Compared to the general population, women with mutations in the BRCA1 or BRCA2 genes have a significantly higher lifetime risk of ovarian and breast cancers (Science. 2003 Oct 24;302:643-6). Since the occurrence of ovarian and breast cancer in BRCA carriers is often prior to menopause, and because we have no screening test to detect early stage ovarian cancer, risk-reducing salpingo-oophorectomy has been recommended around age 40.
It has been shown that risk-reducing salpingo-oophorectomy significantly reduces ovarian cancer risk by 85%-95% in BRCA-affected women. Also, this surgery can reduce breast cancer risk by 53%-68% (N Engl J Med. 2002 May 23;346:1609-15). The 2008 Practice Bulletin from the American College of Obstetricians and Gynecologists recommends that risk-reducing salpingo-oophorectomy should be performed in women with BRCA1 or BRCA2 mutations after the completion of childbearing or age 40 (Obstet Gynecol. 2008 Jan;111:231-41).
Nearly 60% of women who have a BRCA1 or BRCA2 mutation will elect to undergo risk-reducing salpingo-oophorectomy between the ages of 35 and 40 years (Open Med. 2007 Aug 13;1:e92-8). As such, surgical menopause can result in hot flashes, vaginal dryness, sexual dysfunction, sleep disturbances, and cognitive changes, which may significantly impact a woman’s quality of life. In addition, increased risk of cardiovascular disease and osteoporosis following bilateral salpingo-oophorectomy may have a significant impact on a woman’s health.
Since these women undergo surgical menopause as opposed to natural menopause, they have an abrupt loss in hormones, and due to their younger age at the time of surgery, they may also have a longer exposure period to the detrimental effects of hypoestrogenism.
Various treatment options exist for relief of menopausal symptoms, including nonhormonal therapies and hormone replacement therapies (HT).
Nonhormonal therapies include serotonin receptor inhibitors (venlafaxine and paroxetine) and alpha-2 adrenergic agonists (clonidine), which are most appropriate for the treatment of vasomotor symptoms. Unfortunately, these options have proved to be as effective as HT. Also, women should be adequately counseled regarding the various side effects of these nonhormonal medications. Alternative approaches such as phytoestrogens are unproven and are still undergoing investigation. As such, HT remains the standard for treatment of menopausal symptoms, and many trials have confirmed that HT can effectively treat menopausal symptoms following risk-reducing salpingo-oophorectomy.
This then raises the question of safety regarding use of HT in this patient population; especially the possibility of increased risk of breast cancer. Interestingly, only 10%-25% of BRCA1 carriers will have estrogen receptor–positive breast cancer, while 65%-79% of BRCA2-associated breast cancers will be positive for the receptor (Clin Cancer Res. 2004 Mar 15;10:2029-34).
Unfortunately, we do not have adequate trials or studies with sufficient long-term follow-up to validate whether HT increases the risk of breast cancer or recurrence. However, the PROSE Study Group did report on a prospective cohort of 462 women with BRCA1 or BRCA2 mutations. In this study, HT did not alter the reduction in breast cancer risk from risk-reducing salpingo-oophorectomy (J Clin Oncol. 2005 Nov 1;23:7804-10). In addition to a paucity of data regarding systemic HT, there is little data in the BRCA-positive population to confirm the safety of local vaginal estrogen for treatment of vaginal atrophy (J Clin Oncol. 2004 Mar 15;22:1045-54).
Understanding the options
Use of HT in women with BRCA1 and BRCA2 mutations requires further investigation. There should be shared decision making between the patient and provider when counseling on the management of menopausal symptoms following risk-reducing salpingo-oophorectomy. Most importantly, women should understand the options of nonhormonal therapies and their specific side effects. They should also understand the lack of significant data regarding use of systemic HT, and that if use is elected, there may be an increased risk of breast cancer.
Women who do elect to use systemic HT following risk-reducing salpingo-oophorectomy have options that can help reduce the risk of HT-associated breast cancer, including a shorter duration of systemic HT or concurrent hysterectomy to allow for estrogen-only HT, which has a decreased risk of breast cancer compared with combined therapies that include progestins. These women may also be considering prophylactic mastectomy, which would change the concerns regarding HT and an increased risk of breast cancer.
Increased awareness of these options among physicians and patients alike can help to decrease unsatisfactory symptoms and improve quality of life in women undergoing risk-reducing salpingo-oophorectomy.
Dr. Staley is a resident physician in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. They reported having no relevant financial disclosures. Email them at [email protected].