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Effectiveness of Prophylactic Surgeries in BRCA1 Or BRCA2

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Effectiveness of Prophylactic Surgeries in BRCA1 Or BRCA2 Published OnlineFirst March 15, 2016; DOI: 10.1158/1078-0432.CCR-15-1465 Biology of Human Tumors Clinical Cancer Research Effectiveness of Prophylactic Surgeries in BRCA1 or BRCA2 Mutation Carriers: A Meta-analysis and Systematic Review Xiao Li1,2,RanYou3, Xinwei Wang4, Congxin Liu5, Zicheng Xu1, Jin Zhou1, Bin Yu1, Ting Xu1, Hongzhou Cai1, and Qing Zou1 Abstract Purpose: To systematically investigate the effectiveness of tralateral prophylactic mastectomy (CPM) significantly decreased prophylactic surgeries (PS) implemented in women carrying contralateral breast cancer incidence in BRCA1/2 mutation carriers BRCA1/2 mutations. (RR, 0.072; 95% CI, 0.035–0.148). Of note, PBSO was associated Experimental Design: The PubMed database was searched with significantly lower all-cause mortality in BRCA1/2 mutation till August 2014 and 15 studies met the inclusion criteria. carriers without breast cancer (HR, 0.349; 95% CI, 0.190–0.639) Fixed- or random-effects models were conducted according to and those with breast cancer (HR, 0.432; 95% CI, 0.318–0.588). study heterogeneity. We calculated the pooled relative risks In addition, all-cause mortality was significantly lower for patients (RR) for cancer risk or mortality along with 95% confidence with CPM than those without (HR, 0.512; 95% CI, 0.368–0.714). intervals (CI). However, BPM was not significantly associated with reduced all- Results: Prophylactic bilateral salpingo-oophorectomy (PBSO) cause mortality. Data were insufficient to obtain separate esti- and bilateral prophylactic mastectomy (BPM) were both associ- mates of survival benefit with PS in BRCA1 or BRCA2 mutation ated with a decreased breast cancer risk in BRCA1/2 mutation carriers. carriers (RR, 0.552; 95% CI, 0.448–0.682; RR, 0.114; 95% CI, Conclusions: BRCA1/2 mutation carriers who have been trea- 0.041–0.317, respectively). Similar findings were observed in ted with PS have a substantially reduced breast cancer incidence BRCA1 and BRCA2 mutation carriers separately. Moreover, con- and mortality. Clin Cancer Res; 1–11. Ó2016 AACR. Introduction (CBC). The estimated cumulative lifetime risk of CBC is 20% to 83% for BRCA1/2 mutation carriers (3–7). Women, who carry a deleterious mutation in breast cancer BRCA1/2 mutation carriers are advised to consider different susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene risk-reducing strategies, including surveillance (breast self-exam- 2(BRCA2), have a high lifetime risk of developing breast cancer, ination, clinical breast examination, screening using mammog- clearly above the risk for the general population. By the age of 70 raphy and breast magnetic resonance imaging), chemoprevention years, the breast cancer risk is 40% to 80% for BRCA1 or BRCA2 and prophylactic surgery (8). However, the risk-reducing methods mutation carriers (1, 2). Besides, women with BRCA1 or BRCA2 vary in their effectiveness. For about 20 years, researchers have mutation and a history of primary breast cancer (PBC) have a studied whether prophylactic surgery can reduce the cancer and significantly elevated risk of developing contralateral breast cancer mortality risk in BRCA1/2 mutation carriers. Prophylactic mastectomy (PM) implies either a bilateral pro- phylactic mastectomy (BPM) in high-risk unaffected women or a 1Department of Urology, The Affiliated Cancer Hospital of Jiangsu contralateral prophylactic mastectomy (CPM) after a unilateral Province of Nanjing Medical University, Nanjing, China. 2Department therapeutic mastectomy. It has been demonstrated that BPM is a of Urology, The First Affiliated Hospital of Nanjing Medical University, highly effective strategy to reduce the risk of breast cancer at high Nanjing, China. 3Department of Intervention, Affiliated Hospital of Nantong University, Nantong, China. 4Department of Oncology, The risk (9, 10). CPM is also considered to be the most effective option Affiliated Cancer Hospital of Jiangsu Province of Nanjing Medical for CBC risk reduction (11, 12). However, the ultimate goal of PM 5 University, Nanjing, China. Department of General Surgery, Zhongda is to improve survival, eventually being the reason for a woman to Hospital Affiliated to Southeast University, Nanjing, China. decide for this drastic intervention. A prospective cohort study Note: Supplementary data for this article are available at Clinical Cancer carried out by Heemskerk-Gerritsen and colleagues (13) showed Research Online (http://clincancerres.aacrjournals.org/). that after BPM, all-cause mortality and breast cancer–specific X. Li, R. You, and X. Wang contributed equally to this article. mortality rates were reduced, compared with surveillance, but Corresponding Authors: Hongzhou Cai, Department of Urology, The Affiliated significant survival benefits could not be claimed. On the other Cancer Hospital of Jiangsu Province of Nanjing Medical University, 42 Baiziting hand, data on survival of PBC patients with BRCA1/2 mutation Road, Nanjing 210009, China. Phone: 8615950539694; Fax: 8602583780079; who opt for subsequent CPM were inconsistent. Some studies E-mail: [email protected]; and Qing Zou, Phone: 8613905173337, showed improved survival after CPM (14, 15), while others did [email protected] not (11, 16). doi: 10.1158/1078-0432.CCR-15-1465 Prophylactic bilateral salpingo-oophorectomy (PBSO) has Ó2016 American Association for Cancer Research. also been shown to reduce breast cancer risk in mutation www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst March 15, 2016; DOI: 10.1158/1078-0432.CCR-15-1465 Li et al. Translational Relevance Materials and Methods Search strategy This report compiles data from 15 studies independently. In To identify all reports of risk-reducing surgery, including PBSO, this article, we identified that prophylactic bilateral salpingo- BPM, and CPM in BRCA1 or BRCA2 mutation carriers, we oophorectomy (PBSO) and bilateral prophylactic mastectomy searched the PubMed database using the search terms "breast (BPM) were both associated with a decreased breast cancer risk cancer" and "BRCA1"or"BRCA2". The search yielded 4,574 in breast cancer susceptibility gene 1 (BRCA1) or breast cancer studies that were published between August 2014 and September susceptibility gene 2 (BRCA2) mutation carriers. Similar find- 1999. ings were observed in BRCA1 and BRCA2 mutation carriers Three reviewers independently evaluated titles and abstracts of separately. Moreover, contralateral prophylactic mastectomy the identified papers. We also reviewed the references in identified (CPM) significantly decreased contralateral breast cancer inci- articles for possible inclusions. Only those published studies in dence in BRCA1/2 mutation carriers. Notably, PBSO was English language with full-text articles were included in this meta- associated with significantly lower all-cause mortality in analysis. The research did not reveal any additional unpublished BRCA1/2 mutation carriers without breast cancer and those studies. with breast cancer. In addition, all-cause mortality was signif- icantly lower for patients with CPM than those without. Criteria for inclusion and exclusion fi However, BPM was not signi cantly associated with reduced Studies were included in our meta-analysis and systematic all-cause mortality. The results could be utilized by health care review if they met the following criteria: (i) case–control studies professionals. or cohort studies, (ii) both case and control subjects were women who carried a deleterious BRCA1 or BRCA2 mutation, (iii) studies provided estimates of breast cancer risk reduction or mortality due to prophylactic surgeries, including PBSO, BPM, and CPM, and (iv) relative risk (RR) and the corresponding 95% confidence carriers. According to the National Comprehensive Cancer interval (CI) were reported, or sufficient published data for BRCA1/2 Network guidelines, PBSO is recommended for all estimating a RR with 95% CI. Articles reporting only on the mutation carriers by age 35 to 40 or once childbearing is utilization of the prophylactic strategies by BRCA1 or BRCA2 fi complete. However, the reported ef cacy of PBSO in reducing mutation carriers were excluded. Studies of attitudes, reactions, the risk of breast cancer has varied widely, from 38% to 72% screening, and chemoprevention practices in BRCA1/2 mutation – (17 21). It has also been suggested that the effect of PBSO carriers were also excluded. BRCA1 BRCA2 differs between and mutation carriers. Eisen and When two or more articles had overlapping study samples, the colleagues (17) demonstrated that PBSO may be associated most recent article based on the largest study population was BRCA1 with a lower breast cancer risk in mutation carriers than selected. Of the studies identified here, sample overlaps were BRCA2 that in mutation carriers (56% vs. 43%). While Kauff noted in the studies of Rebbeck and colleagues (24, 25), Kauff and fi and colleagues (20) observed a statistically signi cant breast colleagues (20, 26), Domchek and colleagues (23, 27), and BRCA2 BRCA1 cancer risk reduction following PBSO in but not Finkelman and colleagues (21). Finkelman and colleagues (21) mutation carriers. was more recent with larger sample size than the other studies, it Although some studies showed that PBSO reduced the risk of was chosen for inclusion in the meta-analysis. However, among fi breast cancer signi cantly, that such risk reduction translated articles with overlapping study samples,
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