PROPHYLACTIC OOPHORECTOMY IN BRCA CARRIERS
WITH OR WITHOUT HYSTERECTOMY
P. E. Schwartz, MD
Yale University School of Medicine
New Haven, CT, USA
SUMMARY
Introduction: The purpose of this study is to determine whether the addition of a
hysterectomy is beneficial for BRCA carriers undergoing prophylactic oophorectomy(PO).
Materials and Methods: An English language MEDLINE review of “BRCA”,
“prophylactic oophorectomy” and “prophylactic hysterectomy” was performed.
Results: PO is recommended for BRCA1/2 germline mutation carriers to prevent ovarian
cancer. However, several studies have now recognized that fallopian tube cancers and
uterine serous cancers are also associated with BRCA1/2 mutations.
Conclusion: Complete removal of not only the ovaries, but the fallopian tubes and uterus
provides substantial cancer prophylaxis benefits for women with BRCA1/2 germline
mutations.
Schwartz
INTRODUCTION
Inactivating mutations of the BRCA1 and BRCA2 genes are associated with inherited breast and
ovarian cancers.1 These cancers account for up to 10% of all breast and epithelial ovarian
cancers. Unique founder mutations have now been identified in Ashkenazi Jewish, Asian as well
as in Western European populations.2 Carriers of BRCA1 mutations have been reported to have a
lifetime risk for developing breast cancer of 60-85% and their lifetime risk for developing
epithelial ovarian cancer has been reported to be 15-65%.2,3 Carriers of BRCA2 mutations may
have a similar risk of breast cancer but a 10-20% risk of ovarian risk.1 The high risk for ovarian
cancer in women with BRCA1/2 mutations and the lack of effective techniques for the early
detection of ovarian cancer has led many centers to recommend prophylactic oophorectomy to
avoid the development of ovarian cancer.4,5 However, there are many questions regarding the
role of prophylactic oophorectomy in the reduction of ovarian cancer risk as well as it decreasing
the possibilities of breast cancer.6 Additionally, BRCA1/2 germline mutations have now been
associated with fallopian tube, primary peritoneal and uterine serous cancers.7-14 This article will
concentrate on prophylactic oophorectomy in BRCA carriers and whether there is a benefit to
performing a hysterectomy at the same surgery. A MEDLINE review of “BRCA,” “prophylactic
oophorectomy” and “prophylactic hysterectomy” was performed to address this issue.
TIMING OF PROPHYLACTIC OOPHORECTOMY
Prophylactic oophorectomy has been recommended in women known to have BRCA1 or
BRCA2 mutations once they have completed childbearing.4,5 The ideal age to perform this
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surgery has not been identified. Some authorities have recommended that the best opportunity
for achieving a reduction in ovarian cancer risk and prolonging life is to perform the surgery as
close to 30 years of age as possible.15 One recent study reported that the mean age of women
with BRCA1 or BRCA2 mutations who underwent surveillance only and subsequently
developed ovarian cancer was 50.3 years, suggesting that at least half of the patients would still
have benefited from a prophylactic oophorectomy had they waited until their age was well into
the late forties before they underwent the procedure.1 However, another study reported that 70
percent of the women with a BRCA mutation had developed breast cancer when prophylactic
oophorectomy was deferred until 47.5 years of age.4 If prophylactic oophorectomy is beneficial
in reducing breast cancer risk, an earlier age for this surgery is necessary.
The reason for delaying prophylactic oophorectomies in premenopausal women is related to the
well-documented increased risk for cardiovascular events and osteoporosis associated with an
early menopause and hot flashes, sexual dysfunction and cognitive changes associated with the
menopause.4,5 Some centers have routinely recommended administering hormone replacement
therapy (HRT) following prophylactic oophorectomy until the patient reaches age 50.4,5 By
combining progestins with estrogen one can decrease the risk of endometrial cancer in the
retained uterus. HRT in some series has not had an impact on the beneficial effect of
prophylactic oophorectomy in patients with BRCA1 or BRCA2 mutations.4,5
The recently reported Women’s Health Initiative (WHI) study revealed that women who take
estrogen and progestin in combination have a statistically increased risk for the development of
breast cancer.16 Although the breast cancer risk for any one individual in that study was small
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(<1/1000), it was a statistically measurable risk that has frightened many American women into
not taking HRT. Nevertheless, in the second of the two groups of patients participating in the
WHI study, i.e. women who previously had a hysterectomy and were randomized to either
estrogen or placebo, there has been no reported increased risk for breast cancer in the group
taking estrogen only. Removing the uterus at the time of prophylactic oophorectomy would
allow the patient to take estrogen only postoperatively and avoid any deleterious effects due to
the progestin.
FALLOPIAN TUBE CANCER IN BRCA1/2 CARRIERS
Recent studies have suggested that there is an increased risk for fallopian tube carcinoma
associated with BRCA1/2 mutations.7-10 In a genetic, epidemiological study of 44 women with
fallopian tube cancer, 5 cancers were associated with BRCA1 germline mutations and 2 were
associated with BRCA2 mutations.8 The sites of these occult fallopian tube cancers have been
reported to be in the distal end of the fallopian tube. When one performs a prophylactic
oophorectomy only, the interstitial part of the fallopian tube is left in vivo. Performing a total
hysterectomy at the time of the prophylactic oophorectomy will remove the entire fallopian tube.
UTERINE SEROUS CANCER IN BRCA1/2 CARRIERS
The association of uterine cancers in women with germline mutations of the BRCA1/2 genes has
been anecdotal. Recently a series of 20 Ashkenazi Jewish women with uterine serous cancer
have been reported, four of whom had BRCA1 mutations.14 Nine of the 20 had breast cancer
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diagnosed prior to the uterine serous cancer diagnosis. Serous cancers of the uterus tend to occur
in older age women and tend to be hormonally insensitive tumors.17 Their management is
palliative when found in an advanced stage, but can be curative when identified in an early stage.
Tamoxifen is routinely recommended in women with breast cancer to prevent the development
of cancer in the contralateral breast and to prolong the progression-free interval.18 Tamoxifen
has been shown to reduce the incidence of contralateral breast cancer in women with BRCA1/2
germline mutations.19 Tamoxifen has been associated with both low grade and highly curable
endometrioid adenocarcinomas of the uterus as well as with serous cancers of the uterus.18,20
Nevertheless, some authors advocate prophylactic oophorectomy only and tamoxifen in
BRCA1/2 positive breast cancer patients who do not elect to have prophylactic mastectomies.21
Performing a hysterectomy at the time of prophylactic oophorectomy in breast cancer patients
receiving tamoxifen who have a germline BRCA1/2 mutation would seem extremely prudent!
SHOULD A HYSTERECTOMY BE ROUTINELY PERFORMED IN WOMEN WHO
UNDERGO PROPHYLACTIC OOPHORECTOMY?
The identification of fallopian tube cancers in association with women who carry these
BRCA1/2 germline mutations would strongly argue for the routine removal of the entire
fallopian tube including the interstitial part of the tube when a patient undergoes prophylactic
oophorectomy. This can be best accomplished by performing a hysterectomy. The removal of
uterus would also remove the potential for developing a serous cancer of the uterus, particularly
in women who already have been diagnosed to have breast cancer.
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The majority of studies of women who have undergone prophylactic oophorectomy appear to
include women at extremely high risk for developing ovarian cancer. In one study, 69 of 98
(70%)of the participants who underwent prophylactic oophorectomy had already experienced
breast cancer as did similar numbers (45 of 72, 62%)of patients in the surveillance group.4 In
another study, 200 of 551 (36.3%) patients known to have BRCA1 or BRCA2 mutations had
previously been diagnosed to have breast cancer.5 Most physicians encounter patients who do
not have family cancer histories comparable to those included in the latter studies. Alternative
strategies to prophylactic oophorectomy, including the use of oral contraceptives and tubal
ligations, can be employed for lower risk women who do have BRCA1 or BRCA2 mutations.22
However, for those women who have experienced breast cancer at a young age, prophylactic
oophorectomy in combination with a hysterectomy gives the best protection against experiencing
additional gynecologic cancers and will allow patients to take estrogen replacement therapy.4,5
SHOULD A PROPHYLACTIC OMENTECTOMY BE PERFORMED AT THE TIME OF
PROPHYLACTIC OOPHORECTOMY?
Serous cancers of the peritoneum, i.e. primary peritoneal carcinomas, do occur in women who
have BRCA1 and BRCA2 germline mutations. Indeed, one early ovarian cancer detection
program study reported that 7 of the 10 so-called “ovarian cancers” detected were primary
peritoneal cancers.13 Three of four primary peritoneal cancers tested were associated with
BRCA1 mutations. These cancers cannot be recognized early using detection techniques such as
serum tumor markers and endovaginal ultrasounds and have been reported to occur after
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prophylactic oophorectomy was performed.12 The incidence of BRCA1/2 germline mutations in
68 Ashkenazi Jewish women with primary peritoneal cancers in a population based
epidemiologic study was 28% compared to a 30% mutation rate among Stage III and IV ovarian
cancer patients.12
Serous cancers of the peritoneum may be recognized in an advanced stage by a CT scan
revealing the presence of ascites, in association with the dominant mass being in the omentum
and the ovaries not being obviously involved by cancer. Since the dominant mass is routinely
the omentum in this disease, one could argue for prophylactic omentectomy at the time of a
prophylactic bilateral salpingo-oophorectomy and hysterectomy. This may provide additional
prophylaxis of another site at risk for malignant change in women with BRCA1/2 mutations.
The benefits of such a surgical approach are theoretical only. The incidence of serous cancers of
the peritoneum in patients with BRCA1/2 germ line mutations remains unknown. Short followup in many studies limits our opportunity to know how great a risk a patient truly is for a primary
peritoneal cancer and who among the BRCA1 and BRCA2 germline mutation carriers is at high
risk for this disease. Of course, one should routinely perform peritoneal washings at the time of
prophylactic oophorectomy to identify malignant cells that might establish the presence of an
occult primary peritoneal cancer.
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