document: risk - reducing salpingo - oophorectomy ( rrso)the removal of the fallopian tubes and ovaries to reduce the risks of breast and ovarian cancer  is a cancer prevention strategy used by many women who carry germline mutations in the brca1 and/or brca2 genes ( brca1/2 ) . 
   however , the magnitude of the risk reductions in women with brca1/2 mutations who have undergone rrso compared with those who have not is unclear . 
   a fixed - effects meta - analysis of pooled results from 10 published reports of rrso and the risks of breast and/or ovarian or fallopian tube cancer in brca1/2 mutation carriers . 
   rrso was found to be strongly associated with substantial reductions in the risks of breast , ovarian , and fallopian tube cancers among women who carry mutations in brca1 or brca2 . 
   the summary risk reduction estimates should provide guidance to women in planning cancer risk reduction strategies . 
   data were not available to evaluate the effects of birth cohort , timing of surgery , or other factors that may influence the risk reduction estimates associated with rrso . 
   risk - reducing salpingo - oophorectomy ( rrso)the removal of the fallopian tubes and ovaries to reduce the risks of breast and ovarian cancer  is a cancer prevention strategy used by many women who carry germline mutations in the brca1 and/or brca2 genes ( brca1/2 ) . 
   however , the magnitude of the risk reductions in women with brca1/2 mutations who have undergone rrso compared with those who have not is unclear . 
   a fixed - effects meta - analysis of pooled results from 10 published reports of rrso and the risks of breast and/or ovarian or fallopian tube cancer in brca1/2 mutation carriers . 
   rrso was found to be strongly associated with substantial reductions in the risks of breast , ovarian , and fallopian tube cancers among women who carry mutations in brca1 or brca2 . 
   the summary risk reduction estimates should provide guidance to women in planning cancer risk reduction strategies . 
   data were not available to evaluate the effects of birth cohort , timing of surgery , or other factors that may influence the risk reduction estimates associated with rrso . 
   to identify all reports of rrso in brca1/2 mutation carriers , we searched the pubmed database using the search terms  oophorectomy  and  brca1  or  brca2 . 
   this search yielded 346 studies that were published between january 1999 and december 2007 : 309 that included the term  brca1  in the title and 267 that included the term 
   we then evaluated the full text of these citations to identify articles presenting primary data that provided estimates of risk reduction due to rrso . 
   no publications were excluded based on quality , sample size , language of publication , or other objective criteria related to study design and analysis . 
   however , some publications that reported rrso in brca1/2 mutation carriers were not included because they did not estimate risk reduction . 
   these included case reports , psychosocial or behavioral studies , commentaries , and clinical recommendations . 
   because the number of brca1/2 mutation carriers is relatively limited and most research groups studying these women are in routine communication and collaborate with one another , we also undertook personal communications with all of the researchers or consortia that have large series of brca1/2 mutation carriers and were known to have data that could have been used to report data on this topic . 
   we undertook a fixed - effects meta - analysis using the hazard ratios ( hrs ) and/or odds ratios ( as published in the original reports ) to estimate the pooled relative risks and 95% confidence intervals ( cis ) . 
   when two or more studies had overlapping study samples , we included only one published report from each group . 
   of the studies identified here , sample overlaps were noted in the studies of rebbeck et al . 
   ( 16 ) , which had the largest sample size of these five studies , was chosen for inclusion in the meta - analysis . 
   there were no apparent overlaps among the other datasets , although we can not rule out the possibility that a few individuals had participated in more than one study . 
   we carried out separate meta - analyses in brca1 mutation carriers , brca2 mutation carriers , and among women who carried either brca1 or brca2 mutations ( denoted brca1/2 ) . 
   a chi - square test of homogeneity among the individual risk ratio estimates of the identified studies was also performed . to evaluate potential for publication bias 
   , we used the adjusted rank correlation test of begg and mazumdar ( 20 ) . 
   all analyses were conducted using stata / se v9.0 ( statcorp , college station , tx ) . 
   to identify all reports of rrso in brca1/2 mutation carriers , we searched the pubmed database using the search terms  oophorectomy  and  brca1  or  brca2 . 
   this search yielded 346 studies that were published between january 1999 and december 2007 : 309 that included the term  brca1  in the title and 267 that included the term 
   we then evaluated the full text of these citations to identify articles presenting primary data that provided estimates of risk reduction due to rrso . 
   no publications were excluded based on quality , sample size , language of publication , or other objective criteria related to study design and analysis . 
   however , some publications that reported rrso in brca1/2 mutation carriers were not included because they did not estimate risk reduction . 
   these included case reports , psychosocial or behavioral studies , commentaries , and clinical recommendations . 
   because the number of brca1/2 mutation carriers is relatively limited and most research groups studying these women are in routine communication and collaborate with one another , we also undertook personal communications with all of the researchers or consortia that have large series of brca1/2 mutation carriers and were known to have data that could have been used to report data on this topic . 
   we undertook a fixed - effects meta - analysis using the hazard ratios ( hrs ) and/or odds ratios ( as published in the original reports ) to estimate the pooled relative risks and 95% confidence intervals ( cis ) . 
   when two or more studies had overlapping study samples , we included only one published report from each group . 
   of the studies identified here , sample overlaps were noted in the studies of rebbeck et al . 
   ( 16 ) , which had the largest sample size of these five studies , was chosen for inclusion in the meta - analysis . 
   there were no apparent overlaps among the other datasets , although we can not rule out the possibility that a few individuals had participated in more than one study . 
   we carried out separate meta - analyses in brca1 mutation carriers , brca2 mutation carriers , and among women who carried either brca1 or brca2 mutations ( denoted brca1/2 ) . 
   a chi - square test of homogeneity among the individual risk ratio estimates of the identified studies was also performed . to evaluate potential for publication bias 
   , we used the adjusted rank correlation test of begg and mazumdar ( 20 ) . 
   all analyses were conducted using stata / se v9.0 ( statcorp , college station , tx ) . 
   the studies that formed the basis of this meta - analysis included case  control studies as well as prospective and retrospective cohort studies ( table 1 ) . as can be seen in this summary , limitations of the currently available data regarding rrso in brca1/2 mutation carriers include variable study designs , small sample sizes for individual studies , many of which are retrospective in nature , and short post - rrso follow - up times in prospective studies . 
   eight studies ( 8 - 10,12 - 16 ) estimated the risk of breast cancer in brca1/2 mutation carriers who were treated with rrso relative to brca1/2 mutation carriers who did not receive this treatment ( table 2 ) . as summarized in table 3 and figure 1 , 
   three nonoverlapping studies ( 1416 ) , which included 5703 participants , estimated the risk of breast cancer in brca1/2 mutation carriers who received rrso relative to brca1/2 mutation carriers who did not receive the procedure , giving a summary hr estimate of 0.49 ( 95% ci = 0.37 to 0.65 ) . 
   four nonoverlapping studies ( 12,1416 ) estimated the risk reduction associated with rrso for breast cancer in brca1 mutation carriers , giving a summary hr estimate of 0.47 ( 95% ci = 0.35 to 0.64 ) . finally , three nonoverlapping studies ( 1416 ) estimated the relative risk for breast cancer in brca2 mutation carriers , giving a summary hr estimate of 0.47 ( 95% ci = 0.26 to 0.84 ) ( table 3 , figure 1 ) 
   . published studies of risk - reducing salpingo - oophorectomy and cancer risk in brca1/2 mutation carriers * in all but one of the prospective cohort studies , women with a prior diagnosis of breast cancer were included for the ovarian endpoint . in domchek 
   et al . ( 13 ) all patients were unaffected with breast or ovarian cancer at the start of follow - up , as the study was designed to evaluate the impact of rrso on cancer incidence as well as disease - specific and overall survival . 
   b1 = brca1 mutation carriers ; b2 = brca2 mutation carriers ; b1/2 = combined brca1 or brca2 group ; pc = prospective cohort ; rc = retrospective cohort ; cc = case  control ; namc = north american multicenter cohort ; sis = single - institution study ; imc = international multicenter cohort ; ismc = israeli multicenter cohort ; emc = european multicenter cohort ; myfu = mean years of follow - up ; py = person - years ; nr = not reported ; and na = not applicable ; rrso = risk - reducing salpingo - oophorectomy . in the original publications , 
   the prospective and retrospective cohorts were analyzed by survival / failure time analysis methods ; the case  control studies were analyzed by logistic regression . 
   six studies ( 8,10,11,13,16,17 ) ( table 2 ) estimated the risk of gynecologic cancer in brca1/2 mutation carriers treated with rrso relative to brca1/2 mutation carriers who did not receive this treatment . based on data from the three nonoverlapping datasets ( 11,16,17 ) , which included 2840 participants , the summary hr was 0.21 ( 95% ci = 0.12 to 0.39 ) ( table 3 , figure 1 ) . only one study ( 16 ) estimated the risk of gynecologic cancer in brca1 mutation carriers treated with rrso relative to untreated brca1 carriers ( hr = 0.15 , 95% ci = 0.04 to 0.56 ) ( table 2 ) . 
   ( 16 ) did investigate risk reduction in 294 women with brca2 mutations , but observed no post - rrso gynecologic cancers in this sample . 
   published studies of risk - reducing salpingo - oophorectomy and cancer risk in brca1/2 mutation carriers * hazard ratios ( hrs ) , odds ratios ( ors ) ( with 95% confidence intervals ) , and sample size ( n ) are presented . 
   na = not applicable . not included in summary hr estimate because the sample set overlaps with that of other reports . 
   studies included in the summary estimate were chosen to maximize the sample size ( power ) of the meta - analysis . 
   we found no evidence of publication bias of any of our estimates based on the begg and majumder test statistics presented in table 3 . 
   no evidence of study heterogeneity was found based on the x test ( table 3 ) . 
   summary estimates for ovarian / fallopian tube cancer and breast cancer risk reduction associated with salpingo - oophorectomy in brca1/2 mutation carriers * na = not applicable ; hr = hazard ratio ; ci = confidence interval . according to begg and mazumder ( 20 ) . 
   the clinical management of cancer risk in brca1 and brca2 mutation carriers is complex and should consider patient preferences ; these preferences can be informed by accurate knowledge of the risks and benefits of the interventions considered ( table 4 ) . 
   the results of our meta - analysis suggest an 80% reduction in ovarian / fallopian tube cancer risk and a 50% reduction in breast cancer risk associated with rrso in women who carry mutations in brca1 or brca2 . 
   the consistency of these findings across the included studies confirms the strong association of rrso with reduced risks of breast and ovarian cancer in brca1 or brca2 mutation carriers . 
   in addition , modeling studies have also demonstrated that salpingo - oophorectomy has a large effect on years of life added , particularly when adjusted for quality of life ( 31 ) . 
   furthermore , in a prospective study with short - term follow - up , rrso was associated with a 90% reduction in breast cancer  specific mortality , a 95% reduction in gynecologic cancer  specific mortality , and a 76% reduction in overall mortality ( 13 ) . 
   therefore , all of the available data demonstrate the utility of salpingo - oophorectomy in this population of patients . 
   synopsis of management strategies available to brca1 and brca2 mutation carriers * rrso = risk - reducing salpingo - oophorectomy ; er = estrogen receptor ; mri = magnetic resonance imaging . despite the consistent evidence favoring rrso in women with mutations in brca1 or brca2 , 
   first , the influence of cohort effects on cancer risk over time remain unclear , despite evidence that differences in risk over time may reflect changing exposures , lifestyle , reproductive history , and use of screening or preventive surgeries ( 32 ) . 
   we lacked the data necessary to evaluate the effects of birth cohort , timing of surgery , or other factors that may influence the risk reduction estimates associated with rrso . 
   therefore , at this time it is difficult to infer whether specific cohorts , exposure groups , or other strata may experience different risk reduction effects than others . to limit the possibility that reporting bias influenced our findings 
   however , we did not include any studies that reported the association of rrso with cancer risk without providing estimates of risk reduction because these data would not contribute to pooled estimates of risk reduction . because some studies included in the this analysis were limited in sample size and statistical power , their effect estimates for rrso were large but not statistically significant , suggesting that a meta - analysis and presentation of summary statistics was appropriate . 
   two studies ( 15,17 ) were included in the summary estimates even though they used case  control designs , and therefore they yielded odds ratios rather than hazard ratios . 
   although odds ratios may slightly overestimate the risk reduction associated with rrso , the annual incidence of ovarian and breast cancer in brca1/2 mutation carriers is no more than 2%4% , with the result that odds ratios are likely to be similar to hazard ratios in this setting . 
   some of the variability in the individual study estimates reported may reflect study design differences , including the use of retrospective vs prospective samples and poorly characterized selection biases . despite these differences , we noted no statistically significant heterogeneity in the estimates of risk reduction after rrso . 
   in addition , cohort studies estimated a greater reduction in cancer risk associated with rrso ( particularly ovarian / fallopian tube cancers ) compared with the case  control studies ( table 1 ) . 
   as a result , there is some variability in the estimates obtained using case  control and cohort studies ; nonetheless , the estimates all consistently reflect risk reduction associated with rrso . 
   we have included all of the large collaborative group studies that addressed the question of reduced risk conferred by rrso and whose study populations come from and are representative of mutation carriers in north america and europe . 
   no studies of rrso in nonwhite populations have been reported , and additional data may be needed to understand the role of rrso in these groups . finally , the samples of women with brca1/2 mutations reported here represent those who have generally been identified through high - risk clinics . 
   however , they do represent the population of women who receive genetic testing and may be candidates for rrso . 
   therefore , the populations summarized here represent the most relevant group in whom rrso may be applied at this time . despite the strength and consistency of the data in the literature as reflected in our meta - analysis , a number of questions remain . 
   there are only a few estimates of the association of rrso with cancer risk in populations composed exclusively of brca1 mutation carriers or brca2 mutation carriers ( 12,1416 ) , and it is critical to understand how risk reduction may differ by gene . using a prospective cohort approach and a large consortium dataset , we recently estimated gene - specific risks and found that hormonal modulation by rrso may be associated with a greater reduction in breast cancer risk in brca2 mutation carriers than in brca1 mutation carriers ( 16 ) . 
   in contrast , the studies that used retrospective cohort ( 14 ) or case  control approaches ( 14,15 ) did not observe this difference , and therefore , there was no difference in the pooled estimates of breast cancer risk reduction reported in table 1 . 
   thus , differences in study design may influence the inferences we can make about the differences in risk reduction associated with rrso in brca1 vs brca2 mutation carriers . 
   the potentially larger risk reduction associated with rrso in brca2 vs brca1 mutation carriers is of interest , given the high proportion of estrogen receptor ( er)negative breast tumors in brca1 mutation carriers compared with brca2 mutation carriers ( 33 ) . 
   our observation of a higher risk in brca2 mutation carriers should be followed up in larger studies that specifically evaluate tumor markers . 
   in addition , attention needs to be given to the time interval between rrso and breast cancer diagnosis . 
   for example , it is possible that there is greater breast cancer risk reduction in brca2 mutation carriers , in whom the majority of tumors are er positive , given that rrso may treat some subclinical breast tumors . 
   in contrast , in brca1 mutation carriers , who have predominantly er - negative breast cancer , it is unclear whether a  treatment effect  may exist , and any primary prevention effect may require more time to emerge . 
   eisen et al . ( 15 ) reported that the breast cancer risk reduction with rrso was greater in brca1/2 mutation carriers who underwent surgery before age 50 than in women who underwent surgery after age 50 . among brca1 mutation carriers older than age 50 , 
   no statistically significant association of rrso at any age with risk reduction was observed in brca2 mutation carriers . although these findings are consistent with effects of removal of hormone exposures in premenopausal women and not in postmenopausal women , the sample sizes in this analysis ( 15 ) were relatively small . 
   the importance of understanding the optimal age at which a woman should consider rrso is underscored by a recent study ( 34 ) conducted in the general population that suggests that rrso in women younger than age 45 is associated with an increased mortality , particularly if hormone replacement therapy ( hrt ) is not used . 
   an initial report of hrt use after rrso suggests that women can undergo rrso and take hrt for a short time if needed after surgery because breast cancer risk is not substantially elevated in hrt users after rrso ( 35 ) . 
   although data on postmenopausal women do not demonstrate a cardiovascular benefit from hrt ( 36 ) , an important limitation of this study ( 36 ) was the older age of the participants . 
   more recent data have suggested that younger women going through natural menopause may indeed derive a cardiovascular benefit from hrt ( 36,37 ) , and it is possible that brca1/2 mutation carriers undergoing abrupt surgical menopause to reduce ovarian cancer risk who receive hrt may in fact derive important cardiovascular , bone health , and quality - of - life benefits . although the risk  benefit ratio of rrso is very different in brca1/2 mutation carriers than in the general population , and rrso in brca1/2 mutation carriers has been associated with improved overall survival in the short term , these studies pointing to the potentially complex relationship of rrso and hrt exposure raise important and difficult questions . 
   for example , it is not yet clear whether the long - term effects of long - term hrt in unaffected mutation brca1/2 carriers will ultimately be more beneficial in preventing noncancer mortality in these women or more harmful by increasing their risk of breast cancer ( or potentially increasing cardiovascular events ) compared with the general population . given this possibility , studies that address the type , timing , and length of administration of hrt as well as its long - term effects on the association between rrso and cancer risk and on other health factors in brca1/2 mutation carriers 
   , we provide a summary of clinical recommendations related to the detection and prevention of cancer in brca1/2 mutation carriers ( table 4 ) . 
   finally , although rrso has become the standard of care for cancer risk reduction in women who have inherited brca1/2 mutations , other options for risk reduction also exist . 
   women with brca1/2 mutations who have been treated with risk - reducing mastectomy have a substantially reduced breast cancer risk ( 30 ) . 
   furthermore , a study of breast cancer screening that added yearly magnetic resonance imaging to screening mammography suggested that combination of these modalities may also have benefit in the early detection of breast cancer in this group of women ( 28 ) . in conclusion , the summary risk reduction estimates presented here confirm that brca1/2 mutation carriers who have been treated with rrso have a substantially reduced risk of both breast and ovarian cancer . 
   therefore , additional cancer risk reduction and screening strategies are required to maximally reduce cancer incidence and mortality in this high - risk population . 
   forest plots of relative risk ( rr ) estimates for risk reduction associated with risk - reducing salpingo - oophorectomy ( rrso ) . 
   the box sizes reflect the relative sample sizes of the individual studies ; horizontal lines represent 95% confidence intervals ( cis ) . 
   estimates less than a value of 1.0 suggest a favorable reduction in cancer risk associated with rrso . 
   national institutes of health ( r01-ca083855 and r01-ca102776 to trr ) ; the department of defense breast cancer research program ( damd17 - 03 - 1 - 0375 to ndk ) ; the cancer genetics network ( hhsn21620074400c to smd ) ; the eileen genet fund and the project hope fund for ovarian cancer research and education .
summary: backgroundrisk - reducing salpingo - oophorectomy ( rrso ) is widely used by carriers of brca1 or brca2 ( brca1/2 ) mutations to reduce their risks of breast and ovarian cancer . to guide women and their clinicians in optimizing cancer prevention strategies 
   , we summarized the magnitude of the risk reductions in women with brca1/2 mutations who have undergone rrso compared with those who have not.methodsall reports of rrso and breast and/or ovarian or fallopian tube cancer in brca1/2 mutation carriers published between 1999 and 2007 were obtained from a pubmed search . 
   hazard ratio ( hr ) estimates were identified directly from the original articles . 
   pooled results were computed from nonoverlapping studies by fixed - effects meta-analysis.resultsten studies investigated breast or gynecologic cancer outcomes in brca1/2 mutation carriers who had undergone rrso . 
   breast cancer outcomes were investigated in three nonoverlapping studies of brca1/2 mutation carriers , four of brca1 mutation carriers , and three of brca2 mutation carriers . 
   gynecologic cancer outcomes were investigated in three nonoverlapping studies of brca1/2 mutation carriers and one of brca1 mutation carriers . 
   rrso was associated with a statistically significant reduction in risk of breast cancer in brca1/2 mutation carriers ( hr = 0.49 ; 95% confidence interval [ ci ] = 0.37 to 0.65 ) . 
   similar risk reductions were observed in brca1 mutation carriers ( hr = 0.47 ; 95% ci = 0.35 to 0.64 ) and in brca2 mutation carriers ( hr = 0.47 ; 95% ci = 0.26 to 0.84 ) . 
   rrso was also associated with a statistically significant reduction in the risk of brca1/2-associated ovarian or fallopian tube cancer ( hr = 0.21 ; 95% ci = 0.12 to 0.39 ) . 
   data were insufficient to obtain separate estimates for ovarian or fallopian tube cancer risk reduction with rrso in brca1 or brca2 mutation carriers.conclusionthe summary estimates presented here indicate that rrso is strongly associated with reductions in the risk of breast , ovarian , and fallopian tube cancers and should provide guidance to women in planning cancer risk reduction strategies .