INTRODUCTION

Women who carry a mutation in either the BRCA1 or BRCA2 gene face a high lifetime risk of breast cancer¹ 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 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

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 follow-up, 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). 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 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 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 al⁹ 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 their genetic status at a later date.^10-12 Most women who decide to have a contralateral prophylactic mastectomy are satisfied with their decision.^13-15 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 CONFLICTSOF 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

Appendix

Other members of the Hereditary Breast Cancer Clinical Study Group: M. Daly, Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA; H.M. Saal, Hereditary Cancer Program, Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, OH; K. Sweet, Clinical Cancer Genetics Program, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus OH; Dominique Lyonnet, Department of Oncology Genetics, Institut Curie, Paris, France; A. Eisen, Cancer Risk Assessment Clinic, Juravinksi Cancer Centre (Hamilton Regional Cancer Centre), Hamilton, ON, Canada; J. McLennan, University of San Francisco, California; R. Gershoni-Baruch, Institute of Genetics, Rambam Medical Center, Haifa, Israel; J. Garber, Dana Farber Cancer Center; O. Olopade, Center for Clinical Cancer Genetics, University of Chicago, Chicago, IL; B. Karlan and R.N. Kurz, Gynecology Oncology, Cedars Sinai Medical Center, Los Angeles, CA; W. McKinnon and M. Wood, University of Vermont; D. Gilchrist, University of Alberta; A. Chudley, University of Manitoba, Winnipeg, Manitoba; M. Osborne, Strang Cancer Prevention Centre, New York, NY; W.S. Meschino, North York General, North York, ON, Canada; C. Maugard, University of Montreal, Quebec, Canada; Charis Eng, Genomic Medicine Institute, The Cleveland Clinic, Cleveland,OH; Barry Rosen and Susan Armel, Department of Gynecologic Oncology, Princess Margaret Hospital, Toronto, Canada; Fergus Couch, Mayo Clinic, Rochester, MN; Barbara Pasini and Christina Bellati, Universita di Torino, Torino, Italy.