Management of women at high familial risk for breast and ovarian cancer

Authors:

Details:

Division of Hematology and Medical Oncology, Peter MacCallum Cancer Centre, Victoria.

 


Abstract

Women with a strong family history of breast and/or ovarian cancer have a greatly increased risk for the development of these diseases. The key question for these women is what they can do to ameliorate their cancer risk. Fortunately, there are now several interventions which clearly reduce breast and ovarian cancer risk in high risk women. These include risk-reducing bilateral mastectomy and salpingo ophorectomy and chemoprevention with tamoxifen or raloxifene. For those women who do not undergo risk-reducing bilateral mastectomy, screening is generally recommended in order to try and detect breast cancers at an early stage. Breast magnetic resonance imaging has an emerging role in such screening programs. Cancer screening does not reduce cancer risk and its impact on reduction of mortality in this group is uncertain. Women at high risk should be fully informed of their surgical, chemopreventive and screening options. A risk management plan should be tailored to each woman, particularly taking into account the level of her short-term (rather than life-time) risk, her lifestyle plans (such as child-bearing), competing risks (particularly in women with a prior cancer) and her personal preferences. The risk management plan should be reviewed regularly and altered as the individual’s short-term risk level and circumstances change, and as the evidence base for various interventions builds. Participation in appropriate clinical trials should be offered.


Who is at high risk for breast/ovarian cancer?

Breast cancer and ovarian cancer are diagnosed in about 12,000 and 1100 Australian women per year respectively.1 Between 1% and 5% of all breast cancer cases and around 10% of invasive epithelial ovarian cancer cases are due to the inheritance of mutations in known cancer predisposition genes.2,3 In less than 1% of the population, the number of blood relatives affected with cancer, their ages at diagnosis and the types of cancers suggest a high likelihood of a dominantly-inherited mutation in a breast cancer and/or ovarian cancer-predisposition gene (see Table 1). Referral of such women to a family cancer centre for formal risk assessment, consideration of genetic testing and discussion of management options is considered by many to be a standard of care. BRCA1 and BRCA2 are the genes most commonly associated with breast and ovarian cancer predisposition. Carriers of mutations in these genes have a significantly elevated lifetime risk of breast cancer or ovarian cancer.4,5 Several other genes are also associated with an increased risk of breast and/or ovarian malignancy (see Table 2).

Table 1: Risk of breast or ovarian cancer based on family history alone Table 2: High risk genes, frequency and increased risks of breast and ovarian cancer

Families meeting high risk criteria (see Table 1), but in whom a mutation cannot be found, are still considered at high risk because genetic testing is not 100% sensitive, and because there may be a mutation in an as yet unidentified cancer predisposition gene.

What are the risk management options for high-risk women?

Management of women with a strong family history and/or a documented gene mutation is complex and dynamic. Optimal risk management is likely to be in the context of a multidisciplinary team. Multidisciplinary risk management clinics have been set up at several family cancer centres within Australia.6 Figures 1 and 2 outline the options with respect to risk management strategies currently available.

Figure 1: Breast cancer: risk reduction and surveillance strategies Figure 2: Ovarian cancer: risk reduction and surveillance strategies

Risk-reducing surgery

An individual’s level of risk should be fully clarified prior to undertaking risk-reducing surgery. If possible, genetic testing of a family member with cancer should occur. If a mutation is found, the woman contemplating surgery should be tested for that mutation. In that way, unnecessary surgery in women who have not inherited the cancer causing family mutation can be avoided.

Bilateral risk-reducing mastectomy

Bilateral risk-reducing mastectomy (BRRM) is the most effective method of breast cancer prevention, reducing risk by about 90%.7-10 It is usually done in conjunction with immediate reconstruction. Total mastectomy is likely to reduce risk more than subcutaneous mastectomy, however the latter is a reasonable option for women wishing to retain the native nipple and areola complex,11 provided they are informed that the benefits may be slightly less. BRRM carries the risk of surgical complications;12additionally cosmetic complications following reconstruction may occur.13

In descriptive studies women who have undergone BRRM report lessened concern about cancer and decreased perceived cancer risk,14–16 but also dissatisfaction with reconstruction,17 feelings of femininity and sexual relationships.14,18Because BRRM can have adverse psychological and body image consequences, it should not be performed without prior counselling.

In Australia, uptake rates for BRRM have been relatively low by international standards.19In high-risk women attending family cancer clinics, (90% of whom were not known mutation carriers), the uptake rate over a three-year follow-up period was 4.4%. Those who underwent the procedure were more likely to have more first degree relatives with breast cancer than those who did not.16 In another study of mutation carriers in the kConFab research cohort,20 the uptake rate of BRRM was 11%, three years after learning their mutation result.21

Risk-reducing bilateral salpingo-oophorectomy

Risk-reducing bilateral salpingo-oophorectomy (RRBSO) reduces ovarian and fallopian tube cancer risk by about 90% and, for premenopausal women, also reduces breast cancer risk by about 50% in BRCA1 and BRCA2 mutation carriers.22-27 RRBSO has recently been shown to reduce overall and cancer specific mortality.22 It is an appropriate option for women who carry a BRCA1 or BRCA2 mutation, or who have a family history of breast and epithelial ovarian cancer (but is not generally recommended for women with a breast cancer-only family history). In Australia, uptake rates for RRBSO have been higher than for BRRM, with approximately 30% of mutation carriers undergoing RRBSO within three years of learning of their mutation result.21

RRBSO includes removal of the fallopian tube because of the increased risk of fallopian tube cancer in these women. Concurrent hysterectomy increases the complexity of the surgery, but is sometimes advocated to avoid the risk of endometrial cancer if progesterone-containing HRT or tamoxifen is planned for subsequent use. Primary peritoneal carcinoma may occur despite RRBSO,28 with the rates of such malignancies varying from 2-11%.29

For pre-menopausal women, RRBSO causes abrupt menopause. Observational studies suggest that the use of hormone replacement therapy (HRT), after RRBSO in BRCA1/2 mutation carriers, does not offset the breast cancer risk reduction conferred by the procedure.30 Results from the US based Women’s Health Initiative Study suggest caution in advising prolonged postmenopausal HRT in women.31,32

Optimal timing of RRBSO is controversial and needs to be individualised. Clearly it should not be undertaken until childbearing is completed. Ovarian cancer risk does not generally start to increase above that of the general population until about age 40 (BRCA1 carriers) or 50 (BRCA2 carriers). Thus, if ovarian cancer risk reduction is the major objective (eg. the patient is using other strategies to decrease breast cancer risk), surgery can be delayed until age 35-40 in BRCA1 carriers and age 45-50 in BRCA2 carriers. However, if reduction in breast cancer risk is also an objective, earlier RRBSO may be appropriate.

Tubal ligation

Tubal ligation has been associated with decreased risk for ovarian cancer in observational studies.33-35 One case control study showed that tubal ligation reduced ovarian cancer risk by about 60% in BRCA1 carriers. A protective effect was not seen in BRCA2 carriers, however was not excluded.36 In BRCA1/2 mutation carriers who have completed childbearing, but who choose not to undergo premenopausal RRBSO, tubal ligation should be considered as an effective contraceptive means which may also decrease ovarian cancer risk.

Chemoprevention

Breast cancer chemoprevention

Chemoprevention, with the selective oestrogen receptor modulators (SERMs) tamoxifen or raloxifene, reduces breast cancer risk by about 40%.37-42 Tamoxifen is the only evidence-based option for pre-menopausal women; for post-menopausal women raloxifene is also an option. These two agents have been compared in a randomised trial and are equally efficacious in preventing oestrogen receptor positive invasive breast cancers, with tamoxifen superior for prevention of noninvasive cancers.43 Raloxifene is associated with fewer gynaecological side-effects, thromboembolic events and cataracts than tamoxifen. These agents probably should not be used in women with previous history of deep venous thrombosis, smokers, or those with other uncontrolled cardiovascular risk factors.

SERMs have not been shown to reduce risk for oestrogen receptor negative breast cancer and this has been used as an argument against using them in BRCA1 carriers, who usually develop ER negative tumours.44,45 Indeed, a sub-analysis of mutation carriers in the largest prevention trial suggested that the benefit of tamoxifen might be limited to BRCA2 carriers, however the study was under-powered and included fewer than 10 BRCA1 carriers.46 Although BRCA1 associated breast cancers are usually oestrogen receptor negative, initiation of these tumours may well involve the oestrogen pathway,47,48 which is consistent with the observation that interventions reducing oestrogen exposure in these women (eg. pre-menopausal oophorectomy), appear to reduce risk. For this reason, tamoxifen chemoprevention may be considered a reasonable option, although enrolment in trials of novel chemoprevention agents such as retinoids should be considered.49

Aromatase inhibitors show promise as chemopreventive agents, based on their ability to reduce contralateral breast cancer risk in the adjuvant disease setting.50 A clinical trial of anastrozole as chemoprevention (IBIS II) is underway. Participation should be discussed with high risk women, particularly those with a contraindication to SERMs.

Ovarian cancer chemoprevention

While there are no randomised trials, observational studies demonstrate a reduced risk of ovarian cancer in the general population and in high risk individuals who take the oral contraceptive pill.33,51-54 Most studies suggest up to a 50% reduction in the risk of ovarian cancer in BRCA1/2 carriers.53,55,56 Oral contraceptive pill use in this setting has been tempered by concern about the effect on breast cancer risk (discussed below in the ‘lifestyle factors’ section). However, as ovarian cancer carries a higher mortality rate than breast cancer, in premenopausal women who choose not to undergo RRSO, the oral contraceptive pill is a reasonable strategy to reduce risk, while being mindful of the uncertainty regarding impact on breast cancer risk. For women who have undergone BRRM, but wish to postpone RRSO until later, it is potentially a useful strategy as there is no concern about the possible impact on breast cancer risk.

Surveillance strategies

Surveillance strategies do not reduce cancer risk, however are aimed at detecting malignancy at an early stage when it may be amenable to curative treatment. Evidence on the efficacy of intensive surveillance in high risk women is limited.

Breast cancer screening/surveillance

Mammography
In the general population, mammographic screening has been demonstrated to reduce breast cancer mortality in women older than 50 years by 20-25%.57,58 The efficacy of mammographic screening in younger, high risk women remains controversial.59 Anecdotal reports document both success and failure of mammography to detect breast cancer in carriers of BRCA1 mutations,60 and the sensitivity of mammographic screening in highrisk women over a variety of studies ranges from 50-91%.61

Some have suggested that annual mammography may not be frequent enough in BRCA1 mutation carriers because these cancers are usually high grade and may develop between screens.9,62-64 However, enthusiasm for more frequent mammographic screening is limited, partly by the question of whether ionising radiation may induce cancers in mutation carriers, because these individuals may have difficulty repairing DNA damage caused by radiation.65 Studies have had conflicting results. Two studies of BRCA1/2 carriers found no increased risk of breast cancer associated with mammography.66,67However, a recent retrospective cohort study of 1601 BRCA1/2 carriers demonstrated an increased risk of breast cancer (HR1.54, p=0.007) with any reported exposure to chest x-rays, especially in younger women.68

Currently, women at high risk are recommended to undergo annual mammography, either from the age of 40 or five years earlier than the age at diagnosis of the youngest breast cancer case in the family, whichever is earlier. For women with proven gene mutations mammographic screening is often considered in the 30s.

Magnetic resonance imaging
Magnetic resonance imaging (MRI) is an emerging screening modality for high risk women because of its high sensitivity.6975,76 The American Cancer Society supports annual MRI screening for individuals with a known BRCA mutation, individuals untested but with a first-degree relative with a BRCA mutation and individuals with an estimated lifetime breast cancer risk >20-25%.76 The European National Institute for Health and Clinical Excellence (NICE) guidelines recommend annual MRI in similar circumstances and in those with TP53 mutations a 10-year risk of >8% (30-39yo), or a 10- year risk >12% with dense breasts on mammography (40-49yo).77

The high sensitivity of MRI screening is offset to some extent by its low specificity. This results in high false positive rates, which may result in anxiety and unnecessary biopsy. There is no data on mortality benefits and lead-time bias may be a factor. While further research is needed, many Australian clinicians have begun to adopt the practice of MRI surveillance in high-risk women.

Breast clinical and self-examination
Clinical breast examination (CBE) may be an important adjunct in breast cancer screening in young, high risk women, as it may detect mammographically silent cancers, or may detect interval cancers between mammographic screenings. In addition, CBE is a potentially useful modality when women are pregnant or breast-feeding and other screening modalities are contra-indicated. It is generally recommended that CBE be carried out every six to 12 months in high risk women. While there is no evidence of survival benefits from breast self-examinations, women should be encouraged to be aware of how their breasts look and feel, and report any changes promptly.

Ovarian cancer screening/surveillance
Despite mounting evidence from observational studies that it is of no benefit, ovarian screening is sometimes considered for high risk women who have not undergone RRBSO.78 Screening tests usually consist of trans-vaginal ultrasonography with serum CA125 levels.78-81 Women who choose ovarian screening rather than RRBSO should be fully informed of the lack of evidence for any benefit.

Lifestyle factors

Lifestyle and environmental factors may modify breast cancer risk, although the effects are modest compared with surgery or chemoprevention. Current evidence is limited for several reasons. Most studies of modifiers of cancer risk in high risk women have been retrospective, prevalent case control designs, which have a high likelihood of systematic biases, including recall and survivorship bias. The few prospective studies are small or cobbled together from multiple institutions, using non-systematic and non-uniform follow-up strategies. Non-random loss to follow-up is a major potential source of bias in these studies. Additionally, most studies have focused on mutation carriers rather than the much larger population of women who have a strong family history but lack an identified gene mutation.

Parity

Increasing parity and early age at first childbirth are protective in the general population against breast cancer development. While several studies have investigated the effect of parity and age at first birth on breast cancer risk in BRCA1 and BRCA2 mutation carriers, results have been inconsistent.8287 However, the advantage of early childbearing for mutation carriers is that it allows earlier use of other effective risk management strategies such as risk reducing surgery and chemoprevention.

Breastfeeding

In the general population, a woman’s breast cancer risk reduces by about 4% for every 12 months of
breastfeeding.88 Several studies of mutation carriers have shown a reduction in breast cancer risk associated with breastfeeding.85,86,89 The single study which did not show any risk reduction was inadequately powered to exclude benefit.84 Women who are at high risk should breastfeed for as long as practical and preferably beyond one year.

Oral contraceptive use

Use of the combined oral contraceptive pill reduces ovarian cancer risk in the general population and in BRCA1 and BRCA2 mutation carriers. Whether oral contraceptive pill use affects breast cancer in high risk individuals remains controversial. A meta-analysis of 54 studies showed that current oral contraceptive pill use is associated with a 24% increase in breast cancer risk, but the risks were similar for those with and without a family history of breast cancer.90 Two other studies have not demonstrated a significant effect of oral contraceptive pill use on breast cancer risk in women with a family history.91,92 Conversely, one study showed a three-fold increase in breast cancer risk among women who used the oral contraceptive pill and had a first degree relative with breast cancer.93

In BRCA mutation carriers, two studies have shown no increase in risk in BRCA1 carriers who used oral contraceptive pills for at least one year,94,95 and one showed an increased risk of about 20% in ever-users of oral contraceptive pill.96 Of these three studies, two showed no effect of oral contraceptive pills on breast cancer risk in BRCA2 mutations, however one showed an increased risk for BRCA2 carriers after at least five years of use. Thus, at this stage, there is no consistent evidence to suggest that the oral contraceptive pill is either safe or contra-indicated in women at high risk for breast cancer.

Obesity

There is clear evidence in the general population that obesity is associated with significantly increased breast cancer risk.97,98 Data on the effect of weight control on breast cancer risk in mutation carriers is very limited, however the published data does suggest that this may be an important area of risk management.99,100

Alcohol consumption

Alcohol is clearly associated with breast cancer risk in the general population, with risk increasing by about 9% per daily standard drink.101-104 Few studies have addressed the influence of alcohol in high risk women. One study found a 2.4-fold increase in breast cancer risk in daily drinkers with a strong family history of breast cancer.105 Conversely, the only published study in mutation carriers showed no increased risk of breast cancer associated with alcohol consumption in carriers aged less than 50.106 Given the other adverse health effects of excessive alcohol, it may be prudent to recommend that high risk women drink no more than one standard drink per day.

What about risk management in high-risk women with cancer?

Women with a personal diagnosis of breast cancer may be identified as belonging to a high risk family. Risk management for such women should consider the risk for a subsequent breast cancer or ovarian cancer and the competing risk of dying from their prior cancer, which attenuates the prevention benefits. Referral to a family cancer centre for urgent genetic testing may be appropriate in planning both loco regional and systemic management. For women who carry a mutation in BRCA1 or BRCA2, the risk of a second breast cancer is around 40%107,108 and ovarian cancer risk is also increased.109

The most effective preventative strategy against development of a new breast cancer in BRCA1/2 positive individuals with a prior history of breast cancer, is complete mastectomy (if the previous operation on the affected breast was less than a mastectomy) with contralateral mastectomy, which reduces the risk of contralateral breast cancer by 90%.110 In mutation carriers with a low risk of systemic recurrence of their prior breast cancer, this operation should be considered prior to adjuvant breast irradiation, as the latter can limit the reconstructive options. Similarly, RRSO should be considered if the prognosis from the breast cancer is reasonably good; additionally, the subsequent oestrogen deprivation may be an effective adjuvant therapy in pre-menopausal hormone receptor positive women.111 Conversely, in women who are at high risk for systemic recurrence, it may be pertinent to wait two to five years before proceeding with risk reducing surgery, which will be of no benefit if her previous cancer recurs systemically. However, these decisions are complex and should involve the input of experts in breast cancer genetics, the treating oncologist and the woman herself.

If risk reducing mastectomy is not performed, secondary chemoprevention may be considered. Tamoxifen appears to reduce contralateral breast cancer risk by about 50% in mutation carriers, including BRCA1 carriers (who usually do not receive adjuvant tamoxifen for treatment of their hormone receptor negative breast cancers).112

Management of subsequent breast cancer risk in women with prior ovarian cancer will be highly influenced by the stage and prognosis of the ovarian cancer. For women with advanced ovarian cancer, where the five-year survival rates are low (even taking into account the possible better survival from ovarian cancer in BRCA mutation carriers), management of breast cancer risk with screening and/or chemoprevention may be preferable to BRRM, whereas BRRM may be appropriate for women with early stage ovarian cancer.

Conclusion

The management of women at high risk of breast and ovarian cancer is complex and requires individualisation based on a woman’s age, childbearing potential, personal risk and wishes. The great promise of predictive genetic testing for cancer predisposition in improving public health will only be realised with widespread implementation of evidence-based risk reduction strategies by the oncology and genetics community.

Acknowledgement

We would like to thank Dr Prue Francis for her critical review of the section of this article pertaining to management of high risk women with prior cancer.

References

Australian Institute of Health and Welfare [monogram on the Internet]. Interactive Cancer Data [accessed 2007 Aug]. Available from: http://www.aihw.gov.au/cancer/datacubes/index_2007.cfm.

2 Reedy M, Gallion H, Fowler JM, Kryscio R, Smith SA. Contribution of BRCA1 and BRCA2 to familial ovarian cancer: a gynecologic oncology group study. Gynecol Oncol. 2002;85(2):255-9.

3 Pal T, Permuth-Wey J, Betts JA, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-16.

4 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(5):1117-30.

5 Risch HA, McLaughlin JR, Cole DE, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001;68(3):700-10.

6 Antill Y SM, Phillips K-A. The integrated, multidisciplinary clinic: a new model for the ongoing management of women at high genetic risk for breast and ovarian cancer. Cancer Forum. 2005;29(2):107-110.

7 Hartmann LC, Sellers TA, Schaid DJ, et al. Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst. 2001;93(21):1633-7.

8 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. 1999;340(2):77-84.

9 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. 2001;345(3):159-64.

10 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(6):1055-62.

11 Metcalfe KA, Semple JL, Narod SA. Time to reconsider subcutaneous mastectomy for breast-cancer prevention? Lancet Oncol. 2005;6(6):431-4.

12 Barton MB, West CN, Liu IL, et al. Complications following bilateral prophylactic mastectomy. J Natl Cancer Inst Monogr. 2005(35):61-6.

13 Heemskerk-Gerritsen BA, Brekelmans CT, Menke-Pluymers MB, et al. Prophylactic Mastectomy in BRCA1/2 Mutation Carriers and Women at Risk of Hereditary Breast Cancer: Long-Term Experiences at the Rotterdam Family Cancer Clinic. Ann Surg Oncol. Epub 2007 May 31.

14 Frost MH, Schaid DJ, Sellers TA, et al. Long-term satisfaction and psychological and social function following bilateral prophylactic mastectomy. JAMA. 2000;284(3):319-24.

15 Hatcher MB, Fallowfield L, A’Hern R. The psychosocial impact of bilateral prophylactic mastectomy: prospective study using questionnaires and semistructured interviews. Br Med J. 2001;322(7278):76.

16 Antill Y, Reynolds J, Young MA, et al. Risk-reducing surgery in women with familial susceptibility for breast and/or ovarian cancer. Eur J Cancer. 2006;42(5):621-8.

17 Stefanek ME, Helzlsouer KJ, Wilcox PM, Houn F. Predictors of and satisfaction with bilateral prophylactic mastectomy. Prev Med. 1995;24(4):412-9.

18 Payne DK, Biggs C, Tran KN, Borgen PI, Massie MJ. Women’s regrets after bilateral prophylactic mastectomy. Ann Surg Oncol. 2000;7(2):150-4.

19 Wainberg S, Husted J. Utilization of screening and preventive surgery among unaffected carriers of a BRCA1 or BRCA2 gene mutation. Cancer Epidemiol Biomarkers Prev. 2004;13(12):1989-95.

20 Mann GJ, Thorne H, Balleine RL, et al. Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource. Breast Cancer Res. 2006;8(1):R12.

21 Phillips KA, Jenkins MA, Lindeman GJ, et al. Risk-reducing surgery, screening and chemoprevention practices of BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Clin Genet. 2006;70(3):198-206.

22 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(3):223-9.

23 Struewing JP, Watson P, Easton DF, Ponder BA, Lynch HT, Tucker MA. Prophylactic oophorectomy in inherited breast/ovarian cancer families. J Natl Cancer Inst Monogr. 1995(17):33-5.

24 Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346(21):1616-22.

25 Kramer JL, Velazquez IA, Chen BE, Rosenberg PS, Struewing JP, Greene MH. Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. J Clin Oncol. 2005;23(34):8629-35.

26 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(30):7491-6.

27 Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingooophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2002;346(21):1609-15.

28 Tobacman JK, Greene MH, Tucker MA, Costa J, Kase R, Fraumeni JF, Jr. Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian-cancer-prone families. Lancet. 1982;2(8302):795-7.

29 Nguyen HN, Averette HE, Janicek M. Ovarian carcinoma. A review of the significance of familial risk factors and the role of prophylactic oophorectomy in cancer prevention. Cancer. 1994;74(2):545-55.

30 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(31):7804-10.

31 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(3):321-33.

32 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. 2003;289(24):3243-53.

33 Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol. 1992;136(10):1184-203.

34 Hankinson SE, Hunter DJ, Colditz GA, et al. Tubal ligation, hysterectomy, and risk of ovarian cancer. A prospective study. JAMA. 1993;270(23):2813-8.

35 Rosenblatt KA, Thomas DB. Reduced risk of ovarian cancer in women with a tubal ligation or hysterectomy. The World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives. Cancer Epidemiol Biomarkers Prev. 1996;5(11):933-5.

36 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. 2001;357(9267):1467-70.

37 Cuzick J, Forbes J, Edwards R, et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet. 2002;360(9336):817-24.

38 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. 1998;90(18):1371-88.

39 Powles T, Eeles R, Ashley S, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomized chemoprevention trial. Lancet. 1998;352(9122):98-101.

40 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. 1998;352(9122):93-7.

41 Cuzick J, Powles T, Veronesi U, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet. 2003;361(9354):296-300.

42 Ganz P. The study of tamoxifen and raloxifene (STAR): First report of patient-reported outomes from the NSABP P-2 breast cancer prevention study. Proceedings of the American Society of Clinical Oncology; 2006 June 2-6; Atlanta GA, USA.

43 Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295(23):2727-41.

44 Phillips KA. Breast carcinoma in carriers of BRCA1 or BRCA2 mutations: implications of proposed distinct histologic phenotypes. Cancer. 1998;83(11):2251-4.

45 Phillips KA, Nichol K, Ozcelik H, et al. Frequency of p53 mutations in breast carcinomas from Ashkenazi Jewish carriers of BRCA1 mutations. J Natl Cancer Inst. 1999;91(5):469-73.

46 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 (NSABPP1) Breast Cancer Prevention Trial. JAMA. 2001;286(18):2251-6.

47 Li W, Xiao C, Vonderhaar BK, Deng CX. A role of estrogen/ERalpha signaling in BRCA1-associated tissue-specific tumor formation. Oncogene. Epub 2007 May 14.

48 Hilakivi-Clarke L. Estrogens, BRCA1, and breast cancer. Cancer Res. 2000;60(18):4993-5001.

49 Decensi A, Serrano D, Bonanni B, Cazzaniga M, Guerrieri-Gonzaga A. Breast cancer prevention trials using retinoids. J Mammary Gland Biol Neoplasia. 2003;8(1):19-30.

50 Cuzick J. Aromatase inhibitors for breast cancer prevention. J Clin Oncol. 2005;23(8):1636-43.

51 Gwinn ML, Lee NC, Rhodes PH, Layde PM, Rubin GL. Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer. J Clin Epidemiol. 1990;43(6):559-68.

52 Franceschi S, Parazzini F, Negri E, et al. Pooled analysis of 3 European case-control studies of epithelial ovarian cancer: III. Oral contraceptive use. Int J Cancer. 1991;49(1):61-5.

53 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(7):424-8.

54 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(7):613-8.

55 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(4):235-40.

56 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(11):1911-5.

57 Smith RA, Duffy SW, Gabe R, Tabar L, Yen AM, Chen TH. The randomized trials of breast cancer screening: what have we learned? Radiol Clin North Am. 2004;42(5):793-806, v.

58 Nystrom L, Andersson I, Bjurstam N, Frisell J, Nordenskjold B, Rutqvist LE. Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet. 2002;359(9310):909-19.

59 Kerlikowske K, Grady D, Barclay J, Sickles EA, Eaton A, Ernster V. Positive predictive value of screening mammography by age and family history of breast cancer. JAMA. 1993;270(20):2444-50.

60 Evans DG, Ribiero G, Warrell D, Donnai D. Ovarian cancer family and prophylactic choices. J Med Genet. 1992;29(6):416-8.

61 Kriege M, Klijn JG. Efficacy of MRI and mammography for breast cancer screening in women with genetic predisposition. Educational Book; Proceedings of the American Society of Clinical Oncology; 2007 June 1-5; Chicago, USA p.135-41.

62 Komenaka IK, Ditkoff BA, Joseph KA, et al. The development of interval breast malignancies in patients with BRCA mutations. Cancer. 2004;100(10):2079-83.

63 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. 2002;20(5):1260-8.

64 Phillips KA. Re biologic characteristics of interval and screen-detected breast cancers [letter]. J Natl Cancer Inst. 2001;93:151-152.

65 Jasin M. Homologous repair of DNA damage and tumorigenesis: the BRCA connection. Oncogene. 2002;21(58):8981-93.

66 Narod SA, Lubinski J, Ghadirian P, et al. Screening mammography and risk of breast cancer in BRCA1 and BRCA2 mutation carriers: a casecontrol study. Lancet Oncol. 2006;7(5):402-6.

67 Goldfrank D, Chuai S, Bernstein JL, et al. Effect of mammography on breast cancer risk in women with mutations in BRCA1 or BRCA2. Cancer Epidemiol Biomarkers Prev. 2006;15(11):2311-3.

68 Andrieu N, Easton DF, Chang-Claude J, et al. Effect of chest X-rays on the risk of breast cancer among BRCA1/2 mutation carriers in the international BRCA1/2 carrier cohort study: a report from the EMBRACE, GENEPSO, GEO-HEBON, and IBCCS Collaborators’ Group. J Clin Oncol. 2006;24(21):3361-6.

69 Morris EA, Liberman L, Ballon DJ, et al. MRI of occult breast carcinoma in a high-risk population. AJR Am J Roentgenol. 2003;181(3):619-26.

70 Hartman AR, Daniel BL, Kurian AW, et al. Breast magnetic resonance image screening and ductal lavage in women at high genetic risk for breast carcinoma. Cancer. 2004;100(3):479-89.

71 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(5):427-37.

72 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(11):1317-25.

73 Lehman CD, Blume JD, Weatherall P, et al. Screening women at high risk for breast cancer with mammography and magnetic resonance imaging. Cancer. 2005;103(9):1898-905.

74 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(9473):1769-78.

75 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(33):8469-76.

76 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(2):75-89.

77 National Institute for Health and Clinical Excellence. Familial breast cancer. The classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care. Partial update of NICE clinical guideline 41. October 2006.

78 Hogg R, Friedlander M. Biology of epithelial ovarian cancer: implications for screening women at high genetic risk. J Clin Oncol. 2004;22(7):1315-27.

79 NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. JAMA. 1995;273(6):491-7.

80 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. 1997;277(12):997-1003.

81 Antill Y PK. Ovarian cancer screening for high risk women. In: Gershenson D MW, Gore M, Quinn MA, Thomas G., editors. Gynecologic Cancer: Controversies In Management. Philadelphia: Elsevier, 2004. p341-54.

82 Antoniou AC, Shenton A, Maher ER, et al. Parity and breast cancer risk among BRCA1 and BRCA2 mutation carriers. Breast Cancer Res. 2006;8(6):R72.

83 Kotsopoulos J, Lubinski J, Lynch HT, et al. Age at first birth and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat. Epub 2007 Jan 24.

84 Andrieu N, Goldgar DE, Easton DF, et al. Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS). J Natl Cancer Inst. 2006;98(8):535-44.

85 Gronwald J, Byrski T, Huzarski T, et al. Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland. Breast Cancer Res Treat. 2006;95(2):105-9.

86 Tryggvadottir L, Olafsdottir EJ, Gudlaugsdottir S, et al. BRCA2 mutation carriers, reproductive factors and breast cancer risk. Breast Cancer Res. 2003;5(5):R121-8.

87 Cullinane CA, Lubinski J, Neuhausen SL, et al. Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers. Int J Cancer. 2005;117(6):988-91.

88 Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet. 2002;360(9328):187-95.

89 Jernstrom H, Lubinski J, Lynch HT, et al. Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2004;96(14):1094-8.

90 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. 1996;347(9017):1713-27.

91 Silvera SA, Miller AB, Rohan TE. Oral contraceptive use and risk of breast cancer among women with a family history of breast cancer: a prospective cohort study. Cancer Causes Control. 2005;16(9):1059-63.

92 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. 1996;88(6):365-71.

93 Grabrick DM, Hartmann LC, Cerhan JR, et al. Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer. JAMA. 2000;284(14):1791-8.

94 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(2):350-6.

95 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(10):1863-70.

96 Narod SA, Dube 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(23):1773-9.

97 Friedenreich CM. Review of anthropometric factors and breast cancer risk. Eur J Cancer Prev. 2001;10(1):15-32.

98 Loi S, Milne RL, Friedlander ML, et al. Obesity and outcomes in premenopausal and postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev. 2005;14(7):1686-91.

99 Kotsopoulos J, Olopado OI, Ghadirian P, et al. Changes in body weight and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res. 2005;7(5):R833-43.

100 Nkondjock A, Robidoux A, Paredes Y, Narod SA, Ghadirian P. Diet, lifestyle and BRCA-related breast cancer risk among French- Canadians. Breast Cancer Res Treat. 2006;98(3):285-94.

101 Smith-Warner SA, Spiegelman D, Yaun SS, et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA. 1998;279(7):535-40.

102 Schatzkin A, Longnecker MP. Alcohol and breast cancer. Where are we now and where do we go from here? Cancer. 1994;74(3 Suppl):1101-10.

103 Longnecker MP. Alcoholic beverage consumption in relation to risk of breast cancer: meta-analysis and review. Cancer Causes Control. 1994;5(1):73-82.

104 Ellison RC, Zhang Y, McLennan CE, Rothman KJ. Exploring the relation of alcohol consumption to risk of breast cancer. Am J Epidemiol. 2001;154(8):740-7.

105 Vachon CM, Cerhan JR, Vierkant RA, Sellers TA. Investigation of an interaction of alcohol intake and family history on breast cancer risk in the Minnesota Breast Cancer Family Study. Cancer. 2001;92(2):240-8.

106 McGuire V, John EM, Felberg A, et al. No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages <50 years. Cancer Epidemiol Biomarkers Prev. 2006;15(8):1565-7.

107 Metcalfe K, Lynch HT, Ghadirian P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2004;22(12):2328-35.

108 Kirova YM, Stoppa-Lyonnet D, Savignoni A, Sigal-Zafrani B, Fabre N, Fourquet A. Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy. Eur J Cancer. 2005;41(15):2304-11.

109 Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994;343(8899):692-5.

110 Van Sprundel TC, Schmidt MK, Rookus MA, et al. Risk reduction of contralateral breast cancer and survival after contralateral prophylactic mastectomy in BRCA1 or BRCA2 mutation carriers. Br J Cancer. 2005;93(3):287-92.

111 Wirk B. The role of ovarian ablation in the management of breast cancer. Breast J. 2005;11(6):416-24.

112 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(9):2281-4.

113 Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med. 2005;143(5):355-61.

114 National Breast Cancer Centre. Clinical practice guidelines for the management of women with epithelial ovarian cancer. Camperdown (Australia): National Breast Cancer Centre; 2004.

115 Robson M, Offit K. Clinical practice. Management of an inherited predisposition to breast cancer. N Engl J Med. 2007;357(2):154-62.

116 Kasprzak L, Foulkes WD, Shelling AN. Forth nightly review: hereditary ovarian carcinoma. Br Med J. 1999;318(7186):786-9.

Be the first to know when a new issue is online. Subscribe today.