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© 2003 American Society for Clinical Oncology Use of Genetic Testing and Prophylactic Mastectomy and Oophorectomy in Women With Breast or Ovarian Cancer From Families With a BRCA1 or BRCA2 MutationFrom the Rotterdam Family Cancer Clinic, Department of Clinical Genetics; and Department of Medical Oncology, Department of Surgical Oncology, and Department of Gynecology, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands. Address reprint requests to J.G.M. Klijn, MD, Department of Medical Oncology, Daniel den Hoed Cancer Center, Erasmus MC Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, Netherlands; email: j.g.m.klijn{at}erasmusmc.nl.
Purpose: To analyze the use of genetic testing, prophylactic mastectomy, and oophorectomy among women with breast and/or ovarian cancer from families with a BRCA1 or BRCA2 mutation. Patients and Methods: We examined prospectively the use of BRCA1/BRCA2 testing in all women with a primary breast or ovarian cancer from a consecutive series of 112 high-risk families in which a BRCA1/BRCA2 mutation eventually was identified. The rate of prophylactic bilateral and contralateral mastectomy and prophylactic oophorectomy was analyzed in the women who carried a BRCA1/BRCA2 mutation and who had no metastatic disease at the time of the genetic test disclosure. We examined predictors for genetic test uptake and prophylactic surgery using univariate and multivariate analysis. Results: Overall, 192 of 220 women (87%) with primary tumors underwent genetic testing. Eleven of these 192 tested women (6%) appeared not to carry the family-specific BRCA1/BRCA2 mutation. Genetic testing occurred significantly more frequently at ages younger than 50 years (P = .04) and in persons with multiple primary tumors (P = .02). Among eligible women, 35 of 101 (35%) requested bilateral or contralateral mastectomy, and 47 of 95 (49%) requested oophorectomy. Women aged younger than 50 years and women who developed their first tumor after the initial identification of a BRCA1/BRCA2 mutation in the family were significantly (both P = .01) more likely to opt for prophylactic bilateral or contralateral mastectomy. Conclusion: In a clinical setting, we show a high demand for BRCA1/BRCA2 testing and for prophylactic surgery by women with breast and/or ovarian cancer from high-risk families.
GERMLINE MUTATIONS in the BRCA1 and BRCA2 genes predispose women to breast cancer and ovarian cancer, typically at early ages.1,2 Moreover, women with breast cancer who carry a BRCA1 or BRCA2 mutation are at increased risk of a second primary contralateral breast cancer and primary ovarian cancer.3,4 Their risk of a contralateral breast cancer is 50% to 60% at age 70 years and their risk of ovarian cancer is 15% to 40%.3,4 More specifically, we showed that the 5-year rate of metachronous contralateral breast cancer in women with a BRCA1 or BRCA2 mutation was 19% and 12%, respectively, whereas in age-matched control patients, this rate was 5% and 2%, respectively.5,6 The risk mutation carriers with breast cancer have of ipsilateral events is also increased.7 At 12 years of follow-up, 49% of mutation carriers had an ipsilateral event in contrast to 21% of patients with sporadic breast cancer.7 Mutation carriers who have already developed breast cancer or ovarian cancer may therefore benefit from strategies that reduce morbidity or mortality. To that end, several avenues currently are being explored. Regular surveillance for breast cancer and ovarian cancer of BRCA1/BRCA2 mutation carriers has thus far not resulted in detection of cancers at earlier stages,8–10 although the application of magnetic resonance imaging seems to be promising.9,11,12 The incidence of contralateral breast cancer in BRCA1/BRCA2 mutation carriers was shown to be reduced by 50% with tamoxifen use,13 by 58% after bilateral oophorectomy,13,14 and by 60% after chemotherapeutical treatment for the first breast cancer.13 Most effectively, the incidence of contralateral breast cancer in familial breast cancer patients (irrespective of BRCA1 or BRCA2 mutation status) was reduced by 95% after prophylactic contralateral mastectomy.15 Prophylactic bilateral oophorectomy prevents ovarian cancer in women with a BRCA1/BRCA2 mutation, but a minimum (long-term) risk of 4% of peritoneal cancer remains after this procedure.14,16 We previously investigated predictive factors for the decision about presymptomatic DNA testing and prophylactic surgery in unaffected women from families with a BRCA1/BRCA2 mutation.17 Until now, no systematic evaluation has been reported on the actual use of BRCA1/BRCA2 testing by women with breast cancer or ovarian cancer from high-risk families and on the use of prophylactic bilateral or contralateral mastectomy and prophylactic bilateral oophorectomy by women with a BRCA1/BRCA2 mutation who previously had primary breast cancer and/or ovarian cancer. The main aims of our study were to assess these items in a setting of a family cancer clinic.
Study Participants We studied a consecutive series of 112 families with a BRCA1 (n = 92) or BRCA2 (n = 20) mutation identified at our Rotterdam Family Cancer Clinic before January 1, 2000. General practitioners and medical specialists had referred the families to us since 1991. Mutational analysis of the full coding sequences and splice junctions of BRCA1 and BRCA2 was performed using a variety of techniques, including single-strand confirmation polymorphism, denaturing gradient-gel electrophoresis for most sequences, protein truncation test for exon 11 of BRCA1 and exons 10 and 11 of BRCA2, and diagnostic polymerase chain reaction analyses for large genomic rearrangements known to be present in the Dutch population.18 In the families under study, a protein-truncating mutation in the BRCA1 or BRCA2 gene was identified between 1994 and January 1, 2000. Informed consents, comprising the items from the American Society of Clinical Oncology,19 were obtained from all individuals involved in this study. For the analysis of the use of genetic testing, all women from the 112 families were eligible that had been diagnosed with breast cancer or ovarian cancer at the time of the initial search for a BRCA1/BRCA2 mutation in the family, or who developed breast cancer or ovarian cancer later on, but before January 1, 2000. A total of 220 women fulfilled these criteria. For the analysis of the use of prophylactic bilateral or contralateral mastectomy and prophylactic bilateral oophorectomy, all women with breast cancer or ovarian cancer from these families that also carried a BRCA1/BRCA2 mutation were eligible. Excluded were women with metastatic disease at the moment of personal genetic diagnosis. Metastatic disease was defined as M1 for breast cancer and as International Federation of Gynecology and Obstetrics stage III or IV for ovarian cancer. Women that previously had both breasts or both ovaries removed for reasons other than prophylaxis were excluded in the analysis of the use of prophylactic mastectomy and oophorectomy, respectively. Only women aged 35 years and older were considered eligible for prophylactic oophorectomy. A total of 101 women were eligible for prophylactic mastectomy, and 95 women were eligible for prophylactic oophorectomy. The end point of interest of this study was January 1, 2002.
Data Collection
Oncogenetic Counseling and Procedures Ovarian surveillance was initiated from the age of 35 years and consisted of physical examination by a gynecologist, vaginal ultrasonography of the ovaries once a year, and assessment of serum CA-125 concentrations once to twice a year. To any woman without evidence of metastatic disease, prophylactic mastectomy was offered at any age, and prophylactic oophorectomy was offered from the age of 35 years or older. A psychologist supported all women who considered prophylactic mastectomy. Prophylactic mastectomy was performed by standard bilateral or contralateral simple mastectomy (including the nipple) and simultaneous breast reconstruction by subpectoral implantation of silicone prostheses when requested. Postmastectomy breast cancer risk and morbidity were monitored by follow-up visits at least twice a year. Prophylactic bilateral salpingo-oophorectomy was preferentially performed by laparoscopy. Annual postoophorectomy gynecologic follow-up was recommended, in particular to monitor the residual peritoneal cancer risk. Hormone-replacement therapy was not prescribed after prophylactic oophorectomy because these women had had breast cancer.
Variables and Statistical Analysis
In the study on the use of prophylactic bilateral or contralateral mastectomy and oophorectomy, the predictive value of the following variables was analyzed: age at the time of personal genetic diagnosis (< 50 v Descriptive statistics were used to determine the rates of genetic testing and of prophylactic surgery. The predictive value of all variables was first assessed by univariate analysis, and odds ratios and 95% confidence intervals (CIs) were calculated. Second, to assess the effect of the variables simultaneously, multivariate logistic regression was used. Odds ratios and 95% CIs were adjusted for the factors with P values below .10 in the univariate model. All P values were two sided; values less than .05 were considered significant. Kaplan-Meier survival probabilities were calculated to assess the time-dependent rate of the decisions about prophylactic surgery. Start points were date of personal DNA test disclosure in affected women or date of first personal cancer diagnosis when the cancer developed after the personal genetic diagnosis. End points were date of prophylactic bilateral or contralateral mastectomy or date of prophylactic bilateral oophorectomy, death, loss to follow-up, or diagnosis of metastatic disease.
Genetic Test Use In the 112 families with a known BRCA1 or BRCA2 mutation, we identified 220 women that had breast cancer (n = 172), ovarian cancer (n = 33), or both breast cancer and ovarian cancer (n = 15). Genetic testing was used by 192 of these 220 women (87%). In the univariate analysis, young age (< 50 years) and having more than one primary cancer tended to be positively correlated with the use of genetic testing, whereas having children and type of cancer were not (Table 1  ). In the multivariate analysis, the correlation of genetic testing with young age and with having multiple primary cancers reached significance (P = .04 and P = .02, respectively; Table 1). The majority (89%) of the women applied for genetic testing within 3 months after the first invitation for testing. The mean time of follow-up after the initial genetic diagnosis in the family was 51 months (range, 24 to 84 months).
Interestingly, 11 of 192 tested women (6%) did not carry the family-specific BRCA1 or BRCA2 mutation. All eleven women had been diagnosed with breast cancer and were at risk for the family-specific mutation. The mean age at breast cancer diagnosis in all living eligible mutation carriers was 51 years (n = 175; range, 23 to 90 years) and was 61 years in the 11 noncarriers (range, 41 to 83 years).
Use of Prophylactic Bilateral or Contralateral Mastectomy and Bilateral Oophorectomy
Several variables were analyzed for their predictive value toward prophylactic surgery (Tables 2
Time Needed to Decide for Prophylactic Mastectomy and Prophylactic Oophorectomy A total of 35 women underwent prophylactic mastectomy, and 47 women underwent prophylactic oophorectomy. The mean time interval from the personal genetic diagnosis to the moment of prophylactic mastectomy and to that of prophylactic oophorectomy was 9 and 8 months, respectively. At a follow-up of 1 and 2 years, 22% and 35%, respectively, of eligible women had decided to undergo prophylactic mastectomy; only one woman had the procedure after a period of follow-up of more than 2 years (Fig 1 ). A similar pattern was observed with respect to the decision about prophylactic oophorectomy. At a follow-up of 1 and 2 years, 40% and 47%, respectively, of eligible women had their ovaries removed (Fig 1). After this period only two women requested this procedure.
Women with breast cancer at a young age or with relatives with breast cancer and/or ovarian cancer may consider genetic testing for BRCA1/BRCA2 mutations. By this means, their risks of contralateral breast cancer, ipsilateral events, and ovarian cancer can be specified, because BRCA1/BRCA2 mutation carriers clearly have higher risks.3,4,7 Women with breast cancer or ovarian cancer may therefore seek genetic testing for personal health management and treatment decisions, apart from concerns about the cancer risks for their children or other relatives. We systematically evaluated the use of genetic testing, prophylactic mastectomy, and prophylactic oophorectomy in a consecutive series of 112 families with a BRCA1/BRCA2 mutation. We found that the overwhelming majority of women with breast cancer or ovarian cancer from high-risk families are interested in genetic testing themselves or are willing to undergo genetic testing for the sake of their family members. One third of affected mutation carriers that had a relatively good prognosis decided to undergo prophylactic mastectomy, and half of them decided to undergo prophylactic oophorectomy. These figures differ from those observed by us in unaffected women from families with a BRCA1/BRCA2 mutation.17 The genetic test rate in unaffected women was lower when compared with the rate in women who already had breast and/or ovarian cancer (48% [198 of 411] v 87% [192 of 220], respectively). This may be related to differences in the motives for genetic testing between affected and unaffected women. For affected women, the issue of learning the cancer risks of children and other relatives may play a more prominent role in the decision about genetic testing when compared with that in unaffected women. This may be particularly so for women with metastatic disease, because knowledge of their own mutation status has no major implications for their personal health management. In contrast, in unaffected women the decision about genetic testing may strongly correlate with the wishes these women have on personal health management in case they carry a mutation; in particular, women who consider prophylactic surgery may proceed with genetic testing. Interestingly, we observed a reverse pattern with respect to the decisions about prophylactic surgery. Unaffected women with a BRCA1 or BRCA2 mutation more frequently requested prophylactic mastectomy when compared with their affected counterparts (51% [35 of 68] v 35% [35 of 101], respectively), and a similar trend was observed for prophylactic oophorectomy (unaffected v affected, 64% [29 of 45] v 49% [47 of 95], respectively). These facts may be largely explained by the aforementioned differences in the main motives for genetic testing between unaffected and affected women. From a theoretical point of view, prophylactic surgery is also more advisable to unaffected women because the potential gain in life expectancy by this procedure will be larger in this group. In affected women, the effect of prophylactic surgery on life expectancy inevitably competes with their risk of dying because of metastases of their prior cancer. Likewise, young women who decide to undergo prophylactic surgery are likely to gain more years when compared with the years gained by older women.20 In our series, for example, young women frequently opted for prophylactic mastectomy. Although the numbers are small, as much as 75% of women who developed breast cancer after the establishment of the genetic diagnosis in their family chose to have a bilateral mastectomy with simultaneous reconstruction at the moment of personal cancer diagnosis. Thus, for women who were just diagnosed with breast cancer without a known BRCA1/BRCA2 mutation in the family, rapid knowledge about their genetic status may also be important. Recent new strategies in high-throughput biologic and genetic investigations pave the way for classifying a breast cancer as a BRCA1- or BRCA2-related cancer at the time of histologic diagnosis.21–24 In particular, women with breast cancer at a young age and women with a family history of breast cancer and ovarian cancer are at increased risk of carrying a BRCA1 and BRCA2 mutation. The prevalence of BRCA1 and BRCA2 mutations in women younger than 36 and 50 years with breast cancer is about 10% and 6%, respectively,25 and may increase to 80% in those who also have a positive family history of breast cancer and ovarian cancer.26 Not only are the potential reduction of cancer risk and prevention of cancer morbidity by bilateral mastectomy relevant, but the timing of this procedure is also important. Cosmetic results of breast reconstruction may be less optimal after radiation therapy of the breasts,27 which is added routinely to the treatment of breast cancer patients who undergo breast-conserving therapy. Bilateral mastectomy plus breast reconstruction may therefore be a reasonable alternative to breast-conserving therapy at the time of diagnosis of the first primary cancer for some women. The psychological effect of receiving a personal cancer and genetic diagnosis in the same time period has not been addressed yet and warrants close attention. However, we believe that the current state of knowledge and technology mandates that doctors inform and counsel just-diagnosed breast cancer patients at high risk of a BRCA1/BRCA2 mutation about the oncogenetic issues of their disease and the related available interventions before decisions are made on the type of breast cancer treatment patients will undergo. For those patients who are interested, a rapid genetic diagnosis should be sought so that their primary treatment for breast cancer also can be tailored toward their genetic status. Most women opting for prophylactic surgery chose to undergo prophylactic mastectomy and/or oophorectomy within 2 years after their genetic diagnosis. The time-dependent rates of prophylactic mastectomy and/or oophorectomy indicate that most women interested in prophylactic surgery have already come forward during the period of our study. It is therefore unlikely that our reported use of prophylactic surgery will significantly increase over time. The use of genetic testing and prophylactic surgery in our center differs from that in other countries. Factors such as potential social and financial discrimination and cultural differences in views on prophylactic surgery by patients and their doctors may result in large differences in the use and accessibility of prophylactic mastectomy and oophorectomy.28 A recent study among United States citizens, for example, revealed that as many as 69% of eligible women opted for BRCA1/BRCA2 testing when the tests were free of charge, as compared with only 22% who opted for testing when it was not free.29 Dutch laws prohibit discrimination of gene mutation carriers, whether by health insurance companies or by employers, and all costs of genetic testing, surveillance, and prophylactic surgery are covered by both private and public health insurance companies. Our reported rates of genetic testing and prophylactic surgery are therefore unlikely to be confounded by financial or social constraints. Prophylactic mastectomy is an irreversible and mutilating intervention, and therefore, issues of regret in women who had a prophylactic mastectomy are a major concern. One study found that 6% (18 of 296) of women with breast cancer who had a prophylactic contralateral mastectomy for any cause expressed regrets regarding their decision.30 At present there are no psychological follow-up data on affected women who had a prophylactic contralateral mastectomy because of a BRCA1 or BRCA2 mutation carrier status. Clearly, it is mandatory to monitor the medical and psychological consequences of all interventions in this group of women on the short and long term. On the basis of current data, it is likely that prophylactic bilateral or contralateral mastectomy is most effective in reducing the risk of a second breast cancer. However, premenopausal prophylactic oophorectomy may be a good alternative for some women because this procedure not only reduces the risk of contralateral breast cancer by 50% but also prevents primary ovarian cancer.13,14,16 Furthermore, adjuvant tamoxifen (at 20 mg/d for 5 years) not only reduces the risk of contralateral breast cancer in unselected patients by approximately 50%31 but may also reduce the risk of contralateral breast cancer in BRCA1/BRCA2 mutation carriers.13 However, at present, the efficacy of chemoprevention with tamoxifen in both BRCA1 and BRCA2 mutation carriers is unclear.32–34 In this respect it should be noted that BRCA1-related breast tumors are frequently estradiol receptor-negative.5 The prognosis of the first tumor in women with a BRCA1/BRCA2 mutation may ultimately overshadow the effect of subsequent interventions that aim to prevent second primary cancers. At present it is of utmost importance to establish the actual gains in life expectancy achieved by these interventions in these women. Notwithstanding, even in the absence of a gain in life expectancy, women may benefit from interventions such as prophylactic mastectomy and prophylactic oophorectomy because these interventions may reduce fear for a second primary cancer and/or reduce physical and psychological morbidity that inevitably accompanies the diagnosis of second primary cancers.
We thank the following clinicians for their care of the patients: Bartels, MD, van der Meer, Oldenburg, MD, Tan, Tilanus-Linthorst, MD, van Vliet, Wagner, MD, van Zuylen, MD; Verhoog, MD, for his contribution to the development of the database; and Niermeijer, MD, for his continuous support.
1. Ford D, Easton DF, Bishop DT, et al: Risks of cancer in BRCA1-mutation carriers. Lancet 343:692–695, 1994[CrossRef][Medline] 2. Easton DF, Steele L, Fields P, et al: Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12–13. Am J Hum Genet 61:120–128, 1997[Medline] 3. Easton DF, Ford D, Bishop DF: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Am J Hum Genet 56:265–271, 1995[Medline]
4. The Breast Cancer Linkage Consortium: Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91:1310–1316, 1999 5. Verhoog LC, Brekelmans CTM, Seynaeve C, et al: Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 351:316–321, 1998[CrossRef][Medline]
6. Verhoog LC, Brekelmans CTM, Seynaeve C, et al: Survival in hereditary breast cancer associated with germline mutations of BRCA2. J Clin Oncol 17:3396–3402, 1999 7. Haffty BG, Harrold E, Khan AJ, et al: Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. Lancet 359:1471–1477, 2002[CrossRef][Medline]
8. Brekelmans CTM, Seynaeve C, Bartels CCM, et al: Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk. J Clin Oncol 19:924–930, 2001
9. Meijers-Heijboer H, van Geel B, van Putten WLJ, et al: Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 345:159–164, 2001 10. Rosenthal A, Jacobs I: Ovarian cancer screening. Semin Oncol 25:315–325, 1998[Medline]
11. Stoutjesdijk MJ, Boetes C, Jager J, et al: Magnetic resonance imaging and mammography in women with a hereditary risk of breast cancer. J Natl Cancer Inst 93:1095–1102, 2001
12. 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 19:3524–3531, 2001 13. Narod SA, Brunet JS, Ghadirian P, et al: Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study. Lancet 356:1876–1881, 2000[CrossRef][Medline]
14. Kauff ND, Satagopan JM, Robson M, et al: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346:1609–1615, 2002
15. McDonnell SK, Schaid DJ, Myers JL, et al: Efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. J Clin Oncol 19:3938–3943, 2001
16. Rebbeck TR, Lynch HT, Neuhausen SL, et al: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346:1616–1622, 2002 17. Meijers-Heijboer EJ, Verhoog LC, Brekelmans CTM, et al: Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation. Lancet 355:2015–2020, 2000[CrossRef][Medline] 18. Petrij-Bosch A, Peelen T, van Vliet M, et al: BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet 17:341–345, 1997[CrossRef][Medline]
19. American Society of Clinical Oncology: Statement of the American Society of Clinical Oncology: Genetic testing for cancer susceptibility. J Clin Oncol 14:1730–1736, 1996
20. Schrag D, Kuntz KM, Garber JE, et al: Life expectancy gains from cancer prevention strategies for women with breast cancer and BRCA1 or BRCA2 mutations. J Am Med Assoc 283:617–624, 2000
21. Hedenfalk I, Duggan D, Chen Y, et al: Gene-expression profiles in hereditary breast cancer. N Engl J Med 344:539–548, 2001 22. Berns EM, van Staveren IL, Verhoog L, et al: Molecular profiles of BRCA1-mutated and matched sporadic breast tumours: Relation with clinico-pathological features. Br J Cancer 85:538–545, 2001[CrossRef][Medline] 23. Van't Veer LJ, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:484–485, 2002[CrossRef][Medline] 24. Berucci F, Houlgatte R, Nguyen C, et al: Gene expression profiling of cancer by use of DNA arrays: How far from the clinic. Lancet Oncol 2:674–682, 2001[CrossRef][Medline]
25. Peto J, Collins N, Barfoot R, et al: Prevalence of BRCA1 and BRCA2 mutations in patients with early-onset breast cancer. J Natl Cancer Inst 91:943–949, 1999 26. Ford D, Easton DF, Stratton M, et al: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62:676–689, 1998[CrossRef][Medline] 27. Kraemer O, Andersen M, Siim E: Breast reconstruction and tissue expansion in irradiated versus not irradiated women after mastectomy. Scand J Plast Reconstr Surg Hand Surg 30:201–206, 1996[Medline] 28. Julian-Reynier CM, Bouchard LJ, Evans GD, et al: Women’s attitudes towards preventive strategies for hereditary breast or ovarian carcinoma differ from one country to another: Differences among English, French and Canadian Women. Cancer 92:959–968, 2001[CrossRef][Medline] 29. Lee S-C, Bernhardt BA, Helzlsouer KJ: Utilization of BRCA1/2 genetic testing in the clinical setting. Cancer 94:1876–1885, 2002[CrossRef][Medline] 30. Montgomery LL, Tran KN, Heelan MC, et al: Issues of regret in women with contralateral prophylactic mastectomies. Ann Surg Oncol 6:546–552, 1999[CrossRef][Medline] 31. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451–1467, 1998[CrossRef][Medline]
32. King M-C, 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. J Am Med Assoc 286:2251–2256, 2001 33. Eeles RA, Powles TJ. Chemoprevention option for BRCA1 and BRCA2 mutation carriers. J Clin Oncol 18:93S–99S, 2000 (suppl 21)
34. Chlebowski RT, Col N, Winer EP, et al: American Society of Clinical Oncology technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition. J Clin Oncol 20:3328–3343, 2002 Submitted September 10, 2002; accepted February 3, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50 years), parenthood (no v yes), number of primary cancers (one v two or more), and type of cancer (breast v ovarian cancer). 
