Hormone therapy after prophylactic risk-reducing bilateral salpingo-oophorectomy in women who have BRCA gene mutation

Abstract

Women with a BRCA1 or BRCA2 gene mutation have substantially higher risk for developing not only breast and ovarian cancers, but also for primary peritoneal, Fallopian tube, colonic, pancreatic cancers, uterine papillary serous adenocarcinoma and malignant melanoma.

The risk for ovarian cancer ranges from 39 to 49% by 70 years of age in BRCA1 mutation carriers and from 11 to 18% for those with a BRCA2 mutation, whilst breast cancer increases similarly within women who have either the BRCA1 mutation or the BRCA2 mutation, from about 20% in women in their forties, 37% by the age of 50 years, 55% by 60 years and more than 70% by the age of 70 years.

Prophylactic risk-reducing bilateral salpingo-oophorectomy (RRBSO) provides significantly greater benefits with the view of reducing the risk for gynecological and breast cancer (decreasing ovarian cancer risk by 85–95%, breast cancer risk by about 53–68% and removes occult or undetected cancers in 2–18% of such women) compared to other conservative options, namely screening/surveillance or use of chemopreventative agents.

RRBSO will result in significant menopausal symptoms, increased risk for bone mineral loss, increasing risk for osteopenia and osteoporosis, and cognitive dysfunction. Risk for cardiovascular disease is also increased if the procedure is performed in women less than 50 years of age.

This article analyzes the role of RRBSO in women with BRCA1/BRCA2 mutations with no personal history of breast cancer and the impact of hormone therapy on risk for breast and gynecological cancers if used after the procedure to alleviate the resulting menopausal symptoms.

Keywords:

• BRCA gene mutation carriers
• prophylactic risk-reducing bilateral salpingo-oophorectomy
• hormone therapy
• risk for gynecological and breast cancers

Women with a germline mutation in BRCA1 or BRCA2 genes have substantially higher risk for developing not only breast and ovarian cancers, but also for primary peritoneal, Fallopian tube, colonic, pancreatic cancers, uterine papillary serous adenocarcinoma and malignant melanoma. Overwhelmingly though, the primary concerns pertain to the development of breast and ovarian cancers. About 84% of hereditary breast cancers and more than 90% of hereditary ovarian cancers are caused by mutations in BRCA1 and BRCA2 genes^1,2.

The risk for ovarian cancer seems to differ according to whether the woman has BRCA1 or BRCA2 gene mutations, namely, the risk ranges from 39 to 49% by 70 years of age in BRCA1 mutation carriers and from 11 to 18% for those with a BRCA2 mutation³. Among women with a BRCA1 mutation, the risk of ovarian cancer starts to increase late in the fourth decade of life, with about 3% developing the cancer by 40 years of age, whilst, in women with BRCA2 mutations, about 3% will develop gynecological cancer by 50 years of age^4,5.

Conversely, breast cancer increases similarly within women who have either the BRCA1 mutation or the BRCA2 mutation, from about 20% in women aged in their forties, 37% by age 50 years, 55% by 60 years and more than 70% by the age of 70 years^4,5. About 10–24% of BRCA1-associated breast cancers and 65–79% of BRCA2-associated breast cancers are estrogen receptor-positive, a statistic that may be pertinent when considering long-term management of these women^6,7.

A careful search was undertaken of articles published in the English literature and the research tools used included PubMed, Medline and Google Scholar. The search words included “women with BRCA1/BRCA2 mutations”, “risk reducing”, “prophylactic”, “bilateral salpingo-oophorectomy”, “hormone therapy”, “estrogen therapy”, “estrogen and progesterone therapy”, “gynecological and breast cancer risk”. A total of 35 articles were identified that were of value but only 11 were specific to the title of this review.

Management strategies of women with BRCA1 and BRCA2 gene mutations with no personal history of breast or ovarian cancers are not clearly defined and include surveillance, chemopreventative measures or prophylactic risk-reducing bilateral salpingo-oophorectomy (RRBSO). The latter will reduce cancer mortality in women with BRCA gene mutation far more than what can be achieved with surveillance/screening or by using chemopreventative agents, with data to support that RRBSO not only reduces breast cancer risk by about 53–68% and ovarian cancer risk by 85–95%, but it will also remove occult or undetected cancers in 2–18% of such women^8,9.

On the one hand, RRBSO will result in a significant decrease in breast and gynecological cancers, but it will also result in a surgically induced sudden-onset menopause with all its accompanying symptoms of severe hot flushes, vaginal dryness, sexual dysfunction, sleep disturbances, osteoporosis and cognitive dysfunction. There is also now fairly substantive evidence to support that, if RRBSO is performed in women younger than 50 years of age, the risk for cardiovascular disease is increased, and, although there is no obvious increased risk of death from cardiovascular disease if it is performed in the older women when compared to women who have not had RRBSO, mortality is higher if the RRBSO is performed in women less than 45 years old^10,11. Desired fertility, wish to bear children, age and the timing of breast and ovarian cancer will obviously impact whether RRBSO is the appropriate choice and when the procedure should be performed.

In accordance with the above perspectives, it would therefore be appropriate to recommend that RRBSO is performed between 35 and 40 years of age in women with BRCA1 mutation, preferably after completing their family, whilst the procedure could be delayed until 45–50 years of age in women with BRCA2 mutations¹². In both cases, concomitant hysterectomy should ideally be included so as to completely excise the Fallopian tubes in order to avoid the theoretical risk of the cancer developing in the interstitial component of the Fallopian tube, to reduce the risk of endometrial pathology in women taking tamoxifen therapy and to simplify hormone therapy so that estrogen-only therapy is given, eliminating the concomitant use of progestogens, which appears to be responsible for the increase in possible risk for breast cancer¹³.

The rate of occult or undetected ovarian and Fallopian tube cancer is not known exactly but their presence seems to depend on the age of the patient at the time of the surgery and the thoroughness and extent of the histological examination of the operative specimens by the pathologist. Many of the occult cancers are microscopic and require serial sectioning of the ovarian and Fallopian tube specimen, with particular emphasis on detailed examination of the fimbrial end of the Fallopian tube. This ideally mandates examination at 2–3-mm intervals of both the ovary and the Fallopian tube. Appropriate treatment strategies can then be instituted to prevent invasive or recurrent disease¹⁴.

RRBSO is the preferred recommendation, but, as an alternative and less radical option, bilateral salpingectomy only, as opposed to bilateral salpingo-oophorectomy, has been mooted as the initial option for the younger woman in her forties with BRCA mutations; this would remove the possible impact of the Fallopian tube playing a role in the development of ovarian cancer, but would preserve the presence of the ovary and its ongoing supply of estrogen. The definitive RRBSO can then be undertaken between 50 and 52 years of age, when the onset of the natural menopause would be expected. This option will obviously not offer as much protection from cancer risk but it will address the concern that RRBSO at an early age will increase mortality because of cardiovascular disease. Two fairly recent studies have reported that women who have had bilateral oophorectomy at less than 45 years of age experience increased mortality due to cardiovascular disease compared to women who have not had the surgical procedure (hazard ratio (HR) 1.44; 95% confidence interval (CI) 1.01–2.05). The risk was higher for those not treated with estrogen than for those treated with hormone therapy (HR 1.84 vs. 0.65)¹⁵. A meta-analysis by Atsma and colleagues showed that natural menopause did not increase the risk for cardiovascular disease, whilst bilateral oophorectomy before the age of 50 years did (relative risk 4.55)¹⁶.

RRBSO provides significantly greater benefits with a view to reducing the risk for gynecological and breast cancer compared to other conservative options. In a meta-analysis of eight studies, Rebbeck and colleagues showed that RRBSO was associated with a statistically significant reduction in breast cancer risk for both BRCA1 (HR 0.47; 95% CI 0.35–0.64) and BRCA2 (HR 0.47; 95% CI 0.26–0.84) mutation carriers¹⁷, but it results in early menopause and, as stated before, could potentially increase mortality from cardiovascular disease.

In addition to the above, it has been shown that RRBSO, particularly if performed prior to 50 years of age, commonly results in significant hot flushes, night sweats, vaginal dryness and sexual function, all factors that will have a substantial negative impact on quality of life in these women. RRBSO also leads to a greater decline in bone density, increasing the incidence of osteopenia and osteoporosis and cognitive function compared to women undergoing screening or surveillance^17–20. Despite the disturbing symptoms which result from RRBSO, the uptake of this prophylactic surgery ranges from 60 to 90% among women who are BRCA mutation carriers and appears to be well received, although the decision to pursue with the surgery is invariably influenced by the age of the woman, the perceived cancer risk and perceived benefits of the surgery.

Even though RRBSO is a most effective management option, there is still the dilemma of managing the resulting menopausal symptoms. Finch and colleagues addressed very appropriately the earlier studies of outcome in women who have had RRBSO and the impact of the different management strategies⁹. Although there are a number of alternative options to managing the resulting menopausal symptoms, of which selective serotonin reuptake inhibitors or selective norepinephrine reuptake inhibitors are certainly effective, it has been shown that hormone therapy, either as estrogen-only or estrogen + progesterone therapy, still remains the most effective modality to manage the menopause and its symptoms. Women who took hormone therapy experienced fewer and less severe vasomotor symptoms and significantly less vaginal dryness and sexual discomfort than did women who did not take hormone therapy after surgery²¹.

The question, though, is whether hormone therapy is safe in women who are BRCA1 or BRCA2 gene carriers and have had RRBSO, especially if it was performed at less than 50 years of age? The obvious concern pertains possibly to increasing the risk for breast cancer if hormone therapy is used after the RRBSO. There is no obvious evidence that the risk for ovarian cancer will be increased if hormone therapy is used and there are certainly no data to support that there will be any impact on the risk for primary peritoneal, Fallopian tube or pancreatic carcinoma^22–24.

Using a Markov decision analytic model to assess the expected outcomes of RRBSO with or without hormone therapy, it was shown that life expectancy was increased by 3.34–4.65 years, depending at what age the procedure was performed and irrespective of whether hormone therapy was used or not. Use of hormone therapy was associated with only small changes in life expectancy, from +0.17 to –0.34 years and stopped at 50 years of age. If these women had a bilateral mastectomy and RRBSO, life expectancy was increased by 0.39–0.79 years if hormone therapy was also used. The recommendation made by the authors was therefore to use hormone therapy until about 50 years of age, with the primary purpose to improve quality of life, knowing that it will not impact on quantity of life to any substantial effect. After 3.6 years, hormone therapy following RRBSO will not significantly impact on the beneficial decrease in breast cancer risk as a result of the RRBSO²⁵. In another matched controlled study of 462 postmenopausal women with BRCA1 gene mutation, neither the use of estrogen-only therapy or combined estrogen + progestogen therapy was associated with an increase in breast cancer risk. In this study, 28 women took estrogen only and 19 used estrogen + progestogen therapy. An inverse association between estrogen-alone use (odds ratio (OR) 0.51; 95% CI 0.27–0.98) and breast cancer risk was observed, whereas no significant association was seen between combination therapy and risk of breast cancer (OR 0.66; 95% CI 0.34–1.27)²⁶, whilst in a respective study of 73 female BRCA1/2 mutation carriers who underwent RRBSO and in which 33 women took postoperative hormone therapy, there were three breast cancers amongst the women taking hormone therapy compared to nine in the 29 women not using hormone therapy.

In conclusion, it is apparent that RRBSO in women without a personal history of breast cancer and with BRCA1 and BRCA2 mutations plays an important role in the management of these women, particularly if the procedure is performed in women aged 35–40 years. It significantly decreases the risk of gynecological and breast cancer but, of necessity, will result in significant menopausal symptoms and even a possible greater risk of mortality from cardiovascular disease. Despite the limitation of retrospective and prospective observational studies, and despite the fact that the pool of patients who have been analyzed is limited in number and that there are no randomized studies, there is no obvious information to suggest that short-term use of estrogens, be it estrogen-only or estrogen + progestogens therapy, is detrimental in these women after the RRBSO. Hormone therapy significantly decreases menopausal symptoms and does not increase the risk of breast or ovarian cancer, even though it does not specifically increase longevity. Although hormone therapy appears a plausible option to manage the menopausal symptoms in these women, there are little data specifically alluding to the impact in women who have BRCA2 gene mutation. Breast tumors in women with BRCA1 mutation are commonly estrogen-, progesterone- and HER 2 receptor-negative, adding more biological weight to the argument that hormone therapy should not be detrimental; about two-thirds of breast cancers in women who have BRCA2 mutation are estrogen receptor-positive, and thus more evidence is needed that, in these women, hormone therapy is safe. There is also a significant paucity of data on the impact of androgen hormone therapy in these patients. Larger randomized studies are obviously still required^27–29.

Source of funding

Nil.

Conflict of interest

The author reports no conflict of interest. The author alone is responsible for the content and writing of this paper.