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The Role of BRCA Status on the Prognosis of Patients with Epithelial Ovarian Cancer: A Systematic Review of the Literature with a Meta-Analysis

The Role of BRCA Status on the Prognosis of Patients with Epithelial Ovarian Cancer: A Systematic... Objective: The role of BRCA dysfunction on the prognosis of patients with epithelial ovarian cancer (EOCs) remains controversial. This systematic review tried to assess the role of BRCA dysfunction, including BRCA1/2 germline, somatic mutations, low BRCA1 protein/mRNA expression or BRCA1 promoter methylation, as prognostic factor in EOCs. Methods: Studies were selected for analysis if they provided an independent assessment of BRCA status and prognosis in EOC. To make it possible to aggregate survival results of the published studies, their methodology was assessed using a modified quality scale. Results: Of 35 evaluable studies, 23 identified BRCA dysfucntion status as a favourable prognostic factor. No significant differences were detected in the global score of quality assessment. The aggregated hazard ratio (HR) of overall survival (OS) of 34 evaluable studies suggested that BRCA dysfunction status had a favourable impact on OS (HR = 0.69, 95% CI 0.61– 0.79), and when these studies were categorised into BRCA1/2 mutation and low protein/mRNA expression of BRCA1 subgroups, all of them demonstrated positive results (HR = 0.67, 95% CI: 0.57–0.78; HR = 0.62, 95% CI: 0.51–0.75; and HR = 0.51, 95% CI: 0.33–0.78, respectively), except for the subgroup of BRCA1 promoter methylation (HR = 1.59, 95% CI: 0.72–3.50). The meta-analysis of progression-free survival (PFS), which included 18 evaluable studies, demonstrated that BRCA dysfunction status was associated with a longer PFS in EOC (HR = 0.69, 95% CI: 0.63–0.76). Conclusions: Patients with BRCA dysfunction status tend to have a better outcome, but further prospective clinical studies comparing the different BRCA statuses in EOC is urgently needed to specifically define the most effective treatment for the separate patient groups. Citation: Sun C, Li N, Ding D, Weng D, Meng L, et al. (2014) The Role of BRCA Status on the Prognosis of Patients with Epithelial Ovarian Cancer: A Systematic Review of the Literature with a Meta-Analysis. PLoS ONE 9(5): e95285. doi:10.1371/journal.pone.0095285 Editor: Alexander James Roy Bishop, University of Texas Health Science Center at San Antonio, United States of America Received October 18, 2013; Accepted March 26, 2014; Published May 1, 2014 Copyright:  2014 Sun et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. * E-mail: gumpc@126.com (GC); dma@tjh.tjmu.edu.cn (DM) . These authors contributed equally to this work. mutation status and the prognosis of EOC in subsequent studies, Introduction generating conflicting results [3–8]. Although, the mechanism Epithelial ovarian carcinoma (EOC) is the fifth leading cause of underlying the association between BRCA1/2 germline mutations cancer death in women [1], and the five-year relative survival rates and survival is not fully understood, in vitro experiments have for the late stage of EOC were less than 10% between 2004 and shown that BRCA1/2 deficient cells display a deficiency in 2008 [2]. Despite advances in surgery and the wide use of repairing double-strand DNA breaks by homologous recombina- platinum-based chemotherapy, the long-term outcome remains tion [9–11]. This biological mechanism may be responsible for poor as a result of recurrences and the emergence of drug increased chemo-sensitivity, which results in a longer progression- resistance, necessitating the discovery of biomarkers for predicting free survival (PFS) and overall survival (OS) [12]. More inspiringly, which patients will benefit or not benefit from systemic chemo- BRCA1/2 mutation carries can obtain an excellent response from therapy. Moreover, the lack of active therapeutic agents for targeted therapies, such as the poly (ADP) ribose polymerase patients with platinum-resistant cancers impels researchers to (PARP) inhibitor (Olaparib) [13,14]. However, BRCA1/2 germ- discover novel molecular targets helping define subsets of patients line mutation carriers only account for 10% to 15% of EOCs. who may benefit the most from specific treatment. Fortunately, recent data suggest that many sporadic EOCs display In 1996, a detailed case-control analysis reported that BRCA1/ ‘‘BRCAness’’, or dysfunction of BRCA1/2. Additionally, in 2 germline mutations were beneficial prognostic factors for sporadic EOCs, low BRCA1 expression detected by immunohis- patients with EOC [3]. Since then, many scientists have tried to tochemistry (IHC) or RT-PCR or BRCA1 promoter methylation discover the real association between BRCA1/2 germline PLOS ONE | www.plosone.org 1 May 2014 | Volume 9 | Issue 5 | e95285 BRCA Status and Survival of Patients with EOC had also been reported as a clinically useful tool to provide groups of BRCA dysfunction and normal BRCA status was , important information on prognosis [15]. 0.05. The study was called ‘positive’ when BRCA dysfunction The aim of this study was to assess the role of BRCA status was found as a favourable prognostic factor for survival. dysfunction status, including BRCA1/2 germline/somatic muta- Other situations were called ‘negative’, including when a tions, low BRCA1 protein/mRNA expression or BRCA1 significant survival difference was found, but the group of patients promoter methylation in sporadic EOCs, on prognosis in EOCs with BRCA dysfunction status fared worse. by carrying out a systematic review of the literature followed by a Non-parametric tests were used to compare the distribution of meta-analysis, and to estimate to what extent do these BRCA the quality scores according to the value of a discrete variable statuses influence patients’ prognosis. (Mann-Whitney tests). For the quantitative aggregation of the survival results, we measured the impact of BRCA dysfunction status on prognosis by Methods the hazard ratio (HR) between the survival distributions of the two Publication Selection BRCA status groups. For each study, the HR was extracted or This study has been registered at the International Prospective estimated by a method that depended on the results provided in Register of Systematic Reviews (PROSPERO, http://www.crd. the publication. The most accurate method was to retrieve the HR york.ac.uk/prospero/display_record. estimate and its variance from the reported results or to calculate it asp?ID = CRD42011001747) in 2011. An electronic search of directly using parameters provided by the authors for univariate Medline, Embase, and CNKI (China National Knowledge analysis: the confidence interval (CI) for the HR, the log-rank Infrastructure) was used to select articles with the following statistic, its P-value or the O-E statistic (difference between keywords: ‘ovarian neoplasm’, ‘ovarian tumour’, ‘ovarian carci- numbers of observed and expected events). If these parameters noma’, ‘ovarian malignance’ or ‘ovarian cancer’ and ‘BRCA1’, were not available, we evaluated the total number of events, the ‘BRCA2’ or ‘BRCA*’ and ‘prognos*’, ‘surviv*’, ‘outcome’ or number of patients at risk in each group and the log-rank statistic ‘marker’. This search strategy was complemented by examining or it’s P-value, allowing for the calculation of an approximation of the personal bibliography of the authors. To avoid overlap the HR estimate. Finally, if the only useful data were in the form of between patient populations, when authors reported results graphical representations of the survival distributions, we extracted obtained on the same patient cohorts in several publications, only survival rates at specified times to reconstruct the HR estimate and the most recent report or the most complete one was included in its variance, with the assumption that during the study follow-up, the analysis. The search was updated in September 2013. A study the rate of patients censored was constant [17]. If this latter must have been published as a full paper in the English or Chinese method was used, three independent persons read the curves to language. To be eligible for inclusion, studies had to meet the reduce imprecision in the reading variations. following criteria: addressed epithelial ovarian cancer and If survival was reported separately for particular subgroups, analysed patients’ prognosis according to BRCA statuses (assessed these results were included in the meta-analysis of the correspond- BRCA1/2 mutations, assessed BRCA1/2 protein expression ing subgroups. The same patients were never considered more through IHC or assessed mRNA level through RT-PCR, and/ than once in each analysis. The individual HR estimates were or assessed BRCA1 promoter methylation in the primary tumour combined into an overall HR using the method published by (not in metastatic tissue or in tissue adjacent to the tumour)). The Yusuf S and Peto R et al [18]. If the assumption of homogeneity primary outcome was overall survival (OS) and the secondary had to be rejected, we used a random-effects model as a second outcome was progression-free survival (PFS). step. By convention, an observed HR ,1 implied better survival for the group with BRCA dysfunction status. This impact of Data Extraction and Methodological Assessment BRCA status on survival was considered to be statistically The data retrieved from the reports included authors, years of significant if the 95% CI for the overall HR did not include 1. studies and publications, patients’ resources, population size, Horizontal lines indicate the 95% CI, and each box represents methods, histology, stage and treatment. To avoid bias in the data the HR point estimate; the box size is proportional to the number abstraction process, three reviewers (Chaoyang Sun, Na Li, Dong of patients included in the study. A funnel plot and Begg’s linear Ding) abstracted the data independently and subsequently regression test were used to investigate any possible publication compared the results. All of the data were checked for internal bias [19]. consistency, and disagreements were resolved by discussion. For all analyses, a two-sided P value of ,0.05 was considered to To assess methodology, three investigators (Chaoyang Sun, Na be statistically significant. All analyses were performed using SPSS Li, Dong Ding) read each publication independently and scored version 13.0 (SPSS, Chicago, IL) and STATA version 10.0 them according to the European Lung Cancer Working Party software (Stata Corporation, College Station, TX). (ELCWP) scoring scale, with some modification (Method S1 in Studies that were eligible for the systematic review were called File S1) [16]. The scores were compared, and a consensus value ‘eligible’, and those providing data for the meta-analysis were for each item was reached in meetings attended by at least two called ‘evaluable’. investigators. The score evaluates a number of aspects of methodology, which were grouped into four main categories: Results design, laboratory methods, generalisability of results and the analysis of the study data. Each category had a maximum score of Study Selection and Characteristics 10 points, giving a theoretical total maximum score of 40 points. The primary search yielded a total of 1,231 publications, 1030 The final scores were expressed as percentages ranging from 0 to of which were excluded by title screening. Abstracts of the 100%, with higher values reflecting better methodological quality. remaining 201 papers were reviewed, resulting in 162 being excluded and leaving 39 as candidate articles [3–8,15,20–51]. To Statistical Methods reach a final decision on which articles were to be included in the A study was considered to be significant if the P-value for the meta-analysis, we examined all 39 papers in detail, which resulted statistical test comparing the survival distributions between the in the further exclusion of 4 papers because survival information PLOS ONE | www.plosone.org 2 May 2014 | Volume 9 | Issue 5 | e95285 BRCA Status and Survival of Patients with EOC was not available for three papers [29,35,46] and one study’s [42] Quality Assessment subjects overlapped with a subsequent study that the authors Overall, the global quality assessment score, expressed as a published six years later [26] (Figure 1). All eligible articles were percentage, ranged between 36.7% and 89.4%, with a median of reviewed by three independent investigators. The main features of 70.6% (Table S2A in File S1, mean 6 SD values are shown). the 39 studies eligible for the systematic review, which were No statistically significant difference of scores were found published between 1996 and 2013, are shown in Table S1 in File between the 35 evaluable and 4 non-evaluable studies. There was S1. All of the eligible literatures were case-control studies. A total also no statistically significant difference between the scores of the of 26 studies investigated BRCA1/2 germline and/or somatic 26 positive studies and 13 negative studies, except the positive ones mutions, while low BRCA1 protein/mRNA expressions and had better sub-scores for laboratory methodology (P = 0.016). The BRCA1 promoter methylation statuses in sporadic EOCs were difference in the global and four subgroup scores between the studies classified according to the types of BRCA dysfunction studied in nine, two, and two studies, respectively. statuses was not significant. As shown in Table 1, 26 studies were performed on BRCA1/2 Table S2B in File S1 shows the scores for the 35 studies germline and/or somatic mutions. Twenty-one (21/26, 80.8%) classified as evaluable for the meta-analysis. There was no studies investigated the germline BRCA1/2 mutation alone, four significant difference between significant and not significant (4/26, 15.4%) studies investigated BRCA mutation status includ- studies in the global score, except for the sub-score of generali- ing germline and somatic BRCA1/2 mutation together, and the sability (P = 0.013). Moreover, the different types of BRCA one (1/26, 3.8%) study left investigated BRCA1 dysfunction dysfunction status did not affect the overall quality assessment or secondary to germline, somatic BRCA1 mutation or BRCA1 the four subgroup scores. promoter methylation. The detailed information of these 26 studies was listed in Table 1. Eighteen (18/26, 69.2%) papers Meta-analysis of BRCA Status and OS of Ovarian Cancer identified BRCA1/2 mutation as a good prognostic factor for The absence of significant qualitative differences between survival, while the remaining eight (8/26, 30.8%) concluded that positive and negative trials allowed us to perform a quantitative BRCA1/2 mutation was not a prognostic factor for survival. aggregation of the survival data. Subgroup analysis was performed Immunohistochemistry (IHC) was used in 9 studies to detect the because the heterogeneity of the trials was obvious: the studies had low expression of BRCA1 protein in sporadic EOCs. The MS110 reported on patients with different BRCA dysfunction statuses clone antibody was used in 88.9% (8/9) of the studies. Various (BRCA1/2 germline/somatic mutations, low BRCA1 expression experimental procedures were performed with the same cut-off tested by IHC or RT-PCR, and BRCA1 promoter methylation in value (,10% positive cells) except for one study [49], and the sporadic EOCs). In this study, we combined studies of germline, summary proportion of low expression of BRCA1 (with cut-off somatic BRCA1/2 mutations together as one intervention called value as ,10% positive cells) in sporadic ovarian cancer was the BRCA1/2 mutations in subgroup meta-analysis. 55.2% (Table 2). The overall meta-analysis of OS included 34 aggregable studies BRCA1 mRNA expression and BRCA1 promoter methylation with 7,986 patients (one studies only provided PFS). The test of in sporadic EOCs were studied in two papers each. Both articles overall heterogeneity was significant (I = 61.7%, P = 0.000), which identified the low expression of BRCA1 mRNA as a significantly primarily came from the BRCA1/2 mutation subgroup better predictor of prognosis, while the other two papers on (I = 64.4%, P = 0.000), while the heterogeneity of the remaining BRCA1 promoter methylation showed negative results (Table 3). three subgroups (low BRCA1 expression by IHC or RT-PCR and BRCA1 promoter methylation in sporadic EOCs) was not significant. BRCA dysfunction status was associated with a better OS, with HR = 0.69, 95% CI: 0.61–0.79 in random-effects model (HR = 0.72, 95% CI: 0.61–0.79 in fixed-effects model). In the subgroup analyses according to different BRCA statuses, BRCA1/ 2 mutations (1,686 cases and 4,941 controls) and low BRCA1 expression by IHC (500 cases and 362 controls) or RT-PCR (72 cases and 49 controls) were statistically significantly better prognostic factors for survival (HR = 0.69, 95% CI: 0.59–0.80; HR = 0.62, 95% CI: 0.51–0.75; and HR = 0.51, 95% CI: 0.33– 0.78 in the random-effects model, respectively; and HR = 0.72, 95% CI: 0.67–0.78; HR = 0.62, 95% CI: 0.51–0.75; and HR = 0.51, 95% CI: 0.33–0.78 in the fixed-effects model, respectively). However, BRCA1 promoter methylation (62 cases and 196 controls) was not associated with better prognosis (HR = 1.59, 95% CI: 0.72–3.50 in the random-effects model and HR = 1.40, 95% CI: 0.94–2.09 in the fixed-effects model) (Figure 2). When BRCA mutation was subdivided into BRCA1 or BRCA2 subgroups, the meta-analysis showed that both BRCA1 and BRCA2 mutations predicted better OS (HR = 0.78, 95% CI: 0.69–0.87 and HR = 0.65, 95% CI: 0.50–0.86 in a fixed and random-effects model, respectively) (Figure 3A, 3B). Meta-analysis of BRCA Status and PFS of Ovarian Cancer The overall meta-analysis of PFS included 18 evaluable studies Figure 1. Flow chart of publication selection. doi:10.1371/journal.pone.0095285.g001 with 3,394 patients. The overall heterogeneity and the heteroge- PLOS ONE | www.plosone.org 3 May 2014 | Volume 9 | Issue 5 | e95285 BRCA Status and Survival of Patients with EOC PLOS ONE | www.plosone.org 4 May 2014 | Volume 9 | Issue 5 | e95285 Table 1. Characteristics of studies of patients with BRCA1/2 mutated ovarian cancer. No. of Study year, cases/ Laboratory Germline/ Survival First author published year Country Histology Stage controls methods BRCA status somatic Mutation Types Treatment result Aida 1984–1996,1998 Japan se I–III 13/29 SCCP,PCR,seq BRCA1 Germ Deleterious 2 positive Alsop 2002–2006,2012 Austrilia se I–IV 118/536 PCR,seq, MLPA BRCA1/2 Germ Deleterious 2 positive Artioli ,2010 Italian all I–IV 48/40 PCR,seq BRCA1/2 Germ Deleterious 1+2 positive Boyd 1986–1998,2000 U.S.A all I–IV 88/100 PCR,seq BRCA1/2 Germ Deleterious 2 positive Brozek 1995–2004,2008 Poland se+CCC I–IV 21/130 DHPLC,RFLP,seq BRCA1/2 Germ Deleterious+ VUS 2 positive Buller 1990–2000,2002 U.S.A all I–IV 59/59 PTT,SSCP,seq BRCA1 Mixed Deleterious+ VUS 2 negative Cass 1990–2001,2003 U.S.A all III–IV 29/25 SSCR,seq BRCA1/2 Germ Deleterious 2 positive Chetrit 1994–1999,2008 Israel all I–IV 213/392 PCR,seq BRCA1/2 Germ Deleterious 2 positive David 1994–1999,2002 Israel all I–IV 229/549 SCCP,seq BRCA1/2 Germ+Somatic Deleterious 2 positive Dann 1999–2007,2012 U.S.A all II–IV 15/38 PCR,seq BRCA1/2 Germ+Somatic Deleterious 2 negative Gallagher 1996–2006,2011 U.S.A all III–IV 36/74 PCR,seq BRCA1/2 Germ Deleterious 2 positive Hennessy 1990–2006.2010 U.S.A all I–IV 43/192 PCR,seq BRCA1/2 Germ+Somatic Deleterious 2 positive Hyman 2001–2010,2012 U.S.A se III–IV 69/298 PCR,seq BRCA1/2 Germ Deleterious 2 positive Johannsson 1958–1995,1998 Swedish all I–IV 38/97 PTT,SSCP,seq BRCA1 Germ Deleterious 2+3 negative Lacour 1996–2007,2011 U.S.A all III–IV 95/183 PCR,seq BRCA1/2 Germ Deleterious – positive Majdak 1997–2002,2005 Poland se+Mu I–IV 18/171 F-CSGE,seq BRCA1 Germ Deleterious 2 positive McLaughlin 1995–1995,2002–2004,2012 Canada all I–IV 218/1408 PTT, seq,DGGE, DHPLC BRCA1/2 Germ Deleterious 2 negative Pal 2000–2003,2007 West central Florida all III–IV 32/177 PCR,seq BRCA1/2 Germ Deleterious+ VUS – negative Pharoah ,1999 U.K all I–IV 151/119 PTT,SSCP BRCA1/2 Germ Deleterious – negative Ramus 1992–1997,2001 Israel all I–IV 27/71 SSCP,PCR,seq BRCA1/2 Germ Deleterious – negative Rubin ,1996 U.S.A all III–IV 43/43 SSCP,PCR,seq BRCA1 Germ Deleterious+ VUS – positive Tan 1991–2006,2008 U.K all III–IV 22/44 SCCP,seq BRCA1/2 Germ Deleterious+ VUS 2 positive Vencken 1980–2009,2011 Netherlands all I–IV 112/222 PCR,seq BRCA1/2 Germ unknown 2 positive Yang ,2011 multi-country all III–IV 59/251 exom seq BRCA1/2 Germ+Somatic Deleterious+ VUS 2 positive Zweemer ,1999 Netherlands – – 42/84 PTT,PCR BRCA1/2 Germ Deleterious – positive Zweemer ,2001 Netherlands All I–IV 23/17 PTT,PCR,seq BRCA1/2 Germ Deleterious – negative Histology: pathological histology of ovarian cancer, se = serous ovarian cancer, CCC = clear cell cancer of, Mu = mucinous ovarian cancer. all = almost all of the epithelial ovarian cancer types, including serous, mucinous, clear cell cancer, etc. Laboratory methods: laboratory methods used to detect BRCA1/2 mutation, PTT = Protein truncation test, SSCP = Single-Strand Conformation Polymorphism, seq = sequencing, DGGE = fluorescent multiplex denaturing gradient gel electrophoresis, MLPA = multiplex ligation-dependent probe amplification, DHPLC = Denaturing high performance liquid chromatography, RFLP = Restriction fragment length polymorphisms, F-CSGE = Fluorescence-based Conformation Sensitive Gel Electrophoresis. Germline/somatic: Germ = germline mutation, Mixed = BRCA1 germline/somatic mutation or BRCA1 promoter methylation. Mutation types: VUS = variants of unknown significance. Treatment: chemotherapy used, 1 = only Platinum was used, 2 = Platinum-based chemotherapy, 3 = other agents without Platinum, like Paclitaxel, etc. doi:10.1371/journal.pone.0095285.t001 BRCA Status and Survival of Patients with EOC PLOS ONE | www.plosone.org 5 May 2014 | Volume 9 | Issue 5 | e95285 Table 2. Characteristics of studies of patients of ovarian cancer with low BRCA1 expression measured by IHC. First Study year, No. of cases/ Double Cut Survival author published year Country stage Histology controls Clone dilution Retrieval readers blind off Low% treatment result Weberpals 2008,2011 Canada II–IV all 75/41 MS110 1:100 – 2 Yes 10% 65% 1 positive Carser 1998–2004,2011 U.K I–IV all 120/172 MS110 – steam heat 2 Yes 10% 41% 1 positive Gan 1991–2007,2013 U.K I–IV se 112/19 MS110 1:80 microwave 1 Yes #70 84.4% 2 positive Kaern 1990–1992,2005 Norway III all 30/16 MS110 1:200 microwave No 10% 65.20% 2 negative Sirisabya 1996–1999,2007 Thailand I–III all 87/12 – – microwave 1 No 10% 87.80% 1 negative Thrall ,2006 U.S.A I–III all 97/55 MS110 1:50 steam heat 2 Yes 10% 63.8% 1 positive Swisher ,2009 U.S.A I–IV all 39/76 MS110 1:250 steam heat No 10% 34% 2 positive Radosa 2000–2005,2011 Germany III–IV all 12/15 MS110 1:200 heat 2 Yes 10% 44.40% 1 positive Yu 1996–1998,2005 China I–IV all 35/15 MS110 1:100 – – 10% 70% 2 negative Histology: pathological histology of ovarian cancer, all = almost all of the epithelial ovarian cancer types, including serous, mucinous, clear cell cancer, etc, se = serous ovarian cancer. Treatment: chemotherapy used, 1 = only Platinum was used, 2 = Platinum-based chemotherapy. *BRCA1 (H-score#70) defined as the BRCA1-deficient group. doi:10.1371/journal.pone.0095285.t002 Table 3. Characteristics of studies of patients of ovarian cancer with low BRCA1 mRNA expression or BRCA1 promoter methylation. First author Study year, published year Country Histology stage No. of cases/controls Methods of methylation detecting Treatment significance RT-PCR Quinn ,2007 U.K all I–IV 47/23 2 positive Weberpals 1997–2005,2009 Canada all II–IV 25/26 2 positive methylation Wiley 1991–2000,2006 Italy all I–IV 44/171 MSP 2 negative Chiang 1986–2001,2006 USA – I–IV 10/25 MSRE+ Southern blot+ MSP 2 negative Histology: pathological histology of ovarian cancer, all = almost all of the epithelial ovarian cancer types, including serous, mucinous, clear cell cancer, etc. Methods of methylation detecting: methods of methylation detecting, MSP = methylation-specific polymerase chain reaction (PCR) analysis, MSRE = methylation-sensitive restriction enzyme digestion. Treatment: chemotherapy used, 2 = Platinum-based chemotherapy. doi:10.1371/journal.pone.0095285.t003 BRCA Status and Survival of Patients with EOC Figure 2. Summary hazard ratios (HRs) and 95% confidence intervals (CIs) of epithelial ovarian cancer OS for BRCA dysfunction status. Horizontal lines represent 95% CIs; diamonds represent summary estimates with corresponding 95% CIs. Test for heterogeneity: P = .000, I = 61.7%. A random-effects model was used for analysis. doi:10.1371/journal.pone.0095285.g002 PLOS ONE | www.plosone.org 6 May 2014 | Volume 9 | Issue 5 | e95285 BRCA Status and Survival of Patients with EOC Figure 3. Subgroup meta-analysis of summary hazard ratios (HRs) and 95% confidence intervals (CIs) of ovarian cancer OS for different BRCA mutation statuses. A: BRCA1 mutation. B: BRCA2 mutation. Horizontal lines represent 95% CIs; diamonds represent summary 2 2 estimates with corresponding 95% CIs. Test for heterogeneity: A: P = .251, I = 20.2%, a fixed-effects model was used; B: P = .023, I = 55.1%, a random-effects model was used. doi:10.1371/journal.pone.0095285.g003 neity of all subgroups were not significant. BRCA dysfunction subgroup analyses according to different BRCA statuses, status was associated with a better PFS in ovarian cancer, with BRCA1/2 mutation and low BRCA1 expression by IHC were HR = 0.69 (95% CI: 0.63–0.76, fixed-effect model). In the statistically significant predictors for longer PFS (HR = 0.65, 95% PLOS ONE | www.plosone.org 7 May 2014 | Volume 9 | Issue 5 | e95285 BRCA Status and Survival of Patients with EOC Figure 4. Summary hazard ratios (HRs) and 95% confidence intervals (CIs) of ovarian cancer PFS for BRCA dysfunction status. Horizontal lines represent 95% CIs; diamonds represent summary estimates with corresponding 95% CIs. Test for heterogeneity: P = .118, I = 29.3%. A fixed-effects model was used. doi:10.1371/journal.pone.0095285.g004 CI: 0.57–0.73 and HR = 0.69, 95% CI: 0.57–0.83 in a fixed-effect display BRCA1/2 dysfunction, relative to those whose EOC model, respectively). However, BRCA1 promoter methylation was display normal BRCA1/2 function. Although the comparison of not associated with better PFS (HR = 1.40, 95% CI: 0.95–2.05) prognostic benefit between BRCA1 and BRCA2 mutation was not (Figure 4). feasible, the aggregated HRs indicated that patients with a BRCA2 mutation (HR = 0.65) may have a better prognosis than Publication Bias patients with a BRCA1 mutation (HR = 0.78). During the preparation of this manuscript, Bolton et al also reported Publication bias statistics were determined using Begg’s linear regression test. No publication bias was found for the studies used BRCA1/2 germline mutation was associated with improved for the meta-analysis for overall survival (Begg’s test, P = 0.221) survival and BRCA2 carriers had the best prognosis, these (Figure 5A); moreover, there is no publication bias was found for findings are consistent with our results [52]. the studies used for the meta-analysis for PFS (Begg’s test, Although BRCA1/2 germline mutation carriers only account P = 0.880) (Figure 5B). for small proportions of EOCs, fortunately, it has been estimated that approximately 50% sporadic EOCs show dysfunction of BRCA1/2 through different mechanisms. Our study is the first Discussion meta-analysis, to our knowledge, to assess if low BRCA1/2 Our systematic review of the literature and meta-analysis expression status of sporadic EOCs could show similar effects on demonstrate an improved prognosis in patients whose EOC PLOS ONE | www.plosone.org 8 May 2014 | Volume 9 | Issue 5 | e95285 BRCA Status and Survival of Patients with EOC for BRCA2 mutants was lower than that for BRCA1 mutants. It has been established by several research groups that BRCA2- mutated cells are recombination deficient and undergo signifi- cantly reduced homologous recombination repair of DNA double- strand breaks [13,53]. Functionally, the primary function of BRCA2 appears to be regulation of the RAD51 protein, which is required for double-strand break repair by homologous recombi- nation [10], indicating that BRCA2 lesions cause more substantial homologous recombination defects than BRCA1 lesions, because BRCA1 is more versatile. However, to date, there are no reports regarding the association between low BRCA2 expression and the prognosis of patients with sporadic EOCs. So, large population- based studies are urgently needed to discover the proportion of low BRCA2 expression patients among sporadic EOCs and the real role of low BRCA2 expression status on survival. Our results may have important implications for the clinical management of EOCs. Ovarian carcinoma is clinically highly heterogeneous. Our study revealed that both BRCA1/2 mutations and low BRCA1 expression are associated with favourable survival in EOC, so, these BRCA statuses can guide choice of post- operative treatment decisions. Additionally, it has been demon- strated that a deficiency of the BRCA gene confers substantial sensitivity to a new class of agents, namely poly-ADP-ribose polymerase-1 (PARP1) inhibitors [13,14]. A number of phase I and II studies have reported the successful applications of PARP inhibitors in BRCA1/2 mutation carries of ovarian and breast cancer, and phase III studies are underway [13,14,54]. So, routine testing BRCA1/2 germline mutation status of EOCs may now be warranted. A large proportion of sporadic EOCs demonstrate BRCA deficiency, whether these patients could also benefit from Figure 5. Begg’s funnel plots of the natural logarithm of the PARP1 inhibitor are still unclear. Moreover, a reliable assay to hazard ratios (HRs) and the SE of the natural logarithm of the detect these patients is required. Our meta-analysis supports the HRs for all of the included studies reported with OS and PFS. A: IHC technique as a promising assay to detect a portion of sporadic Begg’s funnel plots for all of the included studies reported with OS, the dashed line represents 95% confidence intervals (CIs). Circles represent ovarian cancer displaying BRCAness. Although RT-PCR may individual studies. Begg’s test: P = 0.221. B: Begg’s funnel plots for all of also be a potential assay to discover the BRCAness, the supporting the included studies reported with PFS, the dashed line represents 95% positive literature was limited and without standard experimental confidence intervals (CIs). Circles represent individual studies. Begg’s protocols and uniform cut-off values. Large prospective clinical test: P = 0.880. trials are expected for further validation. doi:10.1371/journal.pone.0095285.g005 In conclusion, EOCs patients with BRCA dysfunction status have better outcomes, but more fundamental studies and further prognosis to BRCA1/2 mutation carriers. Our results showed that prospective clinical studies are urgently needed. Furthermore, low BRCA1 expression measured by IHC or RT-PCR but not EOCs should be stratified by different BRCA statuses to BRCA1 promoter methylation is a good prognostic factor for both specifically define the most effective treatment for the separate OS and PFS in patients of sporadic EOCs, indicating that low patient groups in further clinical studies. BRCA1 expression status in sporadic EOCs show similar clinical effects on prognosis to germline mutations carriers. However, it is still difficult to draw a definite conclusion because these results Supporting Information were based on small numbers and require confirmation in larger File S1 Contains the following files: Method S1: The quality studies, especially for low BRCA1 expression measured by RT- score for methodology modified according to the European Lung PCR and BRCA1 promoter methylation status. Swisher et al had Cancer Working Party (ELCWP) scoring scale [ ]. Table S1: stated that BRCA1 promoter methylation only occurs in a small Main characteristics and results of eligible studies. Table S2: proportion of sporadic ovarian cancer with low BRCA1 expression Methodological assessment. [33], therefore, other mechanisms that could cause low BRCA1 (DOC) expression need to be further investigated. In our study, patients whose EOC displays BRCA dysfunction Checklist S1 PRISMA checklist. had a favourable prognosis. BRCA1/2 gene products play a (DOC) pivotal role in DNA repair mechanisms. The better prognosis of patients with BRCA dysfunction may be explained by their Author Contributions inability to repair double-strand DNA breaks caused by platinum- Conceived and designed the experiments: GC DM. Performed the based chemotherapy. As we mentioned above, although the experiments: NL. Analyzed the data: CYS DHW. Contributed reagents/ comparison of prognostic benefit between the BRCA1 and materials/analysis tools: DD LM. Wrote the paper: CYS. 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(2011) Breast cancer 1 40. Lacour RA, Westin SN, Meyer LA, Wingo SN, Schorge JO, et al. (2011) (BRCA1) protein expression as a prognostic marker in sporadic epithelial Improved survival in non-Ashkenazi Jewish ovarian cancer patients with ovarian carcinoma: an NCIC CTG OV.16 correlative study. Ann Oncol. BRCA1 and BRCA2 gene mutations. Gynecologic Oncology 121: 358–363. 16. Steels E, Paesmans M, Berghmans T, Branle F, Lemaitre F, et al. (2001) Role of 41. Majdak EJ, Debniak J, Milczek T, Cornelisse CJ, Devilee P, et al. (2005) p53 as a prognostic factor for survival in lung cancer: a systematic review of the Prognostic impact of BRCA1 pathogenic and BRCA1/BRCA2 unclassified literature with a meta-analysis. Eur Respir J 18: 705–719. variant mutations in patients with ovarian carcinoma. Cancer 104: 1004–1012. 17. Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform 42. David YB, Chetrit A, Hirsh-Yechezkel G, Friedman E, Beck BD, et al. 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PLOS ONE | www.plosone.org 10 May 2014 | Volume 9 | Issue 5 | e95285 BRCA Status and Survival of Patients with EOC 51. McLaughlin JR, Rosen B, Moody J, Pal T, Fan I, et al. (2013) Long-term 53. Kortmann U, McAlpine JN, Xue H, Guan J, Ha G, et al. (2011) Tumor growth ovarian cancer survival associated with mutation in BRCA1 or BRCA2. J Natl inhibition by olaparib in BRCA2 germline-mutated patient-derived ovarian Cancer Inst 105: 141–148. cancer tissue xenografts. Clin Cancer Res 17: 783–791. 52. Bolton KL, Chenevix-Trench G, Goh C, Sadetzki S, Ramus SJ, et al. (2012) 54. Kummar S, Chen A, Ji J, Zhang Y, Reid JM, et al. (2011) Phase I study of PARP Association between BRCA1 and BRCA2 mutations and survival in women inhibitor ABT-888 in combination with topotecan in adults with refractory solid with invasive epithelial ovarian cancer. JAMA 307: 382–390. tumors and lymphomas. Cancer Res 71: 5626–5634. PLOS ONE | www.plosone.org 11 May 2014 | Volume 9 | Issue 5 | e95285 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png PLoS ONE Pubmed Central

The Role of BRCA Status on the Prognosis of Patients with Epithelial Ovarian Cancer: A Systematic Review of the Literature with a Meta-Analysis

PLoS ONE , Volume 9 (5) – May 1, 2014

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Abstract

Objective: The role of BRCA dysfunction on the prognosis of patients with epithelial ovarian cancer (EOCs) remains controversial. This systematic review tried to assess the role of BRCA dysfunction, including BRCA1/2 germline, somatic mutations, low BRCA1 protein/mRNA expression or BRCA1 promoter methylation, as prognostic factor in EOCs. Methods: Studies were selected for analysis if they provided an independent assessment of BRCA status and prognosis in EOC. To make it possible to aggregate survival results of the published studies, their methodology was assessed using a modified quality scale. Results: Of 35 evaluable studies, 23 identified BRCA dysfucntion status as a favourable prognostic factor. No significant differences were detected in the global score of quality assessment. The aggregated hazard ratio (HR) of overall survival (OS) of 34 evaluable studies suggested that BRCA dysfunction status had a favourable impact on OS (HR = 0.69, 95% CI 0.61– 0.79), and when these studies were categorised into BRCA1/2 mutation and low protein/mRNA expression of BRCA1 subgroups, all of them demonstrated positive results (HR = 0.67, 95% CI: 0.57–0.78; HR = 0.62, 95% CI: 0.51–0.75; and HR = 0.51, 95% CI: 0.33–0.78, respectively), except for the subgroup of BRCA1 promoter methylation (HR = 1.59, 95% CI: 0.72–3.50). The meta-analysis of progression-free survival (PFS), which included 18 evaluable studies, demonstrated that BRCA dysfunction status was associated with a longer PFS in EOC (HR = 0.69, 95% CI: 0.63–0.76). Conclusions: Patients with BRCA dysfunction status tend to have a better outcome, but further prospective clinical studies comparing the different BRCA statuses in EOC is urgently needed to specifically define the most effective treatment for the separate patient groups. Citation: Sun C, Li N, Ding D, Weng D, Meng L, et al. (2014) The Role of BRCA Status on the Prognosis of Patients with Epithelial Ovarian Cancer: A Systematic Review of the Literature with a Meta-Analysis. PLoS ONE 9(5): e95285. doi:10.1371/journal.pone.0095285 Editor: Alexander James Roy Bishop, University of Texas Health Science Center at San Antonio, United States of America Received October 18, 2013; Accepted March 26, 2014; Published May 1, 2014 Copyright:  2014 Sun et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. * E-mail: gumpc@126.com (GC); dma@tjh.tjmu.edu.cn (DM) . These authors contributed equally to this work. mutation status and the prognosis of EOC in subsequent studies, Introduction generating conflicting results [3–8]. Although, the mechanism Epithelial ovarian carcinoma (EOC) is the fifth leading cause of underlying the association between BRCA1/2 germline mutations cancer death in women [1], and the five-year relative survival rates and survival is not fully understood, in vitro experiments have for the late stage of EOC were less than 10% between 2004 and shown that BRCA1/2 deficient cells display a deficiency in 2008 [2]. Despite advances in surgery and the wide use of repairing double-strand DNA breaks by homologous recombina- platinum-based chemotherapy, the long-term outcome remains tion [9–11]. This biological mechanism may be responsible for poor as a result of recurrences and the emergence of drug increased chemo-sensitivity, which results in a longer progression- resistance, necessitating the discovery of biomarkers for predicting free survival (PFS) and overall survival (OS) [12]. More inspiringly, which patients will benefit or not benefit from systemic chemo- BRCA1/2 mutation carries can obtain an excellent response from therapy. Moreover, the lack of active therapeutic agents for targeted therapies, such as the poly (ADP) ribose polymerase patients with platinum-resistant cancers impels researchers to (PARP) inhibitor (Olaparib) [13,14]. However, BRCA1/2 germ- discover novel molecular targets helping define subsets of patients line mutation carriers only account for 10% to 15% of EOCs. who may benefit the most from specific treatment. Fortunately, recent data suggest that many sporadic EOCs display In 1996, a detailed case-control analysis reported that BRCA1/ ‘‘BRCAness’’, or dysfunction of BRCA1/2. Additionally, in 2 germline mutations were beneficial prognostic factors for sporadic EOCs, low BRCA1 expression detected by immunohis- patients with EOC [3]. Since then, many scientists have tried to tochemistry (IHC) or RT-PCR or BRCA1 promoter methylation discover the real association between BRCA1/2 germline PLOS ONE | www.plosone.org 1 May 2014 | Volume 9 | Issue 5 | e95285 BRCA Status and Survival of Patients with EOC had also been reported as a clinically useful tool to provide groups of BRCA dysfunction and normal BRCA status was , important information on prognosis [15]. 0.05. The study was called ‘positive’ when BRCA dysfunction The aim of this study was to assess the role of BRCA status was found as a favourable prognostic factor for survival. dysfunction status, including BRCA1/2 germline/somatic muta- Other situations were called ‘negative’, including when a tions, low BRCA1 protein/mRNA expression or BRCA1 significant survival difference was found, but the group of patients promoter methylation in sporadic EOCs, on prognosis in EOCs with BRCA dysfunction status fared worse. by carrying out a systematic review of the literature followed by a Non-parametric tests were used to compare the distribution of meta-analysis, and to estimate to what extent do these BRCA the quality scores according to the value of a discrete variable statuses influence patients’ prognosis. (Mann-Whitney tests). For the quantitative aggregation of the survival results, we measured the impact of BRCA dysfunction status on prognosis by Methods the hazard ratio (HR) between the survival distributions of the two Publication Selection BRCA status groups. For each study, the HR was extracted or This study has been registered at the International Prospective estimated by a method that depended on the results provided in Register of Systematic Reviews (PROSPERO, http://www.crd. the publication. The most accurate method was to retrieve the HR york.ac.uk/prospero/display_record. estimate and its variance from the reported results or to calculate it asp?ID = CRD42011001747) in 2011. An electronic search of directly using parameters provided by the authors for univariate Medline, Embase, and CNKI (China National Knowledge analysis: the confidence interval (CI) for the HR, the log-rank Infrastructure) was used to select articles with the following statistic, its P-value or the O-E statistic (difference between keywords: ‘ovarian neoplasm’, ‘ovarian tumour’, ‘ovarian carci- numbers of observed and expected events). If these parameters noma’, ‘ovarian malignance’ or ‘ovarian cancer’ and ‘BRCA1’, were not available, we evaluated the total number of events, the ‘BRCA2’ or ‘BRCA*’ and ‘prognos*’, ‘surviv*’, ‘outcome’ or number of patients at risk in each group and the log-rank statistic ‘marker’. This search strategy was complemented by examining or it’s P-value, allowing for the calculation of an approximation of the personal bibliography of the authors. To avoid overlap the HR estimate. Finally, if the only useful data were in the form of between patient populations, when authors reported results graphical representations of the survival distributions, we extracted obtained on the same patient cohorts in several publications, only survival rates at specified times to reconstruct the HR estimate and the most recent report or the most complete one was included in its variance, with the assumption that during the study follow-up, the analysis. The search was updated in September 2013. A study the rate of patients censored was constant [17]. If this latter must have been published as a full paper in the English or Chinese method was used, three independent persons read the curves to language. To be eligible for inclusion, studies had to meet the reduce imprecision in the reading variations. following criteria: addressed epithelial ovarian cancer and If survival was reported separately for particular subgroups, analysed patients’ prognosis according to BRCA statuses (assessed these results were included in the meta-analysis of the correspond- BRCA1/2 mutations, assessed BRCA1/2 protein expression ing subgroups. The same patients were never considered more through IHC or assessed mRNA level through RT-PCR, and/ than once in each analysis. The individual HR estimates were or assessed BRCA1 promoter methylation in the primary tumour combined into an overall HR using the method published by (not in metastatic tissue or in tissue adjacent to the tumour)). The Yusuf S and Peto R et al [18]. If the assumption of homogeneity primary outcome was overall survival (OS) and the secondary had to be rejected, we used a random-effects model as a second outcome was progression-free survival (PFS). step. By convention, an observed HR ,1 implied better survival for the group with BRCA dysfunction status. This impact of Data Extraction and Methodological Assessment BRCA status on survival was considered to be statistically The data retrieved from the reports included authors, years of significant if the 95% CI for the overall HR did not include 1. studies and publications, patients’ resources, population size, Horizontal lines indicate the 95% CI, and each box represents methods, histology, stage and treatment. To avoid bias in the data the HR point estimate; the box size is proportional to the number abstraction process, three reviewers (Chaoyang Sun, Na Li, Dong of patients included in the study. A funnel plot and Begg’s linear Ding) abstracted the data independently and subsequently regression test were used to investigate any possible publication compared the results. All of the data were checked for internal bias [19]. consistency, and disagreements were resolved by discussion. For all analyses, a two-sided P value of ,0.05 was considered to To assess methodology, three investigators (Chaoyang Sun, Na be statistically significant. All analyses were performed using SPSS Li, Dong Ding) read each publication independently and scored version 13.0 (SPSS, Chicago, IL) and STATA version 10.0 them according to the European Lung Cancer Working Party software (Stata Corporation, College Station, TX). (ELCWP) scoring scale, with some modification (Method S1 in Studies that were eligible for the systematic review were called File S1) [16]. The scores were compared, and a consensus value ‘eligible’, and those providing data for the meta-analysis were for each item was reached in meetings attended by at least two called ‘evaluable’. investigators. The score evaluates a number of aspects of methodology, which were grouped into four main categories: Results design, laboratory methods, generalisability of results and the analysis of the study data. Each category had a maximum score of Study Selection and Characteristics 10 points, giving a theoretical total maximum score of 40 points. The primary search yielded a total of 1,231 publications, 1030 The final scores were expressed as percentages ranging from 0 to of which were excluded by title screening. Abstracts of the 100%, with higher values reflecting better methodological quality. remaining 201 papers were reviewed, resulting in 162 being excluded and leaving 39 as candidate articles [3–8,15,20–51]. To Statistical Methods reach a final decision on which articles were to be included in the A study was considered to be significant if the P-value for the meta-analysis, we examined all 39 papers in detail, which resulted statistical test comparing the survival distributions between the in the further exclusion of 4 papers because survival information PLOS ONE | www.plosone.org 2 May 2014 | Volume 9 | Issue 5 | e95285 BRCA Status and Survival of Patients with EOC was not available for three papers [29,35,46] and one study’s [42] Quality Assessment subjects overlapped with a subsequent study that the authors Overall, the global quality assessment score, expressed as a published six years later [26] (Figure 1). All eligible articles were percentage, ranged between 36.7% and 89.4%, with a median of reviewed by three independent investigators. The main features of 70.6% (Table S2A in File S1, mean 6 SD values are shown). the 39 studies eligible for the systematic review, which were No statistically significant difference of scores were found published between 1996 and 2013, are shown in Table S1 in File between the 35 evaluable and 4 non-evaluable studies. There was S1. All of the eligible literatures were case-control studies. A total also no statistically significant difference between the scores of the of 26 studies investigated BRCA1/2 germline and/or somatic 26 positive studies and 13 negative studies, except the positive ones mutions, while low BRCA1 protein/mRNA expressions and had better sub-scores for laboratory methodology (P = 0.016). The BRCA1 promoter methylation statuses in sporadic EOCs were difference in the global and four subgroup scores between the studies classified according to the types of BRCA dysfunction studied in nine, two, and two studies, respectively. statuses was not significant. As shown in Table 1, 26 studies were performed on BRCA1/2 Table S2B in File S1 shows the scores for the 35 studies germline and/or somatic mutions. Twenty-one (21/26, 80.8%) classified as evaluable for the meta-analysis. There was no studies investigated the germline BRCA1/2 mutation alone, four significant difference between significant and not significant (4/26, 15.4%) studies investigated BRCA mutation status includ- studies in the global score, except for the sub-score of generali- ing germline and somatic BRCA1/2 mutation together, and the sability (P = 0.013). Moreover, the different types of BRCA one (1/26, 3.8%) study left investigated BRCA1 dysfunction dysfunction status did not affect the overall quality assessment or secondary to germline, somatic BRCA1 mutation or BRCA1 the four subgroup scores. promoter methylation. The detailed information of these 26 studies was listed in Table 1. Eighteen (18/26, 69.2%) papers Meta-analysis of BRCA Status and OS of Ovarian Cancer identified BRCA1/2 mutation as a good prognostic factor for The absence of significant qualitative differences between survival, while the remaining eight (8/26, 30.8%) concluded that positive and negative trials allowed us to perform a quantitative BRCA1/2 mutation was not a prognostic factor for survival. aggregation of the survival data. Subgroup analysis was performed Immunohistochemistry (IHC) was used in 9 studies to detect the because the heterogeneity of the trials was obvious: the studies had low expression of BRCA1 protein in sporadic EOCs. The MS110 reported on patients with different BRCA dysfunction statuses clone antibody was used in 88.9% (8/9) of the studies. Various (BRCA1/2 germline/somatic mutations, low BRCA1 expression experimental procedures were performed with the same cut-off tested by IHC or RT-PCR, and BRCA1 promoter methylation in value (,10% positive cells) except for one study [49], and the sporadic EOCs). In this study, we combined studies of germline, summary proportion of low expression of BRCA1 (with cut-off somatic BRCA1/2 mutations together as one intervention called value as ,10% positive cells) in sporadic ovarian cancer was the BRCA1/2 mutations in subgroup meta-analysis. 55.2% (Table 2). The overall meta-analysis of OS included 34 aggregable studies BRCA1 mRNA expression and BRCA1 promoter methylation with 7,986 patients (one studies only provided PFS). The test of in sporadic EOCs were studied in two papers each. Both articles overall heterogeneity was significant (I = 61.7%, P = 0.000), which identified the low expression of BRCA1 mRNA as a significantly primarily came from the BRCA1/2 mutation subgroup better predictor of prognosis, while the other two papers on (I = 64.4%, P = 0.000), while the heterogeneity of the remaining BRCA1 promoter methylation showed negative results (Table 3). three subgroups (low BRCA1 expression by IHC or RT-PCR and BRCA1 promoter methylation in sporadic EOCs) was not significant. BRCA dysfunction status was associated with a better OS, with HR = 0.69, 95% CI: 0.61–0.79 in random-effects model (HR = 0.72, 95% CI: 0.61–0.79 in fixed-effects model). In the subgroup analyses according to different BRCA statuses, BRCA1/ 2 mutations (1,686 cases and 4,941 controls) and low BRCA1 expression by IHC (500 cases and 362 controls) or RT-PCR (72 cases and 49 controls) were statistically significantly better prognostic factors for survival (HR = 0.69, 95% CI: 0.59–0.80; HR = 0.62, 95% CI: 0.51–0.75; and HR = 0.51, 95% CI: 0.33– 0.78 in the random-effects model, respectively; and HR = 0.72, 95% CI: 0.67–0.78; HR = 0.62, 95% CI: 0.51–0.75; and HR = 0.51, 95% CI: 0.33–0.78 in the fixed-effects model, respectively). However, BRCA1 promoter methylation (62 cases and 196 controls) was not associated with better prognosis (HR = 1.59, 95% CI: 0.72–3.50 in the random-effects model and HR = 1.40, 95% CI: 0.94–2.09 in the fixed-effects model) (Figure 2). When BRCA mutation was subdivided into BRCA1 or BRCA2 subgroups, the meta-analysis showed that both BRCA1 and BRCA2 mutations predicted better OS (HR = 0.78, 95% CI: 0.69–0.87 and HR = 0.65, 95% CI: 0.50–0.86 in a fixed and random-effects model, respectively) (Figure 3A, 3B). Meta-analysis of BRCA Status and PFS of Ovarian Cancer The overall meta-analysis of PFS included 18 evaluable studies Figure 1. Flow chart of publication selection. doi:10.1371/journal.pone.0095285.g001 with 3,394 patients. The overall heterogeneity and the heteroge- PLOS ONE | www.plosone.org 3 May 2014 | Volume 9 | Issue 5 | e95285 BRCA Status and Survival of Patients with EOC PLOS ONE | www.plosone.org 4 May 2014 | Volume 9 | Issue 5 | e95285 Table 1. Characteristics of studies of patients with BRCA1/2 mutated ovarian cancer. No. of Study year, cases/ Laboratory Germline/ Survival First author published year Country Histology Stage controls methods BRCA status somatic Mutation Types Treatment result Aida 1984–1996,1998 Japan se I–III 13/29 SCCP,PCR,seq BRCA1 Germ Deleterious 2 positive Alsop 2002–2006,2012 Austrilia se I–IV 118/536 PCR,seq, MLPA BRCA1/2 Germ Deleterious 2 positive Artioli ,2010 Italian all I–IV 48/40 PCR,seq BRCA1/2 Germ Deleterious 1+2 positive Boyd 1986–1998,2000 U.S.A all I–IV 88/100 PCR,seq BRCA1/2 Germ Deleterious 2 positive Brozek 1995–2004,2008 Poland se+CCC I–IV 21/130 DHPLC,RFLP,seq BRCA1/2 Germ Deleterious+ VUS 2 positive Buller 1990–2000,2002 U.S.A all I–IV 59/59 PTT,SSCP,seq BRCA1 Mixed Deleterious+ VUS 2 negative Cass 1990–2001,2003 U.S.A all III–IV 29/25 SSCR,seq BRCA1/2 Germ Deleterious 2 positive Chetrit 1994–1999,2008 Israel all I–IV 213/392 PCR,seq BRCA1/2 Germ Deleterious 2 positive David 1994–1999,2002 Israel all I–IV 229/549 SCCP,seq BRCA1/2 Germ+Somatic Deleterious 2 positive Dann 1999–2007,2012 U.S.A all II–IV 15/38 PCR,seq BRCA1/2 Germ+Somatic Deleterious 2 negative Gallagher 1996–2006,2011 U.S.A all III–IV 36/74 PCR,seq BRCA1/2 Germ Deleterious 2 positive Hennessy 1990–2006.2010 U.S.A all I–IV 43/192 PCR,seq BRCA1/2 Germ+Somatic Deleterious 2 positive Hyman 2001–2010,2012 U.S.A se III–IV 69/298 PCR,seq BRCA1/2 Germ Deleterious 2 positive Johannsson 1958–1995,1998 Swedish all I–IV 38/97 PTT,SSCP,seq BRCA1 Germ Deleterious 2+3 negative Lacour 1996–2007,2011 U.S.A all III–IV 95/183 PCR,seq BRCA1/2 Germ Deleterious – positive Majdak 1997–2002,2005 Poland se+Mu I–IV 18/171 F-CSGE,seq BRCA1 Germ Deleterious 2 positive McLaughlin 1995–1995,2002–2004,2012 Canada all I–IV 218/1408 PTT, seq,DGGE, DHPLC BRCA1/2 Germ Deleterious 2 negative Pal 2000–2003,2007 West central Florida all III–IV 32/177 PCR,seq BRCA1/2 Germ Deleterious+ VUS – negative Pharoah ,1999 U.K all I–IV 151/119 PTT,SSCP BRCA1/2 Germ Deleterious – negative Ramus 1992–1997,2001 Israel all I–IV 27/71 SSCP,PCR,seq BRCA1/2 Germ Deleterious – negative Rubin ,1996 U.S.A all III–IV 43/43 SSCP,PCR,seq BRCA1 Germ Deleterious+ VUS – positive Tan 1991–2006,2008 U.K all III–IV 22/44 SCCP,seq BRCA1/2 Germ Deleterious+ VUS 2 positive Vencken 1980–2009,2011 Netherlands all I–IV 112/222 PCR,seq BRCA1/2 Germ unknown 2 positive Yang ,2011 multi-country all III–IV 59/251 exom seq BRCA1/2 Germ+Somatic Deleterious+ VUS 2 positive Zweemer ,1999 Netherlands – – 42/84 PTT,PCR BRCA1/2 Germ Deleterious – positive Zweemer ,2001 Netherlands All I–IV 23/17 PTT,PCR,seq BRCA1/2 Germ Deleterious – negative Histology: pathological histology of ovarian cancer, se = serous ovarian cancer, CCC = clear cell cancer of, Mu = mucinous ovarian cancer. all = almost all of the epithelial ovarian cancer types, including serous, mucinous, clear cell cancer, etc. Laboratory methods: laboratory methods used to detect BRCA1/2 mutation, PTT = Protein truncation test, SSCP = Single-Strand Conformation Polymorphism, seq = sequencing, DGGE = fluorescent multiplex denaturing gradient gel electrophoresis, MLPA = multiplex ligation-dependent probe amplification, DHPLC = Denaturing high performance liquid chromatography, RFLP = Restriction fragment length polymorphisms, F-CSGE = Fluorescence-based Conformation Sensitive Gel Electrophoresis. Germline/somatic: Germ = germline mutation, Mixed = BRCA1 germline/somatic mutation or BRCA1 promoter methylation. Mutation types: VUS = variants of unknown significance. Treatment: chemotherapy used, 1 = only Platinum was used, 2 = Platinum-based chemotherapy, 3 = other agents without Platinum, like Paclitaxel, etc. doi:10.1371/journal.pone.0095285.t001 BRCA Status and Survival of Patients with EOC PLOS ONE | www.plosone.org 5 May 2014 | Volume 9 | Issue 5 | e95285 Table 2. Characteristics of studies of patients of ovarian cancer with low BRCA1 expression measured by IHC. First Study year, No. of cases/ Double Cut Survival author published year Country stage Histology controls Clone dilution Retrieval readers blind off Low% treatment result Weberpals 2008,2011 Canada II–IV all 75/41 MS110 1:100 – 2 Yes 10% 65% 1 positive Carser 1998–2004,2011 U.K I–IV all 120/172 MS110 – steam heat 2 Yes 10% 41% 1 positive Gan 1991–2007,2013 U.K I–IV se 112/19 MS110 1:80 microwave 1 Yes #70 84.4% 2 positive Kaern 1990–1992,2005 Norway III all 30/16 MS110 1:200 microwave No 10% 65.20% 2 negative Sirisabya 1996–1999,2007 Thailand I–III all 87/12 – – microwave 1 No 10% 87.80% 1 negative Thrall ,2006 U.S.A I–III all 97/55 MS110 1:50 steam heat 2 Yes 10% 63.8% 1 positive Swisher ,2009 U.S.A I–IV all 39/76 MS110 1:250 steam heat No 10% 34% 2 positive Radosa 2000–2005,2011 Germany III–IV all 12/15 MS110 1:200 heat 2 Yes 10% 44.40% 1 positive Yu 1996–1998,2005 China I–IV all 35/15 MS110 1:100 – – 10% 70% 2 negative Histology: pathological histology of ovarian cancer, all = almost all of the epithelial ovarian cancer types, including serous, mucinous, clear cell cancer, etc, se = serous ovarian cancer. Treatment: chemotherapy used, 1 = only Platinum was used, 2 = Platinum-based chemotherapy. *BRCA1 (H-score#70) defined as the BRCA1-deficient group. doi:10.1371/journal.pone.0095285.t002 Table 3. Characteristics of studies of patients of ovarian cancer with low BRCA1 mRNA expression or BRCA1 promoter methylation. First author Study year, published year Country Histology stage No. of cases/controls Methods of methylation detecting Treatment significance RT-PCR Quinn ,2007 U.K all I–IV 47/23 2 positive Weberpals 1997–2005,2009 Canada all II–IV 25/26 2 positive methylation Wiley 1991–2000,2006 Italy all I–IV 44/171 MSP 2 negative Chiang 1986–2001,2006 USA – I–IV 10/25 MSRE+ Southern blot+ MSP 2 negative Histology: pathological histology of ovarian cancer, all = almost all of the epithelial ovarian cancer types, including serous, mucinous, clear cell cancer, etc. Methods of methylation detecting: methods of methylation detecting, MSP = methylation-specific polymerase chain reaction (PCR) analysis, MSRE = methylation-sensitive restriction enzyme digestion. Treatment: chemotherapy used, 2 = Platinum-based chemotherapy. doi:10.1371/journal.pone.0095285.t003 BRCA Status and Survival of Patients with EOC Figure 2. Summary hazard ratios (HRs) and 95% confidence intervals (CIs) of epithelial ovarian cancer OS for BRCA dysfunction status. Horizontal lines represent 95% CIs; diamonds represent summary estimates with corresponding 95% CIs. Test for heterogeneity: P = .000, I = 61.7%. A random-effects model was used for analysis. doi:10.1371/journal.pone.0095285.g002 PLOS ONE | www.plosone.org 6 May 2014 | Volume 9 | Issue 5 | e95285 BRCA Status and Survival of Patients with EOC Figure 3. Subgroup meta-analysis of summary hazard ratios (HRs) and 95% confidence intervals (CIs) of ovarian cancer OS for different BRCA mutation statuses. A: BRCA1 mutation. B: BRCA2 mutation. Horizontal lines represent 95% CIs; diamonds represent summary 2 2 estimates with corresponding 95% CIs. Test for heterogeneity: A: P = .251, I = 20.2%, a fixed-effects model was used; B: P = .023, I = 55.1%, a random-effects model was used. doi:10.1371/journal.pone.0095285.g003 neity of all subgroups were not significant. BRCA dysfunction subgroup analyses according to different BRCA statuses, status was associated with a better PFS in ovarian cancer, with BRCA1/2 mutation and low BRCA1 expression by IHC were HR = 0.69 (95% CI: 0.63–0.76, fixed-effect model). In the statistically significant predictors for longer PFS (HR = 0.65, 95% PLOS ONE | www.plosone.org 7 May 2014 | Volume 9 | Issue 5 | e95285 BRCA Status and Survival of Patients with EOC Figure 4. Summary hazard ratios (HRs) and 95% confidence intervals (CIs) of ovarian cancer PFS for BRCA dysfunction status. Horizontal lines represent 95% CIs; diamonds represent summary estimates with corresponding 95% CIs. Test for heterogeneity: P = .118, I = 29.3%. A fixed-effects model was used. doi:10.1371/journal.pone.0095285.g004 CI: 0.57–0.73 and HR = 0.69, 95% CI: 0.57–0.83 in a fixed-effect display BRCA1/2 dysfunction, relative to those whose EOC model, respectively). However, BRCA1 promoter methylation was display normal BRCA1/2 function. Although the comparison of not associated with better PFS (HR = 1.40, 95% CI: 0.95–2.05) prognostic benefit between BRCA1 and BRCA2 mutation was not (Figure 4). feasible, the aggregated HRs indicated that patients with a BRCA2 mutation (HR = 0.65) may have a better prognosis than Publication Bias patients with a BRCA1 mutation (HR = 0.78). During the preparation of this manuscript, Bolton et al also reported Publication bias statistics were determined using Begg’s linear regression test. No publication bias was found for the studies used BRCA1/2 germline mutation was associated with improved for the meta-analysis for overall survival (Begg’s test, P = 0.221) survival and BRCA2 carriers had the best prognosis, these (Figure 5A); moreover, there is no publication bias was found for findings are consistent with our results [52]. the studies used for the meta-analysis for PFS (Begg’s test, Although BRCA1/2 germline mutation carriers only account P = 0.880) (Figure 5B). for small proportions of EOCs, fortunately, it has been estimated that approximately 50% sporadic EOCs show dysfunction of BRCA1/2 through different mechanisms. Our study is the first Discussion meta-analysis, to our knowledge, to assess if low BRCA1/2 Our systematic review of the literature and meta-analysis expression status of sporadic EOCs could show similar effects on demonstrate an improved prognosis in patients whose EOC PLOS ONE | www.plosone.org 8 May 2014 | Volume 9 | Issue 5 | e95285 BRCA Status and Survival of Patients with EOC for BRCA2 mutants was lower than that for BRCA1 mutants. It has been established by several research groups that BRCA2- mutated cells are recombination deficient and undergo signifi- cantly reduced homologous recombination repair of DNA double- strand breaks [13,53]. Functionally, the primary function of BRCA2 appears to be regulation of the RAD51 protein, which is required for double-strand break repair by homologous recombi- nation [10], indicating that BRCA2 lesions cause more substantial homologous recombination defects than BRCA1 lesions, because BRCA1 is more versatile. However, to date, there are no reports regarding the association between low BRCA2 expression and the prognosis of patients with sporadic EOCs. So, large population- based studies are urgently needed to discover the proportion of low BRCA2 expression patients among sporadic EOCs and the real role of low BRCA2 expression status on survival. Our results may have important implications for the clinical management of EOCs. Ovarian carcinoma is clinically highly heterogeneous. Our study revealed that both BRCA1/2 mutations and low BRCA1 expression are associated with favourable survival in EOC, so, these BRCA statuses can guide choice of post- operative treatment decisions. Additionally, it has been demon- strated that a deficiency of the BRCA gene confers substantial sensitivity to a new class of agents, namely poly-ADP-ribose polymerase-1 (PARP1) inhibitors [13,14]. A number of phase I and II studies have reported the successful applications of PARP inhibitors in BRCA1/2 mutation carries of ovarian and breast cancer, and phase III studies are underway [13,14,54]. So, routine testing BRCA1/2 germline mutation status of EOCs may now be warranted. A large proportion of sporadic EOCs demonstrate BRCA deficiency, whether these patients could also benefit from Figure 5. Begg’s funnel plots of the natural logarithm of the PARP1 inhibitor are still unclear. Moreover, a reliable assay to hazard ratios (HRs) and the SE of the natural logarithm of the detect these patients is required. Our meta-analysis supports the HRs for all of the included studies reported with OS and PFS. A: IHC technique as a promising assay to detect a portion of sporadic Begg’s funnel plots for all of the included studies reported with OS, the dashed line represents 95% confidence intervals (CIs). Circles represent ovarian cancer displaying BRCAness. Although RT-PCR may individual studies. Begg’s test: P = 0.221. B: Begg’s funnel plots for all of also be a potential assay to discover the BRCAness, the supporting the included studies reported with PFS, the dashed line represents 95% positive literature was limited and without standard experimental confidence intervals (CIs). Circles represent individual studies. Begg’s protocols and uniform cut-off values. Large prospective clinical test: P = 0.880. trials are expected for further validation. doi:10.1371/journal.pone.0095285.g005 In conclusion, EOCs patients with BRCA dysfunction status have better outcomes, but more fundamental studies and further prognosis to BRCA1/2 mutation carriers. Our results showed that prospective clinical studies are urgently needed. Furthermore, low BRCA1 expression measured by IHC or RT-PCR but not EOCs should be stratified by different BRCA statuses to BRCA1 promoter methylation is a good prognostic factor for both specifically define the most effective treatment for the separate OS and PFS in patients of sporadic EOCs, indicating that low patient groups in further clinical studies. BRCA1 expression status in sporadic EOCs show similar clinical effects on prognosis to germline mutations carriers. However, it is still difficult to draw a definite conclusion because these results Supporting Information were based on small numbers and require confirmation in larger File S1 Contains the following files: Method S1: The quality studies, especially for low BRCA1 expression measured by RT- score for methodology modified according to the European Lung PCR and BRCA1 promoter methylation status. Swisher et al had Cancer Working Party (ELCWP) scoring scale [ ]. Table S1: stated that BRCA1 promoter methylation only occurs in a small Main characteristics and results of eligible studies. Table S2: proportion of sporadic ovarian cancer with low BRCA1 expression Methodological assessment. [33], therefore, other mechanisms that could cause low BRCA1 (DOC) expression need to be further investigated. In our study, patients whose EOC displays BRCA dysfunction Checklist S1 PRISMA checklist. had a favourable prognosis. BRCA1/2 gene products play a (DOC) pivotal role in DNA repair mechanisms. The better prognosis of patients with BRCA dysfunction may be explained by their Author Contributions inability to repair double-strand DNA breaks caused by platinum- Conceived and designed the experiments: GC DM. Performed the based chemotherapy. As we mentioned above, although the experiments: NL. Analyzed the data: CYS DHW. Contributed reagents/ comparison of prognostic benefit between the BRCA1 and materials/analysis tools: DD LM. Wrote the paper: CYS. 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