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Originally published as JCO Early Release 10.1200/JCO.2008.21.0518 on February 17 2009 © 2009 American Society of Clinical Oncology.
Contralateral Prophylactic Mastectomy: Caveat EmptorDepartment of Radiation Oncology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA In this issue of Journal of Clinical Oncology, Tuttle et al1 show that the use of contralateral prophylactic mastectomy (CPM) in patients with newly diagnosed ductal carcinoma in situ (DCIS) increased from 2.1% in 1998 to 5.2% in 2005. This finding is similar to their previous study for patients with stage I to III invasive cancer, for whom the rate of CPM increased from 1.8% in 1998 to 4.5% in 2003.2 This development is even more striking in view of the modest but statistically significant increased rates of ipsilateral breast-conserving therapy (BCT) both studies observed over the same time. Further, these are likely underestimates of the ultimate rates of CPM, as the Surveillance, Epidemiology, and End Results database only captured surgeries occurring within 6 months of initial diagnosis. Is this development justified by what we know about CPM? CPM nearly eliminates patients' risk of developing contralateral breast cancer (CBC).3–7 However, it is much less clear whether or by how much CPM improves long-term breast cancer–specific survival (BCSS) rates. Such an effect would seem most likely for patients with proven BRCA1 or BRCA2 mutations, whose risk of developing CBC (without intervention) is 25% to 30% at 10 years.8–10 A study from Rotterdam of 223 patients with breast cancer (51 of whom had CPM) with a median follow-up of 5.1 years found that CPM did not affect BCSS on multivariate analysis.10 Another study from this group with similar follow-up that included 260 patients (38 of whom had CPM) who underwent genetic testing within 2 years of diagnosis came to the same conclusion.11 Two studies of women not uniformly having genetic testing found improved outcome in patients undergoing CPM. One, performed at the City of Hope National Medical Center in Duarte, CA, compared 64 patients undergoing CPM with 182 patients matched for decade of treatment, age, stage, the presence of lobular carcinoma in situ, type of ipsilateral surgery, and use of chemotherapy and hormonal therapy.12 With a mean follow-up time of 6.8 years, the risk of distant failure in the CPM group was 19%, compared with 29% for the control group. The 15-year overall survival rates in the two groups were 64% and 49%, respectively; BCSS rates were 71% and 53%, respectively, for the 59 CPM and 170 control patients with stage 0 to II disease. However, patients were not matched for length of follow-up before CPM. A much larger retrospective study used the tumor registries of four American health maintenance organizations to compare cancer-specific outcome of 908 patients who had CPM with that of 46,368 patients who did not.13 With median follow-up times of 5.7 years and 4.8 years in the two groups, their respective rates of breast cancer death were 8.1% and 11.7%. Adjustment for tumor and treatment characteristics (including CPM as a time-varying covariate) found CPM to be associated with statistically significant hazard ratios of 0.57 and 0.60, respectively, for death from breast cancer and all-cause mortality. It is difficult to imagine how CPM could produce such large differences in outcome over such short follow-up. This suggests that other factors were responsible, such as differences in patient treatment.14 Neither study examined the effect of socioeconomic status,15 which affects breast cancer outcome even within homogeneous national health care systems.16,17 A recent study in Stockholm found that women attending a genetic clinic were of substantially higher socioeconomic status than the average for the region.18 Socioeconomic status did not affect rates of CPM in a study of patients at high risk in the Netherlands,19 but recent studies showed it influenced rates of immediate breast reconstruction surgery in Maryland20 and how often physicians discussed reconstructive surgery with patients in Los Angeles, CA.21 Hence it seems plausible that CPM was a surrogate for higher socioeconomic status in these two studies, rather than exerting a direct effect on BCSS. Several studies of women not yet having breast cancer found reduced cancer-related anxiety after bilateral prophylactic mastectomy, though the degree varied among patients.22–24 However, a prospective study of high-risk patients with newly diagnosed DCIS or invasive cancer who underwent genetic counseling at Georgetown University before definitive ipsilateral local therapy showed no difference in cancer-specific distress rates at 1 year after genetic testing between patients undergoing CPM and those who did not.25 A retrospective study performed by these investigators found similar results.26 Further, although overall quality of life of patients undergoing CPM seems similar to their presurgical level,25 a significant minority develop changes in body self-image or sexuality after CPM or have lingering doubts about whether they did the right thing.7,24,27–30 If there is so little convincing evidence about the benefits of CPM, why is its use increasing? No studies I know of describe what genetic counselors or breast cancer physicians actually tell patients CPM can accomplish. Physicians' beliefs and recommendations strongly influence patients' decisions whether to have ipsilateral BCT or mastectomy,31,32 and I suspect the same holds for CPM. Still, patients often think interventions can improve survival, even when explicitly told they do not.33,34 I believe another reason is that some caregivers recommend ipsilateral mastectomy for patients with strong family histories or BRCA1/2 mutations because they feel ipsilateral BCT is not effective in this group. This in turn lowers the psychologic barrier to CPM. However, most studies found little or no difference in ipsilateral local failure rates between patients with BRCA1/2 mutations and unaffected patients.9–11,35 Other studies do suggest BRCA1/2 mutation carriers have an increased rate of late local failure, likely as a result of the development of new primary cancers.36,37 This risk, however, can be reduced by tamoxifen or oophorectomy.9 Further, a recent collaboration between investigators in the United States and Israel found that 15-year actuarial distant failure rates were the same (11% and 13%, respectively) for 160 BRCA1/2 mutation carriers treated with BCT (despite an ipsilateral local failure rate of 21.5%), compared with 213 patients treated with mastectomy (60 of whom also received radiotherapy), after a mean follow-up of 10 years.38 In sum, we really know very little about CPM. It nearly completely prevents CBC. However, hormonal manipulation also reduces this risk, albeit less effectively, without the trauma of mastectomy and reconstruction.8,9,39,40 Newer technology, such as magnetic resonance imaging,41–43 may detect CBC at an earlier, more curable point than in the past, though this is not yet proven. Even so, it is not likely that all CBCs will be cured. Thus it is plausible to argue that CPM might result in superior long-term BCSS—but that is not the same as having solid evidence that it does, or (more importantly, perhaps) knowing exactly how much difference it might make. (Would patients have CPM to improve their cure rate by 1% at 10 to 20 years?) Few studies so far have examined this question, and their power to answer it is limited by small patient numbers and short follow-up. Regardless of any survival benefit, some patients may feel CPM will give them greater peace of mind, but they should realize this effect may be substantially diminished by their remaining anxiety about having cancer, even one as highly curable as DCIS.44 Come to think of it, didn't we debate these same issues for the ipsilateral breast when BCT was new? We did—but this time it is unlikely that randomized trials will show which of our prejudices and assumptions are wrong. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
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Eisen A, Lubinski J, Klijn J, et al: Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: An international case-control study. J Clin Oncol 23:7491–7496, 2005. 40. Kauff ND, Domchek SM, Friebel TM, et al: Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: A multicenter, prospective study. J Clin Oncol 26:1331–1337, 2008. 41. Kriege M, Brekelmans CT, Boetes C, et al: Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 351:427–437, 2004. 42. Warner E, Plewes DB, Hill KA, et al: Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA 292:1317–1325, 2004. 43. Kuhl CK, Schrading S, Leutner CC, et al: Mammography, breast ultrasound, and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer. 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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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