How To Choose A Prophylactic Mastectomy

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1 The American Journal of Surgery (2011) 202, Clinical Science Contralateral prophylactic mastectomy in breast cancer patients who test negative for BRCA mutations Marissa Howard-McNatt, M.D.*, Rebecca W. Schroll, M.D., Gail J. Hurt, B.S.N., Edward A. Levine, M.D. Department of Surgical Oncology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC , USA KEYWORDS: Contralateral prophylactic mastectomy; BRCA negative; Breast cancer Abstract BACKGROUND: Determination of BRCA1 and 2 mutation carrier status is important. Although BRCA carriers are offered bilateral mastectomy and oophorectomy, most who test negative decline. Some women choose contralateral prophylactic mastectomy (CPM) at the time of their breast cancer diagnosis despite testing negative. METHODS: A total of 110 women with breast cancer received genetic testing before surgical treatment. Patient demographics, tumor characteristics, surgical treatment, and magnetic resonance imaging use were recorded. RESULTS: Results revealed BRCA1/2 mutation in 33%, variant of unknown significance in 6%, and no mutation in 61% of women. In BRCA-negative women, 37% chose CPM. Marital status was significant for CPM (P.03). Race, age, stage of presentation, and biomarker status were not associated with choice of CPM. Ninety-six percent of CPM recipients underwent breast reconstruction. Magnetic resonance imaging use did not affect CPM rates (P.99). CONCLUSIONS: Increased rates of CPM have been observed. In our study married women were more likely to choose CPM. We recommend genetic genotyping before surgery. These findings warrant further investigation Elsevier Inc. All rights reserved. Determination of BRCA1 and 2 mutation carrier status has become increasingly important. More than 300,000 women in the United States are estimated to carry a mutation in this gene. 1 These women carry a 5- to 20-fold increased risk of developing breast and ovarian cancer. 2 It has been suggested that women with a strong family history of breast and ovarian cancer, breast cancer diagnosis at age younger than 50, and men with breast cancer be offered * Corresponding author. Tel.: ; fax: address: mmcnatt@wfubmc.edu Manuscript received August 17, 2010; revised manuscript April 7, 2011 genetic testing and counseling. The National Comprehensive Cancer Network guidelines for BRCA mutation carriers include early detection with screening mammography plus breast magnetic resonance imaging (MRI), or bilateral mastectomy and/or prophylactic salpingo-oophorectomy for ovarian cancer risk reduction by the age of 40. 3,4 Women who test negative for BRCA mutations typically do not choose to undergo such extensive surgery. However, there is a cohort of women who test negative for BRCA mutations but still decide to have a contralateral prophylactic mastectomy at the time of their breast cancer diagnosis. This is clearly driven by the fear of developing contralateral breast cancer. 5 Contralateral prophylactic mastectomy (CPM) substantially reduces the risk of developing con /$ - see front matter 2011 Elsevier Inc. All rights reserved. doi: /j.amjsurg

2 M. Howard-McNatt et al. BRCA and CPM tralateral breast cancer. 6 Recently, it has been suggested that CPM may increase cancer-specific survival. 7 However, the risk of systemic metastases from the incident cancer often outweighs the risk of contralateral breast cancer. Thus, many patients will not have a survival benefit from this extra procedure. We sought to determine the factors that may influence these patients choices. Materials and Methods This study was approved by the institutional review board at Wake Forest University. We retrospectively examined the charts from women diagnosed with breast cancer who received preoperative genetic counseling and testing at Wake Forest between January 2005 and June Additional information was obtained from a query of a prospectively maintained genetic counseling database maintained by the Surgical Oncology Program. The genetic counseling was performed by our genetic counselor (G.J.H.). Eligible patients were newly diagnosed with breast cancer who had not received definitive local breast cancer treatment and met the clinical criteria designed to identify individuals with a minimum 10% probability of carrying a BRCA mutation. Women who did not meet these criteria and who were younger than age 18 were excluded. The patients were seen by our surgeons (3 male and 1 female surgeon). Patient demographics including age, race, sex, marital status, and parity were noted. Tumor characteristics with regard to stage and receptor status were recorded. Surgical treatment including lumpectomy, unilateral mastectomy, prophylactic mastectomy, and breast reconstruction were analyzed. All patients choosing mastectomy were offered breast reconstructive surgery at the time of their mastectomy. Patients with large breast size were not offered contralateral prophylactic mastectomies to obtain symmetry. Contralateral breast reductions are our preferred method of achieving symmetry. The type of reconstruction (implant vs autologous tissue) was determined by the patient and plastic surgeon. We also documented if these patients had obtained a preoperative MRI. The Fisher exact test was performed on the categoric values. Age was evaluated with an F test. Statistical significance was defined as a P value less than.05 for the purposes of this study. Results 299 We identified 110 women with newly diagnosed breast cancer who underwent preoperative genetic counseling and testing before undergoing definitive surgical treatment from 2005 to The mean patient age at breast cancer diagnosis was 45 years (range, y). Results revealed BRCA1, a known deleterious mutation, in 32 (29%) women, BRCA2 mutation in 4 (3%), variant of unknown significance in 7 (6%), and no mutation in 67 (61%) patients. Patient, tumor, and treatment characteristics of the 65 women who tested negative and received surgery at our institution (2 patients received surgery elsewhere) are reviewed in Table 1. BRCA-positive patients were more Table 1 Characteristics of 65 women who tested BRCA negative with regard to surgical choice Lumpectomy Unilateral mastectomy Bilateral mastectomy Total P value Race.36 Black White Hispanic MRI.49 No Yes Stage Receptor status.31 ER Her-2 positive Triple negative Children.43 No Yes Marital status.035 Married Single, divorced, widowed Mean age, y (SD) 50.2 (11.4) 45.1 (10.9) 45.3 (8.5).193

3 300 The American Journal of Surgery, Vol 202, No 3, September 2011 likely to undergo bilateral mastectomy than patients testing negative (83% vs 37%; P.0009), or those with a variant of unknown significance (25%; P.046). In women who tested BRCA negative, 37% chose CPM. Only 25% of our patients received a preoperative contralateral breast MRI. The rate of CPM was not different among those who had preoperative bilateral breast MRI and those who did not even if an abnormal MRI finding was seen (P.99). Dense breast tissue on mammography or suspicious findings on imaging were not associated with CPM. The stage distribution of disease (stage 0, I, II, III, or IV) for the women who tested negative but had CPM was 15%, 50%, 10.5%, 21%, and 2%, respectively. Stage of presentation was not associated with CPM (P.1). There was no statistical difference in patients undergoing bilateral mastectomy with regard to race, age, estrogen receptor (ER)/ progesterone receptor/her-2/neu status, or parity. In patients testing negative who considered lumpectomy, unilateral mastectomy, and bilateral mastectomy, marital status was an independent predictor for receiving a contralateral mastectomy (P.03). The pathology findings on CPM revealed 92% had benign findings. One patient had ductal carcinoma in situ and another patient was found to have Lobular carcinoma In situ (LCIS) on the final pathology specimen of the contralateral breast. Of the 24 patients who were BRCA negative and underwent bilateral mastectomies, 96% chose immediate breast reconstruction. Most patients chose a 2-staged implant reconstruction (86%), whereas 13% underwent bilateral transrectus abdominus myocutaneous (TRAM) or deep inferior epigastric perforator (DIEP) flap. Comments The preferred treatment of breast cancer has evolved from the Halstedian radical mastectomy to modified radical mastectomy, to breast-conserving surgery. Since the National Cancer Institute s 1991 consensus statement, breastconserving surgery has been the treatment of choice for early stage breast cancers. 8 However, at the time of the consensus statement, genotyping for familial breast cancer conditions such as the BRCA1 and 2 mutations was not yet possible. Recently there has been a trend toward increasing use of CPM. 5,6 At our institution we have noted an increase in the number of contralateral prophylactic mastectomies in women with unilateral breast cancer (Fig. 1). Tuttle et al, 5 using the Surveillance, Epidemiology and End Results (SEER) Program database, showed an increase in the number of patients with unilateral breast cancer choosing a CPM increased from 1.8% to 4.5% during a 6-year period. This finding also was observed in patients with DCIS, a group with a favorable outcome. 9 This study could not stratify outcomes in relation to BRCA status from the SEER database; however, we suspect there would be a relationship between family history of breast/ovarian cancer and the choice for CPM Number Year # CPM Figure 1 Number of contralateral prophylactic mastectomies per year at Wake Forest University Baptist Medical Center. MRI recently has become part of the preoperative assessment of selected women with breast cancer. The use of MRI in this setting has been associated with increased mastectomy rates. 10,11 Sobero et al 11 found that in a cohort of 3,606 women, those who underwent preoperative MRI were nearly twice as likely to have contralateral prophylactic mastectomy (9.2% vs 4.7%; P.001). At our institution we do not perform routine preoperative MRI for all patients with a new diagnosis of breast cancer. Whether preoperative MRI increases CPM rates is not yet clear, and we did not find this effect in this study. We recognize the modest number of patients in this trial obstructs a definitive conclusion on the role of preoperative breast MRI on CPM after genetic testing. Women who were seen at our multidisciplinary breast clinic were routinely referred to a genetic counselor before surgery, because of their family history or age younger than 50 at diagnosis, to undergo genetic testing for BRCA mutations. Most of these women tested negative, but those who still chose CPM were evaluated. The only predictor of choosing CPM was being married. Other studies have noted young patient age, large tumor size, lobular histology, multicentric disease, and positive nodal status to be determinants of choosing this more extensive surgery. 5,12 However, we could not confirm these relationships in our study. This study reports an association between marriage and CPM. Given the small number of patients in this study, these results should be considered hypothesis-generating. The etiology of this finding is unclear. Notably, we did not find that having children, which women often state as a reason for maintaining good health, to be statistically significant. Also, 1 recent study found that high-risk women who underwent CPM can have decreased sexual self-image and sexual functioning. 13 Which of these (or other) factors related to married women s choice toward CPM remains to be determined. We found that BRCA-positive patients were more likely to undergo CPM than patients testing negative. All of these

4 M. Howard-McNatt et al. BRCA and CPM women underwent preoperative genetic counseling and testing. Genetic counseling has been shown to help promote increased surveillance, earlier detection, and even surgical intervention in mutation carriers. 14 Genetic counseling involves a detailed discussion of test results, cancer family history, and risk reduction options regardless of test result outcomes. Furthermore, counseling has been shown to be important in the decision-making process. 15 Information women received during genetic counseling that they perceived as most important for influencing a risk-reduction surgery decision was the BRCA test result (positive or negative), followed by discussion of family cancer history. 16 We continue to suggest genetic counseling and genotyping in at-risk patients before definitive surgery. Although CPM reduces the risk of contralateral breast cancer, patients do have other options that include breast selfexaminations, mammography, and the MRI screening guidelines from the American Cancer Society. 17 Tamoxifen, given in estrogen receptor positive breast cancers, decreases the risk on contralateral breast cancer. 18,19 Aromatase inhibitors may reduce the risk even more than tamoxifen. 20 Despite these findings, BRCA mutation carriers and a subset of high-risk women were more likely to believe prophylactic mastectomy to be the best way to reduce both the risks and anxiety about breast cancer, as found in a recent report from the M.D. Anderson cancer center. 21 The investigators in this study also noted that women did not find prophylactic mastectomies too drastic, too scary, or too disfiguring. Furthermore, Geiger et al 22,23 reported that most women undergoing CPM are satisfied with their decision, comparable with breast cancer survivors without the procedure. Despite the fact that CPM decreases the risk of developing a contralateral breast cancer, it is not completely protective against the development of a new breast cancer. 6 A Cochrane review of multiple studies that included 1,708 women who underwent CPM found that although CPM did decrease the risk of contralateral breast cancer development, it was not associated with any improvements in breast cancer survival rates. 24 However, Bedrosian et al 25 reported that CPM is associated with improved survival among a subgroup of women with breast cancer. This association was best seen in women younger than age 50 with stage I and II ER-negative tumors (hazard ratio of death,.68; P.004). Our study was limited because it was from 1 institution in an academic setting and did not include any community health care systems. Because this was a retrospective study, we cannot know the real reason that these women chose to undergo contralateral mastectomies. A prospective evaluation performed both before and after genetic testing may reveal the impact of genetic testing on risk-reduction methods. In conclusion, the use of CPM for women with a new diagnosis of unilateral breast cancer has increased over the past 10 years as seen in SEER database studies. We confirmed this finding in BRCA mutation carriers and have observed this trend in women with negative BRCA results. In our study, married women were more likely to choose CPM. We continue to suggest genetic counseling/genotyping be performed in at-risk patients as per National Comprehensive Cancer Network guidelines before definitive surgery. This can identify women who are BRCA gene carriers who should be counseled about bilateral mastectomies before their definitive surgery. It is unclear if CPM in women who test negative for BRCA mutations will improve longterm survival. These findings warrant further prospective trials. References John EM, Miron A, Gong G, et al. 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J Clin Oncol 2005;23: NIH Consensus Conference. Treatment of early-stage breast cancer. JAMA 1991;265: Boughey JC, Hoskin TL, Dellars TA, et al. Contralateral prophylactic mastectomy is associated with a survival advantage in high-risk women with a personal history of breast cancer (abstr). Ann Surg Oncol 2010;17(Suppl 1): Tuttle TM, Jarosek S, Habermann EB, et al. Increasing rates of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ. J Clin Oncol 2009;27: Katipamula R, Degnim AC, Hoskin T, et al. Trends in mastectomy rates at the Mayo Clinic Rochester: effects of surgical year and preoperative magnetic resonance imaging. J Clin Oncol 2009;27(25): Sorbero ME, Dick AW, Beckjord EB, et al. Diagnostic breast magnetic resonance imaging and contralateral prophylactic mastectomy. Ann Surg Oncol 2009;16: Arrington AK, Jarosek SL, Virnig BA, et al. Patient and tumor characteristics associated with increased use of contralateral prophylactic mastectomy in patients with breast cancer. Ann Surg Oncol 2009;16: Matloff ET, Barnett RE, Bober SL. Unraveling the next chapter: sexual development, body image, and sexual functioning in female BRCA carriers. Cancer J 2009;15: Scheuer L, Kauff N, Robson M, et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 2002;20: Metcalfe K, Poll A, O Connor A, et al. Development and testing of a decision aid for breast cancer prevention for women with a BRCA1 or BRCA2 mutation. Clin Genet 2007;72: Ray JA, Loescher LJ, Brewer M. Risk-reduction surgery decisions in high-risk women seen for genetic counseling. J Genet Couns 2005;14:

5 302 The American Journal of Surgery, Vol 202, No 3, September Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007;57: Fisher B, Redmond C. New perspective on cancer of the contralateral breast: a marker for assessing tamoxifen as a preventive agent. J Natl Cancer Inst 1991;83: Rutqvist LE, Cedermark B, Glas U, et al. Contralateral primary tumors in breast cancer patients in a randomized trial of adjuvant tamoxifen therapy. J Natl Cancer Inst 1991;83: Baum M, Budzar AU, Cuzick J, et al. ATAC Trialist s Group. Anastrozole alone or in combination with tamoxifen verses tamoxifen alone for adjuvant treatment of post-menopausal patients with breast cancer: first results of the ATAC randomised trial. Lancet 2002;359: Litton JK, Westin SN, Ready K, et al. Perception of screening and risk reduction surgeries in patients tested for a BRCA deleterious mutation. Cancer 2009;15: Geiger A, Nekhlyudov L, Herrinton LJ, et al. Quality of life after bilateral prophylactic mastectomy. Ann Surg Oncol 2007;14: 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 2006;24: Lostumbo L, Carbine N, Wallace J, et al. Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev 2004; 18:CD Bedrosian I, Hu CY, Chang GJ. Population-based study of contralateral prophylactic mastectomy and survival outcomes of breast cancer patients. J Natl Cancer Inst 2010;102:401 9.