Women with a BRCA1 or BRCA2 germline mutation are at increased risk of breast and ovarian cancer compared with the general population. BRCA1 mutation carriers have a 40% to 85% lifetime risk of breast cancer and a 20% to 50% lifetime risk of ovarian cancer.1–3 For BRCA2 mutation carriers, the breast cancer risk is also 40% to 85% and the lifetime ovarian cancer risk is 15% to 20%.1–3
Current options for the prevention or early diagnosis of ovarian cancer in women with a BRCA1 or BRCA2 mutation include screening, chemoprevention, and prophylactic bilateral salpingo-oophorectomy (BSO). Current screening recommendations include annual or semiannual transvaginal ultrasonography and CA 125 level beginning at age 25 to 35 years.4 However, these screening procedures are limited in their ability to detect ovarian cancer at a curable stage.5,6 Given these limitations, prophylactic BSO is currently recommended once child bearing is complete. Recent studies have provided evidence for this recommendation, with prophylactic BSO reducing the risk of ovarian cancer in women with a BRCA mutation by more than 95%.7,8 In addition, prophylactic BSO in premenopausal mutation carriers has been shown to reduce the risk of breast cancer by approximately 50%.7,8
Despite this evidence, not all women with a BRCA mutation choose to undergo prophylactic BSO. Previous studies have shown the rate of uptake rate for this procedure ranges from 13% to 64%.8–11 The purpose of this study was to evaluate the clinical factors associated with choosing prophylactic BSO over surveillance in women with a BRCA1 or BRCA2 mutation.
MATERIALS AND METHODS
After approval from the Institutional Review Board, our study population was identified through a search of the University of Texas MD Anderson Cancer Center Clinical Cancer Genetics database. Between January 1996 and June 2005, 540 women seen at our institution had genetic testing for BRCA1 and BRCA2 mutations. One hundred thirty-nine of these women tested positive and were included in the study. Women with genetic variants of unknown functional significance were excluded.
The women had received pretest and post-test genetic counseling from genetic counselors specializing in hereditary cancer syndromes. The pretest counseling included hereditary cancer risk assessment, discussion of the possible results of genetic testing and their implications for the patient and her family. Post-test counseling included a review of the management options available for individuals testing positive for BRCA mutations. The women then had further discussion of their management options with physicians in our high risk ovarian cancer screening clinic. Prophylactic BSO was routinely recommended as a proven risk reduction strategy. Women who chose surveillance were monitored with pelvic examination, transvaginal ultrasonography and CA 125 level every 6 months.
The medical records were reviewed for patient age at the time of genetic testing, mutation type, parity, history of prophylactic surgery, personal history of cancer, and family history of cancer. Twenty-five women (18%) had one of the three Ashkenazi Jewish founder mutations (185delAG, 5382insC, and 6174delT).12–14 A personal history of ovarian (n=31) or fallopian tube (n=2) cancer before genetic testing was noted in 33 women. These women were excluded, with the remaining 106 women included in the final analysis. The characteristics of the women who underwent prophylactic BSO were compared with those choosing surveillance.
Comparisons of patient characteristics between groups were performed by χ2 and independent t tests. A value of P<.05 was considered statistically significant. All analyses were performed using SPSS 12.0 (Chicago, IL).
Of the 106 BRCA mutation carriers, 65 (61.3%) elected to undergo prophylactic BSO. Nine of the women in our cohort (13.8%) did not have genetic testing before undergoing prophylactic surgery. Seven of these women had a personal history of breast cancer. The results are unchanged if these women are excluded from the analyses. The characteristics of the women who underwent prophylactic BSO compared with those who chose surveillance are shown in Table 1. Mean age at genetic testing was significantly higher in the prophylactic BSO group (46.0 years) compared with the surveillance group (39.2 years) (P<.01). A personal history of breast cancer was noted in a significantly higher proportion of the women who underwent prophylactic BSO (72%) compared with surveillance (46%) (P<.01). Eighty-five percent of women who underwent prophylactic BSO were parous compared with 66% of women undergoing surveillance (P=.03). There were no statistically significant differences in family history of breast or ovarian cancer between women who chose prophylactic BSO and those who did not.
The median age at prophylactic BSO was 45.6 years (range 31.3 to 65.3 years). The age distribution at surgery is shown in Table 2. Median time from disclosure of genetic test results to prophylactic surgery was 4.6 months (mean 9.6 months, range 0.10–84.5 months). A hysterectomy was performed at the time of prophylactic BSO in 52 women (80%). Fourteen patients (22%) had a mastectomy with (n=11) or without (n=3) breast reconstruction performed at the time of prophylactic BSO. Of the 14 premenopausal women without a history of breast cancer who underwent prophylactic BSO, eight (57%) started hormone therapy after surgery.
Surgical or postoperative complications were noted in two patients (3%). The first patient was a 55-year-old woman with a history of left breast cancer who developed pneumonia after a combined procedure consisting of a right prophylactic mastectomy, bilateral breast reconstruction with transverse rectus abdominis muscle flaps, and total abdominal hysterectomy (TAH) and BSO. The patient was treated with antibiotics and discharged home on postoperative day seven without any further complications. The second patient was a 34-year-old woman with bilateral breast cancer who was scheduled for bilateral completion mastectomy followed by a laparascopic-assisted vaginal hysterectomy with BSO. During the bilateral mastectomy, the patient developed elevated pulmonary pressures, and the procedure was changed to a laparotomy with TAH-BSO. During the laparotomy, the patient became hypotensive, and the procedure was limited to a BSO. The patient’s hemodynamic status recovered postoperatively, and she was discharged home on postoperative day four without any further complications.
Two patients (3%) had incidental cancer diagnosed at the time of prophylactic surgery. Both patients underwent TAH-BSO with normal intraoperative findings. In one patient, the final pathology reading revealed a 0.1-cm focus of invasive cancer of the right ovary. She received no further treatment and is currently alive without evidence of disease two years after surgery. The final pathology reading for the second patient revealed normal uterus, tubes, and ovaries; however, the pelvic washings were positive for adenocarcinoma with positive p53 staining. The patient subsequently received four cycles of paclitaxel and carboplatin chemotherapy, followed by a negative second-look surgery. She is currently alive without evidence of disease five years after diagnosis.
Mean follow-up was 31.6 months (range 2.8 to 105.1 months) in the prophylactic BSO group and 24.7 months (range 1.1 to 100.9 months) in the surveillance group. Among the women who underwent prophylactic BSO, one woman is deceased as a result of her breast cancer. No cases of primary peritoneal cancer have been reported to date in our cohort. None of the women in the surveillance group have developed ovarian cancer and all are currently alive.
In the subset of 38 women without a previous diagnosis of breast or ovarian cancer, 16 women (42%) had prophylactic BSO and 10 (26%) had prophylactic mastectomy performed. Two women (5%) underwent both prophylactic BSO and mastectomy. Median age at prophylactic BSO was 43.8 years (mean 44.1, range 33.3–57.4 years) and median age at prophylactic mastectomy was 39.8 years (mean 40.0, range 30.5–48.5 years). The age distribution at prophylactic BSO and prophylactic mastectomy for these unaffected women is shown in Table 3.
Prophylactic BSO has been shown to be effective in preventing ovarian cancer and decreasing the risk of breast cancer in women with a BRCA1 or BRCA2 mutation.7,8 Despite this evidence, many women choose not to undergo this procedure. Little is known about the factors these women consider important in making this decision. Our study compares the clinical characteristics of women with a BRCA mutation who had a prophylactic BSO performed with those who did not.
In our cohort, 61% of the women with a BRCA mutation underwent a prophylactic BSO. The median time from disclosure of genetic testing results to prophylactic BSO was only 4.6 months. This short time interval is likely due to our counseling before genetic testing. At our institution, the genetic counselors and the physicians staffing the high-risk ovarian cancer screening clinic (gynecologic oncologists and general gynecologists) function as a team. Patients who receive positive genetic test results have previously been counseled about the limitations of ovarian cancer screening and the efficacy of prophylactic BSO. For these reasons, many of the women choose to schedule surgery soon after positive results are disclosed.
Age greater than 40 years, parity, and a personal history of breast cancer were associated with choosing prophylactic BSO over surveillance. These findings are consistent with a study by Scheuer et al11 who found that women electing prophylactic BSO were older and more likely to have a prior breast cancer diagnosis. Similar to our study, there were no differences in the number of family members with breast or ovarian cancer between the women electing prophylactic BSO and those choosing surveillance.
The mean age at ovarian cancer diagnosis in women with a BRCA mutation has been reported to be 51 years,7,15 with 54% of women diagnosed before age 50.15 These findings support the recommendation of performing prophylactic BSO as soon as feasible after child bearing is completed. This recommendation is further supported by a recent study by Eisen et al16 that reported the reduction in breast cancer risk in BRCA1 carriers to be greater if oophorectomy is performed before the age of 40. In our cohort, the median age at prophylactic surgery was 45.6 years, with 72% of the women undergoing the procedure after the age of 40. In the subset analysis of the 38 women without a previous diagnosis of breast or ovarian cancer, only 42% underwent prophylactic BSO, and 63% of these women were aged more than 40 years at the time of surgery. These findings are similar to other studies that found the mean age at prophylactic BSO ranged from 40 to 47 years.7,8,11 Our results suggest that many women are delaying prophylactic oophorectomy until closer to the age of natural menopause.
In our cohort, 80% of patients had a hysterectomy performed at the time of prophylactic BSO. When counseling patients, we do not routinely recommend concomitant hysterectomy but we do discuss the risks and benefits and have found that the majority of patients are choosing to have a hysterectomy performed at the time of their prophylactic BSO. Although there is no proven increase in the risk of endometrial cancer in women with BRCA mutations,17 cancer may theoretically develop in the portion of intramural fallopian tube that remains after a BSO, leading some authors to recommend hysterectomy at the time of BSO.18 Concomitant hysterectomy also prevents the need for further gynecologic surgery for benign or malignant indications, simplifies hormone therapy, and decreases the risk of endometrial cancer in women taking tamoxifen for breast cancer treatment or prevention. These advantages must be weighed with the increased morbidity, operative time, and hospital stay that may be associated with performing a hysterectomy.
In premenopausal women, prophylactic BSO results in premature menopause and its associated symptoms including hot flushes, vaginal dryness, sexual dysfunction, sleep disturbances, and increased risk for osteoporosis.19–21 Many of the women in our cohort had a previous diagnosis of breast cancer and were unable to take hormone therapy. However, in premenopausal women without a previous diagnosis of breast cancer, hormone therapy after prophylactic BSO is a reasonable option to assist with management of menopausal symptoms. Of the 14 premenopausal women in our cohort without a history of breast cancer who underwent prophylactic BSO, 57% started hormone therapy after surgery. The surgical complication rate in our cohort was 3%. This figure is consistent with previously published complication rates associated with prophylactic BSO in BRCA mutation carriers8 and for hysterectomy with BSO for benign indications.22,23
Two women (3%) in our study were found to have occult ovarian carcinomas at the time of prophylactic surgery. This is consistent with previous studies which have reported the rate to be 2% to 10%.7,8,24–26 These findings emphasize the need to maintain a high index of suspicion during prophylactic surgery in these women. Our protocol for prophylactic BSO in BRCA mutation carriers includes careful inspection of the tubes, ovaries, and surrounding tissues as well as cytologic examination of peritoneal washings. The pathologist is informed of the increased risk of ovarian and fallopian tube cancer, and the specimens are carefully examined intraoperatively with frozen sections performed if indicated. Serial sectioning of the entire fallopian tubes and ovaries is then performed. A recent study by Powell et al26 reported a seven-fold increase in the detection of occult ovarian carcinoma using a similar protocol in BRCA mutation carriers.
Only 18% of the women in our cohort had one of the three Ashkenazi Jewish founder mutations. This is different from many of the previous reports on BRCA mutation carriers, which have included a high proportion of women of Ashkenazi Jewish descent.2,15,26,27 Although the power was limited by our small sample size, there were no significant differences in the proportion of women diagnosed with ovarian cancer or undergoing prophylactic BSO between the women with the Ashkenazi Jewish founder mutations and those without. Further study is needed to determine if there are significant differences in our BRCA mutation carrier population compared with those previously reported, and the implications this may have on the decision to undergo prophylactic surgery.
In summary, 61% of the women in our cohort elected to undergo prophylactic BSO. A short time interval was noted from disclosure of genetic testing results to prophylactic BSO. Age greater than 40 years, parity, and a personal history of breast cancer were associated with choosing prophylactic BSO. We are currently evaluating quality of life and satisfaction with decision-making in women with a BRCA mutation to gain a better understanding of the factors important in deciding whether or not to undergo prophylactic BSO.
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