PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jcoHomeThis ArticleSearchSubmitASCO JCO Homepage
 
J Clin Oncol. 2010 January 10; 28(2): 222–231.
Published online 2009 December 7. doi:  10.1200/JCO.2009.22.7991
PMCID: PMC2815712

Survival Analysis of Cancer Risk Reduction Strategies for BRCA1/2 Mutation Carriers

Abstract

Purpose

Women with BRCA1/2 mutations inherit high risks of breast and ovarian cancer; options to reduce cancer mortality include prophylactic surgery or breast screening, but their efficacy has never been empirically compared. We used decision analysis to simulate risk-reducing strategies in BRCA1/2 mutation carriers and to compare resulting survival probability and causes of death.

Methods

We developed a Monte Carlo model of breast screening with annual mammography plus magnetic resonance imaging (MRI) from ages 25 to 69 years, prophylactic mastectomy (PM) at various ages, and/or prophylactic oophorectomy (PO) at ages 40 or 50 years in 25-year-old BRCA1/2 mutation carriers.

Results

With no intervention, survival probability by age 70 is 53% for BRCA1 and 71% for BRCA2 mutation carriers. The most effective single intervention for BRCA1 mutation carriers is PO at age 40, yielding a 15% absolute survival gain; for BRCA2 mutation carriers, the most effective single intervention is PM, yielding a 7% survival gain if performed at age 40 years. The combination of PM and PO at age 40 improves survival more than any single intervention, yielding 24% survival gain for BRCA1 and 11% for BRCA2 mutation carriers. PM at age 25 instead of age 40 offers minimal incremental benefit (1% to 2%); substituting screening for PM yields a similarly minimal decrement in survival (2% to 3%).

Conclusion

Although PM at age 25 plus PO at age 40 years maximizes survival probability, substituting mammography plus MRI screening for PM seems to offer comparable survival. These results may guide women with BRCA1/2 mutations in their choices between prophylactic surgery and breast screening.

INTRODUCTION

More than 300,000 women in the United States are estimated to carry a mutation in the BRCA1 or BRCA2 genes1; with these mutations, women inherit 5- to 20-fold increased risks of developing breast and ovarian cancer.2 Cancer risk management strategies for BRCA1/2 mutation carriers incorporate earlier, more frequent, and more invasive intervention than those for the general population. Practice guidelines recommend prophylactic bilateral salpingo-oophorectomy (PO) for ovarian cancer risk reduction by age 40 years (all ages are given in years hereafter) and support various alternatives for managing breast cancer risk: either prevention with prophylactic mastectomy (PM) or early detection with screening mammography plus breast magnetic resonance imaging (MRI).3,4

Although studies in BRCA1/2 mutation carriers have reported efficacy of PO and PM for cancer prevention59 and of mammography plus MRI screening for early breast cancer detection,1013 most were limited in size, and none directly compared survival after screening versus surgery. Moreover, all risk-reducing options have disadvantages. PM and premenopausal PO are permanent procedures that limit reproductive choices; PM can impair body image, and PO may impose health risks of early menopause.1418 Screening MRI yields frequent false positives, thereby increasing anxiety and costs.19 To the best of our knowledge, no randomized trial is planned to compare survival benefit and other health outcomes from different strategies aimed at reducing cancer mortality in BRCA1/2 mutation carriers. Moreover, patients may not accept random assignment between prophylactic surgery and screening, and many clinicians question the ethics of asking them to do so. Therefore, women and their physicians must navigate among disparate and invasive alternatives with little empiric guidance when choosing how best to manage cancer risks. To optimally inform such decisions, we developed a simulation modeling approach to compare the survival probability for BRCA1/2 mutation carriers after several risk-reduction strategies, based on the best available evidence. This approach builds on our prior evaluation of the cost-effectiveness of MRI screening in BRCA1/2 mutation carriers19 and additionally considers PO and PM as alternatives or complements to MRI-based breast screening. We now report survival probability with various clinically relevant risk-reducing strategies for women with BRCA1/2 mutations, aiming to target survival estimates to individual patients and enable personalized cancer risk management.

METHODS

We used a computer simulation model that integrates empiric data from the literature (Table 1) to estimate survival probability and causes of death at ages 70 and 80 years for 25-year-old women with a BRCA1 or BRCA2 mutation. Risk-reducing interventions were modeled alone and in combination, at ages specified by cancer care guidelines3,4: breast screening with mammography plus MRI started at age 25 and continued annually to age 69, PO was performed at age 40 or 50, and PM was evaluated for ages 25 to 50 years.

Table 1.
Tumor, Screening, and Intervention Characteristics

Overview of Computer Simulation Model

We previously developed a Monte Carlo simulation model to analyze the impact of screening and treatment on outcomes of individual breast cancer patients.42,43 We then modified the model to incorporate breast and ovarian cancer incidence, tumor characteristics, prognosis under standard treatments,2,24,37,39,4447 and the performance of screening with mammography and MRI1013 in BRCA1/2 mutation carriers.19 For this study, we added literature-based estimates of the effects of PM and PO on survival probability and causes of death (Table 1).

Patient Characteristics

The model simulates the life histories of a 1980 birth cohort of 1,000,000 female BRCA1 or BRCA2 mutation carriers from age 25 until age 100 or death, whichever occurs first. We extrapolated cancer risks for BRCA1 and BRCA2 mutation carriers from meta-analyses.2,20 Since approximately 30% of BRCA1/2 mutation carriers undergo PO at a mean age of 45,7 we assumed that reported breast cancer incidence2 incorporates 30% use of PO. We adjusted our estimates of breast cancer risk without PO, given that PO in premenopausal BRCA1/2 mutation carriers reduces breast cancer risk by approximately 50%.68,25 We assumed that BRCA1/2 mutation carriers receive standard breast and ovarian cancer therapies and that treatment efficacy and cancer prognosis equal those of the general population39,4548 (Table 1).

Efficacy of Prophylactic Surgery

We assumed that PM reduces breast cancer risk by 90%.9,24 We assumed that PO reduces ovarian cancer risk by 85%7,8 and breast cancer risk by 50% when performed between ages 40 and 50, with no impact on breast cancer risk when performed at or after age 50 (Table 1).6,49 We assumed that the breast cancer risk reduction after premenopausal oophorectomy persists indefinitely.25

Other-Cause Mortality After Premenopausal PO

We assumed no use of menopausal hormone therapy, given uncertainty about its effect on breast cancer in BRCA1/2 mutation carriers.5052 After PO before age 50,3 we assumed a two-fold increased risk of cardiovascular disease40 and a 50% increased risk of osteoporotic hip fracture and dementia16,17,41; as have previous studies,53,54 we assumed these increases would last until age 65. To compute other-cause mortality, we adjusted data from the Berkeley Mortality Database 1980 birth cohort table55 by removing breast and ovarian cancer deaths based on 2004 US rates reported by the Centers for Disease Control and Prevention (diagnostic codes C50 and C56)56 and adjusting mortality rates from cardiovascular disease, dementia, and hip fracture (codes I20-I25, F0, F3, G20-G21, and G30)54,56 according to the assumed relative risks (Table 1).

Sensitivity Analyses

We varied model parameters about which significant uncertainty exists: risk of developing breast and ovarian cancer with a BRCA1 or BRCA2 mutation, breast tumor volume doubling time (TVDT), sensitivity of MRI for cancer detection, impact of oral contraceptive pills on breast and ovarian cancer risk, and impact of premenopausal PO on breast cancer and other-cause mortality (Table 1).2,6,8,17,2023, 2636,38,49 Sensitivity analyses considered four clinically relevant scenarios: no intervention, mammography plus MRI screening without surgery, screening plus PO at age 40, and screening plus PO and PM at age 40.

RESULTS

Cancer Risk by Age 70 in BRCA1 Mutation Carriers

In the absence of breast screening, PM at age 40 reduces breast cancer risk to 27%; PO at age 40 reduces breast cancer risk to 49% and ovarian cancer risk to 9%. Performing PM and PO at age 40 reduces breast cancer risk to 25% and ovarian cancer risk to 9%. Screening has no impact on ovarian cancer risk and minimal impact on breast cancer risk (data not shown).

Overall Survival in BRCA1 Mutation Carriers

With no intervention, survival probability by age 70 years is 53% for BRCA1 mutation carriers versus 84% for the general US population (Table 2). The most effective single intervention is PO at age 40, yielding a survival probability of 68% by age 70, which represents a 15% absolute gain compared with no intervention (68% v 53%). Delaying PO to age 50 yields half the survival gain provided by PO at age 40 (8%: 61% v 53% with no intervention). In comparison, PM at age 25 yields a 13% gain relative to no intervention, whereas delaying PM to age 40 yields a small (2%) decrement in gain compared with PM at age 25. Breast screening alone from ages 25 to 69 yields the lowest gain (6%).

Table 2.
Probability of OS, BCD, OCD, and OD by Ages 70 and 80 in 25-Year-Old Women With BRCA1/2 Mutations

The most effective combination strategy is PM at age 25 plus PO at age 40, providing a 26% survival gain by age 70 compared with no intervention (79% v 53%). Postponing PM until age 40, in the presence of screening from ages 25 to 39 and PO at age 40, reduces survival gain by 2%. Eliminating PM and substituting breast screening from ages 25 to 69 while performing PO at age 40 reduces survival gain by an incremental 3%. When added to PO at age 40, breast screening offers 5% lower survival probability than does PM at age 25 (74% v 79%) and 3% lower survival probability than does PM at age 40 (74% v 77%). If PO is delayed until age 50, breast screening offers 5% lower survival probability than PM at age 40 (69% v 74%). Results by age 80 are similar (Table 2). Figure 1A presents survival probability, and Figure 2A presents distribution of health status by age 70 years in BRCA1 mutation carriers under various intervention scenarios.

Fig 1.
Survival probability after different risk-reducing strategies, including no intervention, screening with mammography plus magnetic resonance imaging (screening), prophylactic mastectomy (PM), and prophylactic oophorectomy (PO) performed at various ages ...
Fig 2.
Distribution of health status, comprising survival probability (Surviving) and probability of death by cause, including breast cancer death (BCD), ovarian cancer death (OCD), and other-cause death (OD), by age 70 years. Interventions include screening ...

Cause-Specific Mortality in BRCA1 Mutation Carriers

Among BRCA1 mutation carriers who choose no intervention, the likelihood of death from breast versus ovarian cancer is similar (41% v 36%, conditional on death by age 70; Table 2). With PO at age 40 only, death from ovarian cancer decreases dramatically, making breast cancer deaths most frequent (45%, followed by other-cause [43%] and ovarian cancer deaths [12%]). When PO is delayed from age 40 to age 50, ovarian cancer deaths nearly double; breast cancer deaths increase less markedly. Among women who choose breast screening until age 40 and then PO plus PM at age 40, 23% will die by age 70; most (64%) die of non-cancer causes, followed by breast cancer (18%) and ovarian cancer (18%). Results are comparable for women who choose breast screening until age 69 and then PO at age 40, but not PM, and follow a similar pattern by age 80 (Table 2).

Cancer Risk by Age 70 in BRCA2 Mutation Carriers

In the absence of breast screening, PM at age 40 reduces breast cancer risk to 14%; PO at age 40 reduces breast cancer risk to 31% and ovarian cancer risk to 2%. Performing PM and PO at age 40 reduces breast cancer risk to 13% and ovarian cancer risk to 2%. Screening has no impact on ovarian cancer risk and minimal impact on breast cancer risk (results not shown).

Overall Survival in BRCA2 Mutation Carriers

With no intervention, survival probability by age 70 is 71% for BRCA2 mutation carriers versus 84% for the general population (Table 2). The most effective single intervention is PM at age 25, yielding an 8% gain compared with no intervention (79% v 71%); postponing PM to age 40 reduces gain by 1%. In comparison, PO at age 40 yields a 6% gain relative to no intervention, and breast screening alone, with annual MRI plus mammography, provides a 4% gain. Delaying PO from age 40 to age 50 reduces gain by 2%.

The most effective combination strategy is PM at age 25 plus PO at age 40, providing a 12% survival gain by age 70 compared with no intervention (83% v 71%). Postponing PM until age 40 in the presence of breast screening from ages 25 to 39 and PO at age 40 reduces survival gain by 1%. Eliminating PM and substituting breast screening from ages 25 to 69 while performing PO at age 40 reduces survival gain by an incremental 2%. In the presence of PO at age 40, screening yields 3% lower survival than does PM at age 25 (80% v 83%), and 2% lower survival than does PM at age 40 (80% v 82%; Table 2). If PO is delayed to age 50, breast screening offers 4% lower survival probability than PM at age 40 (79% v 83%). Results by age 80 are similar (Table 2). Figure 1B presents survival probability and Figure 2B presents distribution of health status by age 70 years in BRCA2 mutation carriers under various intervention scenarios.

Cause-Specific Mortality in BRCA2 Mutation Carriers

Among BRCA2 mutation carriers who choose no intervention, more die from breast than ovarian cancer (36% v 20%, conditional on death by age 70), but non-cancer deaths are more frequent (44%; Table 2). With PO at age 40 only, ovarian cancer deaths decrease substantially; other-cause deaths remain most frequent (66%), followed by death from breast cancer (30%) and ovarian cancer (4%). Delaying PO from age 40 until age 50 yields little increase in ovarian cancer deaths (2% to 3%) but a larger increase in breast cancer deaths (12%). Among women who choose breast screening until age 40 and then PO plus PM at age 40, 18% will die by age 70; most (85%) die of non-cancer causes, followed by breast cancer (9%) and ovarian cancer (6%). Results are comparable for women who choose breast screening until age 69 and then PO at age 40, but not PM, and follow a similar pattern by age 80 (Table 2).

Sensitivity Analyses of Survival Probability by Age 70

We observed the largest differences in overall survival with variation in assumptions about breast cancer risk (9% to 10%), TVDT (4% to 6%), and hazard ratio for breast cancer after premenopausal oophorectomy (3% to 6%). Variation in these three parameters also yielded the greatest differences in breast cancer–specific death (13% to 22%). Ovarian cancer–specific deaths varied most with changes in breast and ovarian cancer risk and TVDT (4% to 20%). Other-cause deaths varied most with breast cancer risk, TVDT, and the hazard ratio for breast cancer after premenopausal oophorectomy in BRCA1 mutation carriers (10% to 16%) and with breast and ovarian cancer risk and TVDT in BRCA2 mutation carriers (9% to 15%). Variations in other model parameters yielded smaller differences in overall and cause-specific survival (Table 3).

Table 3.
Sensitivity Analyses on Probability of OS, BCD, OCD, and OD by Age 70 in 25-Year-Old Women With BRCA1/2 Mutations

DISCUSSION

We developed a Monte Carlo model to simulate and compare different strategies for reducing cancer mortality in BRCA1/2 mutation carriers. The most effective strategy is PO at age 40 plus PM at age 25; for BRCA1 mutation carriers, this approach substantially improves survival by age 70 (79% v 53%, with no intervention), while for BRCA2 mutation carriers, the absolute increase is smaller (83% v 71%) because of their lesser cancer risks. We evaluated a delay in PO until age 50, which is 10 years later than recommended by current practice guidelines3 but which may appeal to women because it approximates the age of natural menopause. In BRCA1 mutation carriers, delayed PO provides half the survival gain of PO at age 40 (8% at 50 v 15% at 40), whereas for BRCA2 mutation carriers, delaying PO makes less difference (4% v 6%). For both BRCA1 and BRCA2 mutation carriers, combining PO at age 40 with PM at age 25 provides survival approaching that of women without mutations (79% for BRCA1, 83% for BRCA2, and 84% for the general population); however, postponing PM until age 40, when it may prove more acceptable than at age 25, reduces survival gain by only 1% to 2%. Most notably, we found that replacing PM with MRI-based breast screening in the presence of PO at age 40 yields only a 3% to 5% decrement in survival. Approximately 36% of US BRCA1/2 mutation carriers now choose PM, whereas 24% undergo breast screening incorporating MRI.57 Our finding that mammography plus MRI screening offers survival probability comparable to that of PM may alter women's choices between these options. In the related field of breast cancer treatment, some women will accept adjuvant chemotherapy for an anticipated survival improvement of 5% or less, whereas others consider its side effects too morbid for such a small gain58,59; current research focuses on targeting chemotherapy to women with larger estimated benefits.60

Many prior model-based analyses have addressed cancer risk management in BRCA1/2 mutation carriers.19,53,6165 Most concluded that prophylactic surgeries improve life expectancy62,64,65; however, few19,63 considered recent improvements in cancer detection with breast MRI.1013,66 Our study represents an advance because we directly compared prophylactic surgery with screening, incorporating an updated understanding of the options available to high-risk women. We modeled the effect of MRI screening on cancer detection and prognosis, on the basis of the tumor grade, growth rate, and hormone receptor profiles in BRCA1/2 mutation carriers.10,37,38,44,67 We incorporated data on age-specific breast cancer risk reduction after premenopausal PO6,8 and considered the use of oral contraceptives,2636 which most prior analyses did not. However, given controversy about chemoprevention with tamoxifen and raloxifene in BRCA1/2 mutation carriers,57,6870 we did not model them. Although some practice guidelines recommend ovarian cancer screening with transvaginal ultrasound and CA125 in BRCA1/2 mutation carriers who do not undergo PO,3 we chose not to model this strategy, given the lack of compelling evidence that it impacts survival or other health outcomes.

As with all modeling studies, our results depend on our assumptions. We performed sensitivity analyses on all major parameters, including BRCA1 and BRCA2 mutation penetrance, the growth patterns of BRCA1/2-associated breast cancers and their detectability by screening, the impact of oral contraceptive use on breast and ovarian cancer risk, and the effect of premenopausal PO on breast cancer and other health outcomes. In sensitivity analyses, none of these factors dramatically affected the ranking of interventions but did alter our absolute estimates of overall and cause-specific survival by up to 22%. Our assumptions about breast cancer risk, breast TVDT, and the risk of breast cancer after PO at age 40 were most influential. If BRCA1/2 mutation carriers have higher breast cancer risks than reported by large meta-analyses,2,20 have more interval breast tumors than reported in MRI screening studies,1013 or gain less benefit than reported from PO at age 40,6,49 then the survival difference between PM and MRI-based breast screening increases, although by a relatively small amount: from 3% up to 8% for BRCA1 and from 2% to 3% for BRCA2 mutation carriers.

Many uncertainties remain about the clinical management of BRCA1/2 mutation carriers. Important questions include the impact of menopausal hormone therapy after premenopausal PO on breast cancer and other health outcomes, the efficacy of nipple or skin-sparing techniques compared with simple prophylactic mastectomy, the potential risk of breast cancer due to mammography, and the prognosis of BRCA1/2-associated cancers as targeted therapies emerge.50,52,7173 Answers to these questions may alter judgments about the relative efficacy and tolerability of different risk-reducing strategies and better inform future decision analyses.

Model-based analyses cannot replace empirical studies but can address clinically important questions that are poorly amenable to randomized trials. Given the complex, personal nature of decisions about prophylactic surgery, women will not likely accept random assignment between PM and breast screening; therefore, direct evidence about survival differences will remain elusive. Our analysis aims to enhance patient care by bridging the evidence gap: we provide a computer model that integrates the best available data, permitting recommendations calibrated to the variable effects of risk, age, intervention efficacy, and personal preferences. Individual women make widely disparate choices about how to manage their cancer risks, depending on their family history, health care access, reproductive concerns, and concurrent diagnoses.18,47,57,7476 Our results can anchor such choices quantitatively, helping a woman weigh strategies that yield small differences in survival, yet potentially larger differences in physical and emotional effects, according to her preferences. Computer-based decision support tools are now widely used to assist patients' cancer treatment choices.58,77 Our model may similarly facilitate shared decision making, guiding women with BRCA1/2 mutations toward better-informed choices between prophylactic surgery and screening alternatives.

Footnotes

See accompanying editorial on page 189

Supported by Grants No. R01 CA829040, U01 CA088248, and R01 CA66785 from the National Institutes of Health; by Stanford University Cancer Center 2007 Developmental Research Award in Population Sciences; and by Robert Wood Johnson Foundation 2008 Physician Faculty Scholars Award (64317).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Allison W. Kurian, Sylvia K. Plevritis

Financial support: Allison W. Kurian, Sylvia K. Plevritis

Provision of study materials or patients: Sylvia K. Plevritis

Collection and assembly of data: Bronislava M. Sigal, Sylvia K. Plevritis

Data analysis and interpretation: Allison W. Kurian, Bronislava M. Sigal, Sylvia K. Plevritis

Manuscript writing: Allison W. Kurian, Bronislava M. Sigal, Sylvia K. Plevritis

Final approval of manuscript: Allison W. Kurian, Bronislava M. Sigal, Sylvia K. Plevritis

REFERENCES

1. John EM, Miron A, Gong G, et al. Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA. 2007;298:2869–2876. [PubMed]
2. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117–1130. [PubMed]
3. National Comprehensive Cancer Network. Genetic Familial High-Risk Assessment: Breast and Ovarian. V. 1.2009. http://www.nccn.org/
4. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57:75–89. [PubMed]
5. Domchek SM, Friebel TM, Neuhausen SL, et al. Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: A prospective cohort study. Lancet Oncol. 2006;7:223–229. [PubMed]
6. Eisen A, Lubinski J, Klijn J, et al. Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: An international case-control study. J Clin Oncol. 2005;23:7491–7496. [PubMed]
7. Finch A, Beiner M, Lubinski J, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutation. JAMA. 2006;296:185–192. [PubMed]
8. Kauff ND, Domchek SM, Friebel TM, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: A multicenter, prospective study. J Clin Oncol. 2008;26:1331–1337. [PMC free article] [PubMed]
9. 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. 2004;22:1055–1062. [PubMed]
10. Kriege M, Brekelmans CT, Boetes C, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med. 2004;351:427–437. [PubMed]
11. Kuhl CK, Schrading S, Leutner CC, et al. Mammography, breast ultrasound, and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer. J Clin Oncol. 2005;23:8469–8476. [PubMed]
12. Leach MO, Boggis CR, Dixon AK, et al. Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: A prospective multicentre cohort study (MARIBS) Lancet. 2005;365:1769–1778. [PubMed]
13. Warner E, Plewes DB, Hill KA, et al. Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA. 2004;292:1317–1325. [PubMed]
14. Bresser PJ, Seynaeve C, Van Gool AR, et al. The course of distress in women at increased risk of breast and ovarian cancer due to an (identified) genetic susceptibility who opt for prophylactic mastectomy and/or salpingo-oophorectomy. Eur J Cancer. 2007;43:95–103. [PubMed]
15. Robson M, Hensley M, Barakat R, et al. Quality of life in women at risk for ovarian cancer who have undergone risk-reducing oophorectomy. Gynecol Oncol. 2003;89:281–287. [PubMed]
16. Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69:1074–1083. [PubMed]
17. Rocca WA, Grossardt BR, de Andrade M, et al. Survival patterns after oophorectomy in premenopausal women: A population-based cohort study. Lancet Oncol. 2006;7:821–828. [PubMed]
18. Staton AD, Kurian AW, Cobb K, et al. Cancer risk reduction and reproductive concerns in female BRCA1/2 mutation carriers. Fam Cancer. 2008;7:179–186. [PubMed]
19. Plevritis SK, Kurian AW, Sigal BM, et al. Cost-effectiveness of screening BRCA1/2 mutation carriers with breast magnetic resonance imaging. JAMA. 2006;295:2374–2384. [PubMed]
20. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007;25:1329–1333. [PMC free article] [PubMed]
21. Evans DG, Shenton A, Woodward E, et al. Penetrance estimates for BRCA1 and BRCA2 based on genetic testing in a Clinical Cancer Genetics service setting: Risks of breast/ovarian cancer quoted should reflect the cancer burden in the family. BMC Cancer. 2008;8:155. [PMC free article] [PubMed]
22. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998;62:676–689. [PubMed]
23. King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302:643–646. [PubMed]
24. Metcalfe K, Lynch HT, Ghadirian P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2004;22:2328–2335. [PubMed]
25. Kramer JL, Velazquez IA, Chen BE, et al. Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. J Clin Oncol. 2005;23:8629–8635. [PubMed]
26. Brohet RM, Goldgar DE, Easton DF, et al. Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: A report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J Clin Oncol. 2007;25:3831–3836. [PubMed]
27. Haile RW, Thomas DC, McGuire V, et al. BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50. Cancer Epidemiol Biomarkers Prev. 2006;15:1863–1870. [PubMed]
28. Jernström H, Loman N, Johannsson OT, et al. Impact of teenage oral contraceptive use in a population-based series of early-onset breast cancer cases who have undergone BRCA mutation testing. Eur J Cancer. 2005;41:2312–2320. [PubMed]
29. Lee E, Ma H, McKean-Cowdin R, et al. Effect of reproductive factors and oral contraceptives on breast cancer risk in BRCA1/2 mutation carriers and noncarriers: Results from a population-based study. Cancer Epidemiol Biomarkers Prev. 2008;17:3170–3178. [PubMed]
30. McGuire V, Felberg A, Mills M, et al. Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations. Am J Epidemiol. 2004;160:613–618. [PubMed]
31. McLaughlin JR, Risch HA, Lubinski J, et al. Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: A case-control study. Lancet Oncol. 2007;8:26–34. [PubMed]
32. Milne RL, Knight JA, John EM, et al. Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev. 2005;14:350–356. [PubMed]
33. 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. 2001;345:235–240. [PubMed]
34. 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. 2002;94:1773–1779. [PubMed]
35. 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. 1998;339:424–428. [PubMed]
36. Whittemore AS, Balise RR, Pharoah PD, et al. Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. Br J Cancer. 2004;91:1911–1915. [PMC free article] [PubMed]
37. Chappuis PO, Nethercot V, Foulkes WD. Clinico-pathological characteristics of BRCA1- and BRCA2-related breast cancer. Semin Surg Oncol. 2000;18:287–295. [PubMed]
38. Tilanus-Linthorst MM, Obdeijn IM, Hop WC, et al. BRCA1 mutation and young age predict fast breast cancer growth in the Dutch, United Kingdom, and Canadian magnetic resonance imaging screening trials. Clin Cancer Res. 2007;13:7357–7362. [PubMed]
39. Early Breast Cancer Trialists' Collaborative Group (EBCTCG) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet. 2005;365:1687–1717. [PubMed]
40. Colditz GA, Willett WC, Stampfer MJ, et al. Menopause and the risk of coronary heart disease in women. N Engl J Med. 1987;316:1105–1110. [PubMed]
41. Melton LJ, 3rd, Khosla S, Malkasian GD, et al. Fracture risk after bilateral oophorectomy in elderly women. J Bone Miner Res. 2003;18:900–905. [PubMed]
42. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353:1784–1792. [PubMed]
43. Plevritis SK, Sigal BM, Salzman P, et al. A stochastic simulation model of U.S. breast cancer mortality trends from 1975 to 2000. J Natl Cancer Inst Monogr. 2006;36:86–95. [PubMed]
44. Atchley DP, Albarracin CT, Lopez A, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol. 2008;26:4282–4288. [PubMed]
45. National Comprehensive Cancer Network. Breast Cancer: V. 1.2009. http://www.nccn.org/
46. Rennert G, Bisland-Naggan S, Barnett-Griness O, et al. Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med. 2007;357:115–123. [PubMed]
47. Stolier AJ, Corsetti RL. Newly diagnosed breast cancer patients choose bilateral mastectomy over breast-conserving surgery when testing positive for a BRCA1/2 mutation. Am Surg. 2005;71:1031–1033. [PubMed]
48. National Comprehensive Cancer Network. Ovarian Cancer: V. 2.2009. http://www.nccn.org/
49. Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst. 2009;101:80–87. [PMC free article] [PubMed]
50. Rebbeck TR, Friebel T, Wagner T, et al. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: The PROSE Study Group. J Clin Oncol. 2005;23:7804–7810. [PubMed]
51. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321–333. [PubMed]
52. Eisen A, Lubinski J, Gronwald J, et al. Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst. 2008;100:1361–1367. [PubMed]
53. Armstrong K, Schwartz JS, Randall T, et al. Hormone replacement therapy and life expectancy after prophylactic oophorectomy in women with BRCA1/2 mutations: A decision analysis. J Clin Oncol. 2004;22:1045–1054. [PubMed]
54. Parker WH, Broder MS, Liu Z, et al. Ovarian conservation at the time of hysterectomy for benign disease. Obstet Gynecol. 2005;106:219–226. [PubMed]
55. Berkeley Mortality Database. http://www .demog.berkeley.edu/~bmd/
56. Centers for Disease Control, National Vital Statistics System, Worktable 292R. Death rates for 358 selected causes by 5-year age groups, race, and sex: United States, 1999-2004. http://www.cdc.gov/nchs/data/dvs/mortfinal2004_worktable292r.pdf.
57. Metcalfe KA, Birenbaum-Carmeli D, Lubinski J, et al. International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers. Int J Cancer. 2008;122:2017–2022. [PMC free article] [PubMed]
58. Peele PB, Siminoff LA, Xu Y, et al. Decreased use of adjuvant breast cancer therapy in a randomized controlled trial of a decision aid with individualized risk information. Med Decis Making. 2005;25:301–307. [PubMed]
59. Sweeney KJ, Ryan E, Canney M, et al. Justifying adjuvant chemotherapy in breast cancer: A survey of women and healthcare professionals. Eur J Surg Oncol. 2007;33:838–842. [PubMed]
60. Goldstein LJ, Gray R, Badve S, et al. Prognostic utility of the 21-gene assay in hormone receptor-positive operable breast cancer compared with classical clinicopathologic features. J Clin Oncol. 2008;26:4063–4071. [PMC free article] [PubMed]
61. Anderson K, Jacobson JS, Heitjan DF, et al. Cost-effectiveness of preventive strategies for women with a BRCA1 or a BRCA2 mutation. Ann Intern Med. 2006;144:397–406. [PubMed]
62. Grann VR, Jacobson JS, Thomason D, et al. Effect of prevention strategies on survival and quality-adjusted survival of women with BRCA1/2 mutations: An updated decision analysis. J Clin Oncol. 2002;20:2520–2529. [PubMed]
63. Lee JM, Kopans DB, McMahon PM, et al. Breast cancer screening in BRCA1 mutation carriers: Effectiveness of MR imaging—Markov Monte Carlo decision analysis. Radiology. 2008;246:763–771. [PubMed]
64. 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. 1997;336:1465–1471. [PubMed]
65. van Roosmalen MS, Verhoef LC, Stalmeier PF, et al. Decision analysis of prophylactic surgery or screening for BRCA1 mutation carriers: A more prominent role for oophorectomy. J Clin Oncol. 2002;20:2092–2100. [PubMed]
66. Kuhl CK, Schrading S, Bieling HB, et al. MRI for diagnosis of pure ductal carcinoma in situ: A prospective observational study. Lancet. 2007;370:485–492. [PubMed]
67. Lakhani SR, Van De Vijver MJ, Jacquemier J, et al. The pathology of familial breast cancer: Predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol. 2002;20:2310–2318. [PubMed]
68. Gronwald J, Tung N, Foulkes WD, et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: An update. Int J Cancer. 2006;118:2281–2284. [PubMed]
69. Jones LP, Li M, Halama ED, et al. Promotion of mammary cancer development by tamoxifen in a mouse model of BRCA1-mutation-related breast cancer. Oncogene. 2005;24:3554–3562. [PubMed]
70. 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. 2001;286:2251–2256. [PubMed]
71. Sacchini V, Pinotti JA, Barros AC, et al. Nipple-sparing mastectomy for breast cancer and risk reduction: Oncologic or technical problem? J Am Coll Surg. 2006;203:704–714. [PubMed]
72. Berrington de Gonzalez A, Berg CD, Visvanathan K, et al. Estimated risk of radiation-induced breast cancer from mammographic screening for young BRCA mutation carriers. J Natl Cancer Inst. 2009;101:205–209. [PubMed]
73. Ashworth A. A synthetic lethal therapeutic approach: Poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008;26:3785–3790. [PubMed]
74. Kurian AW, Hartman AR, Mills MA, et al. Opinions of women with high inherited breast cancer risk about prophylactic mastectomy: An initial evaluation from a screening trial including magnetic resonance imaging and ductal lavage. Health Expect. 2005;8:221–233. [PubMed]
75. Nekhlyudov L, Bower M, Herrinton LJ, et al. Women's decision-making roles regarding contralateral prophylactic mastectomy. J Natl Cancer Inst Monogr. 2005;35:55–60. [PubMed]
76. Uyei A, Peterson SK, Erlichman J, et al. Association between clinical characteristics and risk-reduction interventions in women who underwent BRCA1 and BRCA2 testing: A single-institution study. Cancer. 2006;107:2745–2751. [PubMed]
77. Ravdin PM, Siminoff LA, Davis GJ, et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol. 2001;19:980–991. [PubMed]

Articles from Journal of Clinical Oncology are provided here courtesy of American Society of Clinical Oncology