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Abstract

Owing to the significant breast cancer risk associated with BRCA1 or BRCA2 mutations, women with these mutations have several options available to them by which to reduce the risk of breast cancer. These include surgical (prophylactic mastectomy and prophylactic oophorectomy) and medical (chemoprevention) options. The breast cancer risk reductions associated with these options range from a 90% risk reduction associated with prophylactic mastectomy to approximately 50% with oophorectomy or tamoxifen. This article reviews the efficacy of prophylactic oophorectomy for the prevention of breast cancer in BRCA1 and BRCA2 mutation carriers. The predictors of uptake of the preventive surgery will be discussed, in addition to the psychosocial implications of the surgery.

Keywords

BRCA1 BRCA2 breast cancer prophylactic salpingo-oophorectomy

Background

Clinical genetic testing for BRCA1 and BRCA2 mutations has been available since 1995. Based on a large combined analysis, for women who are identified as having a mutation in BRCA1 the risk of breast cancer is 65% and the risk of ovarian cancer is 39%; for women with a BRCA2 mutation, the risk for breast cancer is 45% and the risk for ovarian cancer is 11% [1]. These cancer risks can be compared with the general population risks of 11 and 1.4% for breast and ovarian cancer, respectively. In addition to these increased risks, women with BRCA1 or BRCA2 mutations are often diagnosed at younger ages than women in the general population.

There are differences in the breast cancer phenotypes observed in BRCA1 compared with BRCA2 mutation carriers. Estrogen receptor status has been demonstrated to be different in these two groups of women. Only 10–24% of BRCA1-associated breast cancers are ER-positive, compared with 65-79% of BRCA2-associated breast cancers [2,3]. This may have implications for the ways in which BRCA breast cancers are treated and the effectiveness of breast cancer risk-reduction strategies.

Options for breast cancer risk reduction

Owing to the significant breast cancer risk associated with BRCA1 or BRCA2 mutations, women with these mutations have several options available to reduce the risk of breast cancer. These include surgical (prophylactic mastectomy and prophylactic oophorectomy) and medical (chemoprevention) options. Breast cancer risk reductions associated with these options range from 90% risk reduction associated with prophylactic mastectomy [4,5] to approximately 50% with oophorectomy or tamoxifen [6 –9]. In addition, there are medical and psychological risks and benefits associated with each option. The remainder of this review focuses on prophylactic oophorectomy for breast cancer prevention.

Prophylactic salpingo-oophorectomy

A prophylactic salpingo-oophorectomy (PSO) involves the removal of both the ovaries and fallopian tubes. It is important that the fallopian tubes are removed since they have become recognized as an important site of occult cancer in BRCA1 and BRCA2 mutation carriers who have undergone prophylactic oophorectomy [10 –13]. Currently, PSO is the most effective option available to women with BRCA1 or BRCA2 mutations by which to prevent ovarian cancer [8,14].

Although it was recognized that PSO would reduce the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers, it was unclear if the procedure would also reduce the risk of breast cancer in this group of high-risk women. In 2002, the first two studies investigating the breast cancer risk reduction associated with prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers were reported [8,15]. Kauff et al. followed 170 BRCA1 and BRCA2 mutation carriers over the age of 35 years for a mean time of 24.2 months [15]. Of the 98 women who underwent PSO, three (3%) developed breast cancer compared with eight of 72 women (11%) who chose surveillance. Similar findings were reported by Rebbeck et al. in a retrospective study of 99 women who had undergone PSO compared with 142 matched controls [8]. The follow-up period was greater than 8 years. Of the 99 women who had undergone PSO, 21 (21%) developed breast cancer compared with 60 (42%) in the control group (hazard ratio [HR] = 0.47; 95% CI: 0.29–0.77). This suggested that PSO was associated with a 53% breast cancer risk reduction. In both of these early studies, there were no specific analyses undertaken to examine the effectiveness of PSO in the prevention of breast cancer specifically for BRCA1 versus BRCA2.

In 2005, Eisen et al. presented a large, international, retrospective study of 1439 women with breast cancer and 1866 matched controls [6]. They reported that a previous history of oophorectomy was associated with a significant 56% reduction in the breast cancer risk for BRCA1 mutation carriers (odds ratio [OR] = 0.44; 95% CI: 0.29–0.66) and a 46% risk reduciton for BRCA2 mutation carriers (OR = 0.57; 95% CI: 0.28–1.15). The protective effect was evident for 15 years post-oophorectomy. This study suggested that PSO may be more effective in preventing breast cancer in BRCA1 mutation carriers compared with BRCA2 mutation carriers.

In contrast to this finding, Kauff et al. reported on 579 women without breast cancer (368 BRCA1 and 229 BRCA2) in a prospective follow-up study [7]. Women self-selected PSO or observation. During a 3-year follow-up period, PSO was associated with a 39% breast cancer risk reduction in BRCA1 mutation carriers (HR = 0.61; 95% CI: 0.30–1.22; p = 0.16) and a 72% risk reduction in BRCA2 mutation carriers (HR = 0.28; 95% CI: 0.08–0.92; p = 0.04). These results suggested that PSO was more effective for BRCA2 mutation carriers than BRCA1 mutation carriers. Although the results of these two studies differ in the effectiveness of PSO in BRCA1 versus BRCA2 mutation carriers, they both support the hypothesis that estrogen deprivation reduces the risk of breast cancer. This has also been supported by research on tamoxifen (antiestrogen) and breast cancer risk (both bilateral and contralateral) [9,16]. All research published to date suggests that PSO is effective at reducing the risk of breast cancer in women with a BRCA1 or BRCA2 mutation (between 39 and 72%) ( Table 1 ).

Table 1.

Summary of studies on breast cancer risk reduction and prophylactic oophorectomy.

Study	No. of carriers included	Mean follow-up	Breast cancer relative risk reduction (1-RR)(%)	Ref.
Kauff et al. (2002)	170 (98 oophorectomy; 72 surveillance)	24.2 months 68	[15]
Rebbeck et al. (2002)	241 (99 oophorectomy; 142 matched controls)	10.7 years (prophylactic oophorectomy) 53 11.9 years (controls)	[8]
Eisen et al. (2005)	Cases: 1439 with breast cancer; Matched controls: 1866 without breast cancer	Not applicable 56	(BRCA1) 46 (BRCA2)	[6]
Kramer et al. (2005)	98 BRCA1 (33 oophorectomy; 65 surveillance)	14.1 years	62	[28]
Kauff et al. (2008)	597 (303 oophorectomy; 294 surveillance)	36.4 months	39 (BRCA1) 72 (BRCA2)	[7]

For PSO to be effective at reducing the risk of breast cancer in BRCA1 and BRCA2 mutation carriers, the procedure must be carried out at an earlier age than when breast cancers are first observed in this group of women. This suggests that the procedure should be ideally performed between 40 and 45 years of age. In addition, research has shown that the level of breast cancer risk reduction is associated with age at PSO, probably owing to the amount of estrogen production. Although women may want to wait until the onset of menopause to have a PSO because of the side effects associated with the surgery, research suggests that PSO should be carried out earlier for maximum breast cancer risk reduction. In the large, international study of BRCA1 and BRCA2 mutation carriers by Eisen et al., age at oophorectomy was found to be associated with breast cancer risk reduction [6]. Women with oophorectomy under the age of 40 years gained the greatest breast cancer risk reduction of 67% (OR = 0.33; 95% CI: 0.15–0.73; p = 0.006). Having the preventive surgery between the ages of 41 and 50 years also offered a significant breast cancer risk reduction (OR = 0.43; 95% CI: 0.25–0.72; p = 0.001). However, having the surgery after the age of 50 years did not significantly reduce a woman's breast cancer risk (OR = 0.64; 95% CI: 0.35–1.17; p = 0.14). It is unclear if there are age differences for BRCA1 mutation carriers compared with BRCA2 mutation carriers. There have been no other studies conducted with a sample size this large that would enable subanalyses on age groups. Although this study suggests that a younger age of PSO is beneficial in terms of breast cancer prevention, other issues including family planning and premature estrogen deficiency must also be considered.

Uptake of prophylactic salpingo-oophorectomy

Many single country studies have reported on uptake rates of PSO by BRCA1 and BRCA2 mutation carriers, and uptake is generally greater than 50% [17 –20]. Recently, a large international study was published that investigated the uptake of preventive options by 2677 BRCA1 and BRCA2 mutation carriers from nine countries [21]. Overall, 57.2% of BRCA1 and BRCA2 mutation carriers elected for a prophylactic oophorectomy. However, there were great discrepancies in the uptake of oophorectomy by BRCA1 and BRCA2 mutation carriers by country of residence, ranging from 35 to 71%. This suggests that there may be a cultural influence on uptake of cancer preventive options. More research is needed in this area in order to determine why there are such differences in uptake of preventive procedures by BRCA1 and BRCA2 mutation carriers.

It has been shown that there are patient characteristics that predict uptake of PSO, including age, family history of cancer, personal history of breast cancer and type of mutation. Although research has demonstrated that a younger age of PSO confers greater breast cancer risk reduction [6], older age has been shown to be a predictor of uptake of oophorectomy [17,18,20]. In the large, international study of BRCA1 and BRCA2 mutation carriers by Metcalfe et al., 26% of women aged 40 years or younger had PSO compared with 70% of women age 41 years or older [21].

A family history of cancer has been shown to influence decisions regarding breast cancer prevention. In a Canadian study of 517 women with BRCA1 or BRCA2 mutations, a family history of cancer significantly predicted the uptake of PSO [22]. Having a mother or sister with ovarian cancer significantly predicted uptake of prophylactic oophorectomy (OR = 1.6; p = 0.04). In addition, women with a mother with breast cancer were less likely to have a prophylactic oophorectomy compared with women whose mothers had not been diagnosed with breast cancer (OR = 0.64; p = 0.03). This has also been demonstrated in an American study of women at increased risk of breast and ovarian cancer [23]. Women with a family history of ovarian cancer were more than twice as likely to have PSO compared with women without a family history of ovarian cancer.

Although PSO is effective at preventing breast cancer, it is also very effective at preventing ovarian cancer in women with a BRCA1 or BRCA2 mutation [14]. In addition, PSO has been demonstrated to be effective in reducing the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers [16]. For this reason, women who have previously been diagnosed with breast cancer may elect for PSO in order to prevent ovarian cancer, and previous research has demonstrated that a personal history of breast cancer is a predictor of uptake of PSO [17,21]. In an international study of BRCA1 and BRCA2 mutation carriers, a higher proportion of women with a history of breast cancer had a prophylactic oophorectomy (65.7%) compared with women without breast cancer (42.9%; p < 10⁻⁴) [21].

Although there is no clear consensus on the difference in effectiveness of PSO in preventing breast cancer in BRCA1 versus BRCA2 mutation carriers, there have been differences in uptake of PSO reported between the two groups. In a large Canadian study of BRCA1 and BRCA2 mutation carriers, women with a BRCA2 mutation were less likely to have a prophylactic oophorectomy than women with a BRCA1 mutation (OR = 0.5; p = 0.008) [22]. This may be due to the higher risk of ovarian cancer in BRCA1 mutation carriers compared with BRCA2 mutation carriers.

Psychosocial implications

Although PSO offers a significant breast and ovarian cancer risk reduction in BRCA1 and BRCA2 mutation carriers, there are side effects that should be considered when making decisions about breast cancer prevention. When a premenopausal woman has an oophorectomy, she is immediately placed into menopause and as a result, experiences menopausal symptoms. Although this is not the focus of this paper, the effects of premature surgical menopause on overall health need to be carefully considered. Hormone therapy (HT) is an option for women who experience menopausal symptoms. However, there has been concern that HT use would increase a woman's risk of developing breast cancer. In a recent large, matched case–control study, Eisen et al. reported that among postmenopausal women with a BRCA1 mutation, HT was not associated with an increased risk of breast cancer [24].

Menopausal symptoms may influence psychosocial functioning in women who undergo prophylactic oophorectomy. There is limited research describing the psychosocial impact of having a prophylactic oophorectomy. Elit et al. conducted a retrospective study of 40 women who had undergone a prophylactic oophorectomy for a family history of ovarian cancer [25]. The mean age of the women at time of oophorectomy was 50 years and the mean age at the time of questionnaire completion was 55 years. Standardized psychosocial questionnaires were used to measure various psychosocial attributes. Women in the study had a good quality of life and a significant decrease in cancer risk perception as a result of the surgery. However, they experienced menopausal symptoms and compromised sexual functioning. A larger study of 846 Dutch women who had undergone prophylactic oophorectomy had similar findings [26]. Compared with gynecologic screening, women with an oophorectomy had fewer breast and ovarian cancer worries (p < 0.001) and more favorable cancer risk perception (p < 0.05). However, the oophorectomy group reported significantly more endocrine symptoms (p < 0.001) and worse sexual functioning (p < 0.05) than the screening group.

The impact of PSO on cancer-related anxiety has also been studied. In an Australian study, Tiller et al. conducted a prospective study of 95 women who were initially assessed at a familial cancer clinic and followed-up 3 years later [27]. There was a higher decrease in cancer-related anxiety for women who had undergone prophylactic oophorectomy compared with those who had not (Z = −2.19; p = 0.03).

The research to date suggests that PSO offers both psychosocial risks and benefits. Women generally have lower cancer risk perception and lower cancer-related anxiety. However, the sexual side effects associated with the surgery and resulting menopause are also evident. In the majority of studies that have examined psychosocial implications of PSO, the average age of subjects has been approximately 50 years, which is close to the age of natural menopause. However, PSO is generally recommended to BRCA1 and BRCA2 mutation carriers at an age younger than 50 years. Therefore, it is unclear if psychosocial implications after PSO in younger women would be the same as those reported previously. More research is needed in this area.

Conclusion

Prophylactic salpingo-oophorectomy is effective at preventing both breast and ovarian cancer in women with BRCA1 or BRCA2 mutations. For maximum breast cancer risk reduction, PSO should be conducted around the age of 40 years. However, older age has been shown to be associated with uptake of PSO. In addition, women with a family history of ovarian cancer, those with a BRCA1 mutation and those with a personal history of breast cancer have the highest uptake rates of PSO. As with any preventive option, there are psychosocial implications associated with the procedure; however, more research is needed in this area.

Future perspective

Many women with BRCA1 and BRCA2 mutations are electing for a PSO. Research has shown that it significantly reduces a woman's risk of developing breast cancer, especially if it is carried out at a young age (before 50 years of age). However, there is little research addressing the psychosocial implications of PSO on women when they are having this surgery carried out prior to menopause. Future research is needed in this area.

Executive summary

Women with BRCA1 or BRCA2 mutations have a very high lifetime risk of developing breast and ovarian cancer.

Women have options to reduce their risk of cancer.

Options to reduce breast cancer risk include prophylactic mastectomy, prophylactic salpingo-oophorectomy and chemoprevention.

Prophylactic salpingo-oophorectomy offers both a breast cancer and ovarian cancer risk reduction.

Prophylactic salpingo-oophorectomy is associated with approximately a 50% reduction in risk of breast cancer.

There are side effects associated with the surgery that need to be considered.

Footnotes

Kelly A Metcalfe is supported by a New Investigator Award from the Canadian Institutes of Health Research and the Ontario Women's Health Council. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Oophorectomy for Breast Cancer Prevention in Women with Brca1 Or Brca2 Mutations

Abstract

Keywords

Background

Options for breast cancer risk reduction

Prophylactic salpingo-oophorectomy

Uptake of prophylactic salpingo-oophorectomy

Psychosocial implications

Conclusion

Future perspective

Footnotes

References