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BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study

BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal... FULL PAPER British Journal of Cancer (2013) 108, 1231–1237 | doi: 10.1038/bjc.2013.70 Keywords: ovarian cancer; intraperitoneal chemotherapy; BRCA1 immunohistochemistry BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study 1 2,8 2,9 3 4 5 6 7 J L Lesnock , K M Darcy , C Tian , J A DeLoia , M M Thrall , C Zahn , D K Armstrong , M J Birrer and ,1 T C Krivak 1 2 Magee-Women’s Hospital of UPMC, Division of Gynecologic Oncology, Pittsburgh PA 15213, USA; Gynecologic Oncology Group Statistical & Data Center, Roswell Park Cancer Institute, Buffalo NY 14263, USA; Georgetown University Medical Center, 4 5 Washington, DC 20057, USA; University of Washington, Seattle WA 98195-6460, USA; Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA; Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore MD 21231-1000, USA and Massachusetts General Hospital, Boston MA 02114, USA Background: Breast cancer 1, early onset (BRCA1) is a tumour-suppressor gene associated with familial epithelial ovarian cancer (EOC). Reduced BRCA1 expression is associated with enhanced sensitivity to platinum-based chemotherapy. We sought to examine the prognostic relevance of BRCA1 expression in EOC patients treated with intraperitoneal platinum/taxane. Methods: The GOG-172 was a phase III, multi-institutional randomised trial of intravenous paclitaxel and cisplatin (IV therapy) vs intravenous paclitaxel, intraperitoneal cisplatin plus paclitaxel (IP therapy) in patients with optimally resected stage III EOC. The BRCA1 expression was assessed with immunohistochemistry (IHC) staining blinded to clinical outcome in archival tumour specimens. Slides with p10% staining were defined as aberrant and 410% as normal. Correlations between BRCA1 expression and progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan–Meier method and Cox regression analysis. Results: Of the 393 patients, 189 tumours had aberrant expression, and 204 had normal BRCA1 expression. There was an interaction between BRCA1 expression and route of administration on OS (P¼ 0.014) but not PFS (P¼ 0.054). In tumours with normal BRCA1 expression, the median OS was 58 months for IP group vs 50 months for IV group (P¼ 0.818). In tumours with aberrant BRCA1 expression, the median OS was 84 vs 47 months in the IP vs IV group, respectively (P¼ 0.0002). Aberrant BRCA1 expression was an independent prognostic factor for better survival in women randomised to IP therapy (hazard ratio (HR)¼ 0.67, 95% confidence interval (CI)¼ 0.47–0.97, P¼ 0.032). Similar survival was observed in the IV and IP patients with normal BRCA1 expression. Multivariate but not univariate modelling demonstrated that IV patients with aberrant vs normal BRCA1 expression had worse survival. Conclusion: Decreased BRCA1 expression is associated with a 36-month survival improvement in patients with EOC treated with IP chemotherapy. Although these results merit validation in future studies, the results suggest that decreased BRCA1 expression predicts for improved response to cisplatin-based IP chemotherapy with cisplatin and paclitaxel. *Correspondence: Dr TC Krivak; E-mail: Tkrivak@mail.magee.edu Current address: Gynecologic Cancer Center of Excellence and the Women’s Health Integrated Research Center at Inova Health System, Annandale, VA 22003, USA Current address: Precision Therapeutics Inc., Pittsburgh, PA 15213, USA Received 24 October 2012; revised 26 January 2013; accepted 27 January 2013; published online 5 March 2013 & 2013 Cancer Research UK. All rights reserved 0007 – 0920/13 www.bjcancer.com | DOI:10.1038/bjc.2013.70 1231 BRITISH JOURNAL OF CANCER BRCA1 expression and improved survival in ovarian cancer patients Epithelial ovarian cancer (EOC) is estimated to affect 22 200 Carser et al, 2011). The primary objective of this study was to women in the United States and lead to B15 550 deaths annually determine if the benefits of IP therapy, measured by progression- (Siegel et al, 2012). Women with EOC typically present with free survival (PFS) and overall survival (OS), varied by the level advanced disease and require aggressive cytoreductive surgery and of BRCA1 protein expressed in archival primary tumours from chemotherapy to achieve remission and possible cure. Despite the patients who participated in the randomised IP vs IV phase III trial fact that most patients will respond to initial therapy, the majority GOG-172 (Armstrong et al, 2006). of patients will have recurrence. Ultimately, most of these patients with recurrent EOC die from the development of chemotherapy- MATERIALS AND METHODS resistant disease (Cannistra, 2004; Lage and Denkert, 2007). Breast cancer 1, early onset (BRCA1) is a tumour-suppressor gene located on chromosome 17q21 that has multiple roles in Patient selection. Patients from GOG-172 protocol with archival cellular functions. Germline mutations significantly increase a tumour were eligible. The GOG-172 was a phase III, multi- woman’s risk of developing breast and/or EOC (Miki et al, 1994; institutional, randomised trial of IV group vs IP group for patients Antonio et al, 2003). In sporadic EOC, BRCA1 dysfunction is with a diagnosis of incident EOC or PPC (Armstrong et al, 2006). frequently observed (Tutt and Ashworth, 2002). The BRCA1 Inclusion criteria were patients with stage IIIC EOC or PPC with protein combines with numerous proteins to regulate transcrip- optimal,o1 cm residual disease and one of the following histologic tion, chromatin remodelling, ubiquitination and repair of double- cell types: serous adenocarcinoma, endometrioid adenocarcinoma, strand DNA breaks induced by DNA crosslinking agents, radiation mucinous adenocarcinoma, undifferentiated carcinoma, clear or other exposures and events via homologous recombination cell adenocarcinoma, mixed epithelial carcinoma, transitional cell, (Tutt and Ashworth, 2002; Venkitaraman 2002; Yoshida and Miki, malignant Brenner’s Tumour or adenocarcinoma not otherwise 2004; Weberpals et al, 2009). Given the various ways that BRCA1 specified. The institutional review board at participating institu- protein expression can be altered in cancers, there is accumulating tions approved the use of archival tissues as did the review board at interest in the contribution of BRCA1 dysfunction on the Magee-Womens Hospital of the UPMC. All patients provided pathogenesis of EOC and sensitivity to chemotherapy (Cass et al, written informed consent consistent with all federal, state and local 2003; Majdak et al, 2005; Wilcox et al, 2005; Chetrit et al, 2008). regulations before receiving treatment on GOG-172. There are data to suggest that patients with reduced BRCA1 IHC for BRCA1 expression and scoring. Sections (5 mm thick) of expression may have improved survival after platinum-based primary tumour on glass slides were sent from each institution to (or DNA damage-based) chemotherapy, yet reduced response to the GOG Tissue Bank. The IHC assays for BRCA1 expression used taxane-based (antimicrotubule) therapy (Foulkes, 2006). the MS110 clone monoclonal antibody Ab-1 (Oncotech Inc., The standard of care for patients with advanced EOC is Tustin, CA, USA) that reacts with the N-terminal portion of the treatment with a combination of platinum and taxane. Although a BRCA1 protein. This antibody has been utilised and validated by series of randomised phase III trials have demonstrated a dramatic several authors (Thrall et al, 2006; Swisher et al, 2008; Mangia et al survival advantage associated with IP (intravenous paclitaxel and 2009). The MCF-7 cells were used as positive controls, whereas cisplatin) vs IV (combination of intravenous paclitaxel and nonimmune serum was used as a negative control. intraperitoneal cisplatin and paclitaxel) platinum and taxane Percentage of staining was determined by two independent chemotherapy, the community has not embraced IP therapy, in readers (JLL and TCK) and reviewed by a gynaecologic pathologist part because of toxicities and other concerns (Albert et al, 1996; (CZ), all of whom were blinded to the identity of the samples and Markman et al, 2001; Armstrong et al, 2006). The Gynecologic clinical outcome. The tumour specimens were scored in five Oncology Group (GOG) has conducted another randomised phase separate locations throughout the slide, and multiple characteristics III trial (GOG-252) to compare different platinum and taxane- of staining were noted, including intensity of staining, location of based IP vs IV regimens in advanced-stage EOC and PPC. staining (nuclear and/or cytoplasmic) and staining percentage.. Currently, there is no test that can select which patients are likely The ascribed score was based on the number of cells with nuclear to benefit from more aggressive and toxic IP therapy. Cisplatin staining, specifically. Slides were scored as 0 if there was no induces intra- and interstrand crosslinks and will activate apoptosis staining, 1 if there was scattered staining (o10%), 2 if 10–50% of if the damaged DNA is not adequately repaired. The IP cells stained, 3 if 50–90% of cells stained and 4 if nearly all (490%) administration of cisplatin produces a 12-fold greater drug the cells were stained. Tumours were categorised as having exposure in the peritoneal cavity (Howel et al, 1982). We speculate aberrant BRCA1 expression for very low to no staining (o10% that patients with aberrant tumour expression of BRCA1 staining; 0 or 1 score) and normal BRCA1 expression for 410% expression will have a diminished ability to repair double-stranded BRCA1 staining (2–4 score). This scoring algorithm was developed DNA breaks and will therefore be more sensitive to IP therapy and and validated by Thrall et al (2006) and others (Swisher et al, 2008; will have better survival when compared with women with normal Carser et al, 2011). BRCA1 tumour expression. We therefore undertook the following study to determine if Statistical analysis. Progression-free survival was calculated as BRCA1 pathway dysfunction, whether via germline mutations, time of randomisation to either disease recurrence or death from somatic mutations or other mechanisms that result in decreased any cause before recurrence, and OS was calculated from protein expression, helps define a group of patients who may randomisation to death from any cause. The PFS and OS were respond to IP platinum-based chemotherapy. To this end, the estimated using the Kaplan–Meier method. The difference in concept of a common expression pattern that correlates with any survival function between patients with normal and aberrant BRCA dysfunction, ‘BRCAness’, was developed to define the role of BRCA1 expression was assessed by the log-rank test. Cox BRCA function and response to cytotoxic chemotherapy (Turner regression modelling was used to assess the association of BRCA1 et al, 2004; Tan et al, 2008). Konstaninopoulos et al (2010) expression and outcome using an unadjusted model and after reported improved responsiveness to platinum in a cohort of adjusting for age, residual disease (microscopic vs gross), sporadic EOC patients with a BRCAness profile defined by gene histological subtype and type of treatment (IP vs IV). The hazard expression analysis. BRCA1 expression can be assessed using ratio (HR) was estimated for disease progression or death by immunohistochemistry (IHC), and studies have shown that BRCA1 expression. The interaction between BRCA1 expression absent/low BRCA1 protein expression can predict for an improved and treatment was tested by extending the Cox model and adding response to chemotherapy (Thrall et al, 2006; Swisher et al, 2008; an interaction term. The w test (for categorical variables) or 1232 www.bjcancer.com | DOI:10.1038/bjc.2013.70 BRCA1 expression and improved survival in ovarian cancer patients BRITISH JOURNAL OF CANCER Wilcoxon rank-sum test (for continuous variables) was performed Table 1. Patient characteristics by BRCA1 expression in tumours to evaluate the association of BRCA1 expression and patient characteristics. All reported P-values are two sided with Po0.05 Aberrant Normal considered statistically significant. (o10%) BRCA1 (410%) BRCA1 expression expression Characteristic (n¼ 189) (n¼ 204) P-value RESULTS Age (years) Median (range) 57.1 (30.8–84.5) 57.5 (25.4–84.9) 0.632 Of the 415 eligible patients enroled in GOG-172, archival formalin- fixed and paraffin-embedded primary tumours were available from Race 393 patients, which represented 95% of all clinical trial partici- pants. At the time of the current analysis, median follow-up for White 168 (88.9) 186 (91.2) 0.749 those who were still alive was 86 months. There were 282 patients Black 6 (3.2) 5 (2.4) Other 15 (7.9) 13 (6.4) who experienced disease progression and 255 who died. The lockout date for this study was similar to that used for the GOG PS GOG-172 phase III trial (Armstrong et al, 2006). Of the 393 patients in this study, 189 (48%) tumours had 0 76 (40.2) 99 (48.5) 0.249 aberrant and 204 (52%) had normal BRCA1 expression. Patient 1 102 (54.0) 94 (46.1) characteristics were similar between the groups (Table 1). When 2 11 (5.8) 11 (5.4) the treatment regimen was ignored, aberrant vs normal BRCA1 Cell type expression was associated with similar OS (Figure 1A) and PFS (Figure 1B). However, statistical evidence of an interaction was Serous 151 (79.9) 164 (80.4) 0.952 observed between tumour expression of BRCA1 and route of Endometrioid 13 (6.9) 15 (7.4) administration for OS (P¼ 0.014), suggesting that treatment Clear cell 10 (5.3) 8 (3.9) efficacy for IP vs IV was modified by expression level of BRCA1. Mucinous 1 (0.5) 2 (1.0) Figure 2 illustrates the extent to which the OS (Figure 2A) and Others 14 (7.4) 15 (7.4) PFS (Figure 2B) varied by tumour expression of BRCA1 and route Tumour grade of administration of therapy. The IP-treated patients with aberrant BRCA1 expression had the best OS (Figure 2A) and PFS 1 19 (10.1) 23 (11.3) 0.867 (Figure 2B). Median OS was 58 months for IP patients with 2 70 (37.0) 78 (38.2) normal BRCA1 expression vs 50 months for IV patients with 3 100 (52.9) 103 (50.5) normal BRCA1 expression (P¼ 0.818). In contrast, median OS was Tumour residual 84 months in the IP patients with aberrant BRCA1 expression vs 48 months in IV patients with aberrant BRCA1 expression Microscopic 75 (39.7) 70 (34.3) 0.270 (P¼ 0.0002). Median PFS for IP patients with aberrant BRCA1 Gross 114 (60.3) 134 (65.7) expression was 35 months compared with o20 months for the Treatment three other subgroups. However, the interaction between level of BRCA expression (aberrant vs normal) and PFS did not achieve IV 93 (49.2) 107 (52.5) 0.520 statistical significance (P¼ 0.054). IP 96 (50.8) 97 (47.6) The influence of the route of administration on the relationship Abbreviations: BRCA1¼ breast cancer 1, early onset; GOG PS¼ Gynecologic Oncology between BRCA1 expression and patient outcome was also assessed Group Performance Status; IV¼ intravenous; IP¼ intraperitoneal. using unadjusted and adjusted Cox regression survival analysis (Table 2). Similar survival was observed for IP vs IV patients with normal BRCA1 expression (unadjusted HR¼ 0.97, 95% confidence we have demonstrated that in this cohort of optimally resected interval (CI)¼ 0.69–1.37, P¼ 0.862; adjusted HR¼ 0.98, 95% patients with stage III EOC or PPC, aberrant BRCA 1 expression CI¼ 0.69–1.38, P¼ 0.895). Significantly better survival was showed an improved PFS and OS when compared with patients observed in the subset of IP patients with aberrant BRCA1 whose tumours had normal BRCA 1 expression when stratified by expression (unadjusted HR¼ 0.68, 95% CI¼ 0.47–0.97, P¼ 0.034). treatment type. In patients whose tumours have aberrant BRCA1 Aberrant BRCA1 expression retained independent prognostic expression, a clinically significant benefit in PFS and OS, 14 and 36 value for survival in the subset of patients randomised to IP months respectively, was seen when those patients were treated therapy after adjusting for age, residual disease (microscopic vs with IP chemotherapy compared with patients whose tumours had gross) and histologic subtype with an adjusted HR¼ 0.67 (95% CI normal expression of BRCA1 (Figure 2A and B). In patients ¼ 0.47–0.97, P¼ 0.0320). Similar survival was observed for IV whose tumours had normal expression of BRCA1, no signi- patients with aberrant vs normal BRCA1 expression (unadjusted ficant improvement in PFS or OS with IV therapy was seen HR¼ 1.30, 95% CI¼ 0.93–1.81, P¼ .121). Multivariate model- (Figure 2A and B). ling adjusting for age, residual disease (microscopic vs gross) and In genomic stability, BRCA1 has an important role. Altered cell type demonstrated that IV patients with aberrant vs normal BRCA1 expression and/or dysfunction may occur as a result of BRCA1 expression exhibited an increased risk of death (adjusted germline mutations, somatic mutations or epigenetic modifica- HR¼ 1.46, 95% CI¼ 1.04–2.03, P¼ 0.028). tions. Our analysis showed a high percentage of patients with aberrant BRCA1 expression in their tumours (52%). This rate is similar to the rate of BRCA1 expression (46%) seen in the analysis DISCUSSION by Thrall et al (2006) and that reported by Carser et al (2011) (41%) (Swisher et al, 2008). Low levels of BRCA1 (aberrant) expression have been reported to vary between 34 and 90% in the In our study, we evaluated BRCA1 protein expression via IHC in tumour specimens from patients enroled in GOG-172 with respect literature (Russell et al, 2000; Thrall et al, 2006 Swisher et al, 2009). This amount of variation may be the result of differences in the to PFS and OS. Utilising IHC expression for BRCA1 in this study, www.bjcancer.com | DOI:10.1038/bjc.2013.70 1233 BRITISH JOURNAL OF CANCER BRCA1 expression and improved survival in ovarian cancer patients 1.0 1.0 0.8 0.8 IP therapy aberrant BRCA1 0.6 0.6 Test for interaction: P = 0.014 0.4 0.4 Log-rank test: P = 0.729 Therapy IHC expression Patients Events Median OS IP Aberrant BRCA1 96 51 84.1 months 0.2 Patients events median OS IP Normal BRCA1 97 62 58.1 months 0.2 IV Aberrant BRCA1 93 74 47.7 months Aberrant BRCA1 189 125 60.1 months IV Normal BRCA1 107 68 50.4 months 0.0 Normal BRCA1 204 130 53.6 months 0.0 0 122436486072 84 Survival time in months 0 12243648607284 Survival time in months 1.0 Therapy IHC expression Patients Events Median PFS IP Aberrant BRCA1 96 71 34.7 months 1.0 Patients events median PFS IP Normal BRCA1 97 76 20.1 months 0.8 IV Aberrant BRCA1 93 81 18.7 months Aberrant BRCA1 189 152 24.1 months IV Normal BRCA1 107 83 17.7 months Normal BRCA1 204 159 18.4 months 0.8 0.6 Log-rank test: P = 0.615 IP therapy 0.6 aberrant BRCA1 0.4 0.4 0.2 Test for interaction: P = 0.054 0.0 0.2 0 12243648607284 Progression free survival in months 0.0 0 12243648607284 Figure 2. Kaplan–Meier estimate of (A) overall survival (OS) Progression free survival in months and (B) progression-free survival (PFS) for aberrant vs normal BRCA1 expression and by intraperitoneal (IP) vs intravenous Figure 1. Kaplan–Meier estimate of (A) overall survival (OS) and (B) (IV) therapy. progression-free survival (PFS) for the entire cohort comparing aberrant with normal BRCA1 expression. Log-rank test was used to compare survival distributions across subgroups. Table 2. Unadjusted and adjusted Cox regression modelling for PFS and OS for tumour expression of BRCA1 protein (normal vs aberrant) and type of therapy (IV vs IP) Univariate analysis Multivariate analysis Group HR (95% CI) P-value HR (95% CI) P-value PFS IV patients with normal BRCA1 Referent Referent IV patients with aberrant BRCA1 1.19 (0.88–1.62) 0.263 1.33 (0.98–1.81) 0.072 IP patients with normal BRCA1 0.97 (0.71–1.32) 0.824 0.95 (0.69–1.30) 0.745 IP patients with aberrant BRCA1 0.74 (0.54–1.02) 0.065 0.72 (0.52–0.99) 0.043 OS IV patients with normal BRCA1 Referent Referent IV patients with aberrant BRCA1 1.30 (0.93–1.81) 0.121 1.46 (1.04–2.03) 0.028 IP patients with normal BRCA1 0.97 (0.69–1.37) 0.862 0.98 (0.69–1.38) 0.895 IP patients with aberrant BRCA1 0.68 (0.47–0.97) 0.034 0.67 (0.47–0.97) 0.032 Abbreviations: BRCA1¼ breast cancer 1, early onset; CI¼ confidence interval; HR¼ hazard ratio; IV¼ intravenous; IP¼ intraperitoneal; OS¼ overall survival; PFS¼ progression-free survival. Adjusted for age, cell type and tumour residual. stage of disease, residual disease status, sample size, IHC assay effects of these genes. The cancer genome atlas project (TCGA) conditions, interpretation of expression and treatment. Jazzeri et al recently published the genomic analysis of serous epithelial ovarian (2002) compared gene expression profiles in BRCA1/2-associated cancer. In this study, BRCA1/2 dysfunction was defined as EOC with sporadic EOC and showed that sporadic tumours may germline mutations, somatic mutations and methylation in have mutations that resemble the molecular pathways seen in BRCA1. The results showed that in 33% of patients with germline mutations as well as dysfunction in the downstream advanced-stage serous ovarian cancer, BRCA1/2 dysfunction 1234 www.bjcancer.com | DOI:10.1038/bjc.2013.70 Proportion progression free Proportion surviving Proportion progression free Proportion surviving BRCA1 expression and improved survival in ovarian cancer patients BRITISH JOURNAL OF CANCER occurs and may provide a target for therapeutic interventions. In (low levels are associated with reduced response to taxanes). fact, B50% of cases exhibited defects in homologous recombina- Normal BRCA1 expression may imply robust DNA repair, and tion (The Cancer Genome Research Network, 2011). These levels therefore neutralising the clinical benefit of high intratumoural are consistent with the 52% of cases with aberrant BRCA1 drug dose levels of platinum following IP therapy. Yang et al expression. Further testing will be required to confirm that EOC/ (2011) reported on BRCA1/2 expression and patient outcomes PPC patients with BRCA1-dependent defects in homologous from the publically available Cancer Genome Atlas Project. recombination exhibit enhanced responsiveness and outcomes This analysis demonstrated that only patients with BRCA2 following IP therapy with cisplatin and paclitaxel. Additional germline mutations had improved OS (Yang et al, 2011). studies will be required to determine if patients with BRCA1- The 3-month difference for OS, although statistically significant, independent defects in homologous recombination benefit from IP is not likely clinically significant. As patients with normal BRCA1 vs IV platinum-based therapy, and whether the benefits from exhibit similar outcome following IV or IP therapy, consideration cisplatin IP-based therapy in women with aberrant BRCA1 might be given to directing these patients to IV therapy and thus expression extends to IP carboplatin as well. avoiding the extra toxicities associated with IP therapy, as these Studies have also shown that patients who have BRCA1 patients are unlikely to have the same clinical benefit from IP germline mutations and develop EOC may have improved survival chemotherapy as those whose tumours have aberrant levels when compared with patients with sporadic EOC (Pharaoh et al, of BRCA1. 1999; Pal et al, 2007; Tan et al, 2008). In our current study we There are a few studies assessing BRCA1 expression via IHC as evaluated PFS and OS with respect to BRCA1 IHC expression and a prognostic marker for survival in patients with advanced-stage stratified by chemotherapy delivery method (IV vs IP). We have EOC (Thrall et al, 2006; Sirisabya et al, 2007; Swisher et al, 2008; shown that patients whose tumours have aberrant BRCA1 Carser et al, 2011). Sirisabya et al (2007) reported on 99 patients expression and were treated with IP cisplatin have a 36-month with EOC, stages I–IV, and showed a positive BRCA1 IHC improvement in OS. This finding in patients whose tumours had expression rate of 12% (defined as staining of410%). Their results did not demonstrate any difference in PFS or OS; however, the aberrant BRCA1 expression and were treated with IP chemother- apy is biologically plausible. In several DNA repair mechanisms authors did not stratify groups with respect to stage or residual including homologous recombination, chromatin remodelling, disease. Swisher et al (2008) evaluated 115 sporadic EOC and regulation of the cell cycle and transcription, BRCA1 is implicated reported a survival benefit in patients whose tumours had low (Venkitaraman 2002; Yoshida and Miki 2004; Weberpals et al, BRCA1 expression. Thrall et al (2006) evaluated BRCA1 IHC 2009). These cellular functions are critical factors in how cells expression relative to stage and histology in a subset of patients respond to cytotoxic agents, and particularly platinum. There are enroled in GOG-172. Of the 152 patients with outcome data, data to suggest that loss of BRCA1 function confers enhanced patients with low BRCA1 expression had an improved PFS and OS chemosensitivity to platinum-based chemotherapy and increase in with a follow-up of 60 months. However, because of the limited resistance to antimicrotubule agents (Quinn et al, 2007; Stordal sample size and follow-up, it was not designed to evaluate the and Davey, 2009). Stordal and Davey (2009) recently reviewed a impact of BRCA1 expression on PFS and OS. Finally, (Carser et al wide range of cell models and showed that modifications in BRCA1 (2011) performed BRCA IHC on 292 ovarian tumours and showed (both increases and decreases) had the highest rate of inverse an improved response to single-agent platinum with absent/low cisplatin/paclitaxel resistance phenotype compared with other gene (o10%) BRCA1 expression. Our report includes the largest series mutations. As such, the role of BRCA1 dysfunction as related to of patients enroled in a randomised trial (n¼ 393) with mature chemotherapy response and patient survival is an important outcome data (median follow-up time of 86 months) using BRCA component in treatment planning for patients with EOC (Quinn IHC. Additionally, our results may be slightly different because of et al, 2009). The IP therapy delivers higher concentrations of the fact that all of the patients in our study had optimally resected cytotoxic chemotherapy (Dedrick et al, 1978; Howel et al, 1982). stage III EOC or PPC and had received combination therapy with Howel et al (1982)) demonstrated 12-fold higher peritoneal cisplatin and paclitaxel. concentrations of cisplatin relative to plasma levels with intraper- There are limitations with our current study. Our data did not itoneal administration, and aberrant BRCA1 expression implies show an overall survival advantage in patients whose tumours impaired DNA repair mechanisms. The additive effect of these exhibited aberrant BRCA1 expression, which is in contrast to some mechanisms, more intensive and prolonged exposure to platinum prior published results (Swisher et al, 2008; Carser et al, 2011). in the setting of defective double-strand break repair, may explain Although atypical, this finding cannot detract from the results of why tumour cells with low expression of BRCA1 will be more the subgroup analysis. We also recognise the limitations of the sensitive to IP chemotherapy. In the subgroup analysis of this assay for protein expression, namely IHC, which is assessed in a cohort, aberrant BRCA1 expression confers a survival benefit for semiquantitative manner by independent reviewers and utilises an patients treated with IP therapy, with a median PFS and OS of 35 antibody that recognises the N-terminal region of BRCA1. This and 84 months, respectively, which extends even beyond the technique has been widely adopted for the assessment of protein survival advantage seen with IP therapy reported by Armstrong expression in other proteins and tumours (oestrogen receptor, et al (2006). This suggests that tumour BRCA1 expression may be progesterone receptor and HER-2 in breast cancer, and MLH1 in an important biomarker in sporadic EOC in determining response colon cancer), and is run in several clinical, commercial and to IP chemotherapy and may provide a way to select ideal research laboratories. The clinical utility of BRCA1 expression candidates for IP therapy. assessment in patients with advanced-stage EOC warrants further These data also showed similar survival in IV and IP patients validation. The results of this study provide provocation for its whose tumour exhibited normal BRCA1 expression. Worse assessment in future trials in conjunction with other methods of survival was observed for IV patients with aberrant BRCA1 evaluating BRCA1, including quantitative mass spectrometry expression using multivariate but not using unadjusted univariate (MS)-based platforms assessing protein mass, sequence and modelling. The negative effect of aberrant BRCA1 expression on concentration as well as modifications, BRCA-1 binding proteins OS required adjustments for age, residual disease and cell type. It via immunoprecipitation followed by immunoblotting and MS and should be noted that the proportion of cases with BRCA1 aberrant BRCA1 transcriptional regulation by chromatin immunoprecipita- did not vary significantly by age, residual disease status or cell type. tion followed by next-generation sequencing for an example. Also, The improved survival seen with normal vs aberrant expression of EOC and PPC may be further studied to characterise the type of BRCA1 may be related to the BRCA1 effect on response to taxanes BRCA dysfunction including somatic vs germline mutations, www.bjcancer.com | DOI:10.1038/bjc.2013.70 1235 BRITISH JOURNAL OF CANCER BRCA1 expression and improved survival in ovarian cancer patients methylation, nuclear localisation and export, ubiquitin-mediated Dedrick RL, Myers CE, Bungay PM, DeVita VT (1978) Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian degradation and chromatin remodelling. cancer. Cancer Treat Rep 62: 1–11. In conclusion, our data demonstrate a significant 3-year Foulkes WD (2006) BRCA1 and BRCA2: chemosensitivity, treatment improvement in OS for patients with advanced EOC whose outcomes and prognosis. Fam Cancer 5: 135–142. tumours exhibit aberrant BRCA1 expression treated with IP Howell SB, Pfeifle CL, Wung WE, Olshen RA, Lucas WE, Yon JL, Green M therapy. These were patients enroled in a phase III trial, with a (1982) Intraperitoneal cisplatin with systemic thiosulfate protection. Ann large sample size, and treatment in each protocol arm was uniform. Intern Med 97: 845–851. The method of IHC used in this report is commercially available Jazaeri A, Yee C, Sotriou C, Brantley K, Boyd J, Liu E (2002) Gene expression and easily reproducible. Our findings suggest that IHC assessment profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers of BRCA1 expression should be prospectively studied as a guide for J Natl Cancer Inst 94: 990–1000. the decision to use IP chemotherapy, and has been incorporated in Konstantinopoulos P, Spentzos D, Karlan B, Taniguchi T, Fountzilas E, the recent randomised phase III trial of IP vs IV in EOC and PPC Francoer N, Levine DA, Cannistra SA (2010) Gene expression profile of conducted by the Gynecologic Oncology Group protocol, GOG BRCAness that correlates with responsiveness to chemotherapy and 252. The significant increase in survival in patients with aberrant with outcome in patients with epithelial ovarian cancer. J Clin Oncol 28: 3555–3561. 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This work is published under the standard license to publish agree- Weberpals J, Garbuio K, O’Brien A, Clark-Knowles K, Doucett S, Antoniouk O, Glenwood G, Dimitroulakos J (2009) The DNA repair proteins BRCA1 ment. After 12 months the work will become freely available and and ERCC1 as predictive markers in sporadic ovarian cancer. Int J Cancer the license terms will switch to a Creative Commons Attribution- 24: 806–815. NonCommercial-Share Alike 3.0 Unported License. www.bjcancer.com | DOI:10.1038/bjc.2013.70 1237 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study

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Copyright © 2013 by The Author(s)
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Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
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10.1038/bjc.2013.70
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Abstract

FULL PAPER British Journal of Cancer (2013) 108, 1231–1237 | doi: 10.1038/bjc.2013.70 Keywords: ovarian cancer; intraperitoneal chemotherapy; BRCA1 immunohistochemistry BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study 1 2,8 2,9 3 4 5 6 7 J L Lesnock , K M Darcy , C Tian , J A DeLoia , M M Thrall , C Zahn , D K Armstrong , M J Birrer and ,1 T C Krivak 1 2 Magee-Women’s Hospital of UPMC, Division of Gynecologic Oncology, Pittsburgh PA 15213, USA; Gynecologic Oncology Group Statistical & Data Center, Roswell Park Cancer Institute, Buffalo NY 14263, USA; Georgetown University Medical Center, 4 5 Washington, DC 20057, USA; University of Washington, Seattle WA 98195-6460, USA; Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA; Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore MD 21231-1000, USA and Massachusetts General Hospital, Boston MA 02114, USA Background: Breast cancer 1, early onset (BRCA1) is a tumour-suppressor gene associated with familial epithelial ovarian cancer (EOC). Reduced BRCA1 expression is associated with enhanced sensitivity to platinum-based chemotherapy. We sought to examine the prognostic relevance of BRCA1 expression in EOC patients treated with intraperitoneal platinum/taxane. Methods: The GOG-172 was a phase III, multi-institutional randomised trial of intravenous paclitaxel and cisplatin (IV therapy) vs intravenous paclitaxel, intraperitoneal cisplatin plus paclitaxel (IP therapy) in patients with optimally resected stage III EOC. The BRCA1 expression was assessed with immunohistochemistry (IHC) staining blinded to clinical outcome in archival tumour specimens. Slides with p10% staining were defined as aberrant and 410% as normal. Correlations between BRCA1 expression and progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan–Meier method and Cox regression analysis. Results: Of the 393 patients, 189 tumours had aberrant expression, and 204 had normal BRCA1 expression. There was an interaction between BRCA1 expression and route of administration on OS (P¼ 0.014) but not PFS (P¼ 0.054). In tumours with normal BRCA1 expression, the median OS was 58 months for IP group vs 50 months for IV group (P¼ 0.818). In tumours with aberrant BRCA1 expression, the median OS was 84 vs 47 months in the IP vs IV group, respectively (P¼ 0.0002). Aberrant BRCA1 expression was an independent prognostic factor for better survival in women randomised to IP therapy (hazard ratio (HR)¼ 0.67, 95% confidence interval (CI)¼ 0.47–0.97, P¼ 0.032). Similar survival was observed in the IV and IP patients with normal BRCA1 expression. Multivariate but not univariate modelling demonstrated that IV patients with aberrant vs normal BRCA1 expression had worse survival. Conclusion: Decreased BRCA1 expression is associated with a 36-month survival improvement in patients with EOC treated with IP chemotherapy. Although these results merit validation in future studies, the results suggest that decreased BRCA1 expression predicts for improved response to cisplatin-based IP chemotherapy with cisplatin and paclitaxel. *Correspondence: Dr TC Krivak; E-mail: Tkrivak@mail.magee.edu Current address: Gynecologic Cancer Center of Excellence and the Women’s Health Integrated Research Center at Inova Health System, Annandale, VA 22003, USA Current address: Precision Therapeutics Inc., Pittsburgh, PA 15213, USA Received 24 October 2012; revised 26 January 2013; accepted 27 January 2013; published online 5 March 2013 & 2013 Cancer Research UK. All rights reserved 0007 – 0920/13 www.bjcancer.com | DOI:10.1038/bjc.2013.70 1231 BRITISH JOURNAL OF CANCER BRCA1 expression and improved survival in ovarian cancer patients Epithelial ovarian cancer (EOC) is estimated to affect 22 200 Carser et al, 2011). The primary objective of this study was to women in the United States and lead to B15 550 deaths annually determine if the benefits of IP therapy, measured by progression- (Siegel et al, 2012). Women with EOC typically present with free survival (PFS) and overall survival (OS), varied by the level advanced disease and require aggressive cytoreductive surgery and of BRCA1 protein expressed in archival primary tumours from chemotherapy to achieve remission and possible cure. Despite the patients who participated in the randomised IP vs IV phase III trial fact that most patients will respond to initial therapy, the majority GOG-172 (Armstrong et al, 2006). of patients will have recurrence. Ultimately, most of these patients with recurrent EOC die from the development of chemotherapy- MATERIALS AND METHODS resistant disease (Cannistra, 2004; Lage and Denkert, 2007). Breast cancer 1, early onset (BRCA1) is a tumour-suppressor gene located on chromosome 17q21 that has multiple roles in Patient selection. Patients from GOG-172 protocol with archival cellular functions. Germline mutations significantly increase a tumour were eligible. The GOG-172 was a phase III, multi- woman’s risk of developing breast and/or EOC (Miki et al, 1994; institutional, randomised trial of IV group vs IP group for patients Antonio et al, 2003). In sporadic EOC, BRCA1 dysfunction is with a diagnosis of incident EOC or PPC (Armstrong et al, 2006). frequently observed (Tutt and Ashworth, 2002). The BRCA1 Inclusion criteria were patients with stage IIIC EOC or PPC with protein combines with numerous proteins to regulate transcrip- optimal,o1 cm residual disease and one of the following histologic tion, chromatin remodelling, ubiquitination and repair of double- cell types: serous adenocarcinoma, endometrioid adenocarcinoma, strand DNA breaks induced by DNA crosslinking agents, radiation mucinous adenocarcinoma, undifferentiated carcinoma, clear or other exposures and events via homologous recombination cell adenocarcinoma, mixed epithelial carcinoma, transitional cell, (Tutt and Ashworth, 2002; Venkitaraman 2002; Yoshida and Miki, malignant Brenner’s Tumour or adenocarcinoma not otherwise 2004; Weberpals et al, 2009). Given the various ways that BRCA1 specified. The institutional review board at participating institu- protein expression can be altered in cancers, there is accumulating tions approved the use of archival tissues as did the review board at interest in the contribution of BRCA1 dysfunction on the Magee-Womens Hospital of the UPMC. All patients provided pathogenesis of EOC and sensitivity to chemotherapy (Cass et al, written informed consent consistent with all federal, state and local 2003; Majdak et al, 2005; Wilcox et al, 2005; Chetrit et al, 2008). regulations before receiving treatment on GOG-172. There are data to suggest that patients with reduced BRCA1 IHC for BRCA1 expression and scoring. Sections (5 mm thick) of expression may have improved survival after platinum-based primary tumour on glass slides were sent from each institution to (or DNA damage-based) chemotherapy, yet reduced response to the GOG Tissue Bank. The IHC assays for BRCA1 expression used taxane-based (antimicrotubule) therapy (Foulkes, 2006). the MS110 clone monoclonal antibody Ab-1 (Oncotech Inc., The standard of care for patients with advanced EOC is Tustin, CA, USA) that reacts with the N-terminal portion of the treatment with a combination of platinum and taxane. Although a BRCA1 protein. This antibody has been utilised and validated by series of randomised phase III trials have demonstrated a dramatic several authors (Thrall et al, 2006; Swisher et al, 2008; Mangia et al survival advantage associated with IP (intravenous paclitaxel and 2009). The MCF-7 cells were used as positive controls, whereas cisplatin) vs IV (combination of intravenous paclitaxel and nonimmune serum was used as a negative control. intraperitoneal cisplatin and paclitaxel) platinum and taxane Percentage of staining was determined by two independent chemotherapy, the community has not embraced IP therapy, in readers (JLL and TCK) and reviewed by a gynaecologic pathologist part because of toxicities and other concerns (Albert et al, 1996; (CZ), all of whom were blinded to the identity of the samples and Markman et al, 2001; Armstrong et al, 2006). The Gynecologic clinical outcome. The tumour specimens were scored in five Oncology Group (GOG) has conducted another randomised phase separate locations throughout the slide, and multiple characteristics III trial (GOG-252) to compare different platinum and taxane- of staining were noted, including intensity of staining, location of based IP vs IV regimens in advanced-stage EOC and PPC. staining (nuclear and/or cytoplasmic) and staining percentage.. Currently, there is no test that can select which patients are likely The ascribed score was based on the number of cells with nuclear to benefit from more aggressive and toxic IP therapy. Cisplatin staining, specifically. Slides were scored as 0 if there was no induces intra- and interstrand crosslinks and will activate apoptosis staining, 1 if there was scattered staining (o10%), 2 if 10–50% of if the damaged DNA is not adequately repaired. The IP cells stained, 3 if 50–90% of cells stained and 4 if nearly all (490%) administration of cisplatin produces a 12-fold greater drug the cells were stained. Tumours were categorised as having exposure in the peritoneal cavity (Howel et al, 1982). We speculate aberrant BRCA1 expression for very low to no staining (o10% that patients with aberrant tumour expression of BRCA1 staining; 0 or 1 score) and normal BRCA1 expression for 410% expression will have a diminished ability to repair double-stranded BRCA1 staining (2–4 score). This scoring algorithm was developed DNA breaks and will therefore be more sensitive to IP therapy and and validated by Thrall et al (2006) and others (Swisher et al, 2008; will have better survival when compared with women with normal Carser et al, 2011). BRCA1 tumour expression. We therefore undertook the following study to determine if Statistical analysis. Progression-free survival was calculated as BRCA1 pathway dysfunction, whether via germline mutations, time of randomisation to either disease recurrence or death from somatic mutations or other mechanisms that result in decreased any cause before recurrence, and OS was calculated from protein expression, helps define a group of patients who may randomisation to death from any cause. The PFS and OS were respond to IP platinum-based chemotherapy. To this end, the estimated using the Kaplan–Meier method. The difference in concept of a common expression pattern that correlates with any survival function between patients with normal and aberrant BRCA dysfunction, ‘BRCAness’, was developed to define the role of BRCA1 expression was assessed by the log-rank test. Cox BRCA function and response to cytotoxic chemotherapy (Turner regression modelling was used to assess the association of BRCA1 et al, 2004; Tan et al, 2008). Konstaninopoulos et al (2010) expression and outcome using an unadjusted model and after reported improved responsiveness to platinum in a cohort of adjusting for age, residual disease (microscopic vs gross), sporadic EOC patients with a BRCAness profile defined by gene histological subtype and type of treatment (IP vs IV). The hazard expression analysis. BRCA1 expression can be assessed using ratio (HR) was estimated for disease progression or death by immunohistochemistry (IHC), and studies have shown that BRCA1 expression. The interaction between BRCA1 expression absent/low BRCA1 protein expression can predict for an improved and treatment was tested by extending the Cox model and adding response to chemotherapy (Thrall et al, 2006; Swisher et al, 2008; an interaction term. The w test (for categorical variables) or 1232 www.bjcancer.com | DOI:10.1038/bjc.2013.70 BRCA1 expression and improved survival in ovarian cancer patients BRITISH JOURNAL OF CANCER Wilcoxon rank-sum test (for continuous variables) was performed Table 1. Patient characteristics by BRCA1 expression in tumours to evaluate the association of BRCA1 expression and patient characteristics. All reported P-values are two sided with Po0.05 Aberrant Normal considered statistically significant. (o10%) BRCA1 (410%) BRCA1 expression expression Characteristic (n¼ 189) (n¼ 204) P-value RESULTS Age (years) Median (range) 57.1 (30.8–84.5) 57.5 (25.4–84.9) 0.632 Of the 415 eligible patients enroled in GOG-172, archival formalin- fixed and paraffin-embedded primary tumours were available from Race 393 patients, which represented 95% of all clinical trial partici- pants. At the time of the current analysis, median follow-up for White 168 (88.9) 186 (91.2) 0.749 those who were still alive was 86 months. There were 282 patients Black 6 (3.2) 5 (2.4) Other 15 (7.9) 13 (6.4) who experienced disease progression and 255 who died. The lockout date for this study was similar to that used for the GOG PS GOG-172 phase III trial (Armstrong et al, 2006). Of the 393 patients in this study, 189 (48%) tumours had 0 76 (40.2) 99 (48.5) 0.249 aberrant and 204 (52%) had normal BRCA1 expression. Patient 1 102 (54.0) 94 (46.1) characteristics were similar between the groups (Table 1). When 2 11 (5.8) 11 (5.4) the treatment regimen was ignored, aberrant vs normal BRCA1 Cell type expression was associated with similar OS (Figure 1A) and PFS (Figure 1B). However, statistical evidence of an interaction was Serous 151 (79.9) 164 (80.4) 0.952 observed between tumour expression of BRCA1 and route of Endometrioid 13 (6.9) 15 (7.4) administration for OS (P¼ 0.014), suggesting that treatment Clear cell 10 (5.3) 8 (3.9) efficacy for IP vs IV was modified by expression level of BRCA1. Mucinous 1 (0.5) 2 (1.0) Figure 2 illustrates the extent to which the OS (Figure 2A) and Others 14 (7.4) 15 (7.4) PFS (Figure 2B) varied by tumour expression of BRCA1 and route Tumour grade of administration of therapy. The IP-treated patients with aberrant BRCA1 expression had the best OS (Figure 2A) and PFS 1 19 (10.1) 23 (11.3) 0.867 (Figure 2B). Median OS was 58 months for IP patients with 2 70 (37.0) 78 (38.2) normal BRCA1 expression vs 50 months for IV patients with 3 100 (52.9) 103 (50.5) normal BRCA1 expression (P¼ 0.818). In contrast, median OS was Tumour residual 84 months in the IP patients with aberrant BRCA1 expression vs 48 months in IV patients with aberrant BRCA1 expression Microscopic 75 (39.7) 70 (34.3) 0.270 (P¼ 0.0002). Median PFS for IP patients with aberrant BRCA1 Gross 114 (60.3) 134 (65.7) expression was 35 months compared with o20 months for the Treatment three other subgroups. However, the interaction between level of BRCA expression (aberrant vs normal) and PFS did not achieve IV 93 (49.2) 107 (52.5) 0.520 statistical significance (P¼ 0.054). IP 96 (50.8) 97 (47.6) The influence of the route of administration on the relationship Abbreviations: BRCA1¼ breast cancer 1, early onset; GOG PS¼ Gynecologic Oncology between BRCA1 expression and patient outcome was also assessed Group Performance Status; IV¼ intravenous; IP¼ intraperitoneal. using unadjusted and adjusted Cox regression survival analysis (Table 2). Similar survival was observed for IP vs IV patients with normal BRCA1 expression (unadjusted HR¼ 0.97, 95% confidence we have demonstrated that in this cohort of optimally resected interval (CI)¼ 0.69–1.37, P¼ 0.862; adjusted HR¼ 0.98, 95% patients with stage III EOC or PPC, aberrant BRCA 1 expression CI¼ 0.69–1.38, P¼ 0.895). Significantly better survival was showed an improved PFS and OS when compared with patients observed in the subset of IP patients with aberrant BRCA1 whose tumours had normal BRCA 1 expression when stratified by expression (unadjusted HR¼ 0.68, 95% CI¼ 0.47–0.97, P¼ 0.034). treatment type. In patients whose tumours have aberrant BRCA1 Aberrant BRCA1 expression retained independent prognostic expression, a clinically significant benefit in PFS and OS, 14 and 36 value for survival in the subset of patients randomised to IP months respectively, was seen when those patients were treated therapy after adjusting for age, residual disease (microscopic vs with IP chemotherapy compared with patients whose tumours had gross) and histologic subtype with an adjusted HR¼ 0.67 (95% CI normal expression of BRCA1 (Figure 2A and B). In patients ¼ 0.47–0.97, P¼ 0.0320). Similar survival was observed for IV whose tumours had normal expression of BRCA1, no signi- patients with aberrant vs normal BRCA1 expression (unadjusted ficant improvement in PFS or OS with IV therapy was seen HR¼ 1.30, 95% CI¼ 0.93–1.81, P¼ .121). Multivariate model- (Figure 2A and B). ling adjusting for age, residual disease (microscopic vs gross) and In genomic stability, BRCA1 has an important role. Altered cell type demonstrated that IV patients with aberrant vs normal BRCA1 expression and/or dysfunction may occur as a result of BRCA1 expression exhibited an increased risk of death (adjusted germline mutations, somatic mutations or epigenetic modifica- HR¼ 1.46, 95% CI¼ 1.04–2.03, P¼ 0.028). tions. Our analysis showed a high percentage of patients with aberrant BRCA1 expression in their tumours (52%). This rate is similar to the rate of BRCA1 expression (46%) seen in the analysis DISCUSSION by Thrall et al (2006) and that reported by Carser et al (2011) (41%) (Swisher et al, 2008). Low levels of BRCA1 (aberrant) expression have been reported to vary between 34 and 90% in the In our study, we evaluated BRCA1 protein expression via IHC in tumour specimens from patients enroled in GOG-172 with respect literature (Russell et al, 2000; Thrall et al, 2006 Swisher et al, 2009). This amount of variation may be the result of differences in the to PFS and OS. Utilising IHC expression for BRCA1 in this study, www.bjcancer.com | DOI:10.1038/bjc.2013.70 1233 BRITISH JOURNAL OF CANCER BRCA1 expression and improved survival in ovarian cancer patients 1.0 1.0 0.8 0.8 IP therapy aberrant BRCA1 0.6 0.6 Test for interaction: P = 0.014 0.4 0.4 Log-rank test: P = 0.729 Therapy IHC expression Patients Events Median OS IP Aberrant BRCA1 96 51 84.1 months 0.2 Patients events median OS IP Normal BRCA1 97 62 58.1 months 0.2 IV Aberrant BRCA1 93 74 47.7 months Aberrant BRCA1 189 125 60.1 months IV Normal BRCA1 107 68 50.4 months 0.0 Normal BRCA1 204 130 53.6 months 0.0 0 122436486072 84 Survival time in months 0 12243648607284 Survival time in months 1.0 Therapy IHC expression Patients Events Median PFS IP Aberrant BRCA1 96 71 34.7 months 1.0 Patients events median PFS IP Normal BRCA1 97 76 20.1 months 0.8 IV Aberrant BRCA1 93 81 18.7 months Aberrant BRCA1 189 152 24.1 months IV Normal BRCA1 107 83 17.7 months Normal BRCA1 204 159 18.4 months 0.8 0.6 Log-rank test: P = 0.615 IP therapy 0.6 aberrant BRCA1 0.4 0.4 0.2 Test for interaction: P = 0.054 0.0 0.2 0 12243648607284 Progression free survival in months 0.0 0 12243648607284 Figure 2. Kaplan–Meier estimate of (A) overall survival (OS) Progression free survival in months and (B) progression-free survival (PFS) for aberrant vs normal BRCA1 expression and by intraperitoneal (IP) vs intravenous Figure 1. Kaplan–Meier estimate of (A) overall survival (OS) and (B) (IV) therapy. progression-free survival (PFS) for the entire cohort comparing aberrant with normal BRCA1 expression. Log-rank test was used to compare survival distributions across subgroups. Table 2. Unadjusted and adjusted Cox regression modelling for PFS and OS for tumour expression of BRCA1 protein (normal vs aberrant) and type of therapy (IV vs IP) Univariate analysis Multivariate analysis Group HR (95% CI) P-value HR (95% CI) P-value PFS IV patients with normal BRCA1 Referent Referent IV patients with aberrant BRCA1 1.19 (0.88–1.62) 0.263 1.33 (0.98–1.81) 0.072 IP patients with normal BRCA1 0.97 (0.71–1.32) 0.824 0.95 (0.69–1.30) 0.745 IP patients with aberrant BRCA1 0.74 (0.54–1.02) 0.065 0.72 (0.52–0.99) 0.043 OS IV patients with normal BRCA1 Referent Referent IV patients with aberrant BRCA1 1.30 (0.93–1.81) 0.121 1.46 (1.04–2.03) 0.028 IP patients with normal BRCA1 0.97 (0.69–1.37) 0.862 0.98 (0.69–1.38) 0.895 IP patients with aberrant BRCA1 0.68 (0.47–0.97) 0.034 0.67 (0.47–0.97) 0.032 Abbreviations: BRCA1¼ breast cancer 1, early onset; CI¼ confidence interval; HR¼ hazard ratio; IV¼ intravenous; IP¼ intraperitoneal; OS¼ overall survival; PFS¼ progression-free survival. Adjusted for age, cell type and tumour residual. stage of disease, residual disease status, sample size, IHC assay effects of these genes. The cancer genome atlas project (TCGA) conditions, interpretation of expression and treatment. Jazzeri et al recently published the genomic analysis of serous epithelial ovarian (2002) compared gene expression profiles in BRCA1/2-associated cancer. In this study, BRCA1/2 dysfunction was defined as EOC with sporadic EOC and showed that sporadic tumours may germline mutations, somatic mutations and methylation in have mutations that resemble the molecular pathways seen in BRCA1. The results showed that in 33% of patients with germline mutations as well as dysfunction in the downstream advanced-stage serous ovarian cancer, BRCA1/2 dysfunction 1234 www.bjcancer.com | DOI:10.1038/bjc.2013.70 Proportion progression free Proportion surviving Proportion progression free Proportion surviving BRCA1 expression and improved survival in ovarian cancer patients BRITISH JOURNAL OF CANCER occurs and may provide a target for therapeutic interventions. In (low levels are associated with reduced response to taxanes). fact, B50% of cases exhibited defects in homologous recombina- Normal BRCA1 expression may imply robust DNA repair, and tion (The Cancer Genome Research Network, 2011). These levels therefore neutralising the clinical benefit of high intratumoural are consistent with the 52% of cases with aberrant BRCA1 drug dose levels of platinum following IP therapy. Yang et al expression. Further testing will be required to confirm that EOC/ (2011) reported on BRCA1/2 expression and patient outcomes PPC patients with BRCA1-dependent defects in homologous from the publically available Cancer Genome Atlas Project. recombination exhibit enhanced responsiveness and outcomes This analysis demonstrated that only patients with BRCA2 following IP therapy with cisplatin and paclitaxel. Additional germline mutations had improved OS (Yang et al, 2011). studies will be required to determine if patients with BRCA1- The 3-month difference for OS, although statistically significant, independent defects in homologous recombination benefit from IP is not likely clinically significant. As patients with normal BRCA1 vs IV platinum-based therapy, and whether the benefits from exhibit similar outcome following IV or IP therapy, consideration cisplatin IP-based therapy in women with aberrant BRCA1 might be given to directing these patients to IV therapy and thus expression extends to IP carboplatin as well. avoiding the extra toxicities associated with IP therapy, as these Studies have also shown that patients who have BRCA1 patients are unlikely to have the same clinical benefit from IP germline mutations and develop EOC may have improved survival chemotherapy as those whose tumours have aberrant levels when compared with patients with sporadic EOC (Pharaoh et al, of BRCA1. 1999; Pal et al, 2007; Tan et al, 2008). In our current study we There are a few studies assessing BRCA1 expression via IHC as evaluated PFS and OS with respect to BRCA1 IHC expression and a prognostic marker for survival in patients with advanced-stage stratified by chemotherapy delivery method (IV vs IP). We have EOC (Thrall et al, 2006; Sirisabya et al, 2007; Swisher et al, 2008; shown that patients whose tumours have aberrant BRCA1 Carser et al, 2011). Sirisabya et al (2007) reported on 99 patients expression and were treated with IP cisplatin have a 36-month with EOC, stages I–IV, and showed a positive BRCA1 IHC improvement in OS. This finding in patients whose tumours had expression rate of 12% (defined as staining of410%). Their results did not demonstrate any difference in PFS or OS; however, the aberrant BRCA1 expression and were treated with IP chemother- apy is biologically plausible. In several DNA repair mechanisms authors did not stratify groups with respect to stage or residual including homologous recombination, chromatin remodelling, disease. Swisher et al (2008) evaluated 115 sporadic EOC and regulation of the cell cycle and transcription, BRCA1 is implicated reported a survival benefit in patients whose tumours had low (Venkitaraman 2002; Yoshida and Miki 2004; Weberpals et al, BRCA1 expression. Thrall et al (2006) evaluated BRCA1 IHC 2009). These cellular functions are critical factors in how cells expression relative to stage and histology in a subset of patients respond to cytotoxic agents, and particularly platinum. There are enroled in GOG-172. Of the 152 patients with outcome data, data to suggest that loss of BRCA1 function confers enhanced patients with low BRCA1 expression had an improved PFS and OS chemosensitivity to platinum-based chemotherapy and increase in with a follow-up of 60 months. However, because of the limited resistance to antimicrotubule agents (Quinn et al, 2007; Stordal sample size and follow-up, it was not designed to evaluate the and Davey, 2009). Stordal and Davey (2009) recently reviewed a impact of BRCA1 expression on PFS and OS. Finally, (Carser et al wide range of cell models and showed that modifications in BRCA1 (2011) performed BRCA IHC on 292 ovarian tumours and showed (both increases and decreases) had the highest rate of inverse an improved response to single-agent platinum with absent/low cisplatin/paclitaxel resistance phenotype compared with other gene (o10%) BRCA1 expression. Our report includes the largest series mutations. As such, the role of BRCA1 dysfunction as related to of patients enroled in a randomised trial (n¼ 393) with mature chemotherapy response and patient survival is an important outcome data (median follow-up time of 86 months) using BRCA component in treatment planning for patients with EOC (Quinn IHC. Additionally, our results may be slightly different because of et al, 2009). The IP therapy delivers higher concentrations of the fact that all of the patients in our study had optimally resected cytotoxic chemotherapy (Dedrick et al, 1978; Howel et al, 1982). stage III EOC or PPC and had received combination therapy with Howel et al (1982)) demonstrated 12-fold higher peritoneal cisplatin and paclitaxel. concentrations of cisplatin relative to plasma levels with intraper- There are limitations with our current study. Our data did not itoneal administration, and aberrant BRCA1 expression implies show an overall survival advantage in patients whose tumours impaired DNA repair mechanisms. The additive effect of these exhibited aberrant BRCA1 expression, which is in contrast to some mechanisms, more intensive and prolonged exposure to platinum prior published results (Swisher et al, 2008; Carser et al, 2011). in the setting of defective double-strand break repair, may explain Although atypical, this finding cannot detract from the results of why tumour cells with low expression of BRCA1 will be more the subgroup analysis. We also recognise the limitations of the sensitive to IP chemotherapy. In the subgroup analysis of this assay for protein expression, namely IHC, which is assessed in a cohort, aberrant BRCA1 expression confers a survival benefit for semiquantitative manner by independent reviewers and utilises an patients treated with IP therapy, with a median PFS and OS of 35 antibody that recognises the N-terminal region of BRCA1. This and 84 months, respectively, which extends even beyond the technique has been widely adopted for the assessment of protein survival advantage seen with IP therapy reported by Armstrong expression in other proteins and tumours (oestrogen receptor, et al (2006). This suggests that tumour BRCA1 expression may be progesterone receptor and HER-2 in breast cancer, and MLH1 in an important biomarker in sporadic EOC in determining response colon cancer), and is run in several clinical, commercial and to IP chemotherapy and may provide a way to select ideal research laboratories. The clinical utility of BRCA1 expression candidates for IP therapy. assessment in patients with advanced-stage EOC warrants further These data also showed similar survival in IV and IP patients validation. The results of this study provide provocation for its whose tumour exhibited normal BRCA1 expression. Worse assessment in future trials in conjunction with other methods of survival was observed for IV patients with aberrant BRCA1 evaluating BRCA1, including quantitative mass spectrometry expression using multivariate but not using unadjusted univariate (MS)-based platforms assessing protein mass, sequence and modelling. The negative effect of aberrant BRCA1 expression on concentration as well as modifications, BRCA-1 binding proteins OS required adjustments for age, residual disease and cell type. It via immunoprecipitation followed by immunoblotting and MS and should be noted that the proportion of cases with BRCA1 aberrant BRCA1 transcriptional regulation by chromatin immunoprecipita- did not vary significantly by age, residual disease status or cell type. tion followed by next-generation sequencing for an example. Also, The improved survival seen with normal vs aberrant expression of EOC and PPC may be further studied to characterise the type of BRCA1 may be related to the BRCA1 effect on response to taxanes BRCA dysfunction including somatic vs germline mutations, www.bjcancer.com | DOI:10.1038/bjc.2013.70 1235 BRITISH JOURNAL OF CANCER BRCA1 expression and improved survival in ovarian cancer patients methylation, nuclear localisation and export, ubiquitin-mediated Dedrick RL, Myers CE, Bungay PM, DeVita VT (1978) Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian degradation and chromatin remodelling. cancer. Cancer Treat Rep 62: 1–11. In conclusion, our data demonstrate a significant 3-year Foulkes WD (2006) BRCA1 and BRCA2: chemosensitivity, treatment improvement in OS for patients with advanced EOC whose outcomes and prognosis. 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This work is published under the standard license to publish agree- Weberpals J, Garbuio K, O’Brien A, Clark-Knowles K, Doucett S, Antoniouk O, Glenwood G, Dimitroulakos J (2009) The DNA repair proteins BRCA1 ment. After 12 months the work will become freely available and and ERCC1 as predictive markers in sporadic ovarian cancer. Int J Cancer the license terms will switch to a Creative Commons Attribution- 24: 806–815. NonCommercial-Share Alike 3.0 Unported License. www.bjcancer.com | DOI:10.1038/bjc.2013.70 1237

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Published: Mar 5, 2013

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