Breast Cancer
        Screening
        Screening Strategies Under Evaluation for Which Utility Has Not Been Established
        Prevention
Ovarian Cancer
        Screening
        Prevention

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. 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.[1] 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, 5 breast cancers were detected by self-examination less than a year after a previous screen (as compared with 1 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.[2] In another series of BRCA1/2 mutation carriers, 4 of 9 incident cancers were diagnosed as palpable masses after a reportedly normal mammogram, further suggesting potential value of self-examination.[3] 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.”[4]

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.[4]

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.[5] 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.[6] Preliminary data suggest that mammography sensitivity is lower in BRCA1 and BRCA2 carriers than in noncarriers.[3] Subsequent observational studies have found that the positive- predictive value of mammography increases with age and is highest among older women and among women with a family history of breast cancer.[7] Higher positive-predictive values may be due to increased breast cancer incidence, higher sensitivity, and/or higher specificity.[8] 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 2 of whom had a BRCA2 mutation. Pushing margins, characteristic of medullary histology, is associated with an absence of fibrotic reaction.[9]

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.[10] 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 6 women at a mean of 20.2 months after receipt of BRCA results.[2] 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.”[4] 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, given accumulating evidence that the BRCA1 and BRCA2 gene products are involved in repair of DNA damage from radiation.[11-13]

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, breast ultrasound, breast ductal lavage, and digital mammography. Studies of these screening techniques are ongoing. There is insufficient evidence regarding screening outcomes to determine their utility in routine practice. A brief review of current evidence is provided here.

All studies to date indicate that screening magnetic resonance imaging (MRI) has higher sensitivity than mammography; specificity is generally lower.[14-18] Positive-predictive value has been estimated in the range of 26% to 33% and negative-predictive value in the range of 97% to 100%.[14-16,19] Uncertainties about MRI screening include the effect of screening on mortality; the rate and outcome of false-positive results; cost; and access to screening and MRI-guided biopsy.

Several studies have reported instances of breast cancer detected by ultrasound (US) that were missed by mammography, as discussed in 1 review.[20] In a pilot study of US as an adjunct to mammography in 149 women with moderately increased risk based on family history, 1 cancer was detected, based on US findings. Nine other biopsies of benign lesions were performed, one based on abnormalities on both mammography and US, the remaining 8 based on abnormalities on US alone.[20] Uncertainties about US include the effect of screening on mortality, the rate and outcome of false-positive results, and access to experienced breast ultrasonographers.

All ductal and lobular breast cancers originate in the epithelial cells that line the breast milk ducts. Breast ductal lavage (BDL) involves the insertion of a catheter into the milk ducts under local anesthesia through breast duct openings on the surface of the nipple, followed by a saline infusion to wash out cells for cytological examination. The technique has been shown to be a feasible method for collecting adequate samples of cells for examination, and cytological atypia can be detected.[21] The finding of atypia on BDL may provide risk information beyond that provided by the Gail risk model.[22] A study involving 426 high-risk women reported on the diagnosis of 2 cases of DCIS following BDL.[21] The risk implications of atypia found on BDL, as compared with atypia found on breast biopsy, are not known; neither is the sensitivity or specificity of BDL as a predictor of early breast cancer known. There are no current data that BDL is an effective screening strategy.

Digital mammography refers to the use of a digital detector to detect and record x-ray images. This technology improves contrast resolution,[23] 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;[24] however, digital mammography resulted in fewer recalls.

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.[25] 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 3 or more have been associated with a lowered risk of breast cancer.[26,27] A relative risk (RR) of 0.85 was estimated for each additional birth, up to 5 or more. As noted in the Ovarian Cancer Prevention section of this summary, however, increasing parity appeared to be associated with an increased risk of ovarian cancer. 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.[28]

Level of evidence: 3

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.[29] 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.[30] 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%).[31]

There was no increased risk associated with use among BRCA2 mutation carriers.

One study examined proliferation of normal breast epithelium among women undergoing reduction mammoplasty.[32] 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.

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

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.) 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,[33,34] a retrospective study of 551 women with disease-associated BRCA1 or BRCA2 mutations found a significant reduction in risk of breast cancer (hazard ratio (HR) 0.47, 95% CI 0.29-0.77) as well as ovarian cancer (HR 0.04, 95% CI 0.01-0.16) after bilateral oophorectomy.[35] A prospective single-institution study of 272 women with BRCA1 or BRCA2 mutations showed a similar trend. With oophorectomy, 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).[36]

Levels of evidence: 3, 4

Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with hormone replacement therapy (HRT) in the general population.[37-40] The Women’s Health Initiative (WHI) is a randomized controlled trial of ~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 2 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.[39,40] 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.[40] 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.[40]

Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased [41-43] or unaffected by a family history of breast cancer;[26,44,45] risk did not vary by family history in the meta-analysis.[29] The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/2 mutations.[40] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.[46]

No data exist on the effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 high-risk mutation.

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 reduced with statistical significance.[47] 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 those without a family history. These benefits were associated with an increased incidence, among women older than 50 years, of endometrial cancers and thrombotic events. Interim data from 2 European tamoxifen prevention trials did not show a reduction in breast cancer risk with tamoxifen after a median follow-up of 48 months [48] and 70 months,[49] respectively. In 1 trial, however, reduction in breast cancer risk was seen among a subgroup who also used HRT.[48] 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 (8 BRCA1 carriers and 11 BRCA2 carriers).[50]

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.[51] 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 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, 3 women were diagnosed with breast cancer after bilateral risk-reducing mastectomy, with a median follow-up of 14 years.[52] As 37.4 cancers were expected, the calculated risk reduction was 92.0% (95% CI 76.6-98.3). In a follow-up subset analysis, 176 of the 214 high-risk women in this cohort study underwent mutational analysis of BRCA1 and BRCA2. Mutations were found in 26 women (18 deleterious, 8 variants of uncertain significance). None of those women had developed breast cancer after a median follow-up of 13.4 years.[53] Two of the 3 women diagnosed with breast cancer after risk-reducing mastectomy 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 risk-reducing mastectomy and followed prospectively for a mean of 2.9 years. No breast cancers were observed in these women, whereas 8 were identified in women undergoing regular surveillance (HR for breast cancer after risk-reducing mastectomy = 0 [95% CI 0-0.36]).[54]

The Prevention and Observation of Surgical End Points (PROSE) study group estimated the degree of breast cancer risk reduction after risk-reducing mastectomy in BRCA1/2 mutation carriers. The rate of breast cancer in 105 mutation carriers who underwent bilateral risk-reducing mastectomy 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%.[55]

Studies describing histopathologic findings in risk-reducing mastectomy specimens from women with BRCA1 or BRCA2 mutations have been somewhat inconsistent. In 2 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 risk-reducing mastectomy.[56,57] In these series, 13% to 15% of patients were found to have previously unsuspected DCIS in the prophylactically removed breast. Among 47 cases of prophylactic bilateral or contralateral mastectomies performed in known BRCA1 or BRCA2 mutation carriers from Australia, 3 (6%) cancers were detected at surgery.[58]

These findings were not replicated in a third retrospective cohort study. In this study, proliferative fibrocystic changes were noted in 0 of 11 bilateral mastectomies from patients with deleterious mutations and in only 2 of 7 contralateral unilateral risk-reducing mastectomies in affected mutation carriers.[59]

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 risk-reducing mastectomy as a treatment option, uptake varies according to culture, geography, healthcare system, insurance coverage, provider attitudes, and other social factors. For example, in 1 setting where the providers made 1 to 2 field trips to family gatherings for family information sessions and individual counseling, only 3% of unaffected carriers obtained risk-reducing mastectomy within 1 year of follow-up.[60] Among women at increased risk of breast cancer due to family history, less than 10% opted for mastectomy.[61] 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 risk-reducing mastectomy.[61]

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, risk-reducing mastectomy would result in an average increased life expectancy of 2.9 to 5.3 years.[62] 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 risk-reducing mastectomy.[63] 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.[64]

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 risk-reducing mastectomy. Almost 90% of the risk-reducing mastectomy surgeries were performed within 1 year of DNA testing. In this study, those most likely to have risk-reducing mastectomy were women younger than 55 years and with children.[65]

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

Level of evidence: 3B

No data exist regarding the impact of abortion, diet, or alcohol on the risk of breast cancer among women at inherited risk of breast cancer. (Refer to the PDQ summary on Prevention of Breast Cancer for information relevant to the general population.) In a retrospective analysis of 104 BRCA1/2 mutation-positive families, physical exercise as a teenager was associated with a delayed onset of breast cancer.[66]

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.

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

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, 1 granulosa cell tumor, 3 tumors of low malignant potential, and 5 epithelial ovarian tumors (1 stage II and 4 stage III) were detected. CA 125 levels were elevated in 1 of the tumors of low malignant potential and 3 of the 4 stage III ovarian carcinomas.[67]

One study examined the role of screening with serum CA 125 among 1,502 women with first-degree or second-degree relatives with ovarian cancer. Of these women, 147 (10%) appeared to have a pedigree consistent with site-specific ovarian cancer susceptibility, and 271 (18%) a pedigree consistent with hereditary nonpolyposis colon cancer (HNPCC). Using an elevated CA 125 threshold value of 35 U/mL, compared with 2 U/mL, increased the positive-predictive value of TVUS from 12.7% to 42.9%. The detection rate, however, dropped from 100% to 43%. Elevated CA 125 levels were noted in 2 of the 4 identified ovarian cancer patients. Among these 4 patients, normal CA 125 levels were noted in 1 patient with stage I disease and 1 patient with stage II disease, while elevated levels of CA 125 were noted in 1 patient with stage I disease and 1 patient with stage III disease.[68]

One 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, although 51 had a pedigree consistent with inherited susceptibility to breast or ovarian cancer, and 7 had a pedigree consistent with HNPCC. Among the premenopausal patients, the elevations in CA 125 were associated with ultrasonographic evidence of endometriosis, adenomyosis, or leiomyomas. Among the 8 postmenopausal patients, all had normal ovarian architecture on ultrasound.[69,70] No data are available to address the effectiveness of ovarian cancer screening in preventing deaths from ovarian cancer.

In 1994, 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 annual or semiannual screening for ovarian cancer with TVUS and serum CA 125.[71] The Cancer Genetics Studies Consortium task force recommended that female carriers of a BRCA1 high-risk mutation undergo annual or semiannual screening using TVUS and serum CA 125 levels, beginning at age 25 to 35 years.[4]

A phase II trial evaluating annual TVUS and serial CA 125 levels in 3,000 high-risk women registered in the United Kingdom Familial Ovarian Cancer Registry is under way. In the United States, the National Cancer Institute (NCI) is conducting a large controlled clinical trial in which 74,000 women are randomized to regular medical care or research-based screening for lung, colorectal, and ovarian cancer. The ovarian cancer screening consists of yearly serum CA 125 and TVUS.[72]

Level of evidence: 5

In the general population, TVUS appears to be superior to transabdominal ultrasound in preoperative diagnosis of adnexal masses. Either technique has lower specificity in premenopausal women than in postmenopausal women due to the cyclic menstrual changes in premenopausal ovaries that can cause difficulty in interpretation. A screening trial of TVUS in 1,300 postmenopausal, asymptomatic women detected abnormalities in 2.5%. 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.[73]

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 2 dysgerminomas, 2 ovarian tumors of low malignant potential, 1 immature teratoma, and 1 Sertoli-Leydig cell tumor. It was concluded that color Doppler ultrasonography was able to increase the positive and negative-predictive value, due to increased sensitivity and specificity of ultrasound evaluation.[74]

Another study reported that the addition of color Doppler ultrasonography was able to increase the positive-predictive value of ultrasound imaging from 25% to 60% among women with a personal history of breast cancer undergoing screening for ovarian cancer.[75] 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.[69]

Data are limited regarding the potential benefit of pelvic ultrasound in screening women at inherited risk of ovarian cancer. One study examined 1,601 women with a family history of ovarian cancer with pelvic ultrasound. Abnormal scans were found in 3.8%. Only 3 of 61 women with abnormal results had ovarian cancer, 2 with stage I and 1 with stage III.[76,77] Another study used gynecologic examination, TVUS, and CA 125 to screen 180 women at high risk of ovarian cancer with or without breast cancer. (Refer to the Serum CA 125 section in this summary.) Abnormal ultrasounds were noted in all 5 women with invasive epithelial ovarian carcinomas. Of these, however, 1 had stage II disease and 4 had stage III disease.[67]

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. One case of an ovarian tumor of low malignant potential, however, was identified.[69,70]

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.[78]

The NIH Consensus Statement on Ovarian Cancer recommended against routine screening of the general population with TVUS and serum CA 125. The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo TVUS and serum CA 125 every 6 to 12 months, commencing at age 35 years.[71] The Cancer Genetics Studies Consortium task force has recommended that female carriers of a BRCA1 high-risk mutation undergo annual or semiannual screening using TVUS and serum CA 125 levels, beginning at age 25 to 35 years.[4]

In the United States, NCI is conducting a large controlled clinical trial in which 74,000 women are randomized to regular medical care or research-based screening for lung, colorectal, and ovarian cancer. The ovarian cancer screening consists of yearly serum CA 125 and TVUS.[72]

Level of evidence: 5

Refer to the PDQ summary on Prevention of Ovarian 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.

It has been suggested that incessant ovulation, with repetitive trauma and repair to the ovarian epithelium, increases the risk of ovarian cancer. In epidemiologic studies in the general population, physiologic states that prevent ovulation have been associated with decreased risk of ovarian cancer. It has also been suggested that chronic overstimulation of the ovaries by luteinizing hormone (LH) plays a role in ovarian cancer pathogenesis.[79] Most of these data derive from studies in the general population, but some information suggests the same is true in women at high risk due to genetic predisposition.

Among the general population, parity decreases the risk of ovarian cancer by 45% compared with nulliparous women. Subsequent pregnancies after the first appear to decrease ovarian cancer risk by 15%.[80] Data are limited regarding the impact of fertility on the risk of ovarian cancer in women at high risk due to genetic predisposition.

One study analyzed the reproductive histories of 333 women with a BRCA1 high-risk mutation. Among these women, the risk of ovarian cancer increased with increasing parity. Each birth was associated with an additional 40% increase in risk up to 5 births. Late birth, however, appeared to convey a protective effect. Each 5-year interval in age at last birth was associated with a risk reduction of 18%. Women who had all their children after age 30 years, or who were nulliparous, formed a low-risk group for ovarian cancer (RR 0.30).[28]

A prospective population-based study of postmenopausal women found that nulliparity slightly increased the risk of developing ovarian cancer in women without a family history of breast or ovarian cancer (RR=1.4, 95% CI 0.9-2.4). This group showed that this risk was further increased in nulliparous women with a family history compared with parous women with a similar family history (RR=2.7, 95% CI 1.1-6.6).[81]

A case-control study was conducted involving 170 women with primary ovarian carcinomas or ovarian tumors of low malignant potential and 170 population-based controls. Late age at last childbirth was protective against development of ovarian cancer among women with a family history of breast or ovarian cancer, but not those without such a family history.[82]

In a study conducted using the Utah Population Database, a genealogy of about 1 million individuals linked to cancer incidence data, parity was not related to the development of ovarian cancer in women with a strong family history of ovarian, uterine, breast, or pancreatic cancer.[83]

Level of evidence: 3

No data exist regarding the impact of lactation or hormone replacement therapy on the risk of ovarian cancer in women at inherited risk of ovarian cancer, although consistent, prolonged exposure to unopposed estrogen HRT may increase the risk of ovarian cancer in the general population.[84] A case-control study among women with BRCA1 or BRCA2 mutations demonstrates a significant reduction in risk of ovarian cancer (OR 0.39) for women who have had a tubal ligation. This protective effect was confined to those women with mutations in BRCA1 and persists after controlling for oral contraceptive pill use, parity, history of breast cancer, and ethnicity.[85] A case-control study of ovarian cancer in Israel found a 40% to 50% reduced risk of ovarian cancer among women undergoing gynecologic surgeries (tubal ligation, hysterectomy, unilateral oophorectomy, ovarian cystectomy, excluding bilateral oophorectomy).[86] The mechanism of protection is uncertain. (Refer to the PDQ summary on Prevention of Ovarian Cancer for information relevant to the general population.)

Data are limited and conflicting regarding the impact of oral contraceptive use on the risk of ovarian cancer among women with a BRCA1 high-risk mutation or women at inherited risk of ovarian cancer. While one study found a decreased risk among oral contraceptive pill users, another study failed to observe any protective effect.[37,85,87]

A case-control study was performed evaluating oral contraceptive use among 207 women with a BRCA1 high-risk mutation and ovarian cancer, and as controls, 161 of their sisters who had not been diagnosed with ovarian cancer. After adjustment for year of birth parity and age at delivery of first child, an association appeared to exist between oral contraceptive use and decreased risk of ovarian cancer. The association increased with duration of use. Women who took oral contraceptives for more than 6 years had a 60% reduction in risk. This reduction was similar for BRCA1 and BRCA2 high-risk mutation carriers.[37] In the Gilda Radner Familial Ovarian Cancer Registry, users of oral contraceptives had a lower incidence of ovarian cancer than nonusers.[88] Another study, however, failed to observe any protective effect. This population-based case-control study of ovarian cancer among Jewish women in Israel found the risk of ovarian cancer among BRCA1 or BRCA2 mutation carriers decreased with each birth, but not with increased use of oral contraceptives.[87]

As noted under oral contraceptives in the Breast Cancer Prevention section of this summary, however, a retrospective case-control study suggested that oral contraceptive use increases the risk of breast cancer in women at inherited risk of breast cancer.[30]

Level of evidence: 3

Several case series of women at inherited risk of ovarian cancer suggest that risk-reducing oophorectomy decreases the risk of ovarian cancer. The peritoneum, however, appears to remain at risk for the development of a Mullerian-type adenocarcinoma, even after oophorectomy.[89-93] Of the 324 women from the Gilda Radner Familial Ovarian Cancer Registry who underwent risk-reducing oophorectomy, 6 (1.8%) subsequently developed primary peritoneal carcinoma. No period of follow-up was specified.[94]

One study analyzed the incidence of breast and ovarian cancer during 1,600 person-years of observation among 12 families with breast and ovarian cancer. They compared the observed number of cases to the number expected based on data from the Connecticut Tumor Registry, adjusted for age, race, and birth cohort. Among the women who underwent oophorectomy, 2 primary peritoneal cancers were reported during 460 person-years of observation. The ratio of observed to expected cases was 13 (95% CI 10-47). For those women who did not undergo oophorectomy, 8 cases of primary peritoneal cancer were observed during 1,665 person-years of observation. The ratio of observed to expected cases was 24 (95% CI 1-47).[33]

The NIH Consensus Statement on Ovarian Cancer recommended that women at inherited risk of ovarian cancer undergo risk-reducing oophorectomy after completion of child-bearing or at age 35 years.[71] The Cancer Genetic Studies Consortium concluded that “there was insufficient evidence to recommend for or against risk-reducing oophorectomy as a measure for reducing ovarian cancer risk.”[4]

Since these consensus statements were published, 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) and ovarian cancer (HR 0.04, 95% CI 0.01-0.16) after bilateral oophorectomy.[35] A prospective single-institution study of 272 women with BRCA1 or BRCA2 mutations showed a similar trend. With oophorectomy, 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). In a case-control study in Israel, bilateral oophorectomy was associated with reduced ovarian/peritoneal cancer risks (odds ratio = 0.12, 95% CI 0.06-0.24).[36]

Levels of evidence: 3, 5

Although the consensus opinion does not address removal of the uterus or the fallopian tubes at the time of risk-reducing oophorectomy, there are several case reports of fallopian tube cancer in BRCA1 and BRCA2 mutation carriers as well as a report of occult fallopian tube carcinoma diagnosed at the time of risk-reducing oophorectomy.[95]

References

1. Thomas DB, Gao DL, Self SG, et al.: Randomized trial of breast self-examination in Shanghai: methodology and preliminary results. J Natl Cancer Inst 89 (5): 355-65, 1997.  [PUBMED Abstract]
   
   
2. Scheuer L, Kauff N, Robson M, et al.: Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 20 (5): 1260-8, 2002.  [PUBMED Abstract]
   
   
3. Brekelmans CT, Seynaeve C, Bartels CC, et al.: Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk. J Clin Oncol 19 (4): 924-30, 2001.  [PUBMED Abstract]
   
   
4. Burke W, Daly M, Garber J, et al.: Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 277 (12): 997-1003, 1997.  [PUBMED Abstract]
   
   
5. Shapiro S: Periodic screening for breast cancer: the Health Insurance Plan project and its sequelae, 1963-1986. Baltimore, Md: Johns Hopkins University Press, 1988. 
   
   
6. Kerlikowske K, Grady D, Barclay J, et al.: Effect of age, breast density, and family history on the sensitivity of first screening mammography. JAMA 276 (1): 33-8, 1996.  [PUBMED Abstract]
   
   
7. Kerlikowske K, Carney PA, Geller B, et al.: Performance of screening mammography among women with and without a first-degree relative with breast cancer. Ann Intern Med 133 (11): 855-63, 2000.  [PUBMED Abstract]
   
   
8. Kerlikowske K, Grady D, Barclay J, et al.: Positive predictive value of screening mammography by age and family history of breast cancer. JAMA 270 (20): 2444-50, 1993.  [PUBMED Abstract]
   
   
9. Tilanus-Linthorst M, Verhoog L, Obdeijn IM, et al.: A BRCA1/2 mutation, high breast density and prominent pushing margins of a tumor independently contribute to a frequent false-negative mammography. Int J Cancer 102 (1): 91-5, 2002.  [PUBMED Abstract]
   
   
10. Miller AB, To T, Baines CJ, et al.: Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst 92 (18): 1490-9, 2000.  [PUBMED Abstract]
    
    
11. Sharan SK, Morimatsu M, Albrecht U, et al.: Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386 (6627): 804-10, 1997.  [PUBMED Abstract]
    
    
12. Gowen LC, Avrutskaya AV, Latour AM, et al.: BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 281 (5379): 1009-12, 1998.  [PUBMED Abstract]
    
    
13. Abbott DW, Freeman ML, Holt JT: Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J Natl Cancer Inst 90 (13): 978-85, 1998.  [PUBMED Abstract]
    
    
14. Stoutjesdijk MJ, Boetes C, Jager GJ, et al.: Magnetic resonance imaging and mammography in women with a hereditary risk of breast cancer. J Natl Cancer Inst 93 (14): 1095-102, 2001.  [PUBMED Abstract]
    
    
15. Warner E, Plewes DB, Shumak RS, et al.: Comparison of breast magnetic resonance imaging, mammography, and ultrasound for surveillance of women at high risk for hereditary breast cancer. J Clin Oncol 19 (15): 3524-31, 2001.  [PUBMED Abstract]
    
    
16. Kuhl CK, Schmutzler RK, Leutner CC, et al.: Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: preliminary results. Radiology 215 (1): 267-79, 2000.  [PUBMED Abstract]
    
    
17. Tilanus-Linthorst MM, Obdeijn IM, Bartels KC, et al.: First experiences in screening women at high risk for breast cancer with MR imaging. Breast Cancer Res Treat 63 (1): 53-60, 2000.  [PUBMED Abstract]
    
    
18. Trecate G, Vergnaghi D, Bergonzi S, et al.: BMRI in early detection of breast cancer in patients with increased genetic risk: our preliminary results. J Exp Clin Cancer Res 21 (3 Suppl): 125-30, 2002.  [PUBMED Abstract]
    
    
19. Podo F, Sardanelli F, Canese R, et al.: The Italian multi-centre project on evaluation of MRI and other imaging modalities in early detection of breast cancer in subjects at high genetic risk. J Exp Clin Cancer Res 21 (3 Suppl): 115-24, 2002.  [PUBMED Abstract]
    
    
20. O'Driscoll D, Warren R, MacKay J, et al.: Screening with breast ultrasound in a population at moderate risk due to family history. J Med Screen 8 (2): 106-9, 2001.  [PUBMED Abstract]
    
    
21. Dooley WC, Ljung BM, Veronesi U, et al.: Ductal lavage for detection of cellular atypia in women at high risk for breast cancer. J Natl Cancer Inst 93 (21): 1624-32, 2001.  [PUBMED Abstract]
    
    
22. O'Shaughnessy JA, Ljung BM, Dooley WC, et al.: Ductal lavage and the clinical management of women at high risk for breast carcinoma: a commentary. Cancer 94 (2): 292-8, 2002.  [PUBMED Abstract]
    
    
23. Shtern F: Digital mammography and related technologies: a perspective from the National Cancer Institute. Radiology 183 (3): 629-30, 1992.  [PUBMED Abstract]
    
    
24. Lewin JM, D'Orsi CJ, Hendrick RE, et al.: Clinical comparison of full-field digital mammography and screen-film mammography for detection of breast cancer. AJR Am J Roentgenol 179 (3): 671-7, 2002.  [PUBMED Abstract]
    
    
25. Colditz GA, Rosner BA, Speizer FE: Risk factors for breast cancer according to family history of breast cancer. For the Nurses' Health Study Research Group. J Natl Cancer Inst 88 (6): 365-71, 1996.  [PUBMED Abstract]
    
    
26. Narod S, Lynch H, Conway T, et al.: Increasing incidence of breast cancer in family with BRCA1 mutation. Lancet 341 (8852): 1101-2, 1993.  [PUBMED Abstract]
    
    
27. Narod SA, Goldgar D, Cannon-Albright L, et al.: Risk modifiers in carriers of BRCA1 mutations. Int J Cancer 64 (6): 394-8, 1995.  [PUBMED Abstract]
    
    
28. McCredie M, Paul C, Skegg DC, et al.: Family history and risk of breast cancer in New Zealand. Int J Cancer 73 (4): 503-7, 1997.  [PUBMED Abstract]
    
    
29. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 347 (9017): 1713-27, 1996.  [PUBMED Abstract]
    
    
30. Ursin G, Henderson BE, Haile RW, et al.: Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 57 (17): 3678-81, 1997.  [PUBMED Abstract]
    
    
31. Narod SA, Dubé MP, Klijn J, et al.: Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 94 (23): 1773-9, 2002.  [PUBMED Abstract]
    
    
32. Olsson H, Jernström H, Alm P, et al.: Proliferation of the breast epithelium in relation to menstrual cycle phase, hormonal use, and reproductive factors. Breast Cancer Res Treat 40 (2): 187-96, 1996.  [PUBMED Abstract]
    
    
33. Struewing JP, Watson P, Easton DF, et al.: Prophylactic oophorectomy in inherited breast/ovarian cancer families. J Natl Cancer Inst Monogr (17): 33-5, 1995.  [PUBMED Abstract]
    
    
34. Rebbeck TR, Levin AM, Eisen A, et al.: Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 91 (17): 1475-9, 1999.  [PUBMED Abstract]
    
    
35. Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002.  [PUBMED Abstract]
    
    
36. Kauff ND, Satagopan JM, Robson ME, et al.: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346 (21): 1609-15, 2002.  [PUBMED Abstract]
    
    
37. Narod SA, Risch H, Moslehi R, et al.: Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 339 (7): 424-8, 1998.  [PUBMED Abstract]
    
    
38. Chen CL, Weiss NS, Newcomb P, et al.: Hormone replacement therapy in relation to breast cancer. JAMA 287 (6): 734-41, 2002.  [PUBMED Abstract]
    
    
39. Writing Group for the Women's Health Initiative Investigators.: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288 (3): 321-33, 2002.  [PUBMED Abstract]
    
    
40. Chlebowski RT, Hendrix SL, Langer RD, et al.: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289 (24): 3243-53, 2003.  [PUBMED Abstract]
    
    
41. Schuurman AG, van den Brandt PA, Goldbohm RA: Exogenous hormone use and the risk of postmenopausal breast cancer: results from The Netherlands Cohort Study. Cancer Causes Control 6 (5): 416-24, 1995.  [PUBMED Abstract]
    
    
42. Steinberg KK, Thacker SB, Smith SJ, et al.: A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 265 (15): 1985-90, 1991.  [PUBMED Abstract]
    
    
43. Colditz GA, Egan KM, Stampfer MJ: Hormone replacement therapy and risk of breast cancer: results from epidemiologic studies. Am J Obstet Gynecol 168 (5): 1473-80, 1993.  [PUBMED Abstract]
    
    
44. Sellers TA, Mink PJ, Cerhan JR, et al.: The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med 127 (11): 973-80, 1997.  [PUBMED Abstract]
    
    
45. Stanford JL, Weiss NS, Voigt LF, et al.: Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA 274 (2): 137-42, 1995.  [PUBMED Abstract]
    
    
46. Gorsky RD, Koplan JP, Peterson HB, et al.: Relative risks and benefits of long-term estrogen replacement therapy: a decision analysis. Obstet Gynecol 83 (2): 161-6, 1994.  [PUBMED Abstract]
    
    
47. Fisher B, Costantino JP, Wickerham DL, et al.: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90 (18): 1371-88, 1998.  [PUBMED Abstract]
    
    
48. Veronesi U, Maisonneuve P, Costa A, et al.: Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 352 (9122): 93-7, 1998.  [PUBMED Abstract]
    
    
49. Powles T, Eeles R, Ashley S, et al.: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 352 (9122): 98-101, 1998.  [PUBMED Abstract]
    
    
50. King MC, Wieand S, Hale K, et al.: Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 286 (18): 2251-6, 2001.  [PUBMED Abstract]
    
    
51. Ariyan S: Prophylactic mastectomy for precancerous and high-risk lesions of the breast. Can J Surg 28 (3): 262-4, 266, 1985.  [PUBMED Abstract]
    
    
52. Hartmann LC, Schaid DJ, Woods JE, et al.: Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 340 (2): 77-84, 1999.  [PUBMED Abstract]
    
    
53. Hartmann LC, Sellers TA, Schaid DJ, et al.: Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst 93 (21): 1633-7, 2001.  [PUBMED Abstract]
    
    
54. Meijers-Heijboer H, van Geel B, van Putten WL, et al.: Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 345 (3): 159-64, 2001.  [PUBMED Abstract]
    
    
55. Rebbeck TR, Friebel T, Lynch HT, et al.: Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 22 (6): 1055-62, 2004.  [PUBMED Abstract]
    
    
56. Kauff ND, Brogi E, Scheuer L, et al.: Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations. Cancer 97 (7): 1601-8, 2003.  [PUBMED Abstract]
    
    
57. Hoogerbrugge N, Bult P, de Widt-Levert LM, et al.: High prevalence of premalignant lesions in prophylactically removed breasts from women at hereditary risk for breast cancer. J Clin Oncol 21 (1): 41-5, 2003.  [PUBMED Abstract]
    
    
58. Scott CI, Iorgulescu DG, Thorne HJ, et al.: Clinical, pathological and genetic features of women at high familial risk of breast cancer undergoing prophylactic mastectomy. Clin Genet 64 (2): 111-21, 2003.  [PUBMED Abstract]
    
    
59. Adem C, Reynolds C, Soderberg CL, et al.: Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers. Cancer 97 (1): 1-11, 2003.  [PUBMED Abstract]
    
    
60. Lerman C, Hughes C, Croyle RT, et al.: Prophylactic surgery decisions and surveillance practices one year following BRCA1/2 testing. Prev Med 31 (1): 75-80, 2000.  [PUBMED Abstract]
    
    
61. Stefanek ME, Helzlsouer KJ, Wilcox PM, et al.: Predictors of and satisfaction with bilateral prophylactic mastectomy. Prev Med 24 (4): 412-9, 1995.  [PUBMED Abstract]
    
    
62. Schrag D, Kuntz KM, Garber JE, et al.: Decision analysis--effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations. N Engl J Med 336 (20): 1465-71, 1997.  [PUBMED Abstract]
    
    
63. Unic I, Stalmeier PF, Verhoef LC, et al.: Assessment of the time-tradeoff values for prophylactic mastectomy of women with a suspected genetic predisposition to breast cancer. Med Decis Making 18 (3): 268-77, 1998 Jul-Sep.  [PUBMED Abstract]
    
    
64. Grann VR, Panageas KS, Whang W, et al.: Decision analysis of prophylactic mastectomy and oophorectomy in BRCA1-positive or BRCA2-positive patients. J Clin Oncol 16 (3): 979-85, 1998.  [PUBMED Abstract]
    
    
65. Meijers-Heijboer EJ, Verhoog LC, Brekelmans CT, et al.: Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation. Lancet 355 (9220): 2015-20, 2000.  [PUBMED Abstract]
    
    
66. King MC, Marks JH, Mandell JB, et al.: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302 (5645): 643-6, 2003.  [PUBMED Abstract]
    
    
67. Dørum A, Kristensen GB, Abeler VM, et al.: Early detection of familial ovarian cancer. Eur J Cancer 32A (10): 1645-51, 1996.  [PUBMED Abstract]
    
    
68. Bourne TH, Campbell S, Reynolds K, et al.: The potential role of serum CA 125 in an ultrasound-based screening program for familial ovarian cancer. Gynecol Oncol 52 (3): 379-85, 1994.  [PUBMED Abstract]
    
    
69. Karlan BY, Platt LD: Ovarian cancer screening. The role of ultrasound in early detection. Cancer 76 (10 Suppl): 2011-5, 1995.  [PUBMED Abstract]
    
    
70. Karlan BY, Raffel LJ, Crvenkovic G, et al.: A multidisciplinary approach to the early detection of ovarian carcinoma: rationale, protocol design, and early results. Am J Obstet Gynecol 169 (3): 494-501, 1993.  [PUBMED Abstract]
    
    
71. NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. JAMA 273 (6): 491-7, 1995.  [PUBMED Abstract]
    
    
72. Kramer BS, Gohagan J, Prorok PC, et al.: A National Cancer Institute sponsored screening trial for prostatic, lung, colorectal, and ovarian cancers. Cancer 71 (2 Suppl): 589-93, 1993.  [PUBMED Abstract]
    
    
73. Van Nagell JR Jr, DePriest PD, Puls LE, et al.: Ovarian cancer screening in asymptomatic postmenopausal women by transvaginal sonography. Cancer 68 (3): 458-62, 1991.  [PUBMED Abstract]
    
    
74. Fleischer AC, Cullinan JA, Peery CV, et al.: Early detection of ovarian carcinoma with transvaginal color Doppler ultrasonography. Am J Obstet Gynecol 174 (1 Pt 1): 101-6, 1996.  [PUBMED Abstract]
    
    
75. Weiner Z, Beck D, Shteiner M, et al.: Screening for ovarian cancer in women with breast cancer with transvaginal sonography and color flow imaging. J Ultrasound Med 12 (7): 387-93, 1993.  [PUBMED Abstract]
    
    
76. Bourne TH, Whitehead MI, Campbell S, et al.: Ultrasound screening for familial ovarian cancer. Gynecol Oncol 43 (2): 92-7, 1991.  [PUBMED Abstract]
    
    
77. Bourne TH, Campbell S, Reynolds KM, et al.: Screening for early familial ovarian cancer with transvaginal ultrasonography and colour blood flow imaging. BMJ 306 (6884): 1025-9, 1993.  [PUBMED Abstract]
    
    
78. Muto MG, Cramer DW, Brown DL, et al.: Screening for ovarian cancer: the preliminary experience of a familial ovarian cancer center. Gynecol Oncol 51 (1): 12-20, 1993.  [PUBMED Abstract]
    
    
79. Risch HA: Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 90 (23): 1774-86, 1998.  [PUBMED Abstract]
    
    
80. Hankinson SE, Colditz GA, Hunter DJ, et al.: A prospective study of reproductive factors and risk of epithelial ovarian cancer. Cancer 76 (2): 284-90, 1995.  [PUBMED Abstract]
    
    
81. Vachon CM, Mink PJ, Janney CA, et al.: Association of parity and ovarian cancer risk by family history of breast or ovarian cancer in a population-based study of postmenopausal women. Epidemiology 13 (1): 66-71, 2002.  [PUBMED Abstract]
    
    
82. Godard B, Foulkes WD, Provencher D, et al.: Risk factors for familial and sporadic ovarian cancer among French Canadians: a case-control study. Am J Obstet Gynecol 179 (2): 403-10, 1998.  [PUBMED Abstract]
    
    
83. Kerber RA, Slattery ML: The impact of family history on ovarian cancer risk. The Utah Population Database. Arch Intern Med 155 (9): 905-12, 1995.  [PUBMED Abstract]
    
    
84. Lacey JV Jr, Mink PJ, Lubin JH, et al.: Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 288 (3): 334-41, 2002.  [PUBMED Abstract]
    
    
85. Narod SA, Sun P, Ghadirian P, et al.: Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet 357 (9267): 1467-70, 2001.  [PUBMED Abstract]
    
    
86. Rutter JL, Wacholder S, Chetrit A, et al.: Gynecologic surgeries and risk of ovarian cancer in women with BRCA1 and BRCA2 Ashkenazi founder mutations: an Israeli population-based case-control study. J Natl Cancer Inst 95 (14): 1072-8, 2003.  [PUBMED Abstract]
    
    
87. Modan B, Hartge P, Hirsh-Yechezkel G, et al.: Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 345 (4): 235-40, 2001.  [PUBMED Abstract]
    
    
88. Piver MS, Baker TR, Jishi MF, et al.: Familial ovarian cancer. A report of 658 families from the Gilda Radner Familial Ovarian Cancer Registry 1981-1991. Cancer 71 (2 Suppl): 582-8, 1993.  [PUBMED Abstract]
    
    
89. Chen KT, Schooley JL, Flam MS: Peritoneal carcinomatosis after prophylactic oophorectomy in familial ovarian cancer syndrome. Obstet Gynecol 66 (3 Suppl): 93S-94S, 1985.  [PUBMED Abstract]
    
    
90. Lynch HT, Bewtra C, Lynch JF: Familial ovarian carcinoma. Clinical nuances. Am J Med 81 (6): 1073-6, 1986.  [PUBMED Abstract]
    
    
91. Lynch HT, Watson P, Bewtra C, et al.: Hereditary ovarian cancer. Heterogeneity in age at diagnosis. Cancer 67 (5): 1460-6, 1991.  [PUBMED Abstract]
    
    
92. Tobacman JK, Greene MH, Tucker MA, et al.: Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian-cancer-prone families. Lancet 2 (8302): 795-7, 1982.  [PUBMED Abstract]
    
    
93. Truong LD, Maccato ML, Awalt H, et al.: Serous surface carcinoma of the peritoneum: a clinicopathologic study of 22 cases. Hum Pathol 21 (1): 99-110, 1990.  [PUBMED Abstract]
    
    
94. Piver MS, Jishi MF, Tsukada Y, et al.: Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. A report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer 71 (9): 2751-5, 1993.  [PUBMED Abstract]
    
    
95. Paley PJ, Swisher EM, Garcia RL, et al.: Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol Oncol 80 (2): 176-80, 2001.  [PUBMED Abstract]
    
    

Back to Top

< Previous Section  |  Next Section >