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Originally published as JCO Early Release 10.1200/JCO.2007.12.3141 on October 22 2007 © 2007 American Society of Clinical Oncology. Increasing Use of Contralateral Prophylactic Mastectomy for Breast Cancer Patients: A Trend Toward More Aggressive Surgical Treatment
From the Department of Surgery, Division of Surgical Oncology; Division of Health Policy and Management, University of Minnesota School of Public Health; and the University of Minnesota Medical School, Minneapolis, MN Address reprint requests to Todd M. Tuttle, MD, University of Minnesota, Department of Surgery, Division of Surgical Oncology, 420 Delaware St SE, Minneapolis, MN; e-mail: tuttl006{at}umn.edu
Purpose Many patients with unilateral breast cancer choose contralateral prophylactic mastectomy to prevent cancer in the opposite breast. The purpose of our study was to determine the use and trends of contralateral prophylactic mastectomy in the United States. Patients and Methods We used the Surveillance, Epidemiology and End Results database to review the treatment of patients with unilateral breast cancer diagnosed from 1998 through 2003. We determined the rate of contralateral prophylactic mastectomy as a proportion of all surgically treated patients and as a proportion of all mastectomies. Results We identified 152,755 patients with stage I, II, or III breast cancer; 4,969 patients chose contralateral prophylactic mastectomy. The rate was 3.3% for all surgically treated patients; 7.7%, for patients undergoing mastectomy. The overall rate significantly increased from 1.8% in 1998 to 4.5% in 2003. Likewise, the contralateral prophylactic mastectomy rate for patients undergoing mastectomy significantly increased from 4.2% in 1998 to 11.0% in 2003. These increased rates applied to all cancer stages and continued to the end of our study period. Young patient age, non-Hispanic white race, lobular histology, and previous cancer diagnosis were associated with significantly higher rates. Large tumor size was associated with a higher overall rate, but with a lower rate for patients undergoing mastectomy. Conclusion The use of contralateral prophylactic mastectomy in the United States more than doubled within the recent 6-year period of our study. Prospective studies are needed to understand the decision-making processes that have led to more aggressive breast cancer surgery.
Women with unilateral breast cancer have a significantly increased risk of developing a second cancer in the contralateral breast. The annual incidence of contralateral breast cancer, about 0.5% to 0.75%, does not change with time.1-6 In contrast, the peak hazard of systemic recurrence of unilateral breast cancer is 1 to 2 years after treatment; the risk decreases consistently after 2 to 5 years.7 Thus, occurrence of contralateral breast cancer is clinically more significant in patients who are likely to survive for a long time. Specific clinical and pathologic factors are associated with an increased risk of developing contralateral breast cancer1,8-11 including: young patient age, a family history of breast cancer, lobular type histology, multicentric cancer, and previous chest radiation. Moreover, patients with unilateral breast cancer who also have BRCA1 or BRCA2 genetic mutations have a markedly increased risk of developing contralateral breast cancer.12,13 The fear of developing contralateral breast cancer leads some patients with unilateral breast cancer to consider contralateral prophylactic mastectomy (CPM). CPM significantly reduces the risk of contralateral breast cancer, but the procedure is more aggressive and irreversible; it is also unnecessary for preventing contralateral breast cancer in most patients.14-17 Moreover, since the risk of systemic metastases often exceeds the risk of contralateral breast cancer, most patients will not experience any survival benefit. The purpose of our study was to evaluate, in a population-based cohort, the rate of and any trends toward CPM for patients with unilateral breast cancer. Until our study, the rate of CPM in the United States had not been determined.
Data We used the Surveillance, Epidemiology and End Results (SEER) cancer registry public-use database to examine rates and trends of CPM in women with unilateral breast cancer from 1998 through 2003. The SEER cancer registries provide population-based cancer surveillance for 16 areas that represent approximately 26% of the United States.18 Given the recent expansion of the SEER program, information covering our entire 6-year study period for 12 registries was available; for the remaining four registries, information was available only for 2000 through 2003. The information collected by SEER includes patient demographic characteristics, primary tumor site, tumor laterality, histology type, tumor stage, tumor grade, diagnostic confirmation, type of surgery, radiation, vital status (through December 31, 2003), and cause of death (as recorded on the death certificate). Beginning with cancers diagnosed in 1998, the SEER site-specific surgery codes included contralateral mastectomy if it was planned as the first course of treatment for patients with unilateral breast cancer.18 However, determining the rate of CPM was complicated by the available surgical choices that breast cancer patients were offered. Some patients (eg, those with large tumors) had only two realistic options: unilateral mastectomy or bilateral mastectomy (including CPM). Yet, most patients had three surgical options: breast-conserving surgery (BCS), unilateral mastectomy, or bilateral mastectomy (including CPM). Therefore, to capture the breadth of surgical options, we determined the overall rate of CPM-all (CPM-A; ie, proportion of all surgically treated patients who underwent CPM) and, in addition, the rate of CPM-mastectomy (CPM-M; ie, proportion of all mastectomy patients who underwent CPM) to exclude patients treated with BCS, since these patients generally did not undergo CPM.
Patients
We defined CPM as mastectomy surgery codes that included the comment "with removal of uninvolved contralateral breast." Lobular type histology was defined by any histologic evidence of lobular component. Tumor grade was classified as I and II versus III. Tumor size was categorized as follows: smaller than 1 cm, 1 to 1.9 cm, 2.0 to 4.9 cm, or
Analysis All statistical analyses were completed using SAS software, version 9.1 (SAS Institute, Cary, NC). Because our study used preexisting data with no personal identifiers, the human subjects committee of the University of Minnesota's (Minneapolis, MN) institutional review board determined that it was exempt from review.
Over our 6-year study period (1998 through 2003), 152,755 women were diagnosed with unilateral breast cancer and treated with surgery. Most underwent either BCS (57.8%) or a unilateral mastectomy (38.9%), but 4,969 underwent CPM (CPM-A, 3.3%). Of those who underwent mastectomy, 7.7% (CPM-M) underwent CPM. Patient and tumor characteristics are presented in Table 1.
Logistic regression analysis (Table 2) demonstrated that young age was associated with significantly higher CPM-A and CPM-M rates: 6.7% of all surgically treated patients age 39 or younger underwent CPM, as compared with only 1.3% of women in their 70s. The CPM-A and CPM-M rates were also significantly higher among patients of non-Hispanic white race, among patients with a previous cancer diagnosis, and among patients with lobular histology. Larger tumor size was associated with a higher CPM-A rate, but with a lower CPM-M rate. In other words, patients with larger tumors were more likely to undergo bilateral mastectomy; however, among mastectomy patients, those with smaller tumors were more likely to choose CPM. Lower tumor grade and negative lymph node status were associated with a significantly higher CPM-M rate. ER status was not associated with either CPM-A or CPM-M. However, the CPM-M rate was significantly lower for patients with ER-unknown/not done status as compared with either ER-positive or ER-negative patients.
The CPM-A (Fig 1) and CPM-M (Fig 2) rates significantly increased for all stages of breast cancer. These trends continued to the end of our study period with no plateau effect. The CPM-A rate significantly increased from 1.8% in 1998 to 4.5% in 2003 (150% increase); similarly, the CPM-M rate significantly increased from 4.2% in 1998 to 11.0% in 2003 (162% increase). The CPM rates also significantly increased for both lobular and nonlobular histology (data not shown). The increased CPM rate occurred simultaneously with a continued increase in the BCS rate (1998, 56.1%; 2003, 59.7%) and a continued decrease in the unilateral mastectomy rate (1998, 42.0%; 2003, 35.9%).
We observed considerable geographic variation in CPM-A and CPM-M rates (P < .0001, 14 df; Table 3). For example, the CPM-A rate was lowest in the Connecticut registry (1.4%) and highest in metropolitan Atlanta (5.6%) and in Iowa (5.6%). The four registries that were added in 2000 had intermediate CPM-A rates (3.1% to 4.2%). We saw similar patterns in CPM-M rates. The CPM rates significantly increased from 1998 to 2003 for all registries except for Rural Georgia, which is exceptionally underpowered. We did not observe any obvious trends in CPM rates based on geographic location in the United States (east coast v west coast v midwest v south).
In 1991, a National Cancer Institute Consensus Conference endorsed BCS or lumpectomy as the preferred treatment for early-stage breast cancer.19 This recommendation was based on the results of prospective randomized trials showing that the survival rates were equal after BCS and mastectomy.20-21 Yet, we found that the CPM rate doubled for all stages of breast cancer in the United States from 1998 through 2003. Importantly, these trends continued to the end of our 6-year study period with no plateau effect. These findings represent a dramatic change toward more aggressive breast cancer surgery in the United States. Still, the rate of BCS also increased during our study period. Thus, patients are increasingly choosing between minimal surgery (BCS) or more aggressive surgery (bilateral mastectomy) instead of unilateral mastectomy. We identified certain clinical and pathologic factors that were associated with CPM rates. Young patient age, non-Hispanic white race, and lobular type histology were associated with significantly higher CPM-A and CPM-M rates. Polednak, 22 using data from the Connecticut Tumor Registry, also reported that young age and lobular histology were associated with higher CPM rates. We also found that CPM rates were significantly higher for patients with a previous history of other cancers. In our study, larger tumor size was associated with a higher CPM-A rate, but with a lower CPM-M rate. Favorable prognostic factors (smaller tumor size, negative lymph node status, and lower tumor grade) were associated with a significantly higher CPM-M rate; such patients are probably more likely to benefit from CPM because their survival time is longer and thus their subsequent risk of contralateral breast cancer is greater. Other investigators have reported geographic variations in the surgical treatment of breast cancer.23,24 Nattinger et al24 reported that BCS rates were highest in the mid-Atlantic and New England regions and lowest in the south central regions. In our study, we found no general geographic trends (east coast v west coast v midwest v south) of CPM rates in the United States. Previous studies have demonstrated the effectiveness of CPM in preventing contralateral breast cancer.14-17 In a study of 745 breast cancer patients with a family history of breast cancer, McDonnell et al15 reported that CPM reduced the incidence of contralateral breast cancer by more than 90%. However, the effectiveness of CPM in preventing breast cancer mortality is not as clear. A recent Cochrane review of eight studies included 1,708 patients who underwent CPM; the authors concluded that CPM decreased the incidence of contralateral breast cancer, but was not associated with any survival improvement.25 Yet, in a retrospective cohort study of 1,072 patients from the Cancer Research Network, Herrinton et al16 reported that CPM was associated with a significant decrease in the breast cancer mortality rate (CPM, 8.1%; no CPM, 11.7%). Peralta et al14 demonstrated that CPM significantly increased the disease-free survival rate, but not the overall survival rate. The potential benefit of CPM is greatest for patients who have the highest risk of contralateral breast cancer. Although absolute indications for CPM are not established, the Society of Surgical Oncology has published criteria that physicians should consider for mastectomy of the contralateral, intact breast.26 The decision to undergo CPM is complex, and many factors likely contribute to its increased frequency. In a review of the National Prophylactic Mastectomy Registry, Montgomery et al27 reported that the most common reason for CPM was physicians’ advice regarding risk of contralateral breast cancer. Patient satisfaction and psychological and social outcomes after CPM have been examined by several investigators.27-29 Frost et al28 reported that 83% of patients were either satisfied or very satisfied with their decision to undergo CPM at a mean of 10 years after surgery. Montgomery et al27 reported that the most common reasons for regret after CPM were a poor cosmetic outcome and diminished sense of sexuality. Geiger et al29 found that patients who underwent CPM were less likely to express breast cancer concern compared with patients who did not undergo CPM. Nevertheless, patients with unilateral breast cancer have options that are less extreme than CPM. Surveillance with clinical breast examination, mammography, and newer imaging modalities such as breast magnetic resonance imaging may detect cancers at earlier stages.30-32 Tamoxifen, given as adjuvant therapy for ER-positive breast cancer, significantly reduces the rate of contralateral breast cancer.33-35 Aromatase inhibitors may reduce the risk of contralateral breast cancer as much as, or even more than, tamoxifen.36 Because hormone therapy reduces the risk of contralateral breast cancer for patients with ER-positive breast cancer, we anticipated that CPM rates would be lower for such patients; however, our data did not show this expected finding. Ovarian ablation and cytotoxic chemotherapy also reduce the risk of contralateral breast cancer.37,38 Because our study used cancer registry data, detailed patient and tumor information that may have influenced treatment decisions were not available. Important factors regarding family history, genetic testing results, reconstructive surgery, tamoxifen use, systemic chemotherapy, and mammographic findings were not available to us. Moreover, our study did not include patients who later chose CPM years after initial treatment, potentially underestimating the true CPM rate. Likewise, our study excluded patients with two breast cancer diagnoses in the same month, even when one was coded as including a CPM. Polednak found that a small proportion of these cases resulted in a cancer diagnosis in the apparently uninvolved breast; therefore, we removed these cases again leading to an underestimation of the true CPM rate.22 Our use of SEER data is supported by a detailed review that confirmed cases coded by one SEER registry as undergoing a CPM did involve a bilateral mastectomy where only one breast was considered to have cancer.39 Despite the potential limitations of our study, SEER is population-based and includes patients from diverse locations and practices in the United States, making our findings broadly reflective of standard practice. Ironically, our population-based study demonstrated that although the BCS rate increased in the United States from 1998 to 2003, the bilateral mastectomy rate also increased while the unilateral mastectomy rate decreased. We found that the CPM-A rate was greater for patients with more advanced stage cancer (because these patients frequently require mastectomy), but the CPM-M rate was greater for patients with earlier stage cancer. These observations are consistent with a study by Nekhlyudov et al,40 which found that 29% of women undergoing CPM had regional disease. Future prospective studies are critically needed to evaluate the decision-making processes leading to CPM.
The author(s) indicated no potential conflicts of interest.
Conception and design: Todd M. Tuttle, Elizabeth B. Habermann, Erin H. Grund, Todd J. Morris, Beth A. Virnig Administrative support: Todd M. Tuttle Collection and assembly of data: Elizabeth B. Habermann, Beth A. Virnig Data analysis and interpretation: Todd M. Tuttle, Elizabeth B. Habermann, Erin H. Grund, Todd J. Morris, Beth A. Virnig Manuscript writing: Todd M. Tuttle, Elizabeth B. Habermann, Erin H. Grund, Todd J. Morris, Beth A. Virnig Final approval of manuscript: Todd M. Tuttle, Elizabeth B. Habermann, Todd J. Morris, Beth A. Virnig
We acknowledge Mary Knatterud, PhD, Department of Surgery, University of Minnesota, Minneapolis, MN, for her editorial assistance.
published online ahead of print at www.jco.org on October 22, 2007. Presented in part at the Annual Meeting of the Society of Surgical Oncology, Washington, DC, March 16, 2007. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5 cm. Estrogen receptor (ER) status was defined as positive, negative, or unknown. Lymph node status was categorized as positive or negative. 
