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Genetics and the Management of Women at High Risk for Breast Cancer

Mayo Clinic, Jacksonville, Florida, USA

Betty A. Mincey, M.D., Senior Associate Consultant, Mayo Clinic, General Internal Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA. Telephone: 904-953-2160; Fax: 904-953-2898; e-mail: mincey.betty{at}mayo.edu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Prevalence of BRCA Mutations Risk for Cancer in... Determining the Probability of... Genetic Counseling Risk Management in Women... Breast Cancer Treatment in... References

 
After completing this course, the reader will be able to:

1. Identify appropriate candidates for consideration of genetic testing for mutations in BRCA1 or BRCA2.
   
2. Explain the importance of appropriate patient counseling prior to proceeding with genetic testing for mutations in BRCA1 or BRCA2, including genetic counseling and education regarding interpretation and implications of test results.
   
3. Discuss risk management options for BRCA mutation carriers and the available evidence regarding their effectiveness.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Prevalence of BRCA Mutations Risk for Cancer in... Determining the Probability of... Genetic Counseling Risk Management in Women... Breast Cancer Treatment in... References

 
It is estimated that 5%–10% of all breast cancers in women are associated with hereditary susceptibility due to mutations in autosomal dominant genes, such as BRCA1 and BRCA2, p53, pTEN, and STK11/LKB1. Another 15%–20% of female breast cancers occur in women with a family history but without an apparent autosomal dominant inheritance pattern, and are probably due to other genetic factors with environmental influence. Approximately 7%–10% of ovarian cancers occur in women with hereditary susceptibility, primarily secondary to mutations in BRCA1 and BRCA2, with smaller contributions from mutations in mismatch repair genes associated with the hereditary nonpolyposis colorectal cancer and other, as yet undiscovered, genes.

Key Words. BRCA mutations • Breast cancer genetics • Ovarian cancer genetics • Hereditary cancer symdromes

	INTRODUCTION

Top Learning Objectives Abstract Introduction Prevalence of BRCA Mutations Risk for Cancer in... Determining the Probability of... Genetic Counseling Risk Management in Women... Breast Cancer Treatment in... References

 
It is estimated that 5%–10% of all breast cancers in women are associated with hereditary susceptibility due to mutations in autosomal dominant genes, such as BRCA1 and BRCA2, p53, pTEN, and STK11/LKB1 [1, 2]. Another 15%–20% of female breast cancers occur in women with a family history but without an apparent autosomal dominant inheritance pattern, and are probably due to other genetic factors with environmental influence [3, 4]. Approximately 7%–10% of ovarian cancers occur in women with hereditary susceptibility [2], primarily secondary to mutations in BRCA1 and BRCA2, with smaller contributions from mutations in mismatch repair genes associated with the hereditary nonpolyposis colorectal cancer and other, as yet undiscovered, genes.

BRCA1 and BRCA2 mutations are responsible for the majority of cases of hereditary breast and ovarian cancer in which an identifiable mutation is present [5] and are the focus of discussion in this review. Li-Fraumeni syndrome (due to mutations in p53), Cowden syndrome (due to mutations in pTEN), and Peutz-Jeghers syndrome (due to mutations in STK11/LKB1) are associated with early-onset breast cancer, in addition to other cancers and characteristic features, and account for a very small proportion of hereditary breast cancers [6]. Abnormalities in a number of other low-penetrance genes, such as ataxia-telangiectasia [7, 8] and CHEK2 [9, 10], have been demonstrated to be associated with increased breast cancer risk, but the importance of their contributions to familial breast cancer remains to be determined.

BRCA1 and BRCA2 are both large tumor suppressor genes, located on chromosomes 17 and 13, respectively. They are transmitted in an autosomal dominant manner. The proteins for which they code have roles in genomic stability, including participation in DNA damage response and repair pathways and regulation of apoptosis [6]. Although a detailed discussion of the biological functions of BRCA1 and BRCA2 is beyond the scope of this review, an excellent reference on this topic is available elsewhere [11].

	PREVALENCE OF BRCA MUTATIONS

Top Learning Objectives Abstract Introduction Prevalence of BRCA Mutations Risk for Cancer in... Determining the Probability of... Genetic Counseling Risk Management in Women... Breast Cancer Treatment in... References

 
Several hundred mutations have been identified in both BRCA1 and BRCA2, and several founder mutations have been identified in each of these two genes in various populations. Three founder mutations are relatively common in Ashkenazi Jewish individuals (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2), with a combined prevalence in this population of 2.3% [12], compared with a general population prevalence of approximately 0.1% for BRCA mutations [13].

Among women with breast cancer, the prevalence of BRCA1 and BRCA2 mutations are higher in women with a younger age at diagnosis and with the following features, derived from pedigree analyses [14, 15]:

• multiple cases of early-onset breast cancer
  
• ovarian cancer occurring in a family with other cases of breast or ovarian cancer
  
• breast and ovarian cancer occurring in the same woman
  
• bilateral breast cancer
  
• male breast cancer
  
• Ashkenazi Jewish heritage
  

Although BRCA mutations seem to be less prevalent in women with ductal carcinoma in situ (DCIS) than in women with invasive breast cancer, a recently published series of 10,000 tested individuals demonstrated mutations in 13% of those women with DCIS who were diagnosed prior to age 50, most of whom also had a family history of breast and/or ovarian cancer [13]. That same series demonstrated no significant racial or ethnic differences in prevalence of mutations, with the exception of a greater prevalence in women of Ashkenazi Jewish ancestry. Of 76 men with breast cancer in that series, 21 (28%) were found to be mutation carriers (one-third with mutations in BRCA1 and two-thirds with mutations in BRCA2).

In women with ovarian cancer, the prevalence of mutations in BRCA1 and BRCA2 has been estimated to be approximately 10% [2]. In a series of 649 ovarian cancer cases, unselected for family history, the overall prevalence was 11.7% [16]. No mutations were identified in women with cancers of borderline or mucinous histology, but 16% of women with invasive serous carcinoma of the ovary were found to have mutations. Prevalence was greater in those women with a suggestive family history.

	RISK FOR CANCER IN MUTATION CARRIERS (PENETRANCE)

Top Learning Objectives Abstract Introduction Prevalence of BRCA Mutations Risk for Cancer in... Determining the Probability of... Genetic Counseling Risk Management in Women... Breast Cancer Treatment in... References

 
BRCA1 and BRCA2 mutations are associated with a greatly increased risk for breast cancer development, with risk estimates ranging from 59%–87% for BRCA1 and from 38%–80% for BRCA2 mutations [17–20]. Risk estimates are based on several different population studies, accounting for their wide ranges. The lower limits of these ranges are taken from a study of BRCA1 carriers who were selected for testing based on their Ashkenazi Jewish heritage rather than on a family history of breast cancer. The upper limits of the risk estimate ranges are derived from studies of groups of individuals selected for testing because of very strong family histories of cancer.

The lifetime risk for second primary breast cancers in BRCA1 or BRCA2 mutation carriers with breast cancer is 40%–60% [21–23], with 5-year risk estimates of 22%–31% [22, 24]. The lifetime risk for male breast cancer in BRCA2 mutation carriers has been reported to be approximately 6.3% [17]. The risk for ovarian cancer in BRCA1 mutation carriers is estimated to be 28%–44% [7, 15, 16], and in BRCA2 carriers, it is somewhat lower at 16%–27% [5, 20].

There appear to be slightly greater risks for other cancers in BRCA mutation carriers as well, although these risks are less well quantified than are the risks for breast and ovarian cancer. Relative risks of 4.1 and 3.3 for colon and prostate cancers, respectively, have been demonstrated in carriers of BRCA1 mutations [16]. BRCA2 mutations have been associated with a relative risk for prostate cancer of 2.89–4.65 and with slightly greater risks for other cancers, including pancreatic, gall bladder/bile duct, stomach, and laryngeal cancers and melanoma [17, 20].

	DETERMINING THE PROBABILITY OF A MUTATION

Top Learning Objectives Abstract Introduction Prevalence of BRCA Mutations Risk for Cancer in... Determining the Probability of... Genetic Counseling Risk Management in Women... Breast Cancer Treatment in... References

 
There are several models that can be used to estimate the probability of a BRCA mutation in an individual patient. Three of these models, the Frank et al. [25], Couch et al. [26], and Shattuck-Eidens et al. [27] models, are based on small numbers of families with numerous cases of breast and/or ovarian cancer. The Myriad Prevalence tables are published on the Myriad Genetics laboratory’s internet site (Salt Lake City, UT; http://www.myriad.com) and updated periodically. These tables give various scenarios of personal and family history, the number of individuals tested for each scenario, and the proportion of those individuals who have tested positive. The BRCAPRO [28, 29] program is a computer program that applies Bayesian analysis to estimate the probability of mutation carrier status for a given individual based on family history, age at diagnosis of cancers in the family, presence of bilateral or male breast cancer, and Ashkenazi Jewish heritage, using data from published studies of prevalence, penetrance, and mutation frequency.

	GENETIC COUNSELING

Top Learning Objectives Abstract Introduction Prevalence of BRCA Mutations Risk for Cancer in... Determining the Probability of... Genetic Counseling Risk Management in Women... Breast Cancer Treatment in... References

 
Informed consent is of paramount importance before proceeding with testing and, in some states, is mandated by law. Informed consent should include at a minimum the following points [30]:

• options for risk estimation without genetic testing
  
• information on the specific test to be conducted, including the accuracy of the test and the fees associated with testing
  
• interpretation of all possible test results
  
• implications of all possible test results for the individual and family
  
• level of confidentiality of results
  
• risk of psychologic distress
  
• risk of insurance and/or employment discrimination
  
• options for and limitations of care after testing
  

Possible explanations for a negative BRCA1 or BRCA2 test result include: A) a true negative result; B) a mutation in BRCA1 or BRCA2 not detected by current technologies, and C) a mutation in a different breast cancer susceptibility gene.

Due to the complexity of these issues and the time required to provide the necessary counseling, referral to a genetic counselor or high-risk clinic is generally recommended for those practitioners who do not have specific training and expertise in this area. This is true of genetic testing in general and is not limited to testing for hereditary predisposition to breast and ovarian cancer.

The difficulty inherent in interpreting genetic test results is illustrated by a report of 42 U.S. breast/ovarian cancer families who underwent polymerase chain reaction testing for BRCA1 exon 13 duplication and Southern blot analysis for large rearrangements in BRCA1, neither of which are detected on conformation-sensitive gel electrophoresis or complete sequencing, as was usually performed at that time for detection of carrier status [31]. All 42 families had tested negative for BRCA mutations by one of the latter two techniques. Five of the 42 families (11.9%) were found to have rearrangement mutations. In those families in which rearrangements were detected, the mean prior probability of a BRCA1 mutation was 70% (range 33%–97%), as estimated by the Couch model, whereas the mean prior probability for those in whom no abnormality was detected was 37% (range 7%–92%). In another recent study [32] of 120 French breast/ovarian cancer cases, large rearrangements in BRCA1 accounted for 3.3% of cases and 9.5% of BRCA1 mutations. Testing for these rearrangements, in addition to full gene sequencing, is now included as part of the standard genetic testing done by the Myriad Genetics laboratory. Testing for these rearrangements may be worthwhile for some individuals who had negative genetic test results for mutations in BRCA1 or BRCA2 prior to the inclusion of such testing as standard.

	RISK MANAGEMENT IN WOMEN WITH BRCA MUTATIONS

Top Learning Objectives Abstract Introduction Prevalence of BRCA Mutations Risk for Cancer in... Determining the Probability of... Genetic Counseling Risk Management in Women... Breast Cancer Treatment in... References

 
Three categories of options for management of women with BRCA mutations are available, and all should be discussed with patients in detail to allow them to make informed decisions regarding their health care. These include screening and surveillance, prophylactic surgeries, and chemoprevention.

Surveillance
According to the Cancer Genetics Studies Consortium Consensus Statement from 1997 [33], surveillance for female BRCA mutation carriers should include:

• beginning by age 18: monthly breast self-examinations
  
• beginning at age 25 or 10 years earlier than the age at which cancer was first diagnosed in the family: annual or semiannual clinical breast examinations; annual mammography; and annual or semiannual transvaginal ultrasounds and serum CA-125 level measurements
  

Although surveillance recommendations have, to date, been mainly based on expert opinion, preliminary data from ongoing observational studies of women with BRCA mutations support current clinical practice based on these recommendations. However, these studies also call into question the adequacy of mammography for screening in this population, point out the importance of both clinician examination (conducted at least twice yearly) and breast self-examination for this high-risk group, and suggest that magnetic resonance imaging (MRI) of the breast may be much more sensitive than mammography for detecting cancer in mutation carriers.

Scheuer et al. [34] reported on an ongoing study of 251 female BRCA1 or BRCA2 mutation carriers, with a mean age of 47.7 years. The mean follow-up at the time of the report was 24.8 months. Twenty-nine of the women opted to undergo bilateral prophylactic mastectomy, and 90 underwent bilateral salpingo-oophorectomy. In those women who did not undergo prophylactic mastectomy, six breast cancers were detected by mammography (five stage 0 or 1) and six were detected by physical examination between mammogram screening intervals (four stage 1). In women who did not undergo prophylactic oophorectomy, screening detected three ovarian cancers (stage I or II) and one early-stage primary peritoneal cancer. Thus, the rate of detection of cancers in this population seems to justify the recommended screening as outlined above. These results also highlight the importance of physical examination in addition to imaging studies for surveillance in women at risk for breast cancer based on genetic predisposition.

Several small studies have suggested that MRI is significantly more sensitive for detecting breast cancers in high-risk women than mammography or ultrasound [35–37]. The high false-negative rate of mammography in women with proven BRCA mutations or with a family or personal history that is highly suspicious for the presence of such a mutation is probably due, at least in part, to a high degree of breast density on mammogram in younger women. A recently reported correlative study of imaging findings and breast cancer pathology suggests an additional possible contribution of prominent pushing margins to breast tumors of mutation carriers [38]. Taken together, these results indicate that larger studies of MRI for breast cancer screening in very-high-risk women, particularly those who are young or have dense breast tissue on mammogram, are warranted. MRI is also a useful adjunctive tool for evaluating abnormalities on clinical breast examination in the face of negative mammogram and ultrasound results, but is not a substitute for biopsy of a clinically suspicious mass.

Prophylactic Surgery
Two prophylactic surgical options should be discussed with patients, with the understanding that patient decisions in this regard are highly individual and should be respected. Hartmann et al. [37] conducted a retrospective analysis of 639 moderate-to-high risk women (based on family history) who underwent prophylactic mastectomy at the Mayo Clinic in Rochester, Minnesota. Sisters of women in the high-risk group who did not undergo prophylactic mastectomy comprised the control group. In that study, the reduction in breast cancer risk with bilateral prophylactic mastectomy was 90% after 14 years of follow-up. More recently, Meijers-Heijboer et al. [39] published the results of a prospective study of 139 BRCA1 or BRCA2 mutation carriers. Seventy-six of the women underwent prophylactic mastectomy, and the remainder chose to undergo close surveillance. After a mean follow-up of 3 years, no breast cancers had been detected in the prophylactic mastectomy group and eight had been detected in the surveillance group. In a decision analysis based on an assumed 85% breast cancer risk reduction from prophylactic mastectomy, Schrag et al. [40] estimated that women 30 years of age with BRCA mutations might gain 2.9–5.3 years of life expectancy from such a procedure, with gains decreasing with age at time of surgery and becoming minimal by 60 years of age.

Prophylactic oophorectomy reduces the risk for ovarian cancer by greater than 90% [41]. When completed prior to menopause (especially if done before the age of 40), prophylactic oophorectomy also reduces the risk for breast cancer development by approximately 50%. Kauff et al. [42] reported on 170 BRCA mutation carriers. Ninety-eight underwent bilateral salpingo-oophorectomy, and 72 chose to undergo ovarian cancer screening instead. After a mean follow-up period of 24.2 months, ovarian or peritoneal cancer had been detected in 6.9% of the ovarian cancer surveillance group (5/72) and in 4.1% of the oophorectomy group (4/98). Of the four cancers detected in the oophorectomy group, three were discovered at the time of the prophylactic surgery. Thirty-nine of the 170 women underwent bilateral prophylactic mastectomy. Of the remaining 131, 62 chose surveillance, and 69 chose prophylactic oophorectomy. Breast cancer was detected in 12.9% of the surveillance group (8/62) and in 4.3% of the oophorectomy group (3/69). The odds ratio for either breast or gynecologic cancer in the oophorectomy group was 0.25.

Rebbeck et al. [43] recently published a retrospective analysis of 551 BRCA mutation carriers, with a follow-up of 8–11 years. The women had been offered the choice of prophylactic oophorectomy or ovarian cancer screening: 292 chose surveillance and 259 chose oophorectomy. During a follow-up period of 8–11 years, ovarian or peritoneal cancer was diagnosed in 19.9% (58/292) of the women in the surveillance group. Cancer was diagnosed at the time of prophylactic oophorectomy in 2.3% (6/259) of the women in the oophorectomy group. Of the remaining 253 women in the oophorectomy group, cancer was diagnosed in two (0.8%) in the follow-up period. Of the 551 BRCA mutation carriers, 210 either had been diagnosed with breast cancer or underwent bilateral prophylactic mastectomy. Of the remaining 241 women, breast cancer was diagnosed during follow-up in 21.2% (21/99) of those who underwent prophylactic oophorectomy and in 42.3% (60/142) of those who chose ovarian cancer surveillance. These results are consistent with those of a previous study by the same group [44] in a small cohort of BRCA1 mutation carriers, 43 of whom underwent prophylactic oophorectomy and 79 of whom did not. After a mean follow-up of 9 years, the hazard ratio for breast cancer development after oophorectomy was 0.53 (95% confidence interval [CI] 0.33–0.84). In that study, the use of hormone replacement therapy after oophorectomy did not negate the associated risk reduction.

Chemoprevention
Chemoprevention is an area of uncertainty in general, and even more so in the population of women with BRCA mutations. Despite mixed results in the initial large prevention trials, tamoxifen has been shown to be effective in reducing risk in high-risk women [45–48], with a risk reduction of approximately 38% when all of the tamoxifen prevention trials to date are taken into account [49]. Although it has been approved for this purpose by the U.S. Food and Drug Administration, important questions remain regarding its use, including at what risk level such an intervention should be initiated and at what age this should be accomplished. Moreover, in women not previously diagnosed with breast cancer, tamoxifen has been shown to reduce the risk of estrogen-receptor-positive tumors only. Women with BRCA1 mutations who develop breast cancer have estrogen-receptor-negative tumors in approximately 80% of cases, whereas women with BRCA2 mutations who develop breast cancer have estrogen-receptor-positive tumors in 80% of cases [49]. Thus, theoretically, we would suspect that tamoxifen might not be particularly helpful for women with BRCA1 mutations, and questions have even been raised as to whether it may be harmful. In the Breast Cancer Prevention Trial-1 study sponsored by the National Surgical Adjuvant Breast and Bowel Project, 7% of the breast cancers diagnosed occurred in BRCA mutation carriers [50]. A lower incidence of breast cancer in BRCA1 mutation carriers was not demonstrated for women randomized to tamoxifen, and the relative risk for breast cancer in that group was 1.67. Conversely, a 62% lower breast cancer incidence was observed in BRCA2 mutation carriers. Because the numbers of women who developed breast cancer and tested positive for a BRCA mutation in that study were small, the results are not statistically significant, but the trends noted are consistent with risk reduction for estrogen-receptor-positive tumors only. Further study is needed but, based on this information, the use of tamoxifen for breast cancer prevention in BRCA1 mutation carriers cannot be routinely recommended, while it appears to be a reasonable choice for risk reduction in BRCA2 mutation carriers based on current evidence.

Several of the ongoing prevention trials will hopefully shed light on the issue of chemoprevention in BRCA mutation carriers. One ongoing trial is of particular interest. The Aromasin prevention study trial, currently being conducted in Italy, is enrolling postmenopausal carriers of BRCA1 or BRCA2 mutations between the ages of 30 and 70 years. Participants are randomized to either exemestane 25 mg daily or placebo for 3 years. Planned accrual is 666 women, and the primary end point is disease-free survival at 7 years of follow-up. Other end points include quality of life, incidence of ductal or lobular carcinoma in situ, and effect on bone density.

The study of tamoxifen and raloxifene (STAR) trial, which includes postmenopausal women at increased risk for breast cancer development based on the modified Gail model (5-year risk 1.66%), has enrolled more than 14,000 women to date, and accrual should be completed within the next 1–2 years, with an accrual target of 19,000 women. Although not specific to BRCA mutation carriers, this trial can be expected to provide important information regarding the use of selective estrogen-receptor modulators for breast cancer prevention. Additional studies are in the planning stages to examine the role of aromatase inhibitors in preventing breast cancer in high-risk populations, including, but not limited to, BRCA mutation carriers.

	BREAST CANCER TREATMENT IN MUTATION CARRIERS

Top Learning Objectives Abstract Introduction Prevalence of BRCA Mutations Risk for Cancer in... Determining the Probability of... Genetic Counseling Risk Management in Women... Breast Cancer Treatment in... References

 
Additional considerations are required when considering BRCA mutation testing for women newly diagnosed with breast cancer. BRCA mutation carriers have a greater risk for second breast primaries, but no clear difference in overall breast cancer prognosis. Pierce et al. [23] demonstrated a 20% incidence of second primary breast cancers at 5 years after initial diagnosis in women with genetic susceptibility to breast cancer, versus a 2% risk at 5 years in those with sporadic cancer. However, there was no significant difference in local recurrence or survival between the genetic and sporadic groups. Haffty et al. [22] evaluated outcome in 127 women with breast cancer who were 42 years of age or younger at the time of diagnosis. Of these, 105 were classified as sporadic cancers, 15 had BRCA1 mutations, and 7 had BRCA2 mutations. After 12 years of follow-up, 49% of those with mutations had developed ipsilateral events and 42% had developed contralateral events, while in those with sporadic cancers, the incidence was 21% for ipsilateral events and 9% for contralateral events. The differences between groups were statistically significant, with p values of 0.007 and 0.001, respectively.

There are no data directly comparing responses to various systemic therapies in women with BRCA mutations. However, tamoxifen was shown, in a case-control study, to reduce the risk of contralateral breast cancer in BRCA mutation carriers by approximately 50% [51]. In that study of 209 women with bilateral breast cancer and 384 controls with unilateral breast cancer, all of whom were known BRCA1 or BRCA2 mutation carriers, the odds ratios for contralateral breast cancer with the use of tamoxifen were 0.38 (95% CI 0.19–0.74) in BRCA1 mutation carriers and 0.63 (95% CI 0.20–1.50) in BRCA2 mutation carriers. In the same study, the odds ratio for contralateral breast cancer with oophorectomy was 0.42 (95% CI 0.22–0.83) and with chemotherapy was 0.40 (95% CI 0.26–0.60). Clearly, more study is needed to determine the relative effects of various systemic therapies in this population.

In a recently published prospective study conducted at a single center in the Netherlands, Meijers-Heijboer et al. [52] found that 87% of 220 women from high-risk families elected to undergo BRCA testing when faced with a new breast or ovarian cancer diagnosis. Of the women in that study who were found to be BRCA mutation carriers, 35% of those who were considered eligible for prophylactic contralateral or bilateral mastectomy, 49% of those who were eligible for prophylactic oophorectomy, and 81% of those who were eligible for both prophylactic surgeries underwent such procedures. It should be noted that, in the Netherlands, the costs of genetic testing and prophylactic surgeries are covered by public and private health insurance, and this probably has substantial bearing on the high acceptance rate of such strategies in this population. However, these results highlight the importance of offering genetic counseling and testing to appropriate candidates with newly diagnosed breast cancer.

Hormone Therapy
The question of using hormonal therapy for purposes of birth control and menopausal management arises for most women, including those with BRCA mutations. A large study conducted by Marchbanks et al. [53] demonstrated no greater risk for breast cancer with oral contraceptive use for women in general. In contrast, a meta-analysis of 54 studies [54] demonstrated a slightly greater risk (relative risk 1.24), with no influence on degree of risk when family history of breast cancer was taken into account. A more recent epidemiologic study [55] demonstrated a threefold greater breast cancer risk for women with a first-degree relative with breast cancer if oral contraceptives were taken prior to 1975, at which time the estrogen dose in oral contraceptives was substantially higher than it is in current preparations. However, Narod et al. [56] demonstrated a small but statistically significant increase in breast cancer risk with oral contraceptive use for BRCA1 mutation carriers in a case-control study involving 1,311 pairs of women with known deleterious BRCA1 or BRCA2 mutations. No greater risk was noted for BRCA2 mutation carriers, but the number of women with BRCA2 mutations was smaller than that for BRCA1 mutations (330 matched pairs versus 981 matched pairs).

Although this evidence seems somewhat contradictory, it does indicate that, if there is a greater breast cancer risk associated with the use of current oral contraceptive formulations, it is probably quite small. Thus, at this time, women with BRCA mutations should be advised of the potential for a slightly greater breast cancer risk with the use of oral contraceptives, but their use is not contraindicated.

Results of recently published studies indicate that hormone therapy after menopause should not be used to prevent chronic disease, and at this time, the only real indication for the use of hormonal therapy in postmenopausal women is for management of menopausal symptoms. Postmenopausal hormone therapy has been shown to lead to a slightly higher risk for breast cancer development with long-term use, and data from the Women’s Health Initiative study of continuous combined hormone therapy [57] indicate a slightly increased risk even with short-term use of only 3 years. Because women with BRCA mutations have a higher risk for breast cancer development at baseline, this slightly increased relative risk is more significant for them than for the average-risk woman. However, the short-term use of hormone therapy for the management of troublesome menopausal symptoms, such as hot flashes and vaginal dryness, may be acceptable. Women with BRCA mutations should be informed of the alternatives to hormone use for management of these symptoms, but should not necessarily be denied the use of hormone therapy when such alternative measures are not successful. For management of vaginal atrophy, use of local estrogen-replacement products may be successful and may lead to less systemic absorption and, theoretically, less effect on breast tissue than systemic hormonal therapy.

	REFERENCES

Top Learning Objectives Abstract Introduction Prevalence of BRCA Mutations Risk for Cancer in... Determining the Probability of... Genetic Counseling Risk Management in Women... Breast Cancer Treatment in... References

 

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