Breast Cancer
        Screening
        Risk modification
        Breast conservation therapy for BRCA1/2 mutation carriers
        Role of BRCA1 and BRCA2 in response to chemotherapy
Ovarian Cancer
        Screening
        Risk Modification

Few data exist on the outcomes of interventions to reduce risk in people with a genetic susceptibility to breast or ovarian cancer. As a result, recommendations for management are primarily based on expert opinion.[1-5] In addition, as outlined in other sections of this summary, uncertainty is often considerable regarding the level of cancer risk associated with a positive family history or genetic test. In this setting, personal preferences are likely to be an important factor in patients’ decisions about risk reduction strategies.

Refer to the PDQ summary on Screening for Breast Cancer for information on screening in the general population, and to the PDQ summary Cancer Genetics Overview for information on levels of evidence related to screening and prevention.

In the general population, evidence for the value of breast self-examination (BSE) is limited. Preliminary results have been reported from a randomized study of BSE being conducted in Shanghai, China.[6] At 5 years, no reduction in breast cancer mortality was seen in the BSE group compared with the control group of women, nor was a substantive stage shift seen in breast cancers that were diagnosed. (Refer to the PDQ summary on Screening for Breast Cancer for more information.)

Little direct prospective evidence exists regarding BSE among female carriers of a BRCA1 or BRCA2 high-risk mutation, male carriers of a BRCA2 mutation, or women at inherited risk of breast cancer. In the Canadian National Breast Screening Study, women with first-degree relatives with breast cancer had statistically significantly higher BSE competency scores than those without a family history. In a study of 251 high-risk women at a referral center, five breast cancers were detected by self-examination less than a year after a previous screen (as compared with one cancer detected by clinician exam and 11 cancers detected as a result of mammography). Women in the cohort were instructed in self-examination, but it is not stated whether the interval cancers were detected as a result of planned self-examination or incidental discovery of breast masses.[7] In another series of BRCA1/2 mutation carriers, four of nine incident cancers were diagnosed as palpable masses after a reportedly normal mammogram, further suggesting the potential value of self-examination.[8] A task force convened by the Cancer Genetics Studies Consortium has recommended “monthly self-examination beginning early in adult life (e.g., by age 18-21) to establish a regular habit and allow familiarity with the normal characteristics of breast tissue. Education and instruction in self-examination are recommended.”[9]

Level of evidence: 5

Few prospective data exist regarding clinical breast examination (CBE) among female carriers of a BRCA1 or BRCA2 high-risk mutation, male carriers of a BRCA2 mutation, or women at inherited risk of breast cancer.

The Cancer Genetics Studies Consortium task force concluded, “as with self-examination, the contribution of clinical examination may be particularly important for women at inherited risk of early breast cancer.” They recommended that female carriers of a BRCA1 or BRCA2 high-risk mutation undergo annual or semiannual clinical examinations beginning at age 25 to 35 years.[9]

Level of evidence: 5

In the general population, strong evidence suggests that regular mammography screening of women aged 50 to 59 years leads to a 25% to 30% reduction in breast cancer mortality. (Refer to the PDQ summary on Screening for Breast Cancer for more information.) For women who begin mammographic screening at age 40 to 49 years, a 17% reduction in breast cancer mortality is seen, which occurs 15 years after the start of screening.[10] Observational data from a cohort study of more than 28,000 women suggest that the sensitivity of mammography is lower for young women. In this study, the sensitivity was lowest for younger women (aged 30-49 years) who had a first-degree relative with breast cancer. For these women, mammography detected 69% of breast cancers diagnosed within 13 months of the first screening mammography. By contrast, sensitivity for women younger than 50 years without a family history was 88% (P = .08). For women aged 50 years and older, sensitivity was 93% at 13 months and did not vary by family history.[11] Preliminary data suggest that mammography sensitivity is lower in BRCA1 and BRCA2 carriers than in noncarriers.[8] Subsequent observational studies have found that the positive predictive value (PPV) of mammography increases with age and is highest among older women and among women with a family history of breast cancer.[12] Higher PPVs may be due to increased breast cancer incidence, higher sensitivity, and/or higher specificity.[13] One study found an association between the presence of pushing margins, a histopathologic description of a pattern of invasion, and false-negative mammograms in 28 women, 26 of whom had a BRCA1 mutation and two of whom had a BRCA2 mutation. Pushing margins, characteristic of medullary histology, is associated with an absence of fibrotic reaction.[14] In addition, rapid tumor doubling times may lead to tumors presenting shortly after an apparently normal study. In one study, mean tumor doubling time in BRCA1/2 carriers was 45 days, compared with 84 days in noncarriers.[15] Another study that evaluated mammographic breast density in women with BRCA mutations found no association between mutation status and mammographic density; however, in both carriers and noncarriers, increased breast density was associated with increased breast cancer risk.[16]

The randomized Canadian National Breast Screening Study-2 (NBSS2) compared annual CBE plus mammography to CBE alone in women aged 50 to 59 years from the general population. Both groups were given instruction in BSE.[17] Although mammography detected smaller primary invasive tumors and more invasive as well as ductal carcinomas in situ (DCIS) than CBE, the breast cancer mortality rates in the CBE-plus-mammography group and the CBE- alone group were nearly identical, and compared favorably with other breast cancer screening trials. After a mean follow-up of 13 years (range 11.3-16.0 years), the cumulative breast cancer mortality ratio was 1.02 (95% confidence interval (CI) = 0.78 to 1.33). One possible explanation of this finding was the careful training and supervision of the health professionals performing CBE.

In a prospective study of 251 individuals with BRCA mutations who received uniform recommendations regarding screening and risk-reducing, or prophylactic, surgery, annual mammography detected breast cancer in six women at a mean of 20.2 months after receipt of BRCA results.[7] The Cancer Genetics Studies Consortium task force has recommended for female carriers of a BRCA1 or BRCA2 high-risk mutation, “annual mammography, beginning at age 25 to 35 years. Mammograms should be done at a consistent location when possible, with prior films available for comparison.”[9] Data from prospective studies on the relative benefits and risks of screening with an ionizing radiation tool versus CBE or other nonionizing radiation tools would be useful.[18-20]

Certain observations have led to the concern that BRCA mutation carriers may be more prone to radiation-induced breast cancer than women without mutations. The BRCA1 and BRCA2 proteins are known to be important in cellular mechanisms of DNA damage repair, including those involved in repairing radiation-induced damage. Mouse embryos lacking Brca1 or Brca2 are hypersensitive to the effects of ionizing radiation. Some studies have suggested intermediate radiation sensitivity in cells that are heterozygous for a BRCA mutation, but this is not consistent and varies by experimental system and endpoint. A large international case-control study of 1,601 mutation carriers described an increased risk of breast cancer (hazard ratio (HR) = 1.54) among women who were ever exposed to chest x-rays, with risk being highest in women age 40 years and younger, born after 1949, and those exposed to x-rays only before age 20 years.[21] In contrast, two studies of the effect of mammogram exposure on carriers (n = 1,600, n = 162) did not support an association between such exposure and subsequent breast cancer risk.[22,23] In a small study,[23] there was a modest association between lifetime mammogram exposure and risk in BRCA1 mutation carriers (HR = 1.08, P = .03). No significant effect was seen after exclusion of postdiagnosis mammograms. At this time there is insufficient evidence to suggest that mutation carriers should avoid mammography.

Level of evidence: 5

The limited sensitivity of mammography and an interest in methods of screening that do not involve ionizing radiation has led to evaluation of other screening techniques, including magnetic resonance imaging (MRI), breast ultrasound, breast ductal lavage, and digital mammography.

Because of the relative insensitivity of mammography in women at hereditary risk for breast cancer, a number of screening modalities have been proposed and investigated in high-risk women, including BRCA mutation carriers. Several studies have described the experience with breast MRI screening in women at risk for breast cancer, including descriptions of relatively large multi-institutional trials.[24-30] Several considerations must be kept in mind when reviewing these reports:

• The studies are variable in terms of the underlying population being studied, equipment and signal processing protocols, the manner of reporting results, and the manner in which sensitivity and specificity are calculated.
• The different screening tests (MRI and mammogram with or without ultrasound) are performed nearly simultaneously in these studies, and the screening modalities are compared to each other. Therefore, sensitivity is defined somewhat differently in these studies than in the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) of follow-up and outcome reporting.
• The number of screening rounds is limited, and the distinction between prevalent (first round) and incident cancer detection rates is often unclear.

Despite these caveats, the reported studies consistently demonstrate that breast MRI is more sensitive than either mammography or ultrasound for the detection of hereditary breast cancer. The results of four large studies are presented in Table 5, Summary of MRI Screening Studies in Women at Hereditary Risk for Breast Cancer.[24-28] Most cancers in these programs were screen detected with only 6% of cancers presenting in the interval between screenings. The sensitivity of MRI (as defined by the study methodology) ranged from 71% to 100%. Of the combined studies, 82% of the cancers were identified by MRI compared with 40% by mammography.

Concerns have been raised about the reduced specificity of MRI compared with other screening modalities. In one study, after the initial MRI screen, 16.5% of the patients were recalled for further evaluation, and 7.6% of subjects were recommended to undergo a short-interval follow-up examination at 6 months.[28] These rates declined significantly during later screening rounds, with fewer than 10% of the subjects recalled for more detailed MRI and fewer than 3% recommended to have short interval follow-up. In a second study, Magnetic Resonance Imaging for Breast Screening (MARIBS), the recall rate for additional evaluation was 10.7% per year.[27] The benign biopsy rates in the first study were 11% at first round, 6.6% at second round, and 4.7% at third round.[28] In the MARIBS study, the aggregate surgical biopsy rate was 9 per 1,000 screening episodes, though this may underestimate the burden because follow-up ultrasounds, core-needle biopsies, and fine-needle aspirations have not been included in the numerator of the MARIBS calculation.[27] The PPV of MRI has been calculated differently in the various series and fluctuates somewhat, depending on whether all abnormal examinations or only the examinations that result in a biopsy are counted in the denominator. Generally, the PPV of a recommendation for tissue sampling (as opposed to further investigation) is in the range of 50% in most series.

These trials appear to establish that MRI is superior to mammography in the detection of hereditary breast cancer, and that women participating in these trials including annual MRI screening were less likely to have a cancer not detected by screening.[31] However, mammography clearly identifies some cancers that are not identified by MRI. Most of these mammographically detected cancers in women with a negative MRI appear to be ductal carcinomas in situ, presumably presenting as microcalcifications without significant ductal enhancement. While MRI does appear to be more sensitive than mammogram, it is unknown whether MRI screening results in a survival benefit or even in downstaging compared to mammography alone. One screening study demonstrated that patients were more likely to be diagnosed with small tumors and node-negative disease than women in two nonrandomized control groups.[25] However, a randomized study of screening with or without MRI using tumor stage or mortality as an endpoint has not been performed. Despite the apparent sensitivity of MRI screening, some women in MRI-based programs will nevertheless develop life-threatening breast cancer. The American Cancer Society and the National Comprehensive Cancer Network (NCCN) have recommended the use of annual MRI screening for women at hereditary risk for breast cancer.[3,32]

Several studies have reported instances of breast cancer detected by ultrasound that were missed by mammography, as discussed in one review.[34] In a pilot study of ultrasound as an adjunct to mammography in 149 women with moderately increased risk based on family history, one cancer was detected, based on ultrasound findings. Nine other biopsies of benign lesions were performed. One was based on abnormalities on both mammography and ultrasound, and the remaining eight were based on abnormalities on ultrasound alone.[34] However, ultrasound screening appears to have a limited benefit in combination with MRI. In a multicenter study of 171 women (92% of whom were BRCA1/2 mutation carriers) undergoing simultaneous mammography, MRI, and ultrasound, no cancers were detected by ultrasound alone.[29] Uncertainties about ultrasound include the effect of screening on mortality, the rate and outcome of false-positive results, and access to experienced breast ultrasonographers.

Digital mammography refers to the use of a digital detector to detect and record x-ray images. This technology improves contrast resolution,[35] and has been proposed as a potential strategy for improving the sensitivity of mammography. A screening study comparing digital with routine mammography in 6,736 examinations of women aged 40 years and older found no difference in cancer detection rates;[36] however, digital mammography resulted in fewer recalls. In another study (ACRIN-6652) comparing digital mammography to plain-film mammography in 42,760 women, the overall diagnostic accuracy of the two techniques was similar.[37] When Receiver Operating Characteristic (ROC) curves were compared, digital mammography was more accurate in women younger than 50 years, in women with radiographically dense breasts, and in premenopausal or perimenopausal women.

Refer to the PDQ summary on Prevention of Breast Cancer for information on prevention in the general population, and to the PDQ summary Cancer Genetics Overview for information on levels of evidence related to screening and prevention.

In the general population, breast cancer risk increases with early menarche and late menopause, and is reduced at early first full-term pregnancy. (Refer to the PDQ summary on Prevention of Breast Cancer for more information.) In the Nurses’ Health Study, these were risk factors among women who did not have a mother or sister with breast cancer.[38] Among women with a family history of breast cancer, pregnancy at any age appeared to be associated with an increase in risk of breast cancer, persisting to age 70 years.

One study evaluated risk modifiers among 333 female carriers of a BRCA1 high-risk mutation. In women with known mutations of the BRCA1 gene, early age at first live birth and parity of three or more have been associated with a lowered risk of breast cancer. A relative risk (RR) of 0.85 was estimated for each additional birth, up to five or more; however, increasing parity appeared to be associated with an increased risk of ovarian cancer.[39,40] In a case-control study from New Zealand, investigators noted no difference in the impact of parity upon the risk of breast cancer between women with a family history of breast cancer and those without a family history.[41]

Studies of the effect of pregnancy on breast cancer risk have revealed complex results. Although the relationship of parity has been inconsistent, several studies have shown that among parous women, an increased number of full-term births is associated with a decrease in breast cancer risk. The influence of age at first birth may differ between BRCA1 and BRCA2 mutation carriers.[42-44] Of note, neither therapeutic nor spontaneous abortions appear to be associated with an increased breast cancer risk.[42,45]

Level of evidence: 3

In the general population, breastfeeding has been associated with a slight reduction in breast cancer risk in a few studies, including a large collaborative reanalysis of multiple epidemiologic studies,[46] and at least one study suggests that it may be protective in BRCA1 mutation carriers. In a multicenter breast cancer case-control study of 685 BRCA1 and 280 BRCA2 mutation carriers with breast cancer and 965 mutation carriers without breast cancer drawn from multiple-case families, among BRCA1 mutation carriers, breastfeeding for 1 year or more was associated with approximately a 45% reduced risk of breast cancer.[47] No such reduced risk was observed among BRCA2 mutation carriers. A second study failed to confirm this association.[42]

Among the general population, oral contraceptives may produce a slight, short-term increase in breast cancer risk. (Refer to the PDQ summary on Prevention of Breast Cancer for more information.) In a meta-analysis of data from 54 studies, family history of breast cancer was not associated with any variation in risk associated with oral contraceptive use.[48] In a study of 50 Jewish women younger than 40 years with breast cancer, those with a BRCA1 or BRCA2 high-risk mutation had a higher likelihood of long-term oral contraceptive use (>48 months) before their first pregnancy.[49] The authors concluded that oral contraceptive use might increase the risk of breast cancer among carriers of a BRCA1 or BRCA2 mutation more than in noncarriers. In a case-control study of more than 1,300 pairs of women, each case was matched to a woman with a mutation in the same gene, born within 2 years of the case, and in the same country, who had not developed cancer. Oral contraceptive use was associated with a statistically significant 20% (CI, 2%-40%) increase in risk of breast cancer among BRCA1 mutation carriers, particularly if use:

• Began before 1975, a period when estrogen doses were relatively high (38% increase, CI 11%-72%).
• Began before age 30 years (29% increase, CI, 9%-52%).
• Lasted for 5 or more years (33% increase, CI, 11%-60%).[50]

There was no increased risk associated with use among BRCA2 mutation carriers. A Swedish population-based study of 245 women with breast cancer diagnosed before age 41 years, 19 of whom were BRCA1/BRCA2 mutation carriers, suggested that oral contraceptive use before age 20 years was associated with increased breast cancer risk in both mutation carriers and noncarriers, though the small number of carriers limits the conclusions for this subgroup.[51]

In contrast, a population-based study of 47 BRCA1 and 36 BRCA2 mutation carriers with breast cancer diagnosed before age 40 years, matched to population controls without mutations, found no increased risk of early-onset breast cancer associated with ever use of low-dose contraceptive pills for BRCA2 mutation carriers (odds ratio (OR) = 1.02) and a significantly reduced risk for BRCA1 mutation carriers (OR = 0.22; 95% CI, 0.10-0.49).[52]

One study examined proliferation of normal breast epithelium among women undergoing reduction mammoplasty.[53] The study found a substantially higher cellular proliferation rate among women who used oral contraceptives before their first full-term pregnancy. In addition, among women currently on oral contraceptives, women with a family history of breast cancer had much higher cellular proliferation rates than those women without a family history. These findings are consistent with increased breast cancer risk among women with a family history of breast cancer who use oral contraceptives.

In considering contraceptive options and preventive actions, the potential impact of oral contraceptive use upon the risk of both breast and ovarian cancer, as well as other health-related effects of oral contraceptives, needs to be considered. With regard to breast cancer risk associated with oral contraceptive use, despite conflicting results based on small numbers of carriers, several studies have found a significantly increased risk. A number of important issues remain unresolved including the potential differences between BRCA1/2 mutation carriers, age and duration of exposure, and formulation.

Levels of evidence for oral contraceptive studies: 3B, 3

Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with hormone replacement therapy (HRT) in the general population.[54-57] The Women’s Health Initiative (WHI) is a randomized controlled trial of approximately 160,000 postmenopausal women investigating the risks and benefits of strategies that may reduce the incidence of heart disease, breast and colorectal cancer, and fractures, including dietary interventions and two trials of hormone therapy. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined hormone therapy or placebo, was halted early because health risks exceeded benefits.[56,57] One of the adverse outcomes prompting closure was a significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150) breast cancers (RR =1.24; 95% CI, 1.02-1.50, P <.001) in women randomized to receive estrogen and progestin.[57] HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms.[57]

Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased [58-60] or unaffected by a family history of breast cancer;[39,61,62] risk did not vary by family history in the meta-analysis.[48] The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/2 mutations.[57] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.[63]

The effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 mutation has only been studied in the context of bilateral oophorectomy, a procedure known to reduce the risk of breast cancer. In a prospective study of 462 women with BRCA1 or BRCA2 mutations, 155 who had undergone bilateral oophorectomy (139 before age 50 years), the breast cancer risk reduction of 37% was essentially the same among the 93 women who took HRT compared with the reduction of 38% among those without HRT.[64] This finding needs to be confirmed in a larger study but suggests that HRT in this particular setting does not negate the protective effect of oophorectomy on breast cancer risk.

Level of evidence: 4B

Tamoxifen (a synthetic antiestrogen) increases breast-cell growth inhibitory factors and concomitantly reduces breast-cell growth stimulatory factors. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (NSABP-P1), a prospective randomized double-blind trial, compared tamoxifen (20 mg/day) to placebo for 5 years. Tamoxifen was shown to reduce the risk of invasive breast cancer by 49%. The protective effect was largely confined to estrogen receptor–positive breast cancer, which was reduced by 69%. The incidence of estrogen receptor–negative cancer was not significantly reduced.[65] Similar reductions were noted in the risk of preinvasive breast cancer. Reductions in breast cancer risk were noted among women with a family history of breast cancer and in those without a family history. These benefits were associated with an increased incidence of endometrial cancers and thrombotic events among women older than 50 years. Interim data from two European tamoxifen prevention trials did not show a reduction in breast cancer risk with tamoxifen after a median follow-up of 48 months [66] or 70 months,[67] respectively. In one trial, however, reduction in breast cancer risk was seen among a subgroup who also used HRT.[66] These trials varied considerably in study design and populations. (Refer to the PDQ summary on Prevention of Breast Cancer for more information.)

A substudy of the NSABP-P1 trial evaluated the effectiveness of tamoxifen in preventing breast cancer in BRCA1/2 mutation carriers older than 35 years. BRCA2-positive women benefited from tamoxifen to the same extent as BRCA1/2 mutation–negative participants; however, tamoxifen use among healthy women with BRCA1 mutations did not appear to reduce breast cancer incidence. These data must be viewed with caution in view of the small number of mutation carriers in the sample (eight BRCA1 carriers and 11 BRCA2 carriers).[68]

Level of evidence: 1

In contrast to the very limited data on primary prevention in BRCA1 and BRCA2 mutation carriers with tamoxifen, several studies have found a protective effect of tamoxifen on the risk of contralateral breast cancer.[69-71] In one study involving approximately 600 BRCA1/2 mutation carriers, tamoxifen use was associated with a 51% reduction in contralateral breast cancer.[69] An update to this report examined 285 BRCA1/2 mutation carriers with bilateral breast cancer and 751 BRCA1/2 mutation carriers with unilateral breast cancer (40% of these patients were included in their initial study). Tamoxifen was associated with a 50% reduction in contralateral breast cancer risk in BRCA1 mutation carriers and a 58% reduction in BRCA2 mutation carriers. Tamoxifen did not appear to confer benefit in women who had undergone an oophorectomy, although the numbers in this subgroup were quite small.[71] Another study involving 160 BRCA1/2 mutation carriers demonstrated that tamoxifen use following treatment of breast cancer with lumpectomy and radiation was associated with a 69% reduction in the risk of contralateral breast cancer.[70] These studies are limited by their retrospective, case-control designs and the absence of information regarding estrogen-receptor status in the primary tumor.

The STAR trial (NSABP; P-2) included more than 19,000 women and compared 5 years of raloxifene with tamoxifen in reducing the risk of invasive breast cancer.[72] There was no difference in incidence of invasive breast cancer at a mean follow-up of 3.9 years; however, there were fewer noninvasive cancers in the tamoxifen group. The incidence of thromboembolic events and hysterectomy was significantly lower in the raloxifene group. Detailed quality of life data demonstrate slight differences between the two arms.[73] Data regarding efficacy in BRCA1 or BRCA2 mutation carriers are not available.

Level of Evidence: 1

In the general population, both subcutaneous mastectomy and simple (total) mastectomy have been used for prophylaxis. Only 90% to 95% of breast tissue is removed with subcutaneous mastectomy.[74] In a total or simple mastectomy, removal of the nipple-areolar complex increases the proportion of breast tissue removed compared with subcutaneous mastectomy. However, some breast tissue is usually left behind with both procedures. The risk of breast cancer following either of these procedures has not been well established.

The effectiveness of risk-reducing mastectomy (RRM) in women with BRCA1 or BRCA2 mutations has been evaluated in several studies. In one retrospective cohort study of 214 women considered to be at hereditary risk by virtue of a family history suggesting an autosomal dominant predisposition, three women were diagnosed with breast cancer after bilateral RRM, with a median follow-up of 14 years.[75] As 37.4 cancers were expected, the calculated risk reduction was 92% (95% CI, 76.6–98.3). In a follow-up subset analysis, 176 of the 214 high-risk women in this cohort study underwent mutation analysis of BRCA1 and BRCA2. Mutations were found in 26 women (18 deleterious, eight variants of uncertain significance). None of those women had developed breast cancer after a median follow-up of 13.4 years.[76] Two of the three women diagnosed with breast cancer after RRM were tested, and neither carried a mutation. The calculated risk reduction among mutation carriers was 89.5% to 100% (95% CI, 41.4%–100%), depending on the assumptions made about the expected numbers of cancers among mutation carriers and the status of the untested woman who developed cancer despite mastectomy. The result of this retrospective cohort study has been supported by a prospective analysis of 76 mutation carriers undergoing RRM and followed prospectively for a mean of 2.9 years. No breast cancers were observed in these women, whereas eight were identified in women undergoing regular surveillance (HR for breast cancer after RRM = 0 [95% CI, 0–0.36]).[77]

The Prevention and Observation of Surgical End Points (PROSE) study group estimated the degree of breast cancer risk reduction after RRM in BRCA1/2 mutation carriers. The rate of breast cancer in 105 mutation carriers who underwent bilateral RRM was compared with that in 378 mutation carriers who did not choose surgery. Bilateral mastectomy reduced the risk of breast cancer after a mean follow-up of 6.4 years by approximately 90%.[78]

Another study evaluated the effectiveness of contralateral RRM in affected women with hereditary breast cancer. In a group of 148 BRCA1 or BRCA2 mutation carriers, 79 of whom underwent RRM, the risk of contralateral cancer was reduced by 91% and was independent of the effect of risk-reducing oophorectomy. Survival was better among women undergoing RRM, but this result was apparently caused by higher mortality due to the index cancer or metachronous ovarian cancer in the group not undergoing surgery.[79]

Studies describing histopathologic findings in RRM specimens from women with BRCA1 or BRCA2 mutations have been somewhat inconsistent. In two series, proliferative lesions associated with an increased risk of breast cancer (lobular carcinoma in situ, atypical lobular hyperplasia, atypical ductal hyperplasia, DCIS) were noted in 43% to 46% of women with mutations undergoing either unilateral or bilateral RRM.[80,81] In these series, 13% to 15% of patients were found to have previously unsuspected DCIS in the prophylactically removed breast. Among 47 cases of risk-reducing bilateral or contralateral mastectomies performed in known BRCA1 or BRCA2 mutation carriers from Australia, 3 (6%) cancers were detected at surgery.[82]

These findings were not replicated in a third retrospective cohort study. In this study, proliferative fibrocystic changes were noted in none of 11 bilateral mastectomies from patients with deleterious mutations and in only two of seven contralateral unilateral risk-reducing mastectomies in affected mutation carriers.[83]

Although data are sparse, the evidence to date indicates that while a substantial proportion of women with a strong family history of breast cancer are interested in discussing RRM as a treatment option, uptake varies according to culture, geography, healthcare system, insurance coverage, provider attitudes, and other social factors. For example, in one setting where the providers made one to two field trips to family gatherings for family information sessions and individual counseling, only 3% of unaffected carriers obtained RRM within 1 year of follow-up.[84] Among women at increased risk of breast cancer due to family history, fewer than 10% opted for mastectomy.[85] Selection of this option was related to breast cancer–related worry as opposed to objective risk parameters (e.g., number of relatives with breast cancer). In addition, self-perceived risk has been closely linked to interest in RRM.[85]

Assuming risk reduction in the range of 90%, a theoretical model suggests that for a group of 30-year-old women with BRCA1 or BRCA2 mutations, RRM would result in an average increased life expectancy of 2.9 to 5.3 years.[86] While these data are useful for public policy decisions, they cannot be individualized for clinical care as they include assumptions that cannot be fully tested. Another study of at-risk women showed a 70% time-tradeoff value, indicating that the women were willing to sacrifice 30% of life expectancy in order to avoid RRM.[87] A cost-effectiveness analysis study estimated that risk-reducing surgery (mastectomy and oophorectomy) is cost-effective compared with surveillance with regard to years of life saved, but not for improved quality of life.[88]

In contrast, in a Dutch study of highly motivated women being followed every 6 months at a high-risk center, more than half (51%) of unaffected carriers opted for RRM. Almost 90% of the RRM surgeries were performed within 1 year of DNA testing. In this study, those most likely to have RRM were women younger than 55 years and with children.[89]

The Society of Surgical Oncology has endorsed RRM as an option for women with BRCA1/2 mutations or strong family histories of breast cancer.[90]

Individual psychological factors have an important role in decision-making about RRM by unaffected women. Research is emerging about psychosocial outcomes of RRM. (Refer to the Psychological Aspects of Medical Interventions section of this summary.)

Level of evidence: 3B

In the general population, removal of both ovaries has been associated with a reduction in breast cancer risk of up to 75%, depending on parity, weight, and age at time of artificial menopause. (Refer to the PDQ summary on Prevention of Breast Cancer for more information.) A Mayo Clinic study of 680 women at various levels of familial risk found that in women younger than 60 years who had bilateral oophorectomy, the likelihood of breast cancers developing was reduced for all risk groups.[91] Ovarian ablation, however, is associated with important side effects such as hot flashes, impaired sleep habits, vaginal dryness, dyspareunia, and increased risk of osteoporosis and heart disease. A variety of strategies may be necessary to counteract the adverse effects of ovarian ablation.

In support of early small studies,[92,93] a retrospective study of 551 women with disease-associated BRCA1 or BRCA2 mutations found a significant reduction in risk of breast cancer (HR 0.47; 95% CI, 0.29–0.77) as well as ovarian cancer (HR 0.04, 95% CI, 0.01–0.16) after risk-reducing salpingo-oophorectomy (RRSO).[94] A prospective single-institution study of 170 women with BRCA1 or BRCA2 mutations showed a similar trend. With RRSO, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74).[95]

Levels of evidence: 3aii

While lumpectomy plus radiation therapy has become standard local-regional therapy for women with early stage breast cancer, its use in women with a hereditary predisposition for breast cancer who do not choose immediate bilateral mastectomy is less clear. Concern about its use, particularly in women with deleterious BRCA1 and BRCA2 mutations, centers around two issues. The first is the potential for an increased rate of ipsilateral cancers in the treated breast. The second is the potential for therapeutic radiation to induce tumors in BRCA1/2 defective cells. Most of the early studies that used family history of breast/ovarian cancer as a surrogate for hereditary risk failed to find an increase in ipsilateral cancers in women treated with breast conservation.[96-100] However, with the availability of clinical genetic testing for BRCA1/2 mutations, treatment outcomes for carriers of deleterious mutations in BRCA1/2 can now be compared with those of noncarriers.

To understand the role of germline BRCA1/2 mutations in determining outcome among women treated conservatively for breast cancer, the records of Ashkenazi Jewish (AJ) women treated with lumpectomy and radiation therapy for invasive breast cancer were reviewed.[101] Archival pathology material was obtained for analysis of the three founder AJ mutations. Deleterious BRCA mutations were found in 56 (11.3%) of the cases. The rate of ipsilateral cancer for founder mutation carriers was 12% at 10 years compared with 8% for women without mutations (not statistically significant). Women with founder AJ mutations were over three times more likely than women without mutations to develop contralateral cancer, 27% versus 8% (P = .0001). The same investigators also described a separate case series of 87 women with BRCA mutations who were treated with breast conserving surgery.[102] They reported a 12.6% rate of ipsilateral breast cancer at a median of 51.8 months, and a 23% rate of contralateral breast cancer at a median of 67.4 months. No control group was included.[102]

A case-control study from the Netherlands compared women with hereditary breast cancer (identified as either BRCA1/2 positive, or by a strong family history) with women without hereditary breast cancer for treatment outcome after breast conservation therapy. Although rates of ipsilateral breast recurrence were similar at 2 years following diagnosis, by 5 years the rate was twice as high in the hereditary cases (14% vs. 7%), and remained twice as high at 10 and 15 years after diagnosis (30% and 49% in the hereditary group, and 16% and 20% in the sporadic group).[103]

A multi-institution retrospective cohort study compared outcomes after breast conserving treatment between women with known BRCA1/2 mutations and those whose family history was not suggestive of a hereditary pattern. At 10 years, overall rates of ipsilateral breast cancer were not significantly different. However, BRCA1/2 mutation status was significantly associated with a risk of ipsilateral breast cancer when those carriers who underwent oophorectomy were removed from the analysis (7.8% for noncarriers vs. 16.3% for carriers). The 10-year estimates for contralateral breast cancer were 3% for noncarriers and 26% for carriers.[70] One study reported an approximately 40% risk of contralateral breast cancer in BRCA mutation carriers, a risk which is reduced by taking tamoxifen or undergoing oophorectomy.[104]

A study of selected patients diagnosed at age 42 years or younger who had undergone conservative therapy were offered genetic testing for BRCA1/2 mutations. Of 127 participants, 22 were found to have deleterious mutations.[105] At a median of 12.7 years of follow-up, the rate of ipsilateral events was 49% in the mutation carriers and 21% in the noncarriers (P = .007). Clinical and pathological features of the ipsilateral tumors were more consistent with second primaries than with local recurrence. Similarly, the rate of contralateral cancers was 42% in the carriers and 9% in the noncarriers (P = .001). This study has been criticized as having an unacceptable rate of ipsilateral events overall, calling into question the adequacy of the local-regional treatment.[106]

As noted above, there is a growing indication that women with BRCA1/2 mutations who are treated conservatively have an increased, not decreased, rate of ipsilateral breast cancer, occurring usually after 5 years of follow-up.

The second concern stems from the emerging understanding of the role of the BRCA genes in DNA repair activities within the cell, and the implication of the loss of these functions for radiation hypersensitivity. Both BRCA1 and BRCA2 are involved in DNA double-strand break repair, and loss of function in these genes could potentially accelerate the rate of cell kill caused by ionizing radiation. Another potentially relevant mechanism is the defect in the G2-M phase checkpoint displayed by BRCA1-deficient cells, which also alters radiation sensitivity.[107] Furthermore, murine models of Brca1- and Brca2-deficient mice have demonstrated evidence of hypersensitivity to ionizing radiation.[18,108] Clinical manifestations of these findings could include:

1. An increased response to adjuvant radiation therapy with a decrease of in-breast recurrence rates.
2. An increase in ipsilateral and contralateral breast cancers secondary to genetic instability.
3. An increase in radiation-related toxicity.

In one study, the rate of local recurrence among women with strong family histories who were treated with lumpectomy was highest when radiation was omitted, suggesting that these tumors are radiosensitive.[98] Rates of contralateral disease are consistently elevated in this population, but are equal for women treated with conservative therapy and for those who chose mastectomy without radiation, indicating that the increased risk is due to the mutation, not the exposure to radiation. And finally, studies have failed to find an increase in either early acute radiation tissue reactions or late radiation reactions to the skin, underlying tissue or bone.[109-111]

These data are consistent with a model in which hereditary BRCA1/2 cancers are sterilized by radiation therapy equally well, but due to the underlying genetic predisposition, the increased risk of second primaries in the treated breast remains. The findings of a significantly increased risk of contralateral breast cancer in this population is consistent across studies, and increasingly women with BRCA1/2 mutations are considering bilateral mastectomy at the time of first diagnosis of breast cancer, regardless of stage. Finally, there is no evidence for an increase in radiation toxicity among BRCA1/2 mutation carriers.

A small but growing body of preclinical and clinical literature suggests a differential response of BRCA-related breast cancers to systemic chemotherapy. This is based on the emerging understanding of the functions of these genes in response to DNA damage and mitotic spindle machinery control. As several chemotherapeutic agents target either DNA or mitotic spindle structural integrity, the lack of BRCA functions could alter response to these agents. The absence of BRCA-mediated DNA repair could potentially increase sensitivity to these agents, which induce DNA breaks. On the other hand, the failure to activate cell cycle checkpoints in response to DNA damage could allow damaged tumor cells to avoid apoptosis and survive, leading to chemotherapy resistance. In the case of spindle poisons, BRCA1 has a role in the detection of microtubule disruption and induces apoptosis to prevent aberrant mitosis. Its absence could circumvent this mitotic regulation and thereby enhance sensitivity to spindle poisons. Several in vitro studies have begun to explore potential mechanisms for a differential response of BRCA-related breast cancers to several classes of chemotherapy. There are no clinical data at this time indicating that BRCA-associated cancers should be treated with different chemotherapy than non-BRCA-associated cancers.

Cell lines with inducible expression of BRCA1 were generated to explore its potential role in the cellular response to various chemotherapeutic agents.[112] In the presence of the antimicrotubule agents Taxol and vincristine, expression of BRCA1 resulted in a significant increase in cell death associated with an acute arrest in G2/M, suggesting that BRCA1 expression may be an important mediator of response to antimicrotubule agents by preventing progression of the cell into mitosis. BRCA1-deficient tumors, therefore, may exhibit resistance to this class of drugs.

The ability of BRCA1 to sensitize breast cancer cell lines to G2/M arrest in response to antimicrotubule agents was confirmed in a second study.[113] In contrast, BRCA1 induced resistance to DNA-damaging agents that induce double-strand breaks in DNA. Both of these opposing effects were mediated by inhibition or induction of apoptosis.

It has been shown that cell lines deficient in BRCA1 are defective in homology-directed chromosomal break repair, and highly sensitive to the interstrand cross-linking agent mitomycin-C.[114] Additional evidence supporting a role of BRCA1 in response to DNA-damaging drugs is seen in cisplatinum-resistant breast and ovarian cancer cell lines, in which BRCA1 is overexpressed and DNA repair is enhanced.[115]

Decreasing expression of BRCA1 in cell lines has been associated with increased sensitivity to cisplatinum and etoposide, and resistance to the tubule-damaging agents Taxol and vincristine.[116] Resistance was linked to transcriptional modifications in the JNK pathway which mediates apoptosis. Increased sensitivity to cisplatinum was associated with a time-dependent and dose-dependent increase in apoptosis in a mouse mammary epithelial cell line.[117] Another mechanism suggested for increased cisplatinum sensitivity in BRCA mutant cells is the role of both BRCA1 and BRCA2 in the promotion of subnuclear Rad51 foci for DNA repair.[118] A cell culture model was used to study the interaction of cyclin-dependent kinase 2 (CDK2) inhibition and BRCA1 deficiency.[119] CDK2 is a serine/threonine kinase that has a role in cell cycle control. Inhibitors of CDK2 cause delays in DNA damage signaling. CDK2 inhibition was fourfold more toxic in the presence of BRCA1 mutations, suggesting that CDK2 inhibition may be a sensitive target in patients with BRCA1 mutations. Another specific pathway to exploit in BRCA1/2 deficient tumors is the poly (ADP-ribose) polymerase (PARP) pathway. PARP is active in the repair of double-strand breaks by homologous recombination. In vitro studies have shown that PARP inhibition kills BRCA mutant cells with high specificity. This specificity has not yet been demonstrated in vivo,[120] although phase I studies of PARP inhibitors in combination with chemotherapeutic agents are underway.

Overall, the preclinical data supports the conclusion that BRCA1 inhibits apoptosis after treatment with DNA-damaging agents, and its absence promotes apoptosis leading to increased sensitivity. In contrast, BRCA1 promotes apoptosis after exposure to spindle poisons and its absence supports survival of cells damaged by spindle poisons and thereby confers drug resistance.[121] Similarly, an animal model of Brca2 deficiency in murine small intestine showed a reduction in clonogenic survival after exposure to either cisplatinum or mitomycin C.[122]

Evidence of the role of BRCA1/2 mutations in human studies is retrospective in design and very preliminary. Among 38 women treated with neoadjuvant therapy for stages I-III breast cancer, those with BRCA1/2 mutations were significantly more likely to achieve a clinical and pathological complete response, independent of clinical stage.[123]

Thus the preclinical and clinical data are consistent with the emerging understanding of BRCA1 function in DNA-damage response as well as cell cycle regulation. While these findings raise the possibility that germline status may influence treatment choices, there is insufficient evidence at this time to support treating mutation carriers with different regimens.

Refer to the PDQ summary on Screening for Ovarian Cancer for information on screening in the general population, and to the PDQ summary Cancer Genetics Overview for information on levels of evidence related to screening and prevention. The latter also outlines the five requirements that must be met before it is considered appropriate to screen for a particular medical condition as part of routine medical practice.

In the general population, clinical examination of the ovaries has neither the specificity nor the sensitivity to reliably identify early ovarian cancer. No data exist regarding the benefit of clinical examination of the ovaries (bimanual pelvic examination) in women at inherited risk of ovarian cancer.

Level of evidence: None assigned

In the general population, transvaginal ultrasound (TVUS) appears to be superior to transabdominal ultrasound in the preoperative diagnosis of adnexal masses. Both techniques have lower specificity in premenopausal women than in postmenopausal women, due to the cyclic menstrual changes in premenopausal ovaries (e.g., transient corpus luteum cysts) that can cause difficulty in interpretation. A screening trial of TVUS in 1,300 postmenopausal, asymptomatic women detected abnormalities in 2.5% of women. More than 90% of the lesions found were benign. Women with a family history of ovarian cancer were more likely to be found with an ovarian malignancy (RR = 4.0). No such association was noted for those with a family history of breast cancer or colon cancer.[124]

One study reported on the use of transvaginal color Doppler ultrasonography in the evaluation of 126 women with adnexal masses who subsequently underwent surgery. Twenty epithelial ovarian cancers were detected, as well as two dysgerminomas, two ovarian tumors of low malignant potential, one immature teratoma, and one Sertoli-Leydig cell tumor. It was concluded that color Doppler ultrasonography was able to increase the PPV and negative predictive value (NPV) due to increased sensitivity and specificity of ultrasound evaluation.[125]

Another study reported that the addition of color Doppler ultrasonography was able to increase the PPV of ultrasound imaging from 25% to 60% among women with a personal history of breast cancer undergoing screening for ovarian cancer.[126] As noted, however, clinical studies of color Doppler imaging have shown that normal physiologic changes in the premenopausal ovary near the time of ovulation have low impedance flow characteristics similar to those seen in malignancy.[127]

Data are limited regarding the potential benefit of pelvic ultrasound in screening women at inherited risk of ovarian cancer. A 10-year observational study in the United Kingdom of 2,500 asymptomatic women with at least one relative with ovarian cancer has evaluated TVUS and reported sensitivity and specificity with 10 years of follow-up and retrospective analysis of serum CA 125 levels.[128] Most women were screened once, unless the initial scan was positive or the family history was especially strong. There were 11 screening-detected cancers, one false-negative (a stage III cancer occurring within 12 months of ultrasound screening), and 93 false-positive tests, for a test sensitivity of 92% and a specificity of 97.8%. Among the 11 screening-detected cancers, four were stage IA invasive, four borderline stage IA, one invasive stage IC, and two stage II/III serous carcinomas. Sixty-five percent of the subjects were premenopausal, and 9 of the 12 cancers occurred in this group. TVUS was quite sensitive in this high-risk group, but there were still large numbers of women screened (n = 227) and false-positives (n = 9) for each cancer detected. The retrospective analysis of serum CA 125 levels in this study also allowed its evaluation as a potential first-stage screen to reduce the number of ultrasound tests required and the number of false-positives.[128] If only women with CA 125 levels of 20 or higher were to have undergone ultrasound screening, an additional four cancers would have been missed (sensitivity of 58%), but only 22% of the subjects would have been referred for ultrasound screening, reducing the number of false-positives to 21. Ultrasound screening only of those with CA 125 levels of 35 would have resulted in a sensitivity of 33% (seven additional cancers missed).

Another study evaluated 383 high-risk women (152 BRCA1/2 mutation carriers) with annual TVUS and CA 125.[129] Abnormal screening results were noted in 74 women (19.3%), but these resolved spontaneously in 47 women (63.5%). Of the 20 women undergoing exploratory surgery, only one had cancer, which proved to be a breast cancer metastatic to the ovary. No epithelial ovarian cancers were found as a result of screening.

Another study used gynecologic examination, TVUS, and CA 125 to screen 180 women at high risk of ovarian cancer with or without a prior history of breast cancer. (Refer to the Serum CA 125 section in this summary.) Abnormal ultrasounds were noted in all five women with invasive epithelial ovarian carcinomas. Of these, however, one had stage II disease and four had stage III disease.[130] A study from the Netherlands used annual TVUS and CA 125 to screen 269 women at high risk of hereditary ovarian cancer. Of the four prevalent and four incident cancers found, six were detected at an advanced stage.[131]

One study screened 597 women at risk of ovarian cancer with serum CA 125, TVUS, and color Doppler (described in the Serum CA 125 section). No epithelial ovarian cancers were found. However, one ovarian tumor of low malignant potential was identified.[127,132]

Another study reported screening 386 women with first- or second-degree relatives with ovarian cancer. The study used TVUS, color flow Doppler, and serum CA 125. Initial ultrasound was abnormal in 89 of 381 women (23%). Ovarian masses persisted in 15 patients; all of these were benign at surgery. CA 125 levels were higher than 35 U/mL in 42 of 386 women (11%). Two patients who underwent surgery for rising CA 125 levels had normal ovaries.[133]

Level of evidence: 4

Limited data are available on the potential benefit of screening with serum CA 125 in women at inherited risk of ovarian cancer. When 180 women considered at high risk of ovarian cancer based on family history were screened for ovarian cancer by gynecologic examination, transvaginal ultrasound (TVUS), and serum CA 125, one granulosa cell tumor, three tumors of low malignant potential, and five epithelial ovarian tumors (one stage II and four stage III) were detected. CA 125 levels were elevated in one of the tumors of low malignant potential and in three of the four stage III ovarian carcinomas.[130]

A 10-year observational study of 2,500 asymptomatic women with a family history of ovarian cancer who underwent transvaginal ultrasound screening and retrospective analysis of serum CA 125 levels is described in more detail in the Pelvic Ultrasound section of this summary.[128]

Another study found elevated CA 125 levels in 68 of 597 (11.4%) women screened for ovarian cancer. Most of these women had a first-degree or second-degree relative with ovarian cancer, though 51 had a pedigree consistent with inherited susceptibility to breast or ovarian cancer, and seven had a pedigree consistent with Lynch syndrome. Among the premenopausal patients, the elevations in CA 125 were associated with ultrasonographic evidence of endometriosis, adenomyosis, or leiomyomas. Among the eight postmenopausal patients, all had normal ovarian architecture on ultrasound.[127,132] No data are available to address the effectiveness of ovarian cancer screening in preventing deaths from ovarian cancer.

Level of evidence: 5

The National Institutes of Health (NIH) Consensus Statement on Ovarian Cancer recommended against routine screening of the general population for ovarian cancer with serum CA 125. The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo TVUS and serum CA 125 screening every 6 to 12 months, beginning at age 35 years.[134] The Cancer Genetics Studies Consortium task force has recommended that female carriers of a deleterious BRCA1 mutation undergo annual or semiannual screening using TVUS and serum CA 125 levels, beginning at age 25 to 35 years.[9] Both recommendations are based solely on expert opinion and best cl