Study population

      Carriers of deleterious BRCA1 and BRCA2 PV/LPV who underwent genetic counseling at the Cancer Genetics Clinic at the Institute of Oncology Ljubljana between October 1999 and December 2019 and did not have a personal history of cancer at the time of genetic testing were included in the study. The National Cancer Registry of the Republic of Slovenia database was used to verify their personal history of cancer. Subjects with personal history of basal cell carcinoma, in situ melanoma, or cervical intraepithelial neoplasia were included in the study. Subjects with prior unilateral breast cancer were excluded. Subjects who were lost to follow-up or had incomplete patient records were excluded. Clinical data was retrospectively collected: age, PV/LPV type, uptake of RRM (RRM only or RRM combined with RRSO) and reconstructive procedures, date of RRM, type of reconstructive procedure, cancellation of scheduled RRM, occult carcinoma and histopathology result. Subjects who were scheduled for surgery but have not yet had the procedure, were excluded from the study. Time to prophylactic surgery (TTPS) was defined as time from disclosure of genetic test result to RRM. Follow-up was defined as time from disclosure of genetic test result to RRM for women who underwent RRM, and time from disclosure of genetic test result to the present analysis for women who did not. Annual RRM rate was calculated based on the number of unaffected BRCA PV/LPV carriers who had not yet undergone RRM and/or have not been lost to follow-up.

       Statistical analysis

      Descriptive statistics were used for the analysis. Categorical characteristics were presented as frequencies and proportions. Age was presented as mean, median and range. Pearson's Chi-square and the Mann-Whitney U test were used for statistical comparisons; a p-value of ≤0.05 was considered statistically significant. Poisson regression was used for time trend analysis in relation to RRM uptake. All statistical analysis was performed using SPSS v.24.0 (IBM Corp., Armonk, NY, USA).

       Ethical statement

      The study was reviewed and approved by the institutional review board and Ethical Committee (consensus nr. 0110/2019) and was conducted in accordance with the Declaration of Helsinki.

      Results

      Altogether, 1357 carriers of BRCA1 and/or BRCA2 PV/LPV were identified in the period from October 1999 to December 2019. Men were excluded from this study since RRM is not recommended for them. Of 1177 BRCA-positive women, 389 had no prior history of any cancer at the time of genetic testing. 43 patients had incomplete patient records or have been lost to follow-up. One patient was scheduled for RRM, but had not yet had the procedure. Ultimately, 346 unaffected carriers met the eligibility criteria and were included in the analysis (Fig. 1, Table 1). Median time from genetic testing to disclosure of genetic test result was 2.1 months.
      Fig. 1
      Fig. 1Flow chart illustrating the study population selection. Altogether, 346 unaffected female BRCA1/2 pathogenic/likely pathogenic (PV/LPV carriers) were included in the study. IOL - Institute of Oncology Ljubljana; CIN - cervical intraepithelial neoplasia.
      Table 1Characteristics of unaffected BRCA pathogenic/likely pathogenic variant (PV/LPV) carriers and patients undergoing risk-reducing mastectomy (RRM).
      CharacteristicAll unaffected BRCA carriersNo RRMRRM
      N = 346N = 259N = 87
      PV/LPV type
      BRCA1242(69.9%)177(68.3%)65(74.7%)
      BRCA2104(30.1%)82(31.7%)22(25.3%)
      Median age at present analysis (years)43.043.043.0
      Mean age at present analysis (years)44.8(range 22–93)44.6(range 22–93)45.4(range 29–77)
      Median age at PV diagnosis (years)36.036.036.0
      Mean age at PV diagnosis (years)38.3(range 18–87)38.4(range 18–87)37.8(range 22–65)
      Median follow-up (months)
      Calculated as time from disclosure of genetic test result to RRM for women who underwent RRM, and time from disclosure of genetic test result to the present analysis for women who did not.
      46.053.019.0
      Referral to testing by
      general practitioner12(3.5%)4(1.5%)8(9.2%)
      gynaecologist26(7.5%)18(6.9%)8(9.2%)
      oncologist10(2.9%)5(1.9%)5(5.7%)
      other specialist3(0.9%)2(2.3%)2(2.3%)
      relative (carrier)272(78.6%)217(84.4%)55(63.2%)
      self16(4.6%)9(3.5%)7(8.0%)
      other7(2.0%)5(2.0%)2(2.2%)
      a Calculated as time from disclosure of genetic test result to RRM for women who underwent RRM, and time from disclosure of genetic test result to the present analysis for women who did not.

       Uptake of risk-reducing mastectomy

      Eighty-seven (25.1%) of the unaffected BRCA PV/LPV carriers (74.7% BRCA1 carriers and 25.3% BRCA2 carriers) had undergone RRM (Table 2). Of those, 67 (77.9%) had undergone RRM only, and 20 (23.3%) had undergone a combined RRM and RRSO procedure. Median age was 37 years for women who had undergone RRM only, and 42.5 years for women who had undergone RRM with RRSO (p = 0.0867). Median TTPS was 22.6 months for women who had RRM and 8.7 for women who had RRM with RRSO (p = 0.0009). Eighty percent of women who had RRM only or RRM with RRSO had the surgery after July 1, 2013. Almost all women undergoing RRM had reconstructive procedures (96.6%), Table 2). Eighty-one percent of women undergoing reconstructive procedures had an implant-based reconstruction. The type of mastectomy performed (nipple-sparing mastectomy (NSM) vs. skin-sparing mastectomy (SSM)) was equally distributed. The first NSM in this population was performed in 2009. In 2013, 70% of RRMs performed were SSM, whereas in 2019, only 40% were SSM and 60% were NSM. Median age at diagnosis of BRCA PV/LPV did not differ between the three groups.
      Table 2Characteristics of carriers undergoing risk-reducing mastectomy (RRM) only or combined with risk-reducing salpingo-oophorectomy (RRSO).


      Characteristic
      RRM, any (RRM only and RRM with RRSO)RRM onlyRRM with RRSO
      N = 87N = 67N = 20
      PV/LPV type
      BRCA165(74.7%)51(76.1%)14(70.0%)
      BRCA222(25.3%)16(23.9%)6(30.0%)
      Mean age at surgery (years)40.8(range 26–70)40.2(range 26–70)43.0(range 31–55)
      Median age at surgery (years)38.037.042.5
      Age by group
      25–292(2.3%)2(3%)0(0)
      30–3415(17.2%)12(17.9%)3(15.0%)
      35–3930(34.5%)25(37.3%)5(25.0%)
      40–4926(29.9%)20(29.9%)6(30.0%)
      50–5910(11.5%)4(6.0%)6(30.0%)
      >604(4.6%)4(6.0%)0(0)
      Median time to RRM (months)19.722.68.7
      Period of RRM
      before July 1, 201317(19.5%)13(19.4%)4(20.0%)
      after July 1, 201370(80.5%)54(80.6%)16(80.0%)
      Occult breast cancer
      total5(5.7%)4(6.0%)1(5.0%)
      DCIS2(2.3%)1(1.5%)1(5.0%)
      IDC2(2.3%)2(3.0%)0(0)
      Papillary carcinoma1(1.1%)1(1.5%)0(0)
      Reconstructive surgery total

      84


      (96.6%)


      63


      (96.5%)


      19


      (95.0%)
      autologous14(16.1%)14(20.9%)0(0)
      implant68(78.2%)49(73.1%)19(95.0%)
      Type of mastectomy nipple-sparing

      44


      (50.6%)


      36


      (53.7%)


      8


      (40.0%)
      skin-sparing40(46.0%)29(43.3%)11(55.0%)
      simple3(3.4%)2(3.0%)1(5.0%)
      Legend: PV/LPV- pathogenic/likely pathogenic variant; DCIS - ductal carcinoma in-situ; IDC - invasive ductal carcinoma.
      Five patients (1.4% of unaffected carriers) had scheduled RRM, but later cancelled the procedure.
      Out of 87 women who had undergone RRM, five (5.7%) were diagnosed with occult breast cancer (median age 48 years). Of those five, three were BRCA1 PV/LPV carriers (aged 35, 48, and 62) and 2 were BRCA2 carriers (aged 47 and 63). None of 87 developed breast cancer later on (647 person-years, median follow-up 19 months). One woman (1.1%) later developed lung cancer (age 59 years), one developed low grade endometrial stromal sarcoma (1.1%, age 47 years), and another one metastatic squamous cell cancer of unknown origin (1.1%, age 51 years).
      Out of 259 women who had not undergone RRM, 24 (9.3%) developed BRCA1/2-related cancers. Twelve women (4.6%, median age 38 years, range 29–65 years) developed invasive breast cancer and one (0.4%, age 40 years) developed ductal carcinoma in situ. Additionally, two women (0.7%, ages 41 and 24 years) developed cervical cancer, one (0.4%, age 40 years) developed thyroid cancer, and one (0.4%, age 66 years) developed serous endometrial cancer (BRCA1 carrier).
      Out of 259 women who had not undergone RRM, 108 (41.6%) had undergone RRSO and the remaining 151 (58.3%) women had no prophylactic procedures (RRM or RRSO). Among the 151 women who had no prophylactic procedures, five (3.3%, median age 57 years, range 50–63 years) women developed tubal carcinoma and five women (3.3%, median age 57 years, range 35–56 years) developed ovarian cancer.

       Dynamics of uptake of risk-reducing mastectomy

      The distribution of uptake of RRM is presented in Fig. 2. An upward trend in the number of performed RRMs can be observed throughout the timeline (incidence rate ratio 1.10, 95% CI 1.09–1.11; p < 0.001, Poisson regression). We noted an increase in RRM uptake starting in 2013 and rising in the following years. In 2019, 6.83% of unaffected carriers had undergone a RRM. The uptake of RRM was significantly higher in the period from July 1, 2013 to present day compared to the period before July 1, 2013 (p = 0.009).
      Fig. 2
      Fig. 2The uptake of risk-reducing mastectomy (RRM) among unaffected BRCA carriers per year. The ''no RRM” group represents all cases at risk in the corresponding year (including those from prior years who have not undergone RRM and/or have not been lost to follow-up or been diagnosed with cancer). The rate of RRM over time (expressed as %) was calculated as the number of carriers undergoing RRM each year divided by all cases at risk. An upward trend in RRM uptake can be observed (incidence rate ratio 1.10, 95% CI 1.09–1.11; p < 0.001, Poisson regression).
      The distribution of median TTPS is presented in Fig. 3. TTPS was longest in carriers undergoing RRM in 2013 (36.8 months) and shortest in 2011 (8.6 months). No clear trend was observed.
      Fig. 3
      Fig. 3The distribution of median time to prophylactic surgery (TTPS) among unaffected BRCA carriers.

      Discussion

      This study aimed to provide a longitudinal analysis of the rate and timing of RRM among unaffected BRCA PV/LPV carriers in Slovenia. This is the first study to provide Slovenian population-specific data as well as review the incidence and types of cancers in a cohort of carriers who had not undergone RRM, and the corresponding age at which these cancers arose.
      Since the establishment of genetic testing and counseling for women with relevant cancer family history in Slovenia in 1999, 87 (25.1%) unaffected BRCA carriers underwent a RRM. The uptake of RRM was slightly higher among BRCA1 carriers compared to BRCA2 carriers. The rate of RRM uptake observed in our study is in line with other published research of unaffected BRCA PV/LPV carriers [
      • Metcalfe K.A.
      • Birenbaum-Carmeli D.
      • Lubinski J.
      • Gronwald J.
      • Lynch H.
      • Moller P.
      • et al.
      International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers.
      ,
      • Collins I.M.
      • Milne R.L.
      • Weideman P.C.
      • McLachlan S.A.
      • Friedlander M.L.
      • Cuningham K.
      • et al.
      Preventing breast and ovarian cancers in high-risk BRCA1 and BRCA2 mutation carriers.
      ,
      • Metcalfe K.
      • Eisen A.
      • Senter L.
      • Armel S.
      • Bordeleau L.
      • Meschino W.S.
      • et al.
      International trends in the uptake of cancer risk reduction strategies in women with a BRCA1 or BRCA2 mutation.
      ]. In 2019, Metcalfe et al. reported a 27.8% RRM uptake among unaffected BRCA carriers from 10 countries with wide variation across studied countries [
      • Metcalfe K.
      • Eisen A.
      • Senter L.
      • Armel S.
      • Bordeleau L.
      • Meschino W.S.
      • et al.
      International trends in the uptake of cancer risk reduction strategies in women with a BRCA1 or BRCA2 mutation.
      ]. The rate of uptake of RRM in unaffected Slovenian carriers is comparable to the rate of uptake in the neighboring Austria (28.2%) and higher than the rate in the neighboring Italy (10%). The rate of RRM uptake observed in our study is lower than the uptake reported by Singh et al. (42%, United States) and Evans et al. (40%, United Kingdom) [
      • Evans D.G.R.
      • Lalloo F.
      • Ashcroft L.
      • Shenton A.
      • Clancy T.
      • Baildam A.D.
      • et al.
      Uptake of risk-reducing surgery in unaffected women at high risk of breast and ovarian cancer is risk, age, and time dependent.
      ,
      • Singh K.
      • Lester J.
      • Karlan B.
      • Bresee C.
      • Geva T.
      • Gordon O.
      Impact of family history on choosing risk-reducing surgery among BRCA mutation carriers.
      ]. The variability in reported rates is likely multifactorial and related to socioeconomic context. In Slovenia, prophylactic surgery is not associated with any additional costs for the patients and has been fully funded by the national health insurance since the establishment of genetic testing. We assume financial issues are not a factor in the Slovenian patients' decision for prophylactic surgery. On the other hand, women who do not opt for prophylactic surgery are offered organized and centralised high-risk screening in specially dedicated breast unit in a multidisciplinary setting with the highest expertise in public health care service. We believe the high degree of accessibility of Slovenia's organized high-risk screening units may be sufficient to create a sense of security in BRCA PV/LPV carriers, prompting them to decide against prophylactic surgery.
      Interestingly, we observed a significant difference in TTPS between women undergoing RRM only and women undergoing RRM combined with RRSO. This could be related to the age distribution between the two groups (median age 38 vs. 42 years, 60% of women in the RRM with RRSO group were older than 40 years). However, this may also reflect the perception of risk among a certain population of women which prompts them to take more aggressive action sooner and undergo all available prophylactic procedures. We plan to investigate this further in a questionnaire-based study.
      In the longitudinal analysis, we observed an upward trend in the uptake of RRM since the establishment of genetic testing. There was an increase in the number of RRMs performed in 2013 and the years following. Moreover, our data shows the uptake of RRM was significantly higher in the period from July 1, 2013 to the present day compared to the period from the introduction of genetic testing to July 1, 2013. We hypothesize this may be linked to the public announcement made by the actress Angelina Jolie in May 2013 (the so-called ‘Angelina Jolie effect’) [
      • Evans D.G.R.
      • Barwell J.
      • Eccles D.M.
      • Collins A.
      • Izatt L.
      • Jacobs C.
      • et al.
      The Angelina Jolie effect: how high celebrity profile can have a major impact on provision of cancer related services.
      ,
      • Kosenko K.A.
      • Binder A.R.
      • Hurley R.
      Celebrity influence and identification: a test of the Angelina effect.
      ]. In an open editorial, the actress disclosed information about being a BRCA1 carrier and having undergone bilateral RRM, which created publicity worldwide [
      • Evans D.G.R.
      • Barwell J.
      • Eccles D.M.
      • Collins A.
      • Izatt L.
      • Jacobs C.
      • et al.
      The Angelina Jolie effect: how high celebrity profile can have a major impact on provision of cancer related services.
      ,
      • Jolie a
      My medical choice.
      ]. The announcement was followed by an increase in referrals to genetic testing and inquiries into RRM [
      • Evans D.G.R.
      • Barwell J.
      • Eccles D.M.
      • Collins A.
      • Izatt L.
      • Jacobs C.
      • et al.
      The Angelina Jolie effect: how high celebrity profile can have a major impact on provision of cancer related services.
      ,
      • Hawkes N.
      “Angelina effect” led to more appropriate breast cancer referrals, research shows.
      ], as well as an increase in the uptake of RRM [
      • Evans D.G.
      • Wisely J.
      • Clancy T.
      • Lalloo F.
      • Wilson M.
      • Johnson R.
      • et al.
      Longer term effects of the Angelina Jolie effect: increased risk-reducing mastectomy rates in BRCA carriers and other high-risk women.
      ,
      • Lee J.
      • Kim S.
      • Kang E.
      • Park S.
      • Kim Z.
      • Lee M.H.
      Influence of the Angelina Jolie announcement and insurance reimbursement on practice patterns for hereditary breast cancer.
      ,
      • Liede A.
      • Cai M.
      • Crouter T.F.
      • Niepel D.
      • Callaghan F.
      • Evans D.G.
      Risk-reducing mastectomy rates in the US: a closer examination of the Angelina Jolie effect.
      ] and RRSO [
      • Lee J.
      • Kim S.
      • Kang E.
      • Park S.
      • Kim Z.
      • Lee M.H.
      Influence of the Angelina Jolie announcement and insurance reimbursement on practice patterns for hereditary breast cancer.
      ]. Similarly to reports from other countries, we believe our data demonstrates the influence of a high profile celebrity's decision to undergo prophylactic surgery on BRCA carriers facing variable degrees of uncertainty or (mis)understanding about their breast cancer risk, prompting them to proceed more aggressively in diminishing this risk.
      In relation to this observation, we also examined longitudinal trends in median TTPS to see if the Angelina Jolie effect may have also influenced time to decision for RRM. A spike in TTPS was noted in women undergoing RRM in the years 2013 and 2014 (36 and 35 months, respectively). Evans et al. reported similar observations. Their research 6–24 months following May 2013 shows carriers >18 months after testing positive accounted for 74% of RRMs performed at that time, whereas prior to 2013 the majority of women had RRM within 18 months of testing positive [
      • Evans D.G.R.
      • Lalloo F.
      • Ashcroft L.
      • Shenton A.
      • Clancy T.
      • Baildam A.D.
      • et al.
      Uptake of risk-reducing surgery in unaffected women at high risk of breast and ovarian cancer is risk, age, and time dependent.
      ,
      • Evans D.G.
      • Wisely J.
      • Clancy T.
      • Lalloo F.
      • Wilson M.
      • Johnson R.
      • et al.
      Longer term effects of the Angelina Jolie effect: increased risk-reducing mastectomy rates in BRCA carriers and other high-risk women.
      ]. Together with the observed increase in the number of RRMs in 2013 as compared to previous years, the observed delay in decision-making appears to reflect the action of BRCA carriers who may have been hesitant about prophylactic surgery in the previous years to proceed more aggressively about their cancer risk.
      In our studied cohort, almost all women undergoing RRM also underwent breast reconstructive procedures and of those women, 81% had implant-based reconstruction. Although implant reconstruction is generally considered the most commonly performed method of breast reconstruction [
      • Albornoz C.R.
      • Bach P.B.
      • Mehrara B.J.
      • Disa J.J.
      • Pusic A.L.
      • McCarthy C.M.
      • et al.
      A paradigm shift in U.S. Breast reconstruction: increasing implant rates.
      ,
      • Frey J.D.
      • Salibian A.A.
      • Karp N.S.
      • Choi M.
      Implant-based breast reconstruction: hot topics, controversies, and new directions.
      ], there are reports of higher uptake of autologous reconstruction in prophylactic mastectomy patients [
      • Bletsis P.
      • Bucknor A.
      • Chattha A.
      • Kamali P.
      • Chen A.
      • Flecha-Hirsch R.
      • et al.
      Evaluation of contralateral and bilateral prophylactic mastectomy and reconstruction outcomes: comparing alloplastic and autologous reconstruction.
      ]. According to Bletsis et al. autologous reconstruction was also associated with a better complication profile in their patient cohort [
      • Bletsis P.
      • Bucknor A.
      • Chattha A.
      • Kamali P.
      • Chen A.
      • Flecha-Hirsch R.
      • et al.
      Evaluation of contralateral and bilateral prophylactic mastectomy and reconstruction outcomes: comparing alloplastic and autologous reconstruction.
      ].
      The type of mastecomy performed was equally distributed among our patient population with NSM being the predominant surgery performed in the recent years. The long-term oncological safety of both techniques is still a matter of discussion. The oncological safety of the SSM has been primarily investigated in patients with existing breast cancer and its safety is comparable to traditional non-conservative surgeries [
      • Spiegel A.J.
      • Butler C.E.
      Recurrence following treatment of ductal carcinoma in situ with skin-sparing mastectomy and immediate breast reconstruction.
      ,
      • Carlson G.W.
      • Page A.
      • Johnson E.
      • Nicholson K.
      • Styblo T.M.
      • Wood W.C.
      Local recurrence of ductal carcinoma in situ after skin-sparing mastectomy.
      ,
      • Simmons R.M.
      • Fish S.K.
      • Gayle L.
      • La Trenta G.S.
      • Swistel A.
      • Christos P.
      • et al.
      Local and distant recurrence rates in skin-sparing mastectomies compared with non-skin-sparing mastectomies.
      ]. However, in BRCA PV/LPV carriers, the oncologic outcomes have not been well-studied. The longest reported follow-up of 51 months in a cohort of 26 patients undergoing prophylactic SSM implies SSM is an oncologically safe procedure in BRCA carriers [
      • Peled A.W.
      • Irwin C.S.
      • Hwang E.S.
      • Ewing C.A.
      • Alvarado M.
      • Esserman L.J.
      Total skin-sparing mastectomy in BRCA mutation carriers.
      ]. Compared to SSM, NSM conserves the nipple-areolar complex, leaving behind additional ductal tissue which may because for concern especially in patients who carry genetic mutations. In the recent years, many studies reported on the oncologic safety of the NSM in high-risk patients with median follow-up ranging from 28 to 49 months [
      • Jakub J.W.
      • Peled A.W.
      • Gray R.J.
      • Greenup R.A.
      • Kiluk J.V.
      • Sacchini V.
      • et al.
      Oncologic safety of prophylactic nipple-sparing mastectomy in a population with BRCA mutations: a multi-institutional study.
      ,
      • Manning A.T.
      • Wood C.
      • Eaton A.
      • Stempel M.
      • Capko D.
      • Pusic A.
      • et al.
      Nipple-sparing mastectomy in patients with BRCA1/2 mutations and variants of uncertain significance.
      ,
      • Yao K.
      • Liederbach E.
      • Tang R.
      • Lei L.
      • Czechura T.
      • Sisco M.
      • et al.
      Nipple-sparing mastectomy in BRCA1/2 mutation carriers: an interim analysis and review of the literature.
      ]. Despite relatively short follow-ups and retrospective nature of these reports, NSM appears to be highly preventative against breast cancer in BRCA carriers while offering superior cosmetic outcomes [
      • Manning A.T.
      • Wood C.
      • Eaton A.
      • Stempel M.
      • Capko D.
      • Pusic A.
      • et al.
      Nipple-sparing mastectomy in patients with BRCA1/2 mutations and variants of uncertain significance.
      ,
      • Valero M.G.
      • Moo T.A.
      • Muhsen S.
      • Zabor E.C.
      • Stempel M.
      • Pusic A.
      • et al.
      Use of bilateral prophylactic nipple-sparing mastectomy in patients with high risk of breast cancer.
      ,
      • De Alcantara Filho P.
      • Capko D.
      • Barry J.M.
      • Morrow M.
      • Pusic A.
      • Sacchini V.S.
      Nipple-sparing mastectomy for breast cancer and risk-reducing surgery: the memorial sloan-kettering cancer center experience.
      ] and is as such at present the preferred option for unaffected high-risk patients in our institution.
      During the course of genetic counseling, women often raise questions about their cancer burden in relation to not undergoing prophylactic surgery. We observed a 5.7% prevalence of occult breast cancer in the series of 87 consequently operated unaffected BRCA carriers. In a similar patient cohort, Collins et al. reported a 16% occult breast cancer rate [
      • Collins I.M.
      • Milne R.L.
      • Weideman P.C.
      • McLachlan S.A.
      • Friedlander M.L.
      • Cuningham K.
      • et al.
      Preventing breast and ovarian cancers in high-risk BRCA1 and BRCA2 mutation carriers.
      ]. A lower prevalence of occult breast cancer in our series might be the result of breast imaging performed on every woman before surgery. In the period of median 19 months of follow-up, no women developed breast cancer after prophylactic surgery. While our data are encouraging, this follow-up is very short and longer follow-up is required for reliable longitudinal assesment. After 14 years of follow-up, the reported breast cancer incidence in women with family history of breast cancer who underwent RRM is 1.4% [
      • Hartmann L.C.
      • Schaid D.J.
      • Woods J.E.
      • Crotty T.P.
      • Myers J.L.
      • Arnold P.G.
      • et al.
      Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer.
      ].
      Our study provides detailed information on the incidence and age of onset of cancers that arise in women who do not undergo prophylactic procedures. Based on the experience of our genetic clinic, this information is very relevant in the process of genetic counseling to illustrate risk and advise on the age to undergo prophylactic surgery. As expected breast, ovarian and tubal cancer were the most commonly diagnosed cancers in this population.
      We also noted a high percentage of women who have been referred for genetic counseling through a relative (78%) rather than other specialists. This data implies high level of genetic testing uptake and awareness of the importance of cascade testing among the Slovenian population, most probably due to comprehensive pre- and post-testing counseling of an index case (proband).
      Our study is associated with limitations due to its retrospective nature as well as the relatively small sample size and short follow-up. Although the data presented in this study provides relevant population-specific information to the process of genetic counseling, the study reflects trends in a country and the generalizability of results in other countries is questionable. On the other hand, the results presented in this study are derived from a centralised genetic testing facility and therefore provide a reliable source of information for genetic counseling and public health efforts on a national level.

      Conclusions

      The uptake of prophylactic RRM among unaffected BRCA carriers in Slovenia has gradually risen over time. At 25.1%, the uptake of RRM among Slovenian unaffected carriers today is similar to our neighboring countries but lower than in northwestern Europe or the USA. In the present study, a statistically significant Angelina Jolie effect on Slovenian women's decision-making was observed. More than half of the women in our investigated cohort opted for surgery between 35 and 50 years of age, with median age at 38 years. The prevalence of 5.7% of occult breast cancer was detected. No women developed breast cancer after prophylactic surgery while women who did not opt for surgical prevention developed BRCA1/2 related cancers in 9.3% of cases. We believe the results of this study may provide meaningful aid for Slovenian BRCA carriers when deciding on an optimal prevention strategy.

      CRediT authorship contribution statement

      Taja Ložar: Data acquisition, Writing – original draft. Janez Žgajnar: Conceptualization, Methodology, Writing – review & editing. Andraž Perhavec: Conceptualization, Methodology. Ana Blatnik: Writing – review & editing. Srdjan Novaković: Writing – review & editing. Mateja Krajc: Conceptualization, Writing – review & editing, Supervision.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      The study was supported by the research program of the Slovenian research agency P3-0352 .

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