2005 © Oxford University Press
Reproductive Issues for Women With BRCA Mutations
Affiliations of authors: The Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (LCF); Breast Care Center, Baylor College of Medicine and The Methodist Hospital, Houston, Texas (LCF, RMK)
Correspondence to: Lois C. Friedman, PhD, Baylor College of Medicine, The Menninger Department of Psychiatry and Behavioral Sciences, One Baylor Plaza, Houston, TX 77030 (e-mail: loisf{at}bcm.tmc.edu).
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ABSTRACT |
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 Top Abstract REPRODUCTIVE ISSUES FOR WOMEN...CONCLUDING REMARKSReferences |
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Women carrying BRCA1 and BRCA2 mutations face difficult and confusing reproductive decisions that fall into three categories: issues relating to risk-reducing surgeries, issues relating to use of oral contraceptives/tubal ligation, and issues relating to pregnancy and breastfeeding. Risk-reducing surgeries may confer survival benefits, but they also affect quality of life. Oral contraceptives potentially protect mutation carriers against ovarian cancer but increase the risk of early-onset breast cancer, and evidence for the efficacy of tubal ligation in reducing ovarian cancer risk in BRCA mutation carriers is contradictory. Women with BRCA mutations may increase their risk of breast cancer by becoming pregnant before age 40 years, but breastfeeding may decrease risk of breast cancer in women with BRCA mutations, regardless of age. BRCA mutation carriers desiring to become pregnant must deal with a variety of psychosocial issues, some with significant ethical implications, with minimal guidance from research.
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REPRODUCTIVE ISSUES FOR WOMEN WITH BRCA MUTATIONS |
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TopAbstractREPRODUCTIVE ISSUES FOR WOMEN...CONCLUDING REMARKSReferences |
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Women who inherit BRCA1 or BRCA2 mutations have a 50%–80% lifetime risk of developing breast cancer (1,2) and a 16%–65% lifetime risk of developing ovarian cancer (2,3). These risks far exceed the lifetime risks of breast (13%) and ovarian (1.5%) cancer faced by women in the general population (4). Many women turn to genetic counseling and testing to learn about their risk status and its implications (5–7). Although most women who seek counseling and testing are past reproductive age, some still are in their childbearing years. Women carrying BRCA1 or BRCA2 mutations face difficult and confusing reproductive decisions.
Impact of Reproductive History on Cancer Risk
Women at general population risk of developing breast cancer who become pregnant for the first time at a young age have a decreased risk of developing breast cancer; those who delay childbearing to or beyond age 35 years have an increased risk (8). There also is evidence that women of all ages have an increased risk of breast cancer in the first 3–5 years after childbirth (9), and that the relationship between pregnancy and breast cancer risk may be mediated by length of time since the last birth.
The relationship between pregnancy and risk of breast cancer in BRCA1 and BRCA2 mutation carriers is less clear. Women with BRCA1/2 mutations who become pregnant before age 40 years (10–12) are at increased risk of developing breast cancer. Jernstrom et al. (12) analyzed the relationships among full-term pregnancy, number of births, and risk of breast cancer at age less than 40 years in women carrying deleterious mutations in BRCA1 (189 pairs) and BRCA2 (47 pairs). A previous full-term pregnancy was associated with an increased odds ratio of developing breast cancer before age 40 years in both BRCA1 (1.61; 95% confidence interval = 0.99 to 2.63; P = .05) and BRCA2 (2.13; 95% confidence interval = 0.86 to 5.56; P = .11) carriers. Risk increased with number of births, did not diminish with time since last pregnancy, and was not seen in mutation carriers diagnosed with breast cancer after age 40 years.
The literature presents some conflicting data, however. Rebbeck et al. (13) did not limit analysis according to age of cancer diagnosis and found that BRCA1/2 mutation carriers who were nulliparous or had their first live births after age 30 years had a greater risk of breast cancer than women whose first live births occurred before age 30 years. The women were mostly BRCA1 mutation carriers (82.6%), and analysis of this subset revealed results similar to the overall results. The number of women carrying BRCA2 mutations was too small to permit analysis of this subset alone. Tryggvadottir et al. (15) examined the relationship between reproductive history and breast cancer risk in a nested case–control study of Icelandic women who were positive for the 999del5 mutation in BRCA2 (15). This study did not analyze the relationship between nulliparity and cancer risk. However, the study did show that for those women with a full-term pregnancy, each additional birth was associated with an increased, but not statistically significant, risk of breast cancer. King et al. (14) analyzed the association of pregnancy and age of diagnosis of breast cancer in 1008 Ashkenazi Jewish women who carried mutations in the following: BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174del T. The researchers found that pregnancy (compared to nulliparity) was associated with delayed onset of breast cancer in carriers of both BRCA1 and BRCA2 mutations. Breastfeeding may reduce the risk of breast cancer among some BRCA mutation carriers (16). In a case–control study of BRCA1 and BRCA2 mutation carriers, breastfeeding conferred a protective effect on BRCA1 but not BRCA2 mutation carriers. BRCA1 carriers who breastfed for longer than 1 year were 40% less likely to develop breast cancer than those who breastfed for less than 1 year (17). Breastfeeding does not seem to protect against ovarian cancer in BRCA1/2 mutation carriers (18).
Psychosocial Aspects of Decisions About Risk-Reducing Surgeries
Although bilateral mastectomy provides the greatest amount of reduction of risk of developing breast cancer, it does not eliminate the risk totally, leaving an estimated residual risk of 10% (19–21). Bilateral oophorectomy reduces the risk of breast cancer in premenopausal women both in the general population and in BRCA mutation carriers (22,23). Bilateral oophorectomy also reduces the risk of ovarian cancer by approximately 96% (23) but leaves an estimated 2%–4% residual risk of peritoneal carcinomatosis (24). Given the benefits of these potentially risk-reducing surgeries, how frequently do women with BRCA1/2 mutations elect to have these procedures? In a study of unaffected women with BRCA1/2 mutations presenting to the Rotterdam Family Cancer Clinic, 51% chose to have bilateral mastectomies and 64% opted for bilateral oophorectomies (6). In contrast, in a Utah-based study of women with BRCA1 mutations 2 years after genetic testing, none had obtained a bilateral prophylactic mastectomy, and 46% had obtained bilateral oophorectomies (5). In a prospective study of the effect of BRCA1/2 testing on the use of risk-reducing oophorectomy (conducted at the free cancer genetic screening program at the Lombardi Cancer Center in Philadelphia, PA), 27% of mutation carriers, 2% of noncarriers, and 5% of patients who received uninformative test results obtained prophylactic oophorectomies within 1 year after testing (25). Differences in use of risk-reducing surgeries in these studies may reflect differences in follow-up times, cultural factors (26,27), or social or financial constraints (6). More prospective studies are needed.
Psychological Consequences of Bilateral Prophylactic Mastectomy
Although women may be encouraged by the potential benefit of risk-reducing mastectomy, they need to be cognizant of the potential consequences of this procedure on their quality of life. Research exploring the psychosocial impact of prophylactic mastectomy is sparse. Women generally are satisfied with their decision to have this surgery and experience few psychological difficulties (28–30). However, some women experience impaired body image and reduced sexual pleasure (31). A recent population-based study of women who had prophylactic mastectomies showed that younger women were less satisfied with their decisions than older women (32). About a third reported a change for the worse in their sexual lives, independent of whether they had reconstruction. Women who chose reconstruction were more satisfied with their bodies, but women in both groups felt a need to keep their bodies hidden and to avoid physical intimacy. Cancer-related distress was higher among those with BRCA mutations or strong family histories of breast cancer than among those without such histories.
Psychological Consequences of Bilateral Prophylactic Oophorectomy
Although women who have prophylactic oophorectomy generally show adequate health-related quality of life, a substantial number have symptoms of estrogen deprivation (24). In a cross-sectional study of high-risk women who had bilateral oophorectomies, overall quality of life was comparable to that in the general population: About one-fifth experienced intrusive thoughts and avoided cues related to ovarian cancer (33); more than 50% reported vaginal dryness; and over 40% reported lack of sexual desire and arousal, painful intercourse, and difficulty reaching orgasm. Women reporting these problems were significantly less satisfied with the decision to have surgery. Very few of these women were using hormone replacement therapy (33). Without subsequent hormone replacement therapy, women are at increased long-term risk for osteoporosis. The short- and long-term effects of estrogen deprivation in young women need to be carefully weighed.
Does hormone replacement therapy increase breast cancer risk in BRCA mutation carriers? Armstrong et al. (34) used a Markov decision analytic model to predict the outcome of bilateral risk-reducing oophorectomy in BRCA1/2 mutation carriers both with and without hormone replacement therapy. Hormone replacement therapy after oophorectomy was associated with a relatively small decline in life expectancy when the treatment was stopped at age 50 years but with a larger decrease when used for life. The authors recommend that deciding to have short-term hormone replacement therapy after oophorectomy should be based on quality of life rather than life expectancy considerations. Thought should be given to stopping treatment at the time of expected natural menopause. Despite Armstrong et al.'s analyses, Garber and Hartman (35) recommend that clinicians use caution when prescribing hormone replacement therapy to mutation carriers after risk-reducing oophorectomy.
Psychosocial Aspects of Decisions About Oral Contraceptives and Tubal Ligation
Long-term use of oral contraceptives is associated with a modest increase in breast cancer risk among women in the general population (36). Oral contraceptives may increase the risk of early-onset breast cancer among BRCA1 mutation carriers but also might protect them against ovarian cancer. Oral contraceptives do not appear to increase breast cancer risk among BRCA2 carriers (37). Although oral contraceptives reduce ovarian cancer risk in the general population (38), their effect on BRCA mutation carriers is unclear (18). Four case–control studies examined the effect of oral contraceptives on the risk of ovarian cancer among BRCA1 or BRCA2 carriers (39–42). Three showed that oral contraceptives were associated with decreased risk (24–26), but the fourth did not (42). One study demonstrated that duration of oral contraceptive use was inversely related to risk of ovarian cancer (39). The study that did not show a benefit from oral contraceptives focused on Israeli Jewish women positive for the Ashkenazi founder mutations (42). Few subjects had used oral contraceptives for more than 2 years.
Tubal ligation also decreases ovarian cancer risk in the general population (43), but its effect on BRCA1 mutation carriers is also unclear. An international case–control study (36,40) showed that tubal ligation decreased risk of ovarian cancer, but a case–control study of Jewish women with BRCA1 mutations failed to show that tubal ligation provided such protection (18). An understanding of how women make decisions about contraceptive use is important because women who are BRCA1 mutation carriers are less likely than noncarriers to want additional children (44). The psychosocial aspects of use of oral contraceptives and tubal ligation are unexplored areas of investigation and may pose challenges for genetic counselors and physicians counseling women who are BRCA1/2 mutation carriers.
Psychosocial Aspects of Decisions About Pregnancy and Prenatal Diagnostic Techniques
Results of predictive genetic testing for breast/ovarian cancer susceptibility may affect women's decisions about family planning. In a case–control study of men and women of reproductive age who were tested for a BRCA1 mutation, Smith et al. (44) found that 1 and 2 years after genetic testing, female carriers were less likely than female noncarriers to want additional children, a difference that was not found among male carriers. Future studies should evaluate whether such preferences actually result in decreased reproduction.
Women who carry BRCA1/2 mutations and want to become pregnant face a variety of psychosocial issues. Some may forego childbearing (44), but others hope that a cure for breast cancer will be available by the time their children grow up. Technologies such as prenatal diagnosis and preimplantation genetic diagnosis (PGD) can identify known BRCA mutations. Although elective termination of a pregnancy with a BRCA mutation is an alternative, only a minority of parents faced with bearing children susceptible to adult-onset diseases choose this option (45). Parents may find PGD more acceptable because only embryos carrying the target mutation are destroyed. In a study of 67 couples who already had undergone PGD, although about 40% found the procedure stressful, three-quarters of those contemplating a future pregnancy would choose PGD again, 16% would use prenatal diagnosis, and 8% no diagnostic procedure (46).
Ethical concerns may arise regarding whether prenatal diagnosis and PGD should be used for syndromes with relatively late onsets and incomplete penetrance that could be treated successfully without impairing quality of life. Additional concerns include whether a male fetus carrying a mutation should be considered undesirable because of the risks of male breast cancer and other cancers (45,46) and the risk of passing the mutation on to offspring. Although PGD may be preferred to aborting a fetus carrying a gene mutation, the cost of such procedures and the absence of insurance coverage make them unavailable to all but affluent women. Another deterrent is the emotional strain of going through one or more cycles of in vitro fertilization to produce embryos, half of which may need to be discarded. Some women carrying BRCA mutations may be caring for children of other family members with breast/ovarian cancer, which could affect their own childbearing decisions.
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CONCLUDING REMARKS |
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TopAbstractREPRODUCTIVE ISSUES FOR WOMEN...CONCLUDING REMARKSReferences |
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Knowledge of mutations in BRCA1 and BRCA2 genes has made it possible to identify women at increased risk for inherited breast and ovarian cancer. These women can take prophylactic measures if they choose. However, the knowledge gained opens a Pandora's box of dilemmas regarding reproductive decision making. Our understanding of the psychosocial and ethical implications of this new science has not kept pace with advances in the laboratory. Women of reproductive age with BRCA1 and BRCA2 mutations must confront decisions about risk-reducing strategies, contraception, and family planning. Studies concerning these issues often draw contradictory conclusions, challenging genetic counselors and physicians counseling BRCA1/2 mutation carriers about the effect of pregnancy on breast cancer risk, the role of hormone replacement therapy, the use of oral contraceptives and tubal ligation, and the use of prenatal diagnostic techniques. Future prospective studies may assist us in resolving some of these dilemmas. In the meantime, health professionals treating or consulting with these women should discuss the available options with them and inform them that a consensus of opinion does not necessarily exist about these options and their relative efficacy. The use of a multidisciplinary team may be helpful, incorporating the expertise of genetic counselors; medical, surgical, and gynecological oncologists; plastic surgeons; and gynecologists with expertise in assisted reproductive technologies. Given the ambiguity and anxiety associated with these issues, including specially trained mental health professionals in the process is especially important.
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