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Attitude of BRCA1/2 mutation carriers towards surgical risk reduction for breast, ovarian and uterine cancer: still much to be done
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  1. Chen Nahshon1,2,
  2. Yakir Segev1,2,
  3. Meirav Schmidt1,2 and
  4. Ofer Lavie1,2
  1. 1Department of Obstetrics and Gynecology, Lady Davis Carmel Medical Center, Haifa, Israel
  2. 2Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
  1. Correspondence to Chen Nahshon, Department of Obstetrics and Gynecology, Lady Davis Carmel Medical Center, Haifa 3436212, Israel; csarshalom{at}gmail.com

Abstract

Objective To study and quantify the attitude of BRCA1/2 mutation carriers towards surgical risk reduction procedures.

Methods This cross-sectional national study was conducted by distribution of an anonymous questionnaire on social media platforms and to BRCA1/2 carriers’ medical clinic.

Results 530 BRCA1/2 mutation carriers answered the survey. Risk reduction bilateral salpingo-oophorectomy was discussed with 447/489 (91%) of patients and performed in 260/489 (53%). Hormonal replacement therapy was discussed in 280/474 (59%) of patients. Addition of hysterectomy to risk reduction bilateral salpingo-oophorectomy was discussed in 129/481 (27%) of patients and performed in 44/443(10%). Age over 35 years at time of mutation detection was found to be significant in raising risk reduction bilateral salpingo-oophorectomy and hysterectomy performance rates. Risk reduction mastectomy was discussed in 390/471 (83%) of patients and performed in 156/471 (33%). In a multivariate analysis, BRCA1 mutation carriers (OR=1.66 (95% CI 1.07 to 2.57), p=0.024) and a personal cancer history leading to the mutation detection (OR=4.75 (95% CI 1.82 to 12.4), p=0.001) were found to be significant in increasing the likelihood of opting for risk reduction mastectomy. Additionally, highest risk reduction mastectomy performance rates were observed in the group of patients with a first-degree family history of breast cancer under the age of 50 years (OR=1.58 (95% CI 1.07 to 2.32), p=0.01).

Conclusions This study highlights the high performance rates of risk reduction bilateral salpingo-oophorectomy, while hysterectomy was added in 10%, and that despite high awareness and acceptance rates for risk reduction mastectomy, only 33% had the procedure. The data presented provides insights for the clinician counseling BRCA1/2 mutation carriers, with regards to adherence to recommendations, understanding their concerns towards treatment and management alternatives; and finally, to construct a personalized management medical plan.

  • hysterectomy
  • BRCA1 protein
  • BRCA2 protein

Data availability statement

Data are available upon reasonable request. Deidentified participant data are available by reasonable request from the corresponding author.

https://doi.org/10.1136/ijgc-2023-004801

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • BRCA1/2 mutation carriers encounter many dilemmas regarding risk reductive surgery performance and timing; risk reduction bilateral salpingo-oophorectomy and risk reduction mastectomy uptake rates in healthy BRCA1/2 mutation carriers range across the world.

    WHAT THIS STUDY ADDS

    • This study presents acceptance and performance rates of risk reduction bilateral salpingo-oophorectomy and risk reduction mastectomy of BRCA1/2 mutation carriers, as well as rates of prophylactic hysterectomy published for the first time. Influencers on performance rates of risk reduction procedures are analyzed.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • The data presented provide insights for the clinician counseling patients about their BRCA1/2 mutation and serves as a model that may assist caregivers all over the world to provide precise information based on real data of the points of view of local BRCA1/2 mutation carriers, to achieve better personal-based medical counseling.

    INTRODUCTION

    BRCA1/2 mutation carriers have an increased risk of breast, ovarian, fallopian tube, primary peritoneal, pancreatic, prostate cancer, and melanoma.1 2 Risk reducing bilateral salpingo-oophorectomy has been shown to reduce the risk for ovarian carcinoma by up to 95%, and is unequivocally recommended by all societies.3 Risk reduction bilateral salpingo-oophorectomy is recommended for BRCA1 mutation carriers from the age of 35–40 years, and for BRCA2 from the age of 40–45 years, on the completion of childbearing.3 Whether to add prophylactic hysterectomy to the planned risk reduction surgery has been discussed in the literature and may possibly have advantages, including eliminating the risk for uterine serous carcinoma, suggested to be part of the BRCA1/2 cancer syndrome4–8; enabling estrogen-only replacement hormonal therapy; and removing the risk of endometrial cancer due to present or potential future need for tamoxifen treatment.7 On the other hand, adding hysterectomy may require a more complex surgical procedure, with additional risk of complications.9 The balance between the benefit of hysterectomy and surgical complications is not clear, and thus clear indication for hysterectomy is currently limited to women with uterine benign pathologies and/or future potential advantages that should be discussed with patients during the pre-operative decision-making. The Society of Gynecologic Oncology and the National Comprehensive Cancer Network (NCCN) guidelines10 advise discussing the addition of prophylactic hysterectomy with patients with a planned risk reduction bilateral salpingo-oophorectomy surgery.11

    The range of risk reduction bilateral salpingo-oophorectomy uptake rates in healthy BRCA1/2 mutation carriers varies across the world. In the United States the rate of BRCA1/2 carriers who chose to undergo this procedure was as high as 71%, in Poland it was shown to be the lowest at 35%, and in Israel was reported to be 66%.12

    Due to the high risk of breast cancer,13 BRCA1/2 mutation carriers are advised to maintain intensive surveillance examinations, including MRI and mammography every 6 to 12 months; the option of risk reduction bilateral mastectomy is also available.14 Risk reduction mastectomy has been shown to reduce the risk of breast cancer by up to 90–95%.15 The uptake of a risk reduction mastectomy procedure among BRCA1/2 mutation carriers varies among different countries and populations, with rates reported to range from 5% to 42%.12 16 17

    Reasons for variations in uptake rates of risk reduction surgeries around the world may be numerous, including different healthcare access, physicians’ recommendations, social media affects, and individual perception of risk.

    As understood from the above-mentioned recommendations, BRCA1/2 mutation carriers encounter many dilemmas, starting from family planning, whether to perform risk reduction surgeries, and whether or not to receive hormone replacement therapy.

    The purpose of our study was to understand the attitude of BRCA1/2 carriers towards these issues and to identify, on the one hand, what motivates one carrier to undergo risk reduction surgeries, and on the other, what holds them back.

    METHODS

    This national cross-sectional study was conducted by distribution of an anonymous questionnaire on social media platforms and BRCA1/2 mutation carriers’ medical clinic. This survey was based on the principles of Checklist for Reporting Results of Internet E-Surveys (CHERRIES).18

    The survey was announced in several BRCA1/2 mutation closed groups on Facebook, explaining the purpose and importance of the survey, as well as in public social media. Elaboration of the questionnaire is available in Online supplemental document 1.

    Supplemental material

    The survey was open for responses from August 2022 until January 2023. Following completion of the survey, data were downloaded and analyzed.

    The questionnaire was posted in Hebrew; a translated version is available in Online supplemental document 2.

    Supplemental material

    Since no personal identifying information was collected in the questionnaire, and it was voluntary, the survey was considered exempt from institutional review board approval, following a preliminary discussion with the chair of Carmel Medical Center Helsinki committee.

    Categorical variables were presented as numbers (percent), continuous variables as mean and SD. Comparisons were conducted using Pearson’s Χ2 and Fisher’s exact tests. Multivariate analyses were conducted to explore possible independent significant factors affecting the decision on risk reduction procedures by a binary logistic analysis. A p value of <0.05 was considered statistically significant.

    In accordance with the journal’s guidelines, we will provide our data for independent analysis by a team selected by the editorial team for the purposes of additional data analysis or for reproducibility of this study in other centers, if such is requested.

    RESULTS

    Baseline Characteristics of Respondents

    During the eligible questionnaire response period, 530 BRCA1/2 mutation carriers answered the survey. Characteristics of respondents are detailed in Table 1. The average (SD) age at mutation discovery was 36.4 (9.6) years. A total of 390 (74%) women discovered the mutation carrier status due to a family history of relevant cancer, 75 (14%) due to a personal history of malignancy, and 65 (12%) due to a population screening (Table 1).

    View this table:
    Table 1

    Characteristics of BRCA1/2 mutation carriers

    Cancer Risk Reduction

    Rates and details of risk reduction surgeries are shown in Table 2.

    View this table:
    Table 2

    Rates of risk reduction surgeries

    Risk reduction bilateral salpingo-oophorectomy was discussed with 447 (91%) of carriers. The surgery was performed in 260 (53%) patients, at a mean (SD) age of 40.9 (5.9) years for BRCA1 mutation carriers and 45.5 (6.9) years for BRCA2 mutation carriers. Of those who had not had risk reduction bilateral salpingo-oophorectomy, 176 (77%) are planning to do so when achieving the recommended age or on completion of childbearing. An acceptance rate of 83% was found among respondents, agreeing with the importance of this procedure to minimize ovarian cancer risk. Still, 237 (63%) fear from surgery mainly due to appearance of the menopause symptoms which might follow. Hormonal replacement therapy was discussed with 280 (59%) of BRCA1/2 carriers. Of the women who had underwent risk reduction bilateral salpingo-oophorectomy (n=260), 159 (61%) took hormonal replacement therapy.

    Adding hysterectomy to risk reduction bilateral salpingo-oophorectomy was discussed with 129 (27%) patients and performed in 44 (10%) patients at an average (SD) age of 45.7 (7.6). Only an additional 20 (5%) patients are planning to add hysterectomy to their future risk reduction surgery, and 69 patients agree with the need to perform hysterectomy, resulting in an acceptance rate of 15%.

    In a multivariate analysis (Table 3), for both risk reduction bilateral salpingo-oophorectomy and hysterectomy, age over 35 years at time of mutation detection was found to be a significant factor in increasing performance rates (OR=5.85 (95% CI 3.83 to 8.94), p<0.001, OR=5.54 (95% CI 2.26 to 13.59, p<0.001, respectively). The type of BRCA mutation and the reason for mutation detection (family cancer history/personal cancer history/population screening) were not found to be significant factors affecting the decision to undergo surgery.

    View this table:
    Table 3

    Multivariate binary logistic analysis

    Risk reduction mastectomy was discussed with 390 (83%) patients and carried out in 156 (33%) at an average (SD) age of 39.7 (7.9) years. Of the remaining patients, 90 (30%) are planning to undergo risk reduction mastectomy. Two hundred and sixty respondents agreed that risk reduction mastectomy is a justified procedure in BRCA1/2 carriers, resulting in an acceptance rate of 55%.The median time (IQR) from mutation detection to risk reduction mastectomy surgery was 2 (1–7) years.

    Of all respondents, 209 (44%) had undergone a biopsy due to a suspicious lesion, of which 141 were benign (67%). To identify factors motivating risk reduction mastectomy uptake, a subgroup analysis of the respondents according to the need for biopsies and first-degree family history was conducted (Table 4). The highest risk reduction mastectomy performance rates were observed in the group of patients with a first-degree family history of breast cancer under the age of 50 years (OR=1.58 (95% CI 1.07 to 2.32), p=0.01). In a multivariate analysis (Table 3), BRCA1 mutation carriers were found more likely to uptake risk reduction mastectomy surgery compared with BRCA2 mutation carriers (OR=1.66 (95% CI 1.07 to 2.57), p=0.024). Additionally, women with a personal cancer history leading to discovery of a BRCA1/2 mutation were more likely to perform risk reduction mastectomy than women with either a family history or population screening as reasons for BRCA1/2 mutation detection (OR=4.75 (95% CI 1.82 to 12.4) p=0.001).

    View this table:
    Table 4

    Subgroups of risk reduction mastectomy performance rates

    Regarding the timing of risk reductive surgery considering the time of cancer diagnosis, 21 women, out of the 115 diagnosed with breast cancer, completed risk reduction mastectomy in the same year (18%). Eighty women of the 115 diagnosed with breast cancer had not yet completed risk reduction bilateral salpingo-oophorectomy when diagnosed. Of these, six women had risk reduction bilateral salpingo-oophorectomy in the same year as the diagnosis of breast cancer (8%), an additional 11 had risk reduction bilateral salpingo-oophorectomy in the next year (14%).

    Psychological aspects

    To identify the main concerns and motivators of BRCA1/2 mutation carriers towards undergoing risk reduction surgeries, a comparative analysis of reasons for avoiding or undertaking surgery was conducted according to the type of risk reductive procedure (Figure 1, Online supplemental table S1). Fear from surgical and anesthetic complications were lowest for risk reduction bilateral salpingo-oophorectomy (19% and 17%, respectively), compared with hysterectomy and risk reduction mastectomy (61% and 38%, 53% and 36%; respectively). Fear of losing a part of their body was highest for risk reduction mastectomy (68%) and lowest for risk reduction bilateral salpingo-oophorectomy (36%). Of the women who undertook risk reduction surgery, 83%, 77%, and 83% would recommend risk reduction bilateral salpingo-oophorectomy, hysterectomy, and/or risk reduction mastectomy, respectively, for other BRCA1/2 carriers.

    Figure 1
    Figure 1

    Concerns and motivators influencing risk reduction surgery performance rates.

    DISCUSSION

    Summary of Main Results

    Our study which is a questionnaire-based study shows that risk reduction bilateral salpingo-oophorectomy is discussed with almost all BRCA1/2 carriers and performed in more than half of them. Despite high performance rates of risk reduction bilateral salpingo-oophorectomy, hysterectomy was added in 10%. Age at diagnosis of mutation and previous history (personal or first-degree related) were the factors most affecting performing risk reducing procedures. Risk reduction mastectomy was performed in only 33%, mostly those with a young first-degree relative with a history of breast cancer. Fear of surgical complications and fear of a long recovery period were more common for hysterectomy and risk reduction mastectomy than for risk reduction bilateral salpingo-oophorectomy. Surveillance was considered by BRCA1/2 carriers sufficient in substantially higher rates for hysterectomy and risk reduction mastectomy, compared with risk reduction bilateral salpingo-oophorectomy. These concerns should be considered while explaining and discussing prophylactic surgeries. Nevertheless, among women who underwent each risk reduction surgery, relatively high rates of satisfaction and levels of recommendation were observed.

    Results in the Context of Published Literature

    Rates of performing risk reduction bilateral salpingo-oophorectomy in our study are slightly lower than the reported 67.4% in the Israeli population in 2019,19 possibly because we included patients who were not yet at the recommended age for the procedure or had not yet completed childbearing. This is supported by the high percentage of BRCA1/2 carriers who had not yet undergone risk reduction bilateral salpingo-oophorectomy but stated that they will do so when the time comes (77%). Moreover, a high acceptance rate of 83% was found for risk reduction bilateral salpingo-oophorectomy performance. In addition, the average age of the respondents at risk reduction bilateral salpingo-oophorectomy was 42 years, younger than the reported average age worldwide.19 In the analysis of Metcalfe et al of 6223 BRCA1/2 carriers around the world, the mean age at risk reduction bilateral salpingo-oophorectomy was 45 years for BRCA1 carriers and 48 years for BRCA2 carriers. The age at surgery is of course influenced by the age of mutation testing and by the timing of childbirth completion. Our survey demonstrated that 83% of respondents agree that risk reduction bilateral salpingo-oophorectomy is important, reflecting that they had received the information from their caregivers on the substantial reduction of the risk of ovarian cancer and reduction of all-cause mortality following the procedure.20 Moreover, rates of concerns and fear from surgical and anesthetic complications to the point of avoiding prophylactic surgery are relatively low compared with hysterectomy and risk reduction mastectomy, and 86% of respondents agree that surveillance is insufficient in preventing ovarian cancer. This agrees with the literature, unequivocally stating that risk reduction bilateral salpingo-oophorectomy improves overall survival.21–24

    Recently, a questioner-based study of high-risk patients undergoing risk reduction salpingo-oophorectomy provided insights on the post risk reducing procedure experience, indicating decreased emotional distress, but increased sexual dysfunction and poorer short-term quality of life.25 Regardless of the importance of risk reduction surgery, the quality of life following this surgery is much affected by the use of hormone replacement therapy. Risk reduction bilateral salpingo-oophorectomy caused an abrupt surgical menopause in young women, thus discussion of hormone replacement therapy should ideally be part of the surgery discussion. However, our survey reveals that half of the respondents did not receive guidance on this issue. Additionally, BRCA1/2 mutation carriers have increased rates of triple negative breast cancer.26 While hormone replacement therapy is contraindicated in patients with a history of hormone-sensitive breast cancer, the literature on patients with triple negative breast cancer is inconclusive. Hormone replacement therapy is occasionally considered individually in these cases, yet evidence supporting its safety is lacking.27 28

    Previous reports have pointed out the possible increased risk for high-grade histology uterine carcinoma among BRCA carriers (mostly BRCA1),4 5 8 9 and after considering the future need for hormone replacement therapy, both the American College of Obstetricians and Gynecologists (ACOG) and NCCN recommendations include adding a discussion of hysterectomy at the time of risk reduction bilateral salpingo-oophorectomy.10 11 Our survey results indicate that the addition of hysterectomy is not thoroughly discussed in most cases, with only 27% of respondents stating that the issue was discussed by a physician. Most BRCA1/2 carriers are unaware of the advantages and disadvantages of hysterectomy, including the fact that unlike the survival benefit proved for risk reduction bilateral salpingo-oophorectomy, no evidence is available for any survival advantage for hysterectomy. To our knowledge, our study is the first to publish rates of adding hysterectomy to risk reduction bilateral salpingo-oophorectomy. The NCCN recommend that BRCA1/2 carriers be offered risk reduction mastectomy, yet the decision about whether to undergo such surgery is based on personal preference, given that effective screening is available.10 Our study shows that risk reduction mastectomy is also an issue discussed with most patients, yet only one-third complete this surgery. These rates are higher than previously reported from Israel12 17 and may be due to distribution of the survey online, the study was not restricted to a single medical center or geographical area in Israel, as well as a possible increase in risk reduction mastectomy rates. The rates of risk reduction mastectomy vary significantly throughout the world. In the Netherlands 51% of patients with BRCA1/2 mutations opted for risk reduction mastectomy,29 in the United Kingdom 40%,30 while in France only 5% decided to complete risk reduction mastectomy.31

    Making the decision to perform risk reduction mastectomy is suggested to be more difficult than for bilateral salpingo-oophorectomy, as this procedure is discussed with most patients, yet performed in only 33%. Even though bilateral salpingo-oophorectomy may result in post-menopausal symptoms, more patients take up this surgery compared with risk reduction mastectomy due to the substantial risk reduction of cancer and relatively simple surgery. Moreover, as mentioned above, all-cause mortality rates were shown to be improved following risk reduction bilateral salpingo-oophorectomy, whereas for risk reduction mastectomy, even though the procedure reduces the risk for breast cancer by up to 90–95%, mortality and survival are not affected.15 23 24 32 In the decision about whether to perform risk reduction mastectomy, additional aspects come into place. Psychological factors may affect these rates, including the perception of the risk of cancer, trust in the screening methods, previous biopsies, cultural and education level.30 33 34

    In accordance with previously published data,16 35 our survey shows that the main motivator for completing risk reduction mastectomy is a family history of breast cancer in a first-degree relative, under the age of 50. Additionally, women with BRCA1 mutations and women who discovered their mutation due to a personal history of malignancy were naturally more likely to pursue risk reduction mastectomy. Evans et al also showed that risk reduction mastectomy uptake was greater in BRCA1 (52%) than BRCA2 (28%) carriers.30. The main reasons for refraining from risk reduction mastectomy included concerns about the esthetic result and fear of surgical complications. Nevertheless, it has been suggested in a systematic review that following risk reduction mastectomy, 70% of patients are satisfied with the outcomes and report high psychosocial well-being.36

    Strengths and Weaknesses

    The strengths of this study included the wide national distribution of this online survey, accessible to BRCA1/2 carriers in all Israel and for the first time presented rates of hysterectomy performed during risk reduction bilateral salpingo-oophorectomy. The foremost important strength of this study is that we were able to understand the attitude of, and hear opinions directly from, BRCA1/2 mutation carriers. Thus, this study’s limitations mostly stem from the online distribution of the questionnaire. Responders' bias may cause an overestimation of treatment rates as responders may be those who consult their physicians more frequently and maintain their follow-up as recommended.

    Implications for Practice and Further Research

    This knowledge and model aiming to quantify the opinions and attitude of BRCA1/2 mutation carriers may assist caregivers all over the world to provide precise information based on real data of local BRCA1/2 mutation carriers' points of view and to achieve better individual medical counseling.

    CONCLUSIONS

    This study highlights that there are high performance rates of risk reduction bilateral salpingo-oophorectomy, while hysterectomy was added in 10%, and despite high awareness and acceptance rates for risk reduction mastectomy, only 33% accepted the procedure. This is agreement with the survival benefit proved for risk reduction bilateral salpingo-oophorectomy alone. Our study suggests that the public relations concerning risk reduction bilateral salpingo-oophorectomy among BRCA carriers is well organized and efficient. However, the education regarding hysterectomy and the use of hormone replacement therapy after the surgery should be further improved.

    Data availability statement

    Data are available upon reasonable request. Deidentified participant data are available by reasonable request from the corresponding author.

    Ethics statements

    Patient consent for publication

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    Footnotes

    • Contributors CN: conceptualization, distribution, data collection, statistical analysis, writing - original draft, methodology, investigation, guarantor. YS: data collection, writing- review and editing, review. MS: validation, review. OL: conceptualization, writing-review and editing, methodology, investigation, supervision.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.