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Introduction and Aims: For women who carry BRCA mutations, risk-reducing surgeries are an option to decrease breast and ovarian cancer risk. This study aims to determine the uptake, time course, and predictors of risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) in BRCA carriers. Results: In 272 female carriers, followed for a median of 3.7 years, 23% of those eligible chose RRM, and 51% percent chose RRSO. Among BRCA carriers who chose these procedures, median time to both RRM and RRSO was approximately 4 months after learning of BRCA-positive results. Predictors of RRM were as follows: age below 60 years (hazard ratio 1.8, p=0.04), prior breast cancer (hazard ratio 2.4, p=0.0004), and RRSO (hazard ratio 7.2, p<0.0001). Predictors of RRSO were as follows: age below 60 years (hazard ratio 3.6, p=0.006), prior breast cancer (hazard ratio 1.8, p=0.002), and RRM (hazard ratio 5.4, p<0.0001). Conclusions: Many women who undergo BRCA testing use these results to make clinical decisions; those who choose risk-reducing surgeries typically do so within months of receiving BRCA-positive results. Predictors of risk-reducing surgery uptake include the following: age below 60 years, prior breast cancer, and utilization of another risk-reducing surgery. Future research directions include examining other preventive and screening options in BRCA carriers as well as studying motivations for choosing or declining risk-reducing surgeries.
The discovery of the BRCA1 and BRCA2 genes in the mid-1990s (Miki et al., 1994; Wooster et al., 1994) paved the way for personalized medicine, using genetic test results to assess hereditary cancer susceptibility (Chopra, 2004). BRCA testing is now standard of care for families with strong risk factors for hereditary breast and ovarian cancers (Nelson et al., 2005). These risk factors include the following: pre-menopausal breast cancer, bilateral breast cancer, male breast cancer, and ovarian cancer in the proband and/or family members. Other risk factors include Ashkenazi Jewish ancestry and family members with multiple primary cancers, including breast and ovarian cancer in the same woman (Nelson et al., 2005; Robson and Offit, 2007). The autosomal dominant BRCA transmission pattern may be masked in small families and in families that have transmitted BRCA mutations paternally (Weitzel et al., 2007).
Women who test positive for a BRCA1 or a BRCA2 mutation face a lifetime risk of breast cancer of 55–85% (Ford et al., 1994,1998; Antoniou et al., 2003; King et al., 2003) and a lifetime risk of ovarian cancer of 15–60% (Antoniou et al., 2003). About 1/40 Ashkenazi Jews carry a founder mutation in BRCA1 or BRCA2, and rates of breast and ovarian cancer in this population are estimated to be similar to rates in non-Ashkenazi Jews (Levy-Lahad et al., 1997). For women already affected with breast cancer, BRCA1 and BRCA2 mutations are associated with a 35–65% risk of developing a new primary breast cancer (Chen et al., 2001). It is estimated that at least 500,000 American men and women carry BRCA mutations, and that approximately 95% of these carriers are currently unaware of their status (Whittemore et al., 1997).
Prophylactic treatment of BRCA carriers with risk-reducing surgeries has shown greater efficacy than intensive screening or chemoprevention (Grann et al., 2002; Nelson et al., 2005). Intensive screening, aimed at detecting cancer at an early stage, is associated with both false-positive and false-negative screening results (Grann et al., 2002; Kauff et al., 2005). Chemoprevention may reduce cancer risk by about half (e.g., oral contraceptives to avert ovarian cancer and tamoxifen to prevent breast cancer), but chemopreventive agents are also associated with medication side effects (King et al., 2001). Risk-reducing surgeries represent the most aggressive, but also the most effective, way to reduce the risk of breast and ovarian cancer. Risk-reducing mastectomy (RRM), a procedure that removes breast tissue to prevent cancer, lowers the lifetime risk of breast cancer in BRCA carriers by over 90% (Rebbeck et al., 2004). Risk-reducing salpingo-oophorectomy (RRSO), which removes the fallopian tubes and ovaries to prevent ovarian cancer (Powell et al., 2005), similarly lowers the lifetime risk of ovarian cancer in BRCA carriers by over 90% (Rebbeck, 2000). In 2002, two large studies reported that risk-reducing oophorectomy also reduced breast cancer risk by 50% in premenopausal women (Kauff et al., 2002; Rebbeck et al., 2002). Although the efficacy of risk-reducing surgeries has been demonstrated, these procedures are invasive and carry known surgical risks.
In prior studies of risk-reducing surgeries, RRM uptake in BRCA carriers has ranged from 0% to 50% (Lerman et al., 2000; Lodder et al., 2002; Botkin et al., 2003; Wainberg and Husted, 2004; Kram et al., 2006; Metcalfe et al., 2008), and RRSO uptake has ranged from 12% to 78% (Lerman et al., 2000; Botkin et al., 2003; Schwartz et al., 2003; Wainberg and Husted, 2004; Kram et al., 2006; Schmeler et al., 2006; Metcalfe et al., 2008). To date, no study has examined time to risk-reducing surgery as a main outcome. Our research analyzes data from a BRCA genetic counseling and testing service that includes three hospital sites: university, public, and community (Lee et al., 2005). We have identified several significant predictors and trends in the uptake time to RRM and RRSO that are important factors to take into account when making risk-reducing recommendations to BRCA carriers.
The Cancer Risk Program (CRP) at the University of California San Francisco (UCSF ) is a clinical and research program that provides cancer risk assessment and recommendations, including genetic counseling and testing, to families at high risk of hereditary cancer. Population characteristics of the CRP have been described elsewhere (Lee et al., 2005). Approximately two-thirds of CRP patients are referred by oncologists and surgeons, and about one-third of CRP patients are either self-referred or are referred by primary care providers and gynecologists. In addition to the university hospital program at UCSF's Mt. Zion Hospital, the CRP also serves two satellite sites: (1) Sutter Cancer Center in Sacramento, a community hospital, and (2) San Francisco General Hospital, a county hospital.
Identical clinical and research protocols are followed at all three sites. Before the first visit, patients are contacted by telephone to confirm their appointment and to answer basic questions. All patients are mailed a detailed questionnaire regarding their family history and potential risk factors for cancer, which they are instructed to bring to their first visit. At that “intake and education” visit, genetic counselors discuss hereditary breast and ovarian cancer, review the baseline questionnaire, and create a detailed 3–4 generation pedigree. Patients (and family members if possible) sign medical records release forms to permit verification of family cancer histories.
A thorough assessment of cancer risk is provided at the second visit, and BRCA testing, when appropriate, is offered at that time. Patients are also offered participation in an institutional review board (IRB)-approved research protocol at this visit. Over 97% of patients provide written informed consent to this 20-year follow-up research protocol. BRCA test results are disclosed at the third visit, typically 1 month after the second visit.
For women who test BRCA positive, the results disclosure visit is typically 1–2 h and includes screening and prevention recommendations as well as psychosocial support. Women who need additional psychosocial support are referred to individual counselors. In accordance with guidelines from the American Society of Gynecologic Oncologists, BRCA-positive women are counseled to consider RRSO at age 35 or when childbearing is complete.
Because of U.S. patent rights, all full-sequence BRCA testing is preformed by Myriad Genetics (Salt Lake City, UT). Testing for the three common founder mutations in the Ashkenazi Jewish population was preformed either at Myriad or at UCSF. Full sequence testing done after 2002 included a panel of five common rearrangements according to Myriad Genetics protocol.
Research participants receive systematic follow-up by telephone, in person, and by mailed questionnaires. All participants are instructed to contact the CRP between follow-ups if they are diagnosed with cancer or if they receive any risk-reducing surgery. All cancer diagnoses are confirmed with pathologic reports, or medical records, when available. All risk-reducing surgeries are confirmed with surgical reports or medical records. Deaths are confirmed by death certificates and/or medical records.
In this study, we report on all female research participants who tested positive for a known BRCA mutation between October 1996 and October 2006 (study subjects).
Time to RRM and time to RRSO were calculated from the date of receipt of BRCA-positive results to the date of risk-reducing surgery. All dates were verified by medical records.
Demographic information and past medical history were summarized by site using means, standard deviations, medians, interquartile ranges, and proportions. Women who underwent RRM before receiving BRCA results were excluded from the RRM analysis, and women who underwent RRSO before receiving BRCA results were excluded from the RRSO analysis. Study subjects who did not undergo risk-reducing surgery were censored at diagnosis of metastatic cancer, death, and otherwise last contact. For RRM, additional study subjects were censored at the date of removal of the breasts for any reason other than risk reduction. Similarly, study subjects were censored in the analysis of RRSO at the date of removal of the ovaries for any reason other than risk reduction.
Kaplan-Meier curves were used to estimate the cumulative proportions having undergone RRM and RRSO, stratified by age at testing and by prior history of breast cancer. Cox proportional hazard models were used to examine the hazard ratio and trends for choosing RRM and RRSO in relation to age, prior breast cancer, clinical site, and calendar year of testing. All statistical analyses were implemented using SAS version 9.2 (SAS Institute, Cary, NC).
Of 1187 research participants who underwent BRCA testing between October 1996 and October 2006, 285 (24%) tested positive for a known BRCA1 or BRCA2 deleterious mutation. Of these positive BRCA testers, 272 were women and 13 were men. Men were excluded from this study, as they are not candidates for RRSO, and RRM is not recommended for them. Of the 272 BRCA-positive women, 14 had metastatic cancer at the time of testing and were therefore not surgical candidates. Fifteen of the 272 women had bilateral mastectomies, 12 had bilateral oophorectomies, and 6 had both surgeries before receiving BRCA results. Thus, 237 women were candidates for RRM, and 240 women were candidates for RRSO.
Table 1 presents demographic data and past medical histories of the study subjects. Overall, the median age at BRCA testing was 45 years (25–75% interquartile ratio [IQR]=37–52 years), and the median follow-up time was 3.7 years (range 1–10 years). Subjects at UCSF/Mt. Zion were more likely to be white and Ashkenazi (Eastern European) Jewish than were subjects at either Sutter Cancer Center or San Francisco General Hospital.
Fifty-four (23%) candidates with at-risk breast tissue chose RRM, and 122 (51%) candidates with at-risk ovarian tissue chose RRSO. The youngest age for RRSO in this study was 30. For women choosing RRM, the median interval from receiving BRCA results to undergoing this surgery was 124 days (25–75% IQR=49–453 days). For women choosing RRSO, the median interval from receiving BRCA results to undergoing this surgery was 123 days (25–75% IQR=56–331 days).
Women aged 60 years and above were least likely to undergo RRM and RRSO, and this group was used as a reference for age analyses. For RRM, age was inversely associated with surgery uptake, with women under 40 most likely to undergo RRM (Table 2, p for trend =0.019 for ages 20–79). For RRSO, age was positively associated with surgery uptake until age 60, with women 50–59 years old most likely to undergo RRSO. (Table 2, p for trend =0.002 for ages 20–59). Kaplan–Meier curves in Figures 1 and and22 show uptake of RRM and RRSO over time, stratified by age.
Women with a personal history of breast cancer before BRCA testing were more likely to undergo both RRM and RRSO compared with women with no such personal history (Table 3). Kaplan–Meier curves in Figures 3 and and44 show uptake of RRM and RRSO over time, stratified by prior history of breast cancer. Thirty-five women (of 137 with prior breast cancer history) learned of their BRCA-positive status within 4 months of also being diagnosed with breast cancer. These women could be considered to have a nearly simultaneous diagnosis of breast cancer and BRCA-positive test results. At UCSF and at our satellite clinics, women with new diagnoses of breast cancer, as well as strong family histories of breast or ovarian cancer, are typically seen by breast specialists and genetic counselors at their initial visit. In all study subjects with nearly simultaneous diagnoses, BRCA testing was preformed either within 4 months of the diagnosis or beyond 13 months from the diagnosis of breast cancer. Thus, this 4-month window was used to capture women with simultaneous diagnoses.
Of these 35 women who received BRCA-positive results within 4 months of also receiving a diagnosis of breast cancer, 11 (31%) chose to undergo bilateral mastectomies: a treatment mastectomy in the affected breast and an RRM in the contralateral breast. These women were approximately three times more likely to undergo RRM (in the contralateral breast) than women with no prior history of breast cancer (Table 3). For women with simultaneous diagnoses, median time to RRM after results disclosure was 70 days (25–75% IQR=24–102 days). When these women were excluded from the time to RRM analysis, the median time to RRM after results disclosure was 154 days (25–75% IQR=66–564 days), about 1 month longer than the entire RRM group.
There was no significant difference in utilization of RRM and RRSO based on hospital site of testing (data not shown), although the number of BRCA carriers at Sutter Cancer Center and at San Francisco General Hospital is small compared with that at UCSF/Mt. Zion. Secular trends were examined by comparing utilization of risk-reducing surgeries by year of testing using 1-, 2-, and 5-year intervals. These analyses showed no significant secular trends in utilization of RRM or RRSO (data not shown).
Women choosing RRM were significantly more likely to opt for RRSO (hazard ratio 5.4; 95% confidence intervals 3.5–8.6; p<0.0001). Similarly, women choosing RRSO were significantly more likely to opt for RRM (hazard ratio 7.2, 95% confidence interval 4.1–12.7, p<0.0001).
Many women who pursue BRCA testing use genetic test results to make critical decisions about risk-reducing strategies, including risk-reducing surgeries. BRCA carriers who choose risk-reducing surgeries undergo these procedures surprisingly quickly—within months of receiving positive results. Predictors of utilizing risk-reducing surgeries include prior history of breast cancer and age below 60 years. Women choosing one risk-reducing surgery are significantly more likely to then opt for another.
The uptake of RRM and RRSO in this study is consistent with that of other centers (Lerman et al., 2000; Lodder et al., 2002; Botkin et al., 2003; Schwartz et al., 2003; Wainberg and Husted, 2004; Kram et al., 2006; Schmeler et al., 2006; Metcalfe et al., 2008), but most prior studies did not comment on the time to RRM or RRSO. One U.S. study that reported on time to RRSO (Schmeler et al., 2006) showed a median time from results disclosure to surgery of 4.6 months (range 0.10–84.5 months), which is consistent with our finding of a median time from results disclosure to RRSO of approximately 4 months.
As with prior studies that have examined RRM and RRSO in a single institution (Lerman et al., 2000; Botkin et al.,2003; Kram et al., 2006), we found a higher uptake of RRSO than RRM. One prior study suggested that the acceptability of RRSO is greater than that for RRM (Kram et al., 2006). Reasons for this may include cultural factors, different counseling practices, body image effects of these surgeries, and the greater accuracy of screening tests for breast cancer compared with those for ovarian cancer. Although our program offers psychological support with medical decision making, most BRCA carriers do not use these services to discuss RRM; this could also possibly account for a lower rate of RRM compared to RRSO.
Other potential reasons for higher rates of RRSO compared to RRM in our study include a shorter post-op recovery time and, for postmenopausal women, minimal physiologic menopausal symptoms post-op. For premenopausal women undergoing RRSO, hormone replacement therapy (HRT) and alternative treatments for menopausal symptoms are also acceptable and available.
The variability of reported RRM and RRSO uptake is likely multifactorial and related to study design, follow-up, and study population. Three prior studies have noted international variations in uptake of risk-reducing surgeries ( Julian-Reynier et al., 2001; Wainberg and Husted, 2004; Metcalfe et al., 2008). It is unclear whether these variations are related to counseling practices, medical systems (including insurance coverage and reimbursement), cultural factors, or other causes.
A notable finding of our study is that BRCA carriers aged 60 years and over are least likely to choose RRM or RRSO, despite their high and increasing risks for breast and ovarian cancers with age. We can only speculate that competing morbidities or some degree of fatalism could contribute to their decreased uptake. Further, these older women may be counseled differently, or they may be unaware of their continuing risk of breast and ovarian cancer. In our experience, women who undergo BRCA testing at age 60 and above often report that their motivation is to alert their daughters and the next generations of their cancer risk. Whatever the reason, special attention should be paid to risk reduction in older BRCA carriers whose lifetime cancer risk remains high.
Our study has several strengths. The large study population, the long-term follow-up, and the careful measurement of primary outcomes contribute to the robustness of our results. Because participants were drawn from a single program, the genetic counseling dispensed was homogeneous. We chose to include women who were found to be BRCA positive soon after their diagnosis of breast cancer (within a 4-month window) because they represent a small (13%) but important part of our entire BRCA-positive population. We presume that a diagnosis of breast cancer soon after the disclosure of a positive BRCA test strongly influences surgical decisions. If this group is excluded from the overall analysis, the time to RRM increases only slightly, from 4 to 5 months.
Observational cohort studies examining the efficacy and uptake of risk-reducing surgeries are especially subject to selection bias (Klaren et al., 2003). Women who undergo BRCA testing may also be women who will act on their results. The pretest counseling process alerts women to potential interventions, which may shorten the time from results disclosure to risk-reducing surgery. Further, knowledge of BRCA test results can influence risk-reducing surgery when breast cancer is diagnosed in close proximity to genetic testing. Although our findings could differ in other populations, the uptake of RRM and RRSO in the CRP population is similar to uptakes in a prior study in a tertiary care setting (Schmeler et al., 2006). Because uptake and time-course were similar across all three of our sites, it is possible that our results may generalize to other tertiary care centers as well as to community and county hospitals in the United States. Unknown is whether the results would generalize to countries with different insurance coverage for testing and risk-reducing surgeries, and in more diverse populations.
An ongoing double-cohort study (Green et al., 2008) is currently comparing CA-125 screening with RRSO in women at increased genetic risk of ovarian cancer, and it includes a substantial number of BRCA carriers. This double-cohort study hopes to shed light on both quality-of-life and effectiveness data with respect to RRSO and screening CA-125. When results of this study are available, subgroup analysis within it could provide more data regarding the uptake and time-course of RRSO in BRCA carriers.
Risk-reducing surgeries in BRCA carriers have been shown to be both clinically effective (Rebbeck, 2000; Grann et al., 2002; Kauff et al., 2002; Rebbeck et al., 2002, 2004; Bermejo-Perez et al., 2007) and cost effective (Anderson et al., 2006). Bolstered by recent U.S. Preventive Service Task Force recommendations (Nelson et al., 2005) and widespread insurance coverage for risk-reducing surgeries (Kauff et al., 2001), it is likely that both BRCA testing and uptake of risk-reducing surgeries will increase. Together with genetic counselors, medical providers who are experienced in discussing risk assessment, screening, and preventive options will play key roles in counseling and caring for unaffected women at high risk of hereditary breast and ovarian cancer.
The authors acknowledge Mr. David Crawford and Ms. Pamela Han for their research assistance. This research was made possible by Grant KL2 RR024130 from the National Center for Research Resources, a component of the NIH and NIH Roadmap for Medical Research, which supports Dr. Beattie, Dr. Vittinghoff, and Ms. Lin. Dr. Beattie was also supported by the American Cancer Society Cancer Control Career Development Award for Primary Care Providers and by the UCSF Mt. Zion fund.
None of the authors have a relationship with a for-profit company or institution. No competing financial interests exist.