Risk-Reducing Bilateral Salpingo-Oophorectomy for BRCA Mutation Carriers and Hormonal Replacement Therapy: If It Should Rain, Better a Drizzle than a Storm

Abstract

Women carrying a BRCA mutation have an increased risk of developing breast and ovarian cancer. The most effective strategy to reduce this risk is the bilateral salpingo-oophorectomy, with or without additional risk-reducing mastectomy. Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is recommended between age 35 and 40 and between age 40 and 45 years for women carriers of BRCA1 and BRCA2 mutations, respectively. Consequently, most BRCA mutation carriers undergo this procedure prior to a natural menopause and develop an anticipated lack of hormones. This condition has a detrimental impact on various systems, affecting both the quality of life and longevity; in particular, women carrying BRCA1 mutation, who are likely to have surgery earlier as compared to BRCA2. Hormonal replacement therapy (HRT) is the only effective strategy able to significantly compensate the hormonal deprivation and counteract menopausal symptoms, both in spontaneous and surgical menopause. Although recent evidence suggests that HRT does not diminish the protective effect of RRBSO in BRCA mutation carriers, concerns regarding the safety of estrogen and progesterone intake reduce the use in this setting. Furthermore, there is strong data demonstrating that the use of estrogen alone after RRBSO does not increase the risk of breast cancer among women with a BRCA1 mutation. The additional progesterone intake, mandatory for the protection of the endometrium during HRT, warrants further studies. However, when hysterectomy is performed at the time of RRBSO, the indication of progesterone addition decays and consequently its potential effect on breast cancer risk. Similarly, in patients conserving the uterus but undergoing risk-reducing mastectomy, the addition of progesterone should not raise significant concerns for breast cancer risk anymore. Therefore, BRCA mutation carriers require careful counselling about the scenarios following their RRBSO, menopausal symptoms or the fear associated with HRT use.

Management of patients with BRCA mutation from the point of view of a breast surgeon

“…Women with BRCA1 mutation are recommended prophylactic bilateral salpingo-oophorectomy (PBSO) at the age between 35 and 40. Women with BRCA2 mutation are recommended the same procedure at a later age, preferably between 40 and 45 [ 30 ]. The benefit of this procedure is a reduction of ovarian cancer incidence of 96% and a reduction in breast cancer incidence of up to 50% [ 31 ].…”

“…Hormone replacement therapy (HRT) is the only effective strategy to compensate for the lack of hormones induced surgically. The addition of estrogen alone does not increase the risk of breast cancer in these women but the addition of progesterone, which is needed to protect the endometrium, is not adequately studied to confirm its safety ([ 30 , [44] , [45] , [46] ]). The risk associated with progestins/progesterone may be of little clinical impact in women undergoing both PBSO and RRM [ 30 ].…”

“…The addition of estrogen alone does not increase the risk of breast cancer in these women but the addition of progesterone, which is needed to protect the endometrium, is not adequately studied to confirm its safety ([ 30 , [44] , [45] , [46] ]). The risk associated with progestins/progesterone may be of little clinical impact in women undergoing both PBSO and RRM [ 30 ]. The reduction of breast cancer risk for BRCA positive women with pre-menopause due to PBSO is not affected using HRT([ 45 , 47 ]).…”

Ovarian reserve of women with and without BRCA pathogenic variants: A systematic review and meta-analysis

“…Once the BRCA1m is detected, NCCN guidelines clearly recommend risk-reducing bilateral salpingo-oophorectomy between ages 35 and 40 and upon completion of childbearing [ 2 ]. The early onset of menopause in these patients is currently a topic of interest and strategies to reduce the symptoms are currently promoted [ 33 ]. However, many women are nulliparous when they receive this diagnosis and there is no specific recommendation for routine evaluation of fertility potential and ovarian reserve in female BRCAm carriers.…”

<p>Subsequent Development of Epithelial Ovarian Cancer After Ovarian Surgery for Benign Ovarian Tumor: A Population-Based Cohort Study</p>

“…Finally, we had neither profile of gene (for example, BRCA status) nor the data of parity, and also did not have information about the detailed of infertility and other surgery or medication history, such as oral contraceptive, hormone therapy in the database, all of which are associated with the increased or decreased risk of development of EOC. [111][112][113][114][115] In Taiwan, the examination of BRCA status is not covered by insurance of the Taiwan Bureau of National Health Insurance and Ministry of Health and Welfare. There are many current clinical studies showing better outcomes in EOC patients with BRCA1/BRCA2 mutants after maintenance therapy of PARP inhibitors.…”