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Originally published as JCO Early Release 10.1200/JCO.2004.01.925 on February 23 2004 © 2004 American Society of Clinical Oncology.
Prophylactic Mastectomy for BRCA1/2 Carriers: Progress and More QuestionsDepartments of Oncology, General Surgery, and Division of Biostatistics, Department of Health Sciences Research at Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN In the mid 1990s, genetic testing to identify carriers of BRCA alterations came into the clinical arena. But once a high-risk carrier was identified, what did we have to offer to reduce her risk? Regarding prophylactic mastectomy, a high-risk woman was often confronted with strongly held views—both for and against the procedure—with no supporting data. The literature contained several case reports of chest wall cancer occurring after prophylactic mastectomy [1-3]. These, along with a widely cited negative study of prophylactic surgery in a rat mammary model of chemical carcinogenesis [4], led to understandable concerns that the procedure might be ineffective in high-risk women. The 1997 Consensus Statement for BRCA1/2 carriers by the Cancer Genetics Studies Consortium [5] stated that no recommendation for prophylactic mastectomy could be made because of lack of evidence of benefit. Since that time, there have been retrospective and prospective studies of prophylactic mastectomy showing a high degree of risk reduction with the procedure [6-8]. The current report adds additional information regarding the efficacy of prophylactic mastectomy in BRCA1/2 carriers [9]. Rebbeck et al [9] have assembled a group of 105 BRCA1/2 mutation carriers who had bilateral prophylactic mastectomy. They followed this surgical group for 5.5 years and two of the women subsequently developed breast cancer at 2.3 and 9.2 years after prophylactic mastectomy. Both had subcutaneous mastectomy, and the authors say that one of these cancers developed in "substantial residual" breast tissue. Some points to take away from this study: 1) If your patient decides to have prophylactic mastectomy, do not leave substantial breast tissue behind. The total mastectomy is the procedure of choice; 2) their findings support the procedure's efficacy. Only 1.9% of these highest-risk women developed breast cancer after prophylactic mastectomy over 5.5 years of follow-up. What might have been expected in these women had surgery not been performed? Enter the control group and the weakest link in this study. The investigators identified 378 matched controls (matched by study center, BRCA1 versus BRCA2 mutation, and age). Over a mean follow-up of 6.4 years, 184 of them (49%) developed breast cancer. That is a remarkably high likelihood of breast cancer, even in mutation carriers. What, besides their mutation status, might explain this? In their overall analysis, all events that had occurred in cases and controls before their visit to the study center could be included (their group 1). Women who had previously had bilateral prophylactic mastectomy (BPM) were included. Controls had to be cancer-free when their matched cases had prophylactic surgery, but they could have developed breast cancer before being seen at the center. It is certainly conceivable that the development of a breast cancer, or a recurrence of breast cancer, would motivate women to be seen at a major medical center. This selection bias could artificially increase the number of breast cancers in the control group and, thus, overestimate the benefit of the procedure. A hypothetical example may be helpful: hypothetical case 1 (Fig 1) had her BPM in 1988. She was first seen at her respective high-risk center in 1991 and she was last followed in 1996, cancer-free. Control number 1 (Fig 2) had to be cancer-free in 1988, when her matched case had her surgery. But this control developed breast cancer in 1994 and was seen subsequently at a major center.
Recognizing this potential bias, the authors went a step further to their analysis 3, in which they excluded events that had occurred before a participant's first center visit. This drops the number of cases from 102 to 57, and the number of controls from 378 to 107. Now the outcomes clock is reset, and only events after the first clinic visit count. But does this eliminate bias in the controls? What, besides an actual cancer diagnosis, might motivate a high-risk woman to be seen at a referral medical center? What about a concerning breast finding? If we look at the 107 controls in analysis 3, we see that 24 of them developed breast cancer at a mean of 1.3 years of follow-up (range, 0.1 to 4.8 years). With such a short interval to breast cancer, especially one-tenth of a year, the investigators may be including women who requested evaluations because of active breast concerns, some of which proved to be malignant. This could have been avoided by excluding controls who were diagnosed with breast cancer within, for example, 6 months of their first center visit. One way to explore the potential for bias in the controls is to compare them to a prospectively ascertained control group. The Rotterdam group published a prospective study of prophylactic mastectomy in BRCA1/2 carriers in 2001 [8]. In that study, carriers chose between prophylactic mastectomy (n = 76) and surveillance (n = 63). Table 1 illustrates the experience in their control (surveillance) group. In fact, the likelihood of cancer in the Rebbeck et al [9] controls is almost twice that seen in the Rotterdam report [8], with similar length of follow-up. Other factors that could increase the cancers in the Rebbeck et al controls is their inclusion of ductal carcinoma-in-situ as an event, the controls' comparatively older ages, and earlier menarche (as compared to the Rebbeck cases). Countering these factors, however, was greater hormone replacement use in cases.
Despite the potential for bias in the controls in this study, there are considerable strengths to the work. Importantly, it provides 5.5 years of follow-up for 105 BRCA1/2 carriers who had BPM. Even if there is bias toward excess cancers in the controls, the low number of actual breast cancers in the cases (two of 105) substantiates a high degree of risk reduction with prophylactic mastectomy. The investigators' adjustment for duration of subjects' endogenous estrogen (analyses 2 and 4) is also important. Realizing the difficulties inherent in the conduct of retrospective studies of various interventions in high-risk women [10], we concur with the sentiments expressed by Rebbeck et al [9] that the ideal "gold standard" prospective randomized trial of prophylactic mastectomy will not be performed. Moreover, even a prospective, nonrandomized trial is subject to biases inherent in the decision making of individual women and their physicians. Taken altogether, the body of data on the efficacy of prophylactic mastectomy is derived from a number of approaches and populations and is quite solid. The procedure results in a marked decrease in the risk of breast cancer. So where does that leave us? Again, we concur with the sentiments of Rebbeck et al [9] in their desire to provide effective nonsurgical breast cancer prevention to all high-risk women. But to do so, we probably need to look beyond antiestrogens that work through an intact estrogen receptor. In this report, 78.4% of carriers had mutations in BRCA1. Recent data from the Breast Cancer Linkage Consortium remind us that 90% of breast cancers developing in BRCA1 carriers are estrogen receptor–negative [11]. To our knowledge, there are no data showing that tamoxifen reduces the risk of estrogen receptor–negative breast cancer, in either the adjuvant or prevention setting [12-14]. Granted, prophylactic oophorectomy in premenopausal BRCA1 carriers reduces breast cancer risk, suggesting protection with hormonal strategies in these women [15,16]. But oophorectomy exerts more than just an antiestrogenic effect. Other major questions facing high-risk women include the following: for the woman who has developed a first breast cancer and is facing her options for primary therapy, systemic therapy, and contralateral risk reduction, how can we simplify this very complex decision-making process? How can we help women who feel pressured to have prophylactic mastectomy, because of its high efficacy, but who fundamentally do not want to have this procedure performed? Where do we stand with respect to insurance coverage for this procedure and reconstruction? What about the women in breast cancer families, where an autosomal dominant defect appears operative, but BRCA testing is negative (currently the case in the majority of breast cancer-only families)? Rebbeck et al [9] and his team are to be commended for their efforts to bring additional data forward on the efficacy of prophylactic mastectomy. All would agree that many substantive questions still remain before us. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES 1. Ziegler LD, Kroll SS: Primary breast cancer after prophylactic mastectomy. Am J Clin Oncol 14:451-454, 1991[Medline] 2. Eldar S, Meguid MM, Beatty JD: Cancer of the breast after prophylactic subcutaneous mastectomy. Am J Surg 148:692-693, 1984[CrossRef][Medline] 3. Goodnight JE Jr, Quagliana JM, Morton DL: Failure of subcutaneous mastectomy to prevent the development of breast cancer. J Surg Oncol 26:198-201, 1984[Medline] 4. Wong JH, Jackson CF, Swanson JS, et al: Analysis of the risk reduction of prophylactic partial mastectomy in Sprague-Dawley rats with 7,12-dimethylbenzanthracene-induced breast cancer. Surgery 99:67-71, 1986[Medline]
5. Burke W, Daly M, Garber J, et al: Recommendations for follow-up care of individuals with an inherited predisposition to cancer: II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 277:997-1003, 1997
6. 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
7. Hartmann LC, Sellers TA, Schaid DJ, et al: Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 93:1633-1637, 2001
8. Meijers-Heijboer H, van Geel B, van Putten WL, et al: Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 345:159-164, 2001
9. Rebbeck T, Friebel T, Lynch H, et al: Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group. J Clin Oncol 22:1055-1062, 2004
10. Klaren HM, van't Veer LJ, van Leeuwen FE, et al: Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and BRCA2 mutation. J Natl Cancer Inst 95:941-947, 2003
11. Lakhani SR, van de Vijver MJ, Jacquemier J, et al: The pathology of familial breast cancer: Predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20:2310-2318, 2002 12. Cuzick J, Powles T, Veronesi U, et al: Overview of the main outcomes in breast-cancer prevention trials. Lancet 361:296-300, 2003[CrossRef][Medline]
13. Chlebowski RT, Col N, Winer EP, et al: American Society of Clinical Oncology technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition. J Clin Oncol 20:3328-3343, 2002
14. Fisher B, Anderson S, Tan-Chiu E, et al: Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 19:931-942, 2001
15. Kauff ND, Satagopan JM, Robson ME, et al: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346:1609-1615, 2002
16. Rebbeck T, Lynch H, Neuhausen S, et al: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346:1616-1622, 2002
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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