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Originally published as JCO Early Release 10.1200/JCO.2005.12.904 on March 28 2005 © 2005 American Society of Clinical Oncology.
Contralateral Prophylactic Mastectomy: Quantifying Benefits and Weighing the HarmsPrevention and Research Center, Women's Center for Health & Medicine, Mercy Medical Center, Baltimore, MD Breast cancer is a disease that no woman wants to experience, let alone experience it more than once. For this and other reasons, some women choose to undergo prophylactic removal of the unaffected breast at their initial diagnosis of breast cancer. The path to this decision may be most clear for women who carry a mutation in the BRCA1 or BRCA2 gene, for whom the risk of a second primary cancer is high. However, for the vast majority of women with breast cancer, the risk of a contralateral breast cancer is lower. For these women at lower risk, how do they reconcile undergoing prophylactic mastectomy with the option of breast conservation, which has been shown to have an equivalent survival outcome compared with mastectomy?1 The decision is complex, and the benefits must be carefully evaluated against the risks and potential harms. Until recently, the extent of the benefit has not been quantified. The article by Herrinton et al2 in this issue not only quantifies the benefit for preventing a new breast cancer, but it also evaluates the impact on breast cancer mortality. However, careful interpretation of their results is needed to appropriately apply this information to help women make decisions regarding contralateral prophylactic mastectomy. The study by Herrinton et al,2 a large collaborative investigation by six health maintenance organizations, demonstrates the strength that can be gained by large collaborative networks, as well as the challenges in harvesting valuable clinical data from medical practices. The study examined 56,400 women with breast cancer diagnosed between 1979 and 1999, of whom 1.9% underwent a contralateral prophylactic mastectomy. Despite the availability of computerized records, culling the data was a daunting challenge. More than 2,200 records of women were reviewed, and less than half of the women (n = 1,072) were ultimately proven to have had a contralateral prophylactic mastectomy. Why was there difficulty in identifying these women? One problem is that there is no specific code to identify this procedure. Studying the impact of the procedure on health outcomes can be greatly facilitated by developing unique procedure codes. Another complexity in the design and interpretation of the study is the sampling scheme used to assess the impact of prophylactic mastectomy on breast cancer occurrence, taking into account all other individual patient characteristics. Despite a large proportion of computerized records, detailed chart abstraction was required and could only be performed for a subset of the women in the study. The occurrence of contralateral breast cancer is a rare event, with an estimated rate of 2.7%. These women were oversampled to have adequate numbers to compare with women who underwent prophylactic mastectomy, while also adjusting for potential confounders. Although it permits valid estimation of outcome, unfortunately, this sampling scheme does not allow direct statistical comparison of differences in characteristics between the two groups. Further examination of the underlying differences in the women who chose to either have or not have prophylactic contralateral mastectomy would be valuable. With the increasing availability of electronic records, this type of research will be facilitated without the need for such complex sampling schemes. The observed impact of contralateral mastectomy on the occurrence of breast cancer was, as one would expect, profound. The risk was reduced by 97%, adjusting for primary and adjuvant therapy, characteristics of the tumor, and family history.2 Five women (0.5%) in the contralateral prophylactic mastectomy group developed a contralateral breast cancer despite this procedure. From these data, women may be counseled that their risk will be dramatically reduced but not completely eliminated. Additional information on other factors associated with a contralateral breast cancer is also provided. Interestingly, chemotherapy, but not hormonal therapy, was associated with a reduced risk of contralateral breast cancer. Radiation therapy was associated with an excess risk of contralateral breast cancer, although this risk was of borderline significance. Lumpectomy was associated with a decreased risk of contralateral breast cancer. These are seemingly contradictory findings because radiation and lumpectomy are usually associated. Increasing age was a risk factor, but family history was not. How these factors should be used in considering who may be advised to undergo the procedure is not clear. A principle contribution of this study is in quantifying the potential impact of a contralateral prophylactic mastectomy on breast cancer mortality. The clinical dilemma has been whether or not contralateral mastectomy would impact on breast cancer mortality, given the underlying breast cancer diagnosis and the overall low risk of second primary tumors. This cohort analysis was restricted to four of the six centers with cancer registries, and statistical adjustment could be made only for stage of disease and primary treatment options available from registry databases. Eight percent of the women who underwent a contralateral mastectomy died from breast cancer compared with 12% of women in the comparison group; this resulted in a risk difference of 4% or a 43% relative reduction in the risk of death.2 The following question is raised: how much of this benefit can be attributed to contralateral prophylactic mastectomy? There are dramatic differences between these two groups of women that present difficulties both in adequately adjusting for and in interpreting the results. The vast majority of women (95%) in the contralateral mastectomy group had a mastectomy as their primary breast cancer treatment.2 Presumably, the other 5% had a mastectomy at the time of their contralateral mastectomy. Only 53% of the women in the comparison group had a mastectomy. These disparate statistics make adjustment for these factors difficult. In addition, because surgical choices are highly correlated with adjuvant radiation therapy, separating the effects of adjuvant therapy from primary treatment choices is difficult. Almost all women treated with lumpectomy had radiation therapy, whereas only 3% of women who had mastectomy also had radiation therapy. Because of these differences, it would have been most helpful to have included additional analyses stratified by underlying primary treatment. Lumpectomy was associated with reduced breast cancer mortality, as was hormonal therapy, but radiation therapy and chemotherapy were associated with excess breast cancer mortality. So, how much of this 43% reduced breast cancer mortality rate can be directly attributed to contralateral prophylactic mastectomy? The answer remains uncertain. The women who underwent this procedure were healthier. They were less likely to die from all causes compared with other women with breast cancer. This suggests a strong selection bias for who would be advised to undergo the prophylactic procedure. Although Herrinton et al2 suggest reasons why this selection bias, which is most likely attributed to existing comorbidities, would not affect breast cancer–specific mortality, the question remains unanswered because underlying coding of death may be influenced.3 Short of a randomized clinical trial, how can this be sorted out? Although it would be a massive undertaking, more detailed clinical information should be obtained to assess the degree of coexisting conditions, as well as to gain more details on specific adjuvant therapies. Additional stratified analyses would also help. What should we be telling women concerning this procedure? We can, with confidence, tell women that a contralateral prophylactic mastectomy will reduce the risk of a second breast cancer by 87% to 99%. Women are also likely to have a reduction in breast cancer mortality; however, without additional investigation, the overall clinical benefit directly attributable to this procedure is less certain. Decades were spent in demonstrating the equivalency between mastectomy and breast-conserving therapy for the treatment of breast cancer. Although women should be informed of the potential benefit of prophylactic mastectomy, this must be done in the context of stressing that this is a rare event, affecting less than 3% of women in this large study of women with breast cancer. Women should also be informed of other options that reduce the risk of a second breast cancer, namely, hormonal therapy with selective estrogen receptor modifiers and aromatase inhibitors. These treatments have been shown to reduce the occurrence of contralateral breast cancer in randomized clinical trials.4-6 More research is also needed to develop preventive strategies that extend to the prevention of estrogen receptor–negative tumors. This is one advantage of prophylactic surgery over hormonal interventions. How can this information be applied in the clinical setting to help women choose among ever increasing options for the management of their breast cancer? Weighing the risks and benefits of options to reduce second breast cancer in women with a personal history of breast cancer requires the quantification of harms as well as benefits. This study provides critical information on the benefits. The next step is quantifying the harms, both physical and psychological, so women can weigh all of their options and make informed choices. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233-1241, 2002
2. Herrinton LJ, Barlow WE, Yu O, et al: Efficacy of prophylactic mastectomy in women with unilateral breast cancer. J Clin Oncol 23:4275-4286, 2005
3. Newschaffer CJ, Otani K, McDonald MK, et al: Causes of death in elderly prostate cancer patients and in a comparison nonprostate cancer cohort. J Natl Cancer Inst 92:613-621, 2000
4. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388, 1998
5. Gail MH, Costantino JP, Bryant J, et al: Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 91:1829-1846, 1999 6. Baum M, Buzdar A, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: Results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 98:1802-1810, 2003[CrossRef][Medline] Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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