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Keywords:

  • BRCA1/2 mutations;
  • breast/ovarian cancer risk;
  • Jewish Israeli women;
  • Risk-reducing surgery

Abstract

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. References

The frequency of BRCA1 and BRCA2 mutations is higher in Israel than in almost all other countries. One strategy to reduce the burden of hereditary breast and ovarian cancers is to offer genetic testing followed by risk-reducing surgery (mastectomy and salpingo-oophorectomy) for mutation carriers. The extent to which Israeli women who carry mutations undergo these surgeries is not well characterized. Israeli women who are BRCA1 or BRCA2 mutation carriers and followed at a single high-risk clinic were asked to complete a questionnaire detailing their clinical histories at the time of genetic results disclosure and a follow-up questionnaire was completed 18 or more months thereafter. A total of 205 mutation carriers completed the questionnaires. Of 170 women with no cancer history, 84 (49%) had a risk-reducing bilateral salpingo-oophorectomy and 22 (13%) had a risk-reducing mastectomy. Five of 35 (14.3%) women with breast cancer opted for contralateral mastectomy. Approximately one half of Israeli women with a BRCA1 or BRCA2 mutation opt for risk-reducing oophorectomy, but the rate of risk-reducing mastectomy is only 13%.

Women with a BRCA1 or BRCA2 gene mutation are at high lifetime risk for developing both breast and ovarian cancer [1]. Options for prevention include primary chemoprevention (tamoxifen or oral contraceptives), heightened surveillance [annual magnetic resonance imaging (MRI)] [2, 3] and risk-reducing surgery – either mastectomy (RRM) or bilateral salpingo-oophorectomy (RRBSO) [4, 5]. Oophorectomy is associated with reductions in both the risks of breast and ovarian cancer [5]. The rates for these surgical procedures vary widely from country to country: RRM is performed on 3% of Polish BRCA1 mutation carriers [6] compared with 56% of carriers in the Netherlands [7-10]. On the basis of data collected a decade ago, the rates of uptake of RRM and RRBSO in Israel were reported to be 4% and 67%, respectively [6]. In the past decade, these surgeries have become more widely accepted in North America and Western Europe. We sought to know if the uptake of risk-reducing surgeries in Israel among genetically predisposed women has increased since the early 2000s and if these rates are comparable to those of other western countries.

Patients and methods

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. References

Study population

Women aged 25 years or older who carried a pathogenic germline mutation in either the BRCA1 or BRCA2 gene were eligible for the study. Patients who were followed at the high-risk clinic of the Oncogenetics Unit of the Sheba Medical Center from 1 January 1998 to 31 December 2010 were eligible. The study was approved by the institutional ethics committee. Participants had been tested for one of three founder mutations in the Jewish population [185delAG 5382InsC (BRCA1) 6174delT (BRCA2)], with all mutations confirmed by direct sequencing, as previously described [11].

Data acquisition

All participants completed a baseline questionnaire during the initial counseling session. This included information on personal and family history of cancer, demographic characteristics, reproductive histories, and hormonal exposures. During the counseling process, all of the options available for mutation carriers were extensively discussed. These included breast cancer surveillance using annual breast MRI [as approved and covered by the Israeli Health Management Organizations (HMOs) for mutation carriers], semi-annual clinical breast exam, ovarian cancer surveillance using pelvic examination, trans-vaginal ultrasound and CA-125. The risks and benefits of each intervention were detailed, including the lack of proven benefit for ovarian cancer screening. Primary chemoprevention for breast cancer using tamoxifen and for ovarian cancer using oral contraceptives was also discussed, as well as risk-reducing surgery.

Participants were initially seen by a genetic counselor and genetic test results were disclosed by a physician-geneticist. Mutation carriers were offered consultations with surgeons, gynecologists and plastic surgeons affiliated with the institution for further discussion regarding risk-reducing surgery. Mutation carriers were also encouraged to seek advice regarding preventive options from their primary care physician or from specialists who are not affiliated with the Sheba Medical Center.

During a follow-up visit to the clinic, which took place a minimum of 18 months after the results disclosure session, a follow-up questionnaire focusing on risk-reducing surgery was administered. The questionnaire asked if the patient had received an additional consultation from a primary care physician or specialist not affiliated with Sheba Medical Center regarding the risks and benefits of risk-reducing surgery. The subject was asked to judge if the physician recommended for or against surgery.

Statistical analysis

The chi-squared test was used to compare categorical variables frequencies, and the t-test was used to compare the mean values of continuous variables. All statistical tests were performed using statistical software (sas, version 9.1.3; SAS Institute, Cary, NC).

Results

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. References

Participants' characteristics

Overall, 205 women participated in the study: 119 women carried a BRCA1 mutation (103 with the 185delAG mutation and 16 with the 5382insC mutation) and 86 carried the 6174delT BRCA2 mutation. Of these, 170 women (79%) were cancer-free at the time of counseling. Their mean age was 39.4 years (range 25–66 years). Thirty-five participants had been treated for unilateral breast cancer. The mean age at diagnosis was 42.3 years (range 31–62 years). All breast cancer patients underwent genetic counseling and testing within 6 months of breast cancer diagnosis.

The average time from genetic counseling to the date of completion of the follow-up questionnaire was 66 months (range 18–144 months). At the follow-up clinic visits, all participants undergo annual MRI, semi-annual clinical breast examination by a physician, pelvic examination, trans-vaginal ultrasound, and serum CA-125 determination. In addition to MRI, women over age 40 have a breast mammogram every 18–24 months.

Risk-reducing surgery

Overall, 22 of 170 cancer-free women (12.9%) underwent RRM, including 15 of 98 BRCA1 carriers (15.3%) and 7 of 72 BRCA2 carriers (9.7%). Of these 170 healthy women, 84 (49%) had a RRBSO. The earliest age of RRBSO was 25 years (mean 43.7 years; range 25–66 years). The mean age at RRBSO for BRCA1 mutation carriers was 42.1 years and for BRCA2 mutation carriers was 46.2 years. All 35 breast cancer patients were treated with unilateral mastectomy before receiving their genetic test result. Five of these women later went on to have a contralateral mastectomy, at a mean of 4 months after the initial surgery.

Physicians' recommendations regarding risk-reducing surgery

In addition to participating in a detailed results disclosure session, the study subjects also consulted with their primary care physician, surgeon or gynecologist, at which time both surveillance and prevention options were further discussed. Overall, 108 of 170 cancer-free women reported that their physician recommended RRM. The uptake of preventive mastectomy was 20 of 108 (18.5%) for those women whose physician recommended the procedure, compared with only 2 of 62 (3.2%) for those women whose physician recommended against the procedure (p < 0.01).

Overall, 127 of 170 women (74.7%) reported that their physician recommended RRBSO. The uptake of RRBSO was 51.2% for those women whose physician recommended the procedure, compared with 38.8% for those women whose physician recommended against the procedure (Table 1).

Table 1. Rates of the uptake of RRM and RRBSO according to the recommendations of the treating physician (non-specialist)
Treating physician, gynecologist, or surgeonRRM Yes (n = 24)RRBSO Yes (n = 84)
  1. RRBSO, risk-reducing bilateral salpingo-oophorectomy; RRM, risk-reducing mastectomy.

Recommended10 (50%)60 (61%)
Favorably consider10 (11%)5 (23%)
Not recommend2 (4%)17 (38%)
Recommend against2 (13%)2 (50%)

Chemoprevention

No cancer-free participant opted for tamoxifen treatment as a primary chemoprevention.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. References

We report here that uptake of risk-reducing mastectomy is 13% among Jewish Israeli cancer-free BRCA1 or BRCA2 mutation carriers – this number has increased to a modest extent since 2001, at which time the published rate was 9%, but that earlier study was based on only 11 healthy mutation carriers [12]. In a second study of 95 cancer-free carriers from three Israeli centers, published in 2008, the mastectomy rate was 4.2% [6]. Thus, the rate of risk-reducing mastectomy among Israeli mutation carriers in this study appears to be greater than that reported in earlier studies, but RRM remains a relatively infrequent procedure. The rates of studies published over the last decade that focused on the rates of uptake of risk-reducing surgery in ethnically diverse BRCA1 BRCA2 mutation carriers that are not covered in published reviews [13] or international collaborations [6, 7] are enumerated in Table 2.

Table 2. Rates of uptake of RRM and/or RRBSO by country and study
Country (references)RRM N/N (%)RRBSO N/N (%)RRM + RRBOS (N/N%)
  1. RRBSO, risk-reducing bilateral salpingo-oophorectomy; RRM, risk-reducing mastectomy. N/A, data not available.

United Kingdom [9]84/211 (39.8)96/211 (45.5)N/A
Germany [14]N/A175/306 (57.2)N/A
United States [15]57/136 (41.9)71/137 (52.2)N/A
United States [16]13/90 (14.4)39/90 (43.3)6/90 (6.6)
United States [17]19/146 (13)47/114 (43)N/A
United States [18]54/237 (23)122/240 (51)N/A
Denmark92/306 (30.1)155/306 (50.6)63/306 (20.6)

Data accumulated over the past few years has demonstrated the value of RRM as an effective means for breast cancer prevention in BRCA mutation carriers [4, 8, 19, 20]. This information was conveyed to all study participants during genetic test disclosure. In this study, the uptake of mastectomy was greater if the recommendation was reinforced by the primary caregiver. The impact of the recommendation of the health-care provider has been shown to be important in other cancer-related settings, such as prostate cancer patients' decision to opt for active surveillance vs surgery [21], and decisions regarding sperm banking prior to therapy [22].

One possible factor that may have impacted upon uptake rates of RRM in Israeli women is the recent establishment of a non-profit organization developed to support BRCA gene mutation carriers – BRACHA (http://www.bracha.org.il/website/). One of the goals of BRACHA is to facilitate open discussion of the available preventive modalities with mutation carriers and encourages them to actively pursue risk-reducing surgery. BRACHA hosts an interactive web site and sponsors educational conferences and informal meetings with patients, physicians and genetic counselors.

The rate of acceptance of RRBSO over the past decade has been relatively constant [6, 7, 10]. The fact that these rates are lower in this study compared with the previous one from Israel [6] may reflect different age groups (over 40 years of age vs under 40 years of age), sample size, and the recommendations made by physicians who are not members of the oncogenetics team. To address this latter possibility, ongoing educational workshops led by oncogenetecists and sponsored by the Israel cancer association, sessions within Israeli gynecological and family physicians society's annual conferences are ongoing. The most likely reason for the consistently high uptake of RRBSO in high-risk women is the lack of an effective screening alternative, combined with the relatively poor prognosis of ovarian cancer. Oophorectomy is also seen as beneficial both in terms of preventing breast and ovarian cancer.

There are several limitations to our study. The number of carriers was relatively small and did not permit precise analyses for the relevant subgroups, e.g. by mutation or by age. We did not survey the primary care physician regarding their attitudes toward preventive surgery and we did not have information about how much was discussed during these sessions. In particular, we do not have details as to why a physician might have recommended against preventive surgery. We relied on the opinion of the study subject and the physician's position was interpreted in light of the choice the participant has already made. This study was conducted in a single institution in a large metropolitan center and the physicians and patients at this single institution may not be representative of the Israeli population of mutation carriers as a whole.

In conclusion, the rate of risk-reducing oophorectomy in Israel among BRCA mutation carriers is similar to the rates seen in other Western countries. However, the rate of risk-reducing mastectomy is lower in Israel than in academic centers in North America and Western Europe. The recommendation of the primary caregiver strongly influences the uptake of risk-reducing surgery and new strategies to increase the awareness and participation of all health-care providers in the genetic counseling process may lead to a reduction in the number of new cancers among BRCA carriers. It is also a reasonable goal to develop a national consensus regarding guidelines for risk-reducing surgery in Israeli women carrying BRCA mutations so that regional disparities in patterns or practice can be minimized.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. References

This study was partially funded by the Israel Cancer Association through the Israeli Hereditary breast cancer consortium.

References

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. References
  • 1
    Antoniou A, Pharoah PD, Narod S 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. Am J Hum Genet 2003: 72 (5): 11171130.
  • 2
    Warner E, Plewes DB, Hill KA et al. Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA 2004: 292 (11): 13171325.
  • 3
  • 4
    Rebbeck TR, Friebel T, Lynch HT et al. Bilateral prophylactic mastectomy reduces breast cancer risks in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004: 22: 10551062.
  • 5
    Rebbeck TR, Lynch HT, Neuhausen SL et al. Reduction in cancer risk after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers. N Engl J Med 2002: 346: 16161622.
  • 6
    Metcalfe KA, Birenbaum-Carmeli D, Lubinski J et al. International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers. Int J Cancer 2008: 122: 20172022.
  • 7
    Evans DG, Baildam AD, Anderson E et al. Risk reducing mastectomy: outcomes in 10 European centres. J Med Genet 2009: 46: 254258.
  • 8
    Lerman C, Hughes C, Croyle RT et al. Prophylactic surgery decisions and surveillance practices one year following BRCA1/2 testing. Prev Med 2000: 31: 7580.
  • 9
    Evans DG, Lalloo F, Ashcroft L et al. Uptake of risk-reducing surgery in unaffected women at high risk of breast and ovarian cancer is risk, age, and time dependent. Cancer Epidemiol Biomarkers Prev 2009: 18 (8): 23182324.
  • 10
    Skytte AB, Gerdes AM, Andersen MK et al. Risk-reducing mastectomy and salpingo-oophorectomy in unaffected BRCA mutation carriers: uptake and timing. Clin Genet 2010: 77 (4): 342349.
  • 11
    Laitman Y, Simeonov M, Herskovitz L et al. Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel. Breast Cancer Res Treat 2012: 133 (3): 11531157.
  • 12
    Kram V, Peretz T, Sagi M. Acceptance of preventive surgeries by Israeli women who had undergone BRCA testing. Fam Cancer 2005: 5: 327335.
  • 13
    Wainberg S, Husted J. Utilization of screening and preventive surgery among unaffected carriers of a BRCA1 or BRCA2 gene mutation. Cancer Epidemiol Biomarkers Prev 2004: 13 (12): 19891995.
  • 14
    Rhiem K, Foth D, Wappenschmidt B et al. Risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers. Arch Gynecol Obstet 2011: 283 (3): 623627.
  • 15
    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. Am J Obstet Gynecol 2013: 208 (4): 329.e1-6.
  • 16
    Stuckey A, Dizon D, Scalia Wilbur J et al. Clinical characteristics and choices regarding risk-reducing surgery in BRCA mutation carriers. Gynecol Obstet Invest 2010: 69 (4): 270273.
  • 17
    O'Neill SC, Valdimarsdottir HB, Demarco TA et al. BRCA1/2 test results impact risk management attitudes, intentions, and uptake. Breast Cancer Res Treat 2010: 124 (3): 755764.
  • 18
    Beattie MS, Crawford B, Lin F, Vittinghoff E, Ziegler J. Uptake, time course, and predictors of risk-reducing surgeries in BRCA carriers. Genet Test Mol Biomarkers 2009: 13 (1): 5156.
  • 19
    Arver B, Isaksson K, Atterhem H et al. Bilateral prophylactic mastectomy in Swedish women at high risk of breast cancer: a national survey. Ann Surg 2011: 253 (6): 11471154.
  • 20
    Domchek SM, Friebel TM, Singer CF et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010: 304 (9): 967975.
  • 21
    Davison BJ, Breckon E. Factors influencing treatment decision making and information preferences of prostate cancer patients on active surveillance. Patient Educ Couns 2012: 87 (3): 369374.
  • 22
    Yee S, Fuller-Thomson E, Dwyer C, Greenblatt E, Shapiro H. “Just what the doctor ordered”: factors associated with oncology patients' decision to bank sperm. Can Urol Assoc J 2012: 6 (5): E174E178.