Originally published as JCO Early Release 10.1200/JCO.2005.10.080 on March 28 2005

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Efficacy of Prophylactic Mastectomy in Women With Unilateral Breast Cancer: A Cancer Research Network Project

From the Cancer Research Network, Kaiser Permanente Northern California, Oakland; Kaiser Permanente Southern California, Pasadena, CA; Group Health Cooperative; University of Washington Department of Biostatistics and School of Medicine, Seattle, WA; Harvard Pilgrim Health Care and Harvard Medical School, Boston, MA; Kaiser Permanente Northwest Center for Health Research, Portland, OR; and HealthPartners, Minneapolis, MN

Address reprint requests to Lisa J. Herrinton, PhD, Division of Research, Northern California Kaiser Permanente, 2000 Broadway Ave, Oakland, CA 94612; e-mail: lisa.herrinton{at}kp.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
PURPOSE: We investigated the efficacy of contralateral prophylactic mastectomy (CPM) in reducing contralateral breast cancer incidence and breast cancer mortality among women who have already been diagnosed with breast cancer.

METHODS: This retrospective cohort study comprised approximately 50,000 women who were diagnosed with unilateral breast cancer during 1979 to 1999. Using computerized data confirmed by chart review, we identified 1,072 women (1.9%) who had CPM. We obtained covariate information for these women and for a sample of 317 women who did not undergo CPM.

RESULTS: The median time from initial breast cancer diagnosis to the end of follow-up was 5.7 years. Contralateral breast cancer developed in 0.5% of women with CPM, metastatic disease developed in 10.5%, and subsequent breast cancer developed in 12.4%; 8.1% died from breast cancer. Contralateral breast cancer developed in 2.7% of women without CPM, and 11.7% died of breast cancer. After adjustment for initial breast cancer characteristics, treatment, and breast cancer risk factors, the hazard ratio (HR) for the occurrence of contralateral breast cancer after CPM was 0.03 (95% CI, 0.006 to 0.13). After adjustment for breast cancer characteristics and treatment, the HRs for the relationship of CPM with death from breast cancer, with death from other causes, and with all-cause mortality were 0.57 (95% CI, 0.45 to 0.72), 0.78 (95% CI, 0.57 to 1.06), and 0.60 (95% CI, 0.50 to 0.72), respectively.

CONCLUSION: CPM seems to protect against the development of contralateral breast cancer, and although women who underwent CPM had relatively low all-cause mortality, CPM also was associated with decreased breast cancer mortality.

	INTRODUCTION

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Although bilateral prophylactic mastectomy in high-risk women reduces subsequent breast cancer occurrence by at least 95%,^1-3 the role of contralateral prophylactic mastectomy (CPM) in women with prior breast cancer is unclear. Each year in the United States, approximately 180,000 women develop unilateral breast cancer.⁴ Two studies among women with prior unilateral breast cancer found that CPM decreased the risk of contralateral breast cancer but did not examine breast cancer–specific mortality.^5,6 It is important to determine the influence of CPM on the prognosis of women with breast cancer. We conducted a retrospective cohort study of women with unilateral breast cancer to determine the efficacy of CPM in reducing the incidence of contralateral breast cancer occurrence and breast cancer death. The study was conducted among six members of the Cancer Research Network, which is a consortium of geographically dispersed research organizations based in health maintenance organizations (HMOs) funded by the National Cancer Institute (Bethesda, MD) to conduct cancer control research.

	METHODS

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Setting and Design Overview
Six HMOs of the Cancer Research Network collaborated on the study (Group Health Cooperative, Washington; Harvard Pilgrim Health Care, Massachusetts; HealthPartners, Minnesota; and three Kaiser Permanente regions: Northwest, Northern California, and Southern California). The combined enrollment of these HMOs in 1998 was approximately 7.5 million persons. Each of the six participating institutions obtained institutional review board approval.

This cohort study included all women who were identified as having had CPM, documenting through computerized data and chart review the percentage of women with subsequent contralateral breast cancer, subsequent breast cancer regardless of site, metastatic breast cancer, and death. To determine the efficacy of CPM, we used two different statistical methods, one to examine contralateral breast cancer occurrence and a different one to examine breast cancer mortality (Fig 1).

View larger version (28K): [in this window] [in a new window]   Fig 1. Study population and sampling. (A) Women assessed for occurence of contralateral breast cancer (computerized data and chart review). (B) Women assessed for breast cancer mortality (computerized data only). HMOs, health maintenance organizations; CPM, contralateral prophylactic mastectomy.

To determine the effect of CPM on breast cancer mortality, we used an ordinary cohort study design, including the entire cohort of women in four of the study sites and obtaining information on death from available Surveillance, Epidemiology, and End Results and institutional cancer registries. This method did not use covariate information from the chart and did not require oversampling or a weighted analysis.

Population
Female HMO members with a first breast cancer diagnosed at age 18 to 79 years during 1979 to 1999 (1981 to 1999 at one site) were potentially eligible for the study. To identify potential subjects, we used computerized data, including hospitalization (to identify women with a CPM), cancer registry (four sites), and electronic ambulatory care (two sites) data. Chart review was then used to determine final eligibility. We excluded women diagnosed with bilateral or metastatic breast cancer diagnosed either initially or within 60 days, to allow time for work-up of the extent of disease, because these women would be ineligible for a CPM. We further excluded women with unknown extent of disease or no surgical treatment.

Selection of Women With CPM
CPM was defined as subcutaneous mastectomy or a more extensive procedure performed to prevent breast cancer. To ascertain women who had undergone CPM during 1979 to 1999, we linked hospitalization data identifying women having a mastectomy (International Classification of Disease, 9th edition, codes 85.33-85.36, and 85.41-48) with cancer registry data. Women with a unilateral mastectomy procedure without a concurrent diagnosis of breast cancer and women coded with a bilateral mastectomy (because the code for bilateral mastectomy often is used incorrectly for unilateral mastectomy) were identified as having a possible CPM. The contralateral mastectomy procedure was considered as prophylactic only when the note accompanying the doctor’s order in the chart mentioned "breast cancer prevention," "family history," "suspicious but benign" radiologic or pathologic findings, or "high risk." Computerized linkage with cancer registry data identified 2,261 women with a possible CPM, of whom 1,057 (47%) were determined to have had CPM through chart review, with most of the remaining women having had second therapeutic mastectomy (Table 1). In addition, 15 women who had been sampled for the non-CPM group were found to have an eligible CPM during chart review. Thus, we identified 1,072 eligible women with CPM.

Selection of Women Without CPM to Determine Effect of CPM on Contralateral Breast Cancer
We used a case-cohort design to increase statistical efficiency by oversampling unexposed group members with the outcome of interest,⁷ and therefore, we oversampled women without CPM who subsequently developed a contralateral breast cancer. We then took the oversampling into account in the analysis. To do this, we used computerized data from a large HMO to establish sampling frequencies for women without CPM who did and did not develop a contralateral breast cancer. For women who did not develop a contralateral breast cancer, we sought to sample 0.5% of women born before 1945 and 1% of women born during or after 1945; and for women who developed a contralateral breast cancer, we sought to sample 5% and 10%, respectively. We then assigned each of the comparison women a random number from 0 to 1,000, and women whose random numbers were smaller than the desired sampling frequency for their stratum were selected for the chart review. Thus, a younger woman who developed a contralateral breast cancer was included in the study if her random number was less than 100 (ie, 10% of 1,000). Because women who did and did not develop a contralateral breast cancer were sampled at different frequencies, it is inappropriate to directly compare their proportions without first adjusting the results according to the sampling scheme.

CPM, contralateral breast cancer, and birth year were confirmed during chart review, and women who had been classified into the wrong stratum on the basis of incomplete computerized data were moved into the correct stratum only if they met the sampling criteria for that stratum, including the criterion that their random number be sufficiently low; otherwise, they were excluded. The predetermined sampling frequencies yielded 536 non-CPM subjects, of whom 306 were eligible after chart review (Table 1). In addition, 11 women sampled as having CPM, in fact, did not have CPM and were eligible for the comparison group, making a total of 317 women.

Data Collection
Data sources included computerized HMO databases, medical charts, and, for four sites, cancer registry and state mortality files. Thirteen chart reviewers abstracted data after an extensive training period using a training video, standardized coding manual, and regular conference calls with the lead author (L.J.H.). For each abstractor, quality control was assessed monthly by having a second abstractor review one of the initial abstractor’s completed charts; we noted differences in the interpretation of the data for 5.9% of the data fields. Often, these differences related to the dates of events, so that the abstractors would differ from each other by several days. Women with unclear CPM status were discussed during meetings to minimize misinterpretation of this key variable.

Information on the initial breast cancer diagnosis included the histologic type, tumor size, stage, lymph node involvement, and scope of surgery and adjuvant therapy (chemotherapy, radiation therapy, and hormonal therapy). In addition, the date, type, and reason for each breast surgery were obtained from chart review. Possible reasons for breast surgery included a concurrent or prior breast cancer diagnosis, a positive family history of breast or ovarian cancer, radiologic findings of suspicious but benign microcalcifications, benign pathologic findings, and high-risk indications that were not specified.

For the evaluation of contralateral breast cancer risk, information on potentially confounding breast cancer risk factors was obtained from the medical chart. Contralateral breast cancer occurrence was determined from available cancer registries and computerized outpatient data and by chart review. For the evaluation of breast cancer mortality, only information that could be obtained from the cancer registries was used. Cause of death was obtained from cancer registry data, which were linked to the state mortality files.

Outcomes
Follow-up began on the diagnosis date of the initial breast cancer. For the evaluation of contralateral breast cancer, follow-up ended on the earliest date of a diagnosis of contralateral breast cancer; December 31, 1999; the woman’s 80th birthday; or the date of death or disenrollment from the HMO. Contralateral breast cancers diagnosed within 60 days of CPM (n = 25) were considered to be incidental to the CPM and not counted as outcomes because it was the CPM that led to the cancer detection. However, these women were observed for a new contralateral breast cancer occurrence. For the evaluation of breast cancer mortality, follow-up ended on the date of death or the date of last contact, whichever occurred first, as recorded in cancer registries.

Data Analysis
We first examined the CPM group, evaluating time from CPM to contralateral breast cancer, any subsequent breast cancer (new primary or recurrent), metastatic breast cancer, and breast cancer death using a Kaplan-Meier plot. We evaluated time from CPM rather than time from initial breast cancer diagnosis because the timing of CPM after breast cancer diagnosis varied somewhat (median time, 3 months from diagnosis), and we could not display the timing in the Kaplan-Meier plot. We then compared the risks of contralateral breast cancer and breast cancer death among women who underwent CPM with the risks among women who did not undergo CPM using Cox proportional hazards regression. Analysis of each outcome was stratified by age group and HMO, and CPM was fitted as a time-dependent covariate.

For the analysis of contralateral breast cancer, we adjusted for characteristics of the initial breast cancer and treatment as well as potential confounders including family history of breast or ovarian cancer and number of breast cancer risk factors. Family history was time dependent, and chart notes of family history were not used until the date they were recorded. Because women without CPM who developed contralateral breast cancer were oversampled, it was essential that the analysis also took into consideration the sampling plan. We can correct for the oversampling when analyzing the time to occurrence of a new primary breast cancer because the sampling was by outcome. However, it precludes significance testing of differences in covariates between women with CPM versus women without CPM because of the difference in sampling methods. For time to diagnosis of a new primary breast cancer, we obtained an unbiased estimate of the hazard ratio (HR) with appropriate SEs by using a variant of the methodology developed for a standard case-cohort analysis with a robust covariance matrix.^7,8 This methodology included adjusting for differences of all examined covariates. The data were analyzed using SAS procedure PHREG (Version 8.2; SAS Institute, Cary, NC) with an offset to accommodate the sampling probabilities and an empirical sandwich estimator of the covariance matrix.

For the analysis of breast cancer mortality, characteristics of the initial breast cancer and treatment that were available in the cancer registries were included. Because all women who had an initial breast cancer recorded in the cancer registries were included in the analysis and, thus, no sampling plan was involved, a standard Cox proportional hazards regression was used.

	RESULTS

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Women With Unilateral Breast Cancer Who Underwent CPM
From 1979 to 1999, 56,400 women were diagnosed with breast cancer and were eligible for CPM according to our criteria; 1.9% of these women (1,072) underwent CPM. The median time from the initial diagnosis to CPM was 3 months, and 47 women (4.4%) underwent the CPM after an ipsilateral breast cancer recurrence.

Characteristics of the Women
Table 2 shows descriptive characteristics for women who underwent CPM versus women who did not. Women who underwent CPM seemed to be younger at initial diagnosis, disproportionately white, and more likely to have had a family history of breast or ovarian cancer and seemed to have more risk factors for breast cancer than women without CPM. The extent of the initial disease was similar in the two groups, but more women with CPM had tumors that were greater than 2 cm and initially underwent mastectomy, whereas fewer women with CPM received adjuvant therapy. Because the study was not designed to test these differences, but only the outcomes in these two groups, we cannot show P values in the table.

Outcomes Among Women With CPM
Of the 1,072 women who underwent CPM among the six HMOs, 133 (12.4%) were diagnosed with a new or recurrent breast cancer 60 days or more after CPM, five (0.5%) developed a contralateral breast cancer, 112 (10.5%) developed metastatic disease, and 77 died of breast cancer during the follow-up period (Fig 2). Initial staging and treatment of these 133 women were as follows: 127 women had been diagnosed with invasive disease (local, n = 39; and regional, n = 88); 125 women had been treated with mastectomy, and eight had been treated with lumpectomy (followed by mastectomy at the time of their CPM); and 95 women had received chemotherapy, 54 had received hormone therapy, 44 had received radiotherapy, and 22 had received no adjuvant therapy. Among the 25 women who were diagnosed with incidental contralateral breast cancer within 60 days of their CPM, two developed subsequent breast cancer; one woman developed ipsilateral breast cancer 3 years after CPM, and one woman developed regional lymph node involvement 9 years after CPM. Neither woman had died by the end of the study.

View larger version (15K): [in this window] [in a new window]   Fig 2. Time from contralateral prophylactic mastectomy (CPM) to each of the four breast cancer outcomes for 1,072 women with CPM: five with contralateral breast cancer, 77 with breast cancer death, 112 with metastatic breast cancer, and 133 with any subsequent breast cancer.

	DISCUSSION

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Among 1,072 women with a history of unilateral breast cancer who underwent CPM, 12.4% developed a subsequent breast cancer, 0.5% developed a contralateral breast cancer, and 10.5% developed metastases after CPM. The percentage of women who died of breast cancer was 8.1%. The risk of subsequent contralateral breast cancer was dramatically reduced by 97% in women who underwent CPM (HR = 0.03; 95% CI, 0.006 to 0.13) compared with similar women who did not undergo the procedure. Although the women who underwent CPM may have had lower mortality from causes other than breast cancer than women who did not undergo CPM (HR = 0.78; 95% CI, 0.57 to 1.06), their breast cancer mortality was even further reduced (HR = 0.57; 95% CI, 0.45 to 0.72). Therefore, overall, the procedure protected women against subsequent contralateral breast cancer occurrence and breast cancer mortality. These results took into account extent of disease, treatment characteristics, the woman’s age, the year of breast cancer diagnosis, and, for the analysis of contralateral breast cancer risk, a family history of breast or ovarian cancer and the number of breast cancer risk factors.

To our knowledge, this is the first study to report the efficacy of CPM in preventing breast cancer death. The study included more than 1,000 women with CPM as well as appropriate comparison groups. By using computerized databases with a valid and efficient study design, we identified a large group of women who had undergone the procedure. In addition, the patients were drawn from community settings across a wide geographic area in five states.

CPM reduces the risk of breast cancer occurrence and death by reducing the risk of development of new primary breast cancer. In addition, we found that CPM removed, before it was otherwise detected, breast cancer in the contralateral breast. However, the risk of metastatic breast cancer in locations other than the contralateral breast is not reduced by CPM. Therefore, it is not surprising that we found CPM to be less effective at preventing breast cancer mortality than preventing subsequent contralateral breast cancer. For the same reason, it is to be expected that the mortality reduction associated with CPM is less than the mortality reduction for bilateral prophylactic mastectomy.^1-3

Prudent interpretation of this study requires consideration of its limitations. We identified five limitations that could have resulted in a protective effect of CPM being exaggerated or minimized. First, women who chose to undergo CPM may have been healthier than women who did not. One aspect of overall health is comorbidity, and women with CPM may have had less comorbidity than women without CPM (as evidenced by their 27% lower risk of death from causes other than breast cancer), and this may have reduced their apparent breast cancer mortality. Because the cancer registries do not collect information on comorbidity, we were unable to evaluate this possibility directly. However, two previous studies have examined the effect of comorbidity on mortality with breast cancer, observing that the increased mortality rate among women with comorbid conditions is focused almost exclusively on non–breast cancer–specific mortality. In a study of 13,358 breast cancer patients diagnosed at Kaiser Permanente Northern California and Group Health Cooperative during 1985 to 1992, patients with higher Charlson/Deyo comorbidity index scores had higher overall mortality (compared with comorbidity score = 0: score = 1, risk ratio [RR] = 1.7; and score = 2+, RR = 2.7) but similar breast cancer mortality (compared with score = 0: score = 1, RR = 1.1; and score = 2+, RR = 1.1).⁹ Similarly, in a study of 936 women diagnosed with breast cancer in metropolitan Detroit, there was a relationship of the number of comorbidities with risk of death from causes other than breast cancer (compared with none: one comorbidity, RR = 2.9; two comorbidities, RR = 6.8; and three or more comorbidities, RR = 19.5) but not with risk of death from breast cancer (compared with none: one comorbidity, RR = 1.2; two comorbidities, RR = 1.4; and three or more comorbidities, RR = 1.2).¹⁰ The associations were observed after adjustment for age, stage, and other covariates. These studies suggest that our findings for non–breast cancer–related mortality may be related to comorbidity and that this difference in comorbidity is unlikely to explain the observed difference in risk of death from breast cancer. Other than comorbidity, which has been assessed in past studies, we cannot comment on the role of other aspects of health as they relate to breast cancer mortality.

Second, it is possible that CPM women received higher quality treatment than women who did not undergo CPM. For example, women undergoing CPM may have been more likely to receive anthracycline chemotherapy, which is more effective than earlier chemotherapies. We did not obtain data on the chemotherapy agent used, but generally, we did not see evidence for differences in treatment in our data. As expected, CPM patients were more likely to undergo mastectomy than lumpectomy as initial treatment of their breast cancer (92% in CPM group v 53% in non-CPM group), and they were less likely to receive radiation (7% in CPM group v 26% in non-CPM group); thus, it was necessary to adjust for treatment in the analysis of efficacy. The proportions of patients who received chemotherapy (42% in CPM group v 39% in non-CPM group) or hormonal therapy (27% in CPM group v 34% in non-CPM group) were similar.

Third, we observed an inverse relationship between CPM and death from unknown cause. If a disproportionate number of non-CPM women whose deaths were coded as having unknown cause in fact died from breast cancer, we may have underestimated the protective effect of CPM. But, if these women died disproportionately from causes other than breast cancer, we would have overestimated the protective effect of CPM. However, because the cause of death was unknown for so few women, combining deaths of unknown cause with deaths of known cause other than breast cancer did not change our findings to an important degree.

Fourth, for the mortality analysis, we relied on tumor registry data for treatment. Although there has been concern expressed that registry information on adjuvant therapy is poor, a recent report gives evidence that the quality of chemotherapy data from HMOs is quite complete (88%).¹¹ Incomplete information on adjuvant therapy would make it more difficult for us to observe a protective effect. Similarly, for the mortality analysis, we did not obtain data on breast cancer risk factors that may have differed between women who did and did not undergo CPM; whereas, for the analysis of contralateral breast cancer incidence, the data we obtained were somewhat incomplete for family history and age at first birth. If these risk factors were more common in women who underwent CPM, then we would have underestimated the efficacy of CPM.

Fifth, 15% of the study population disenrolled before the end of the study. Considering that the period of observation was as long as 20 years for some women, this is not surprising. Nonetheless, if the rate of disenrollment differed by CPM and by outcome (development of a contralateral breast cancer or breast cancer death), then we may have misestimated the protective effect of CPM. Although such a bias may have affected the study to some degree, it could not have resulted in the magnitude of protection that we observed.

As explained in Methods, we categorized breast cancers discovered at the time of CPM as incident and did not count them as outcomes because it was the CPM that led to the cancer detection. These women were observed for a new contralateral breast cancer occurrence. Of the 25 women with breast cancer discovered during the CPM procedure, 16 had the CPM procedure within 60 days of the initial breast cancer diagnosis. By our cohort definitions, women diagnosed with bilateral breast cancer within 60 days were excluded to ensure adequate work-up of the initial disease. This leaves nine women whose incidental breast cancer was diagnosed more than 60 days after the initial diagnosis. If we count these nine breast cancers as outcomes, then the protective effect of CPM is less strong but still highly significant (HR = 0.17; 95% CI, 0.06 to 0.45). However, we believe it is highly inappropriate to include these as outcomes because CPM clearly cannot prevent breast cancers that are already present at the time the surgery is performed, whereas removal of these breast cancers, through CPM, can prevent their progression to metastasis and death.

Generalizing our findings to other practice settings should be possible because the breast cancer survival of our patients seems similar to the survival observed nationally. In our cohort of women without CPM, we observed a survival rate of 90% after a median of 4.8 years of follow-up. This compares to a 5-year survival rate of 92% among women in the National Surveillance, Epidemiology, and End Results registry (1992 to 1997) after taking into consideration stage distribution.¹² However, our study included women with an initial breast cancer diagnosed during 1979 to 1999. Since then, there have been treatment changes that likely have reduced mortality among women who do not undergo CPM. Also, our study identified few women at very high risk for breast cancer, for whom we cannot comment on the efficacy of CPM.

Two earlier reports have examined the effect of CPM on subsequent contralateral breast cancer and found protective effects similar to our results. After a mean of 6.8 years of follow-up, Peralta et al⁵ observed no contralateral breast cancers among 64 women who underwent CPM but found 36 contralateral breast cancers (19.8%) among 182 women who did not undergo CPM (HR = 0; 95% CI, 0 to 0.17). The disease-free survival rate was 55% in the CPM group versus 28% in the comparison group (P = .01), and the overall survival rate was 64% in the CPM group versus 49% in the comparison group (P = .26). The study did not report data on breast cancer mortality. McDonnell et al⁶ observed 745 women with both a personal history of breast cancer and a family history of breast or ovarian cancer for a median 10 years of follow-up. Eight women (1.1%) were diagnosed with contralateral breast cancer, for a risk reduction of 94% when baseline risk was computed using the Anderson model (proportion expected, 17.9%); however, the study did not report on mortality.

Although our results compare well with these two earlier reports, the rate of occurrence of contralateral breast cancer in our study (2.7% among women without CPM) was lower than reported in those studies (19.8% and 17.9%). The rate we report is close to the rate reported in a national study of 72,000 Swedish women diagnosed during 1970 to 1996, among whom 3.5% developed contralateral breast cancer during an unspecified follow-up period.¹³ Differences in rates among the three efficacy studies may have resulted from differences in the period of follow-up (4.8 years in the present study v 6.8 and 10 years), family history of breast cancer (19% in the present study v 46% and 100%), and use of adjuvant therapy (frequency of use was not reported in the two earlier studies).

We observed that approximately 2% of women with unilateral breast cancer according to our criteria undergo CPM. Most of these women (65%) had no recorded first- or second-degree family history of breast or ovariancancer. The frequency of CPM in other practices is not clear, but in the study by Peralta et al,⁵ approximately 2.2% of patients underwent the procedure between 1973 and 1998. The Society of Surgical Oncology has indicated that CPM is justified in certain patients.¹⁴ The procedure may be undertaken more often in practice than previously recognized. With increasing attention to bilateral prophylactic mastectomy in both the medical^1-3 and lay press, CPM procedures may further increase. Therefore, it is important to determine whether the procedure has a place in the management of breast cancer. Our results suggest that, for women and their doctors considering the effect of CPM, the procedure may have a role against contralateral breast cancer occurrence and death.

	Authors’ Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Joe Selby, MD, MPH, Noel Weiss, MD, DPH, Alice Whittemore, PhD, Diana Petitti, MD, MPH, Michael Retsky, PhD, Dekun Li, MD, PhD, and Sarah Greene, MPH, for their helpful comments.

	NOTES

 
Supported by grant No. U19 CA NCI 79689 from the National Cancer Institute, Bethesda, MD.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
1. 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 340:77-84, 1999[Abstract/Free Full Text]

2. Hartmann LC, Sellers TA, Schaid DJ, et al: Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. N Engl J Med 93:1633-1637, 2001

3. 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[Abstract/Free Full Text]

4. Greenlee RT, Murray T, Bolden S, et al: Cancer statistics, 2000. Ca Cancer J Clin 50:7-33, 2000[Abstract]

5. Peralta EA, Ellenhorn JD, Wagman LD, et al: Contralateral prophylactic mastectomy improves the outcome of selected patients undergoing mastectomy for breast cancer. Am J Surg 180:439-445, 2000[CrossRef][Medline]

6. McDonnell SK, Schaid DJ, Myers JL: Efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. J Clin Oncol 19:3938-3943, 2001[Abstract/Free Full Text]

7. Barlow WE: Robust variance estimation for the case-cohort design. Biometrics 50:1064-1072, 1994[CrossRef][Medline]

8. Barlow WE, Ichikawa L, Rosner D, et al: Analysis of case-cohort designs. J Clin Epidemiol 52:1165-1172, 1999[CrossRef][Medline]

9. Potosky AL, Merrill RM, Riley GF, et al: Breast cancer survival and treatment in health maintenance organization and fee-for-service settings. J Natl Cancer Inst 89:1683-1691, 1997[Abstract/Free Full Text]

10. Satariano WA, Ragland DR: The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 120:104-110, 1994[Abstract/Free Full Text]

11. Cress RD, Zaslavsky AM, West DW, et al: Completeness of information on adjuvant therapies for colorectal cancer in population-based cancer registries. Med Care 41:1006-1012, 2003[CrossRef][Medline]

12. National Cancer Institute: Surveillance, Epidemiology, and End Results (SEER) Program Public-Use Data (1973-1998). Bethesda, MD, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2001, based on the August 2000 submission

13. Vaittinen P, Hemminki K: Risk factors and age-incidence relationships for contralateral breast cancer. Int J Cancer 88:998-1002, 2000[CrossRef][Medline]

14. Bilimoria M, Morrow M: The woman at increased risk for breast cancer: Evaluation and management strategies. CA Cancer J Clin 45:263-278, 1995[Abstract]

Submitted October 10, 2003; accepted September 15, 2004.

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				K. A. Metcalfe, J. Lubinski, P. Ghadirian, H. Lynch, C. Kim-Sing, E. Friedman, W. D. Foulkes, S. Domchek, P. Ainsworth, C. Isaacs, et al. Predictors of Contralateral Prophylactic Mastectomy in Women With a BRCA1 or BRCA2 Mutation: The Hereditary Breast Cancer Clinical Study Group J. Clin. Oncol., March 1, 2008; 26(7): 1093 - 1097. [Abstract] [Full Text] [PDF]

				D. J. Brenner, I. Shuryak, S. Russo, and R. K. Sachs In Reply: J. Clin. Oncol., February 20, 2008; 26(6): 1015 - 1016. [Full Text] [PDF]

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				L. Nekhlyudov, M. Bower, L. J. Herrinton, A. Altschuler, S. M. Greene, S. Rolnick, J. G. Elmore, E. L. Harris, A. Liu, K. M. Emmons, et al. Women's Decision-Making Roles Regarding Contralateral Prophylactic Mastectomy J Natl Cancer Inst Monographs, November 1, 2005; 2005(35): 55 - 60. [Abstract] [Full Text] [PDF]

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				K. J. Helzlsouer Contralateral Prophylactic Mastectomy: Quantifying Benefits and Weighing the Harms J. Clin. Oncol., July 1, 2005; 23(19): 4251 - 4253. [Full Text] [PDF]

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