J Clin Oncol 26: by American Society of Clinical Oncology INTRODUCTION

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1 VOLUME 26 NUMBER 7 MARCH JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Predictors of Prophylactic in Women With a BRCA1 or BRCA2 Mutation: The Hereditary Breast Cancer Clinical Study Group Kelly A. Metcalfe, Jan Lubinski, Parviz Ghadirian, Henry Lynch, Charmaine Kim-Sing, Eitan Friedman, William D. Foulkes, Susan Domchek, Peter Ainsworth, Claudine Isaacs, Nadine Tung, Jacek Gronwald, Shelly Cummings, Teresa Wagner, Siranoush Manoukian, Pål Møller, Jeffrey Weitzel, Ping Sun, Steven A. Narod From the Lawrence Bloomberg Faculty of Nursing; Women s College Research Institute, Women s College Hospital, University of Toronto; Epidemiology Research Unit, Research Centre, Centre Hospitalier de l Universitaire Montréal, CHUM Hôtel Dieu, Département de Nutrition, Faculte du Medicine, Toronto; London Regional Program, London Health Sciences Centre, London, Ontario; Departments of Medicine, Human Genetics, and Oncology, McGill University, Montréal, Quèbec; British Columbia Cancer Agency Vancouver, British Columbia, Canada; Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland; Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, NE; Suzanne Levy Gertner Oncogenetics Unit; Chaim Sheba Medical Center, Tel-Hashomer; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Departments of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA; Georgetown University Medical Center, Washington, DC; Beth Israel Deaconess Medical Centre, Boston, MA; Center for Clinical Cancer Genetics, University of Chicago, Chicago, IL; Department of Gynecology, Division of Senology, Medical University of Vienna and Private Trust for Breast Health, Vienna, Austria; Medical Genetics Service, Department of Experimental Oncology and Laboratories, Istituto Nazionale Tumori, Milan, Italy; Section for Inherited Cancer, Department of Medical Genetics, Rikshospitalet- Radiumhospitalet Medical Centre, Oslo, Norway; and the Department of Cancer Genetics, City of Hope National Medical Center, Duarte, CA. Submitted May 28, 2007; accepted November 14, 2007; published online ahead of print at on January 14, Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Steven A. Narod, MD, Women s College Research Institute, 790 Bay St, Room 750, Toronto, Ontario M5G 1N8; steven.narod@ wchospital.ca by American Society of Clinical Oncology X/08/ /$20.00 DOI: /JCO A B S T R A C T Purpose To evaluate the rate of prophylactic contralateral mastectomy in an international cohort of women with hereditary breast cancer and to evaluate the predictors of uptake of preventive surgery. Patients and Methods Women with a BRCA1 or BRCA2 mutation who had been diagnosed with unilateral breast cancer were followed prospectively for a minimum of 1.5 years. Information was collected on prophylactic surgery, tamoxifen use, and the occurrence of contralateral breast cancer. Results Nine hundred twenty-seven women were included in the study; of these, 253 women (27.3%) underwent a contralateral prophylactic mastectomy after the initial diagnosis of breast cancer. There were large differences in uptake of contralateral prophylactic mastectomy by country, ranging from 0% in Norway to 49.3% in the United States. Among women from North America, those who had a prophylactic contralateral mastectomy were significantly younger at breast cancer diagnosis (mean age, 39 years) than were those without preventive surgery (mean age, 43 years). Women who initially underwent breast-conserving surgery were less likely to undergo contralateral prophylactic mastectomy than were women who underwent a mastectomy (12% v 40%; P 10 4 ). Women who had elected for a prophylactic bilateral oophorectomy were more likely to have had their contralateral breast removed than those with intact ovaries (33% v 18%; P 10 4 ). Conclusion Age, type of initial breast cancer surgery, and prophylactic oophorectomy are all predictive of prophylactic contralateral mastectomy in women with breast cancer and a BRCA mutation. The acceptance of contralateral preventive mastectomy was much higher in North America than in Europe. J Clin Oncol 26: by American Society of Clinical Oncology INTRODUCTION Women who carry a mutation in either the BRCA1 or BRCA2 gene face a high lifetime risk of breast cancer 1 and, after a diagnosis of unilateral breast cancer, face a high risk of a new primary cancer in the contralateral breast. 2-5 On the basis of a retrospective cohort of 492 women with a BRCA1or BRCA2 mutation, we reported in 2004 that, among women with an intact breast (ie, no prophylactic contralateral mastectomy), the risk of contralateral breast cancer was 29.5% at 10 years, or approximately 3% per year. 5 Because of this high risk, many women in this situation now elect for a prophylactic mastectomy of the contralateral breast, either at the time of initial surgery or thereafter. Prophylactic contralateral mastectomy has been shown to reduce the risk of contralateral breast cancer by up to 97% in women with a BRCA1 or BRCA2 mutation. 5,6 A reduction in the risk of contralateral breast cancer was also associated with oophorectomy and tamoxifen use. Although the effectiveness of contralateral prophylactic mastectomy is well established, it is not known what proportion of women with hereditary breast cancer elect to have this preventive procedure. In addition, it is unclear what factors predict the uptake of contralateral prophylactic mastectomy in 1093

2 Metcalfe et al women with a BRCA1 or BRCA2 mutation. In this study, we report on an international cohort of women with hereditary breast cancer, and we evaluate the predictors of uptake of contralateral prophylactic mastectomy. PATIENTS AND METHODS Study Population Eligible participants were drawn from a database of carriers of deleterious mutations in either the BRCA1 or the BRCA2 gene. These women have been assessed for genetic risk at 43 centers in eight countries (Austria, Canada, France, Israel, Italy, Norway, Poland, and the United States) and were found to carry a BRCA1 or BRCA2 mutation. All study participants provided written informed consent for genetic testing. The study has been approved by the ethics committees of all participating centers. In most cases, testing was offered initially to women who were affected by either breast or ovarian cancer. When a mutation in either the BRCA1 or BRCA2 gene was found in a proband or in her relative, testing was offered to other at-risk women in her family. However, in some cases (fewer than 10% of total) an affected woman in the family was not available for study, and an unaffected woman was the first member of the family to be tested. Mutation detection was performed using a range of techniques, but in all cases nucleotide sequences were confirmed with direct sequencing of genomic DNA. A woman was eligible for the study when the molecular analysis established that she was a mutation carrier. We studied both unaffected and affected women with breast cancer. Participants were eligible for this study if they were known to be a BRCA1 or BRCA2 mutation carrier, were between 25 and 80 years old, reported a diagnosis of unilateral invasive breast cancer (not in situ) at the time of baseline questionnaire, and had no previous history of another cancer. Procedures All participants completed a baseline questionnaire, which assessed personal cancer history and past use of cancer prevention options and screening tests, at the time of genetic testing. Follow-up questionnaires were administered by telephone or by mail. Questions assessed uptake of various cancer preventive options, including prophylactic contralateral mastectomy, prophylactic oophorectomy, and tamoxifen or raloxifene use. Information on cancer recurrences and new primary cancers was collected. Statistical Analysis The actuarial risk of second primary cancer in the entire cohort was estimated by survival analysis. Patients were followed from the date of study entry (date of baseline questionnaire completion) until the date of last followup, contralateral breast cancer, or death. The cumulative incidence of contralateral breast cancer was compared for women in North American and in Europe using the log-rank test. To estimate the frequency of contralateral mastectomy and the predictors of contralateral mastectomy, we restricted the analysis to participants who had at least 18 months of follow-up after completion of the baseline questionnaire and were alive at the date of follow-up. The 2 test was used to compare frequencies of categoric variables, such as different preventive options among regions, and analysis of variance was used to compare the mean values of continuous variables among different regions. All statistical tests were performed using statistical software (SAS, version 9.1.3; SAS Institute, Cary, NC). RESULTS The database contained 1,949 women with a BRCA1 or BRCA2 mutation with breast cancer at the time of baseline questionnaire. Of these women, 704 were not eligible for the present study (432 women had bilateral breast cancer at baseline, eight women had no primary surgery, two women were younger than 25 years, five women were older than 80 years, 88 women died within 1.5 years of follow-up, and 169 women had another cancer at time of genetic testing). Of the remaining 1,245 women, we included 1,022 (82%; 58 women refused to complete the follow-up questionnaire, 59 women were lost to followup, data were missing on first surgery for 89 women, and 17 women were deceased without date of death). Twenty women received genetic testing and counseling in Austria (from one center), 343 women in Canada (from 14 centers), 26 women in France (from one center), 58 women from Israel (from three centers), 20 women in Italy (from one center), 20 women in Norway (from one center), 203 women in Poland (from one center), and 332 women in the United States (from 18 centers). Fifty-eight of the 1,022 women experienced a contralateral invasive breast cancer during the follow-up period. No woman was diagnosed with a ductal carcinoma in situ (DCIS) in the follow-up period. The actuarial rate of invasive contralateral breast cancer in the cohort was 7.1% at 5 years. We then studied a subgroup of 927 women who were followed for at least 1.5 years from the time of the baseline questionnaire The 927 participants had a mean of 4.1 years of follow-up (range, 1.5 to 10.1 years). This subgroup was chosen to evaluate predictors of contralateral mastectomy. The average age of diagnosis of the first breast cancer was 42.2 years. On average, 6.7 years had elapsed from the diagnosis of the first breast cancer until the date of questionnaire completion. Of the 927 women, 253 (27.3%) had a contralateral prophylactic mastectomy after the initial diagnosis of breast cancer. Of these, 7.9% had the preventive surgery at the time of initial surgery (ie, bilateral mastectomy), and the remainder (92.1%) had a second surgery. All 253 women who had a contralateral mastectomy were also treated with mastectomy for the first primary cancer. Seventy-three and a half percent of the women had the preventive surgery before baseline questionnaire. For those with two operations, the mean time elapsed between primary surgery and contralateral prophylactic mastectomy was 3.5 years, and the mean time between baseline questionnaire and prophylactic contralateral mastectomy was 3.2 years. Women who elected for a prophylactic contralateral mastectomy were significantly younger at the time of breast cancer diagnosis (mean age, 39 years) than were those without the preventive surgery (mean age, 43 years; Table 1). The highest uptake rates were in women diagnosed younger than age 40 (Table 2). There were large differences in the uptake of contralateral prophylactic mastectomy by country. Rates of uptake rates ranged from 0% in Norway to 49% in the United States (Table 3). Only 14 of 307 women from Europe or Israel (5%) elected for a prophylactic mastectomy compared with 238 of 620 North American women (38%). Women from Europe or Israel were also more likely to experience a contralateral breast cancer at 5 years of follow-up than were women from North America (11.7% v 5.6%; P.03; Fig 1). We then sought to determine which factors were associated with contralateral mastectomy. Because of the small number of European women who underwent the procedure (n 15), these analyses are limited to the 620 women from North America, 238 of whom had a preventive mastectomy. Women who underwent lumpectomy as the initial surgery for breast cancer were less likely to undergo contralateral prophylactic mastectomy than were women with a mastectomy (14.9% v 62.6%; P 10-4 ; Table 4) JOURNAL OF CLINICAL ONCOLOGY

3 Prophylactic Variable Table 1. Predictors of Uptake of Prophylactic Did Not Undergo (n 674) Underwent (n 253) Mean date of birth, calendar year Mean age at baseline, years Mean age at follow-up, years Mean follow-up, years Mean age at breast cancer diagnosis, years Time from diagnosis to testing, months Oophorectomy No Yes Missing 2 2 Chemotherapy No Yes Missing 8 2 Tamoxifen No Yes Missing 2 3 Parity Nulliparous Parous Mean parity P Women who had received tamoxifen were less likely to have elected for a prophylactic contralateral mastectomy than were women who did not receive tamoxifen (21.7% v 33.1%; P.0007). Of the women who did not have a contralateral mastectomy, 45% received tamoxifen. In contrast to tamoxifen, women who elected for a prophylactic bilateral oophorectomy were more likely to have had their contralateral breast removed than women who did not undergo oophorectomy (32.6% v 17.8%, P 10 4 ). Chemotherapy as a treatment for initial breast cancer was not associated with the uptake of prophylactic contralateral mastectomy (P.77; Table 1). Overall, 83% of the women took one or more steps to reduce the risk of contralateral breast cancer (ie, mastectomy or oophorectomy or tamoxifen), including 87% of North American and 75% of European/Israeli women. DISCUSSION In 2004, we reported that, after a woman with a BRCA1 or BRCA2 mutation is diagnosed with unilateral breast cancer, the risk of contralateral breast cancer is approximately 3% per year. The annual risk was similar for BRCA1 and BRCA2 carriers and did not vary with age at diagnosis or time since surgery. Bilateral mastectomy was shown to offer protection against contralateral breast cancer in women with a Table 2. Type of Surgery and Age at Breast Cancer Diagnosis As Predictors of Uptake of Prophylactic by Women From North America Did Not Undergo Underwent Characteristic P First surgery type 10 4 Lumpectomy Age group, years Total

4 Metcalfe et al Table 3. Distribution of the 927 Participants With More Than 1.5 Years of Follow-Up by Country Country Did Not Undergo Underwent Total No. Austria Canada France Israel Italy Norway Poland United States Total BRCA1 or BRCA2 mutation. 5 In our earlier study, one contralateral breast cancer occurred among the 146 women with a prophylactic contralateral mastectomy, compared with 97 contralateral breast cancers in the 336 women who retained the contralateral breast (hazard ratio [HR] 0.03; P.0005). In a smaller study from the Netherlands (n 118) contralateral prophylactic mastectomy was also shown to significantly reduce the risk of contralateral breast cancer (HR 0.09; 95% CI, 0.01 to 0.78). 6 Given the elevated risk and the proven effectiveness of preventive surgery, we were interested to know the proportion of women in this situation who are accepting of the procedure. In this multinational cohort of 972 women with a BRCA1 or BRCA2 mutation and unilateral breast cancer, 27% of women with unilateral breast cancer elected to have the contralateral breast removed. However, the practice seems to be popular only in Canada and the United States only 5% of European women elected to undergo the procedure. It is not clear whether this marked variation is a result of patient preference, or because the operation is not routinely offered in European countries or Israel. All women received post-test genetic counseling; however, it is not known to what extent contralateral mastectomy Cumulative Incidence Log rank P = Time of Follow-Up (years) Europe North America Fig 1. Cumulative incidence of contralateral breast cancer in BRCA1/BRCA2 carriers (Europe v North America). was discussed with patients during post-test counseling sessions in the different centers. These differences are not without consequence: European women were twice as likely to experience a contralateral cancer within 5 years of diagnosis as women from North America. The uptake rates of prophylactic contralateral mastectomy parallel the rates of uptake of bilateral prophylactic mastectomy in unaffected women with a BRCA1 or BRCA2 mutation. We recently reported that 18% of unaffected women from eight countries elected for bilateral prophylactic mastectomy. 7 Again, European women were far less likely to undergo the procedure (6%) than were women from North America (29%). It is possible that the adoption of national guidelines for preventive practices may lead to more homogeneity in surgery rates from country to country. Among premenopausal women, bilateral oophorectomy offers a reduction of approximately 60% in the risk of contralateral breast cancer. 5 In the current study, women who had undergone a prophylactic oophorectomy were more likely to opt for a preventive mastectomy than were women with both ovaries intact (33% v 18%). This suggests that women who opt for preventive surgery at one site may be favorably disposed to surgery at a second site. However, in practical terms, this also means that many women who might benefit most from prophylactic mastectomy are those least likely to accept it. This is in contrast to the situation with tamoxifen; women who had both breasts intact were more likely to take tamoxifen than were those who had preventive surgery. Women who had a mastectomy as their initial surgery for breast cancer were also much more likely to have a contralateral prophylactic mastectomy than were women treated with breast-conserving surgery. This has also been seen in the noncarrier population. 8 To our knowledge, this is the first large international study to evaluate the rates of contralateral mastectomy in BRCA carriers. Graves et al 9 surveyed 73 women with a BRCA1 or BRCA2 mutation from the United States 1 year after genetic testing. Fifty-three percent of the women elected for contralateral prophylactic mastectomy after receiving a positive genetic test result. This reported rate of uptake is similar to what we observed in the subgroup of US women. There are several limitations to our study. We did not have information on breast cancer stage, and invasive breast cancers of all stages were included in this study. Prophylactic contralateral mastectomy is generally not offered to women with advanced-stage breast cancer, and although these women are likely to be few, we were unable to exclude them. We could not obtain follow-up information on 18% of eligible women. The participants studied here are patients followed in several teaching hospitals associated with our research program and may not be representative of all women undergoing genetic testing in their country. Furthermore, for some European countries only a single center was represented, and for some centers the number of contributed patients was small. All of the women included in this study had been diagnosed with the initial breast cancer before genetic testing for BRCA1 or BRCA2. Previous research from the United States and the United Kingdom has shown that uptake of bilateral mastectomy is higher if the woman knows she carries a BRCA1 or BRCA2 mutation at the time of diagnosis, (ranging from 48% to 100%), compared with women who learn 1096 JOURNAL OF CLINICAL ONCOLOGY

5 Prophylactic Variable Table 4. Odds Ratio for Predictors of Prophylactic in Women From North America Univariate Multivariate * Odds Ratio 95% CI P Odds Ratio 95% CI P First surgery type (lumpectomy v to to unilateral mastectomy) Year of birth (trend) to to Tamoxifen (yes v no) to to Bilateral oophorectomy (yes v no) to to * Variables used in the multivariate analyses include all the variables listed in the first column and country of residence and breast reconstruction (yes/no). their genetic status at a later date Most women who decide to have a contralateral prophylactic mastectomy are satisfied with their decision In a large study of 583 (noncarrier) women who had undergone a contralateral prophylactic mastectomy, 83% of women were satisfied with their decision 10 years later. 13 In addition, no differences in quality of life have been observed between women with and without contralateral prophylactic mastectomy. 14 However, breast cancer worry was reported to be significantly lower in women with a contralateral prophylactic mastectomy (P.004). Overall, there were great differences in uptake of contralateral prophylactic mastectomy by country of residence. As a result, women from Europe or Israel had a significantly higher risk of developing contralateral breast cancer. Further research should be done to investigate why these differences exist in addition to investigating their impact on survival. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Kelly A. Metcalfe Provision of study materials or patients: Jan Lubinski, Parviz Ghadirian, Henry Lynch, Charmaine Kim-Sing, Eitan Friedman, William D. Foulkes, Susan Domchek, Peter Ainsworth, Claudine Isaacs, Nadine Tung, Jacek Gronwald, Shelly Cummings, Teresa Wagner, Siranoush Manoukian, Pål Møller, Jeffrey Weitzel, Steven A. Narod Collection and assembly of data: Kelly A. Metcalfe, Jan Lubinski, Parviz Ghadirian, Henry Lynch, Charmaine Kim-Sing, Eitan Friedman, William D. Foulkes, Susan Domchek, Peter Ainsworth, Claudine Isaacs, Nadine Tung, Jacek Gronwald, Shelly Cummings, Teresa Wagner, Siranoush Manoukian, Pål Møller, Jeffrey Weitzel, Ping Sun, Steven A. Narod Data analysis and interpretation: Kelly A. Metcalfe, Ping Sun, Steven A. Narod Manuscript writing: Kelly A. Metcalfe, Ping Sun, Steven A. Narod Final approval of manuscript: Kelly A. Metcalfe, Jan Lubinski, Parviz Ghadirian, Henry Lynch, Charmaine Kim-Sing, Eitan Friedman, William D. Foulkes, Susan Domchek, Peter Ainsworth, Claudine Isaacs, Nadine Tung, Jacek Gronwald, Shelly Cummings, Teresa Wagner, Siranoush Manoukian, Pål Møller, Jeffrey Weitzel, Ping Sun, Steven A. Narod REFERENCES 1. Ford D, Easton DF, Bishop DT, et al: Risks of cancer in BRCA1 mutation carriers. Lancet 343: , Haffty BG, Harrold E, Khan AJ, et al: Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. Lancet 359: , Verhoog LC, Brekelmans CT, Seynaeve C, et al: Survival and tumour characteristics of breastcancer patients with germline mutations of BRCA1. Lancet 351: , Robson M, Gilewski T, Haas B, et al: BRCAassociated breast cancer in young women. J Clin Oncol 16: , Metcalfe K, Lynch HT, Ghadirian P, et al: breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 22: , 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 93: , Metcalfe K, et al: International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers. Int J Cancer (in press) 8. Herrinton LJ, Barlow WE, Yu O, et al: Efficacy of prophylactic mastectomy in women with unilateral breast cancer: A cancer research network project. J Clin Oncol 23: , Graves KD, Peshkin BN, Halbert CH, et al: Predictors and outcomes of contralateral prophylactic mastectomy among breast cancer survivors. Breast Cancer Res Treat 104: , Evans DG, Lalloo F, Hopwood P, et al: Surgical decisions made by 158 women with hereditary breast cancer aged 50 years. Eur J Surg Oncol 31: , Schwartz MD, Lerman C, Brogan B, et al: Impact of BRCA1/BRCA2 counseling and testing on newly diagnosed breast cancer patients. J Clin Oncol 22: , Weitzel JN, McCaffrey SM, Nedelcu R, et al: Effect of genetic cancer risk assessment on surgical decisions at breast cancer diagnosis. Arch Surg 138: , Frost MH, Slezak JM, Tran NV, et al: Satisfaction after contralateral prophylactic mastectomy: The significance of mastectomy type, reconstructive complications, and body appearance. J Clin Oncol 23: , Geiger AM, West CN, Nekhlyudov L, et al: Contentment with quality of life among breast cancer survivors with and without contralateral prophylactic mastectomy. J Clin Oncol 24: , Montgomery LL, Tran KN, Heelan MC, et al: Issues of regret in women with contralateral prophylactic mastectomies. Ann Surg Oncol 6: , 1999 Appendix The Appendix is included in the full-text version of this article, available online at It is not included in the PDF version (via Adobe Reader )