Search

Background Ovarian carcinosarcoma (OCS) is an uncommon, biphasic and highly aggressive ovarian cancer type, which has received relatively little research attention. Methods We curated the largest pathologically confirmed OCS cohort to date, performing detailed histopathological characterisation, analysis of features associated with survival and comparison against high-grade serous ovarian carcinoma (HGSOC). Results Eighty-two OCS patients were identified; overall survival was poor (median 12.7 months). In all, 79% demonstrated epithelial components of high-grade serous (HGS) type, while 21% were endometrioid. Heterologous elements were common (chondrosarcoma in 32%, rhabdomyosarcoma in 21%, liposarcoma in 2%); chondrosarcoma was more frequent in OCS with endometrioid carcinomatous components. Earlier stage, complete resection and platinum-containing adjuvant chemotherapy were associated with prolonged survival; however, risk of relapse and mortality was high across all patient groups. Histological subclassification did not identify subgroups with distinct survival. Compared to HGSOC, OCS patients were older (P P = 0.025), demonstrated lower chemotherapy response rate (P = 0.001) and had significantly poorer survival (P Conclusion OCS represents a distinct, highly lethal form of ovarian cancer for which new treatment strategies are urgently needed. Histological subclassification does not identify patient subgroups with distinct survival. Aggressive adjuvant chemotherapy should be considered for all cases, including those with early-stage disease.

SV loads in non-BRCA1/2 HR genes per sample by SV type

Supplementary Data from Multiomic Characterization of High-Grade Serous Ovarian Carcinoma Enables High-Resolution Patient Stratification

Purpose:The abundance and effects of structural variation at BRCA1/2 in tumors are not well understood. In particular, the impact of these events on homologous recombination repair deficiency (HRD) has yet to be demonstrated.Experimental Design:Exploiting a large collection of whole-genome sequencing data from high-grade serous ovarian carcinoma (N = 205) together with matched RNA sequencing for the majority of tumors (N = 150), we have comprehensively characterized mutation and expression at BRCA1/2.Results:In addition to the known spectrum of short somatic mutations (SSM), we discovered that multi-megabase structural variants (SV) were a frequent, unappreciated source of BRCA1/2 disruption in these tumors, and we found a genome-wide enrichment for large deletions at the BRCA1/2 loci across the cohort. These SVs independently affected a substantial proportion of patients (16%) in addition to those affected by SSMs (24%), conferring HRD and impacting patient survival. We also detail compound deficiencies involving SSMs and SVs at both loci, demonstrating that the strongest risk of HRD emerges from combined SVs at both BRCA1 and BRCA2 in the absence of SSMs. Furthermore, these SVs are abundant and disruptive in other cancer types.Conclusions:These results extend our understanding of the mutational landscape underlying HRD, increase the number of patients predicted to benefit from therapies exploiting HRD, and suggest there is currently untapped potential in SV detection for patient stratification.

Supplementary methods and supplementary figures

OBJECTIVE Investigate the clinical landscape of ovarian carcinoma (OC) over time. DESIGN Register-based prospectively collected data. SETTING South East Scotland. SAMPLE A total of 2805 OC patients diagnosed in 1981-2015. METHODS Survival times were visualised using the Kaplan-Meier method; median survival, 5-year survival probabilities and associated restricted mean survival time analyses were used to quantify survival differences. MAIN OUTCOME MEASURES Disease-specific survival. RESULTS A significant increase in disease-specific survival (DSS) from 1981-1985 to 2011-2015 was observed (median 1.73 versus 4.23 years, P

BackgroundLow-grade serous ovarian carcinoma (LGSOC) is a distinct, under-investigated and relatively chemotherapy-resistant ovarian cancer type. Understanding the molecular landscape is crucial to maximise the impact of molecularly-targeted therapy.MethodsWhole exome sequencing and copy number data were integrated with histopathological patterns, ER/PR expression, and detailed clinical annotation, including survival, in a carefully curated LGSOC cohort.Results63 tumours were analysed in the largest comprehensive genomic LGSOC study to date. Three genomic subgroups were identified: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated mutation (27%, 14 MAPK-associated genes) and MAPK wild-type (MAPKwt: 21%). MAPKwt patients were younger at diagnosis (median 47 versus 62 years in the cMAPKm subgroup) and demonstrated shorter survival [multivariable HR (mHR) 4.17]. The inferior survival in the MAPKwt subgroup was due to shorter post-relapse survival (mHR 5.22) rather than shorter time to first progression (mHR 1.15). Patients in the MAPK-associated mutation subgroup had similar survival to cMAPKm cases. The cMAPKm subgroup more frequently demonstrated macropapillary invasion. Desmoplasia and micropapillary invasion were independently associated with poor survival. NOTCH pathway activation occurred independently of MAPK subgroup.ConclusionsLGSOC comprises multiple genomic subgroups with distinct clinical, molecular and histopathological features. True MAPKwt cases represent around a fifth of patients: they are younger but have poorer survival. New therapeutic strategies with activity in this subgroup are urgently required. NOTCH inhibitors represent a therapeutic strategy worthy of exploration.

BackgroundHigh grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer; most patients experience disease recurrence which accumulates chemoresistance, leading to treatment failure. Previous investigations have characterised HGSOC at the genomic and transcriptomic level, identifying subtypes of patients with differential outcome and treatment response. However, the relationship between molecular events identified at the gene sequence, gene copy number and gene expression levels remains poorly defined.MethodsWe perform multi-layer molecular characterisation of a large retrospective HGSOC cohort (n=362) with detailed clinical annotation to interrogate the relationship between patient groups defined by gene mutation, copy number events, gene expression patterns and infiltrating immune cell burden. We construct a high resolution picture of the molecular landscape in HGSOC and identify features of tumours associated with distinct clinical behaviour in patients.ResultsBRCA2-mutant (BRCA2m) andEMSY-overexpressing cases demonstrated prolonged survival (multivariable hazard ratio 0.40 and 0.53) and higher chemotherapy response rates at first- and second-line treatment.CCNE1-gained (CCNE1g) cases demonstrated shorter survival (multivariable hazard ratio 1.52, 95% CI 1.10-2.10), under-representation of FIGO stage IV cases (P=0.017) and no significant difference in treatment response. We demonstrate marked overlap between the TCGA- and derived subtypes: the TCGA DIF, IMR, PRO and MES subtypes correlated with the Tothill C4, C2, C5 and C1 subtypes (PBRCA1/2m frequency (25.5% and 32.5%) and significantly greater infiltration of immune cells (PCCNE1g rate (23.9% and 22.2%) and were uniformly low in immune cell infiltration. The survival benefit for cases with aberrations in homologous recombination repair (HRR) genes was apparent across all transcriptomic subtypes (hazard ratio range 0.48-0.68). There was significant co-occurrence of RB loss and HRR gene aberrations (P=0.005); RB loss was further associated with favourable survival within cases harbouring HRR aberrations (multivariable hazard ratio 0.50, 95% CI 0.30-0.84).ConclusionsThese data paint a high resolution picture of the molecular landscape in HGSOC, better defining patients who may benefit most from specific molecular therapeutics and highlighting those for whom novel treatment strategies are needed to improve outcomes.

Simple Summary Mucinous ovarian carcinoma (MOC) is a unique type of ovarian cancer. While many MOC patients have excellent survival, patients who experience recurrence have extremely poor prognosis. Identifying patients at the highest risk of recurrence is important for identifying which patients need the most aggressive treatment, and to identify where new treatment strategies are needed to improve survival. We use a large cohort of MOC patients to identify factors associated with high and low risk of recurrence. We show that once patients reach 5 years from diagnosis, their risk of recurrence is low. Patients with more advanced-stage disease and higher pathological grade of disease are more likely to experience recurrence, and their survival is significantly shorter. For early-stage MOC patients, survival time was similar whether they were treated with surgery plus chemotherapy, or whether they only had surgery. Patient survival time following recurrence is extremely poor (median 5 months); new treatment options are urgently needed to improve their survival. Abstract Mucinous ovarian carcinoma (MOC) is a unique form of ovarian cancer. MOC typically presents at early stage but demonstrates intrinsic chemoresistance; treatment of advanced-stage and relapsed disease is therefore challenging. We harness a large retrospective MOC cohort to identify factors associated with recurrence risk and survival. A total of 151 MOC patients were included. The 5 year disease-specific survival (DSS) was 84.5%. Risk of subsequent recurrence after a disease-free period of 2 and 5 years was low (8.3% and 5.6% over the next 10 years). The majority of cases were FIGO stage I (35.6% IA, 43.0% IC). Multivariable analysis identified stage and pathological grade as independently associated with DSS (p < 0.001 and p < 0.001). Grade 1 stage I patients represented the majority of cases (53.0%) and demonstrated exceptional survival (10 year DSS 95.3%); survival was comparable between grade I stage IA and stage IC patients, and between grade I stage IC patients who did and did not receive adjuvant chemotherapy. At 5 years following diagnosis, the proportion of grade 1, 2 and 3 patients remaining disease free was 89.5%, 74.9% and 41.7%; the corresponding proportions for FIGO stage I, II and III/IV patients were 91.1%, 76.7% and 19.8%. Median post-relapse survival was 5.0 months. Most MOC patients present with low-grade early-stage disease and are at low risk of recurrence. New treatment options are urgently needed to improve survival following relapse, which is associated with extremely poor prognosis.

Endometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and oestrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathological assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes. We demonstrate significant correlation between subtyping approaches: PR-high (PR + /ER + , PR + /ER−) cases were predominantly CTNNB1-mutant (73.2% vs 18.4%, P TP53 mutation frequency (38.8% vs 7.3%, P = 0.001), greater genomic complexity (P = 0.007) and more frequent copy number alterations (P = 0.001). PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features (HR = 0.16, 95% CI 0.04–0.71). TP53 mutation further delineates the outcome of patients with PR-low tumours (HR = 2.56, 95% CI 1.14–5.75). A simple, routinely applicable, classification algorithm utilising immunohistochemistry for PR and p53 recapitulated these subtypes and their survival profiles. The genomic profile of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT pathways, alongside PARP inhibitors, represent promising candidate agents for improving patient survival. Patients with PR-low TP53-mutant EnOC have the greatest unmet clinical need, while PR-high tumours—which are typically CTNNB1-mutant and TP53 wild-type—experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy.

Background Numerous studies have investigated the association between hormone receptor expression and clinical outcome in ovarian carcinoma (OC); however, these have largely focussed on serous OCs, with few studies reporting specifically on endometrioid OCs (EnOC). Where analyses have been stratified by histotype, expression has been assessed using the percentage of positive tumor cells, without accounting for nuclear expression intensity. Methods Here we assess the expression levels of progesterone receptor (PR), estrogen receptor alpha (ER) and androgen receptor (AR) using histoscore – a nuclear scoring method incorporating both proportion of positive cells and the intensity of nuclear staining – across a cohort of 107 WT1 negative EnOCs. Results Hierarchical clustering by PR, ER and AR histoscores identified four EnOC subgroups (PR+/ER+, PR+/ER−, PR−/ER+ and PR−/ER−). EnOC patients in the PR+/ER+ and PR+/ER− groups displayed favorable outcome (multivariable HR for disease-specific survival 0.05 [0.01–0.35] and 0.05 [0.00–0.51]) compared to the PR−/ER+ group. Ten-year survival for stage II PRhigh and PRlow cases was 94.1% and 42.4%. ERhigh EnOC patients (PR+/ER+, PR−/ER+) had higher body mass index compared to ERlow cases (P = 0.015) and high grade serous OC patients (P, Highlights • We identify four subgroups of endometrioid ovarian carcinoma (EnOC) defined by hormone receptor expression patterns. • EnOC patients in the PRhigh (PR+/ER+, PR+/ER−) groups demonstrate markedly favorable outcome. • Stage II EnOC patients in the PRhigh groups display a ten-year survival of approximately 95%. • ERhigh (PR+/ER+, PR−/ER+) EnOC patients had a higher body mass index vs ERlow cases and high grade serous carcinoma patients.

PURPOSE: The abundance and effects of structural variation at BRCA1/2 in tumours are not well understood. In particular, the impact of these events on homologous recombination repair deficiency (HRD) has yet to be demonstrated. EXPERIMENTAL DESIGN: Exploiting a large collection of whole genome sequencing data from high grade serous ovarian carcinoma (N=205) together with matched RNA-seq for the majority of tumours (N=150), we have comprehensively characterised mutation and expression at BRCA1/2. RESULTS: In addition to the known spectrum of short somatic mutations (SSMs), we discover that multi-megabase structural variants (SVs) are a frequent, unappreciated source of BRCA1/2 disruption in these tumours, and we find a genome wide enrichment for large deletions at the BRCA1/2 loci across the cohort. These SVs independently affect a substantial proportion of patients (16%) in addition to those affected by SSMs (24%), conferring homologous recombination repair deficiency (HRD) and impacting patient survival. We also detail compound deficiencies involving SSMs and SVs at both loci, demonstrating that the strongest risk of HRD emerges from combined SVs at both BRCA1 and BRCA2 in the absence of SSMs. Further, these SVs are abundant and disruptive in other cancer types. CONCLUSIONS: These results extend our understanding of the mutational landscape underlying HRD, increase the number of patients predicted to benefit from therapies exploiting HRD, and suggest there is currently untapped potential in SV detection for patient stratification.

Endometrioid ovarian carcinoma (EnOC) demonstrates substantial clinical and molecular heterogeneity. Here, we report whole exome sequencing of 112 EnOC cases following rigorous pathological assessment. We detect a high frequency of mutation in CTNNB1 (43%), PIK3CA (43%), ARID1A (36%), PTEN (29%), KRAS (26%), TP53 (26%) and SOX8 (19%), a recurrently-mutated gene previously unreported in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy is constructed, identifying clinically distinct EnOC subtypes: cases with TP53 mutation demonstrate greater genomic complexity, are commonly FIGO stage III/IV at diagnosis (48%), are frequently incompletely debulked (44%) and demonstrate inferior survival; conversely, cases with CTNNB1 mutation, which is mutually exclusive with TP53 mutation, demonstrate low genomic complexity and excellent clinical outcome, and are predominantly stage I/II at diagnosis (89%) and completely resected (87%). Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC., The molecular classification of endometroid ovarian carcinomas (EnOC) has not been established, preventing the development of stratified therapeutic approaches. Here the authors characterise the molecular landscape of EnOC by whole exome sequencing, identifying clinically distinct disease subtypes.

Purpose National outcomes for epithelial ovarian cancer in the UK are inferior to those in other European countries. This study aimed to assess the impact of a multidisciplinary approach to cytoreductive surgery on residual disease status and progression free survival in a single UK region. Methods Consecutive patients undergoing surgery for stage III/IV epithelial ovarian cancer between November 2011 and November 2015 in South East Scotland were analysed. Regular multidisciplinary surgery was established on 1st November 2013. Outcomes for patients diagnosed in the two years prior to (group 1) and following this change (group 2) in practice were examined. Results 224 consecutive patients underwent surgery. There was no difference between groups in terms of age, FIGO stage or histological subtype. Patients in group 2 were more likely to undergo primary surgery (p=0.01) and bowel resection (p=0.002). Rates of optimal cytoreduction were not significantly different between group 1(69.6%) and group 2 (66.1%) (p=0.67). The upper abdomen was the most common site of residual disease. No difference in PFS (median PFS; 15.5 vs. 14.0 months, p=0.13), morbidity (p=0.82) or mortality (p=1.00) was identified. PFS was improved in those patients undergoing primary surgery compared to neoadjuvant chemotherapy (p=0.04). Conclusion Robust quality improvement strategies are required to overcome historic barriers to cytoreductive surgery in the UK. Comprehensive attempts at debulking in the upper abdomen are required if rates of complete cytoreduction are to be improved. We have extended the multidisciplinary model in our institution to include upper abdominal surgery and anticipate an improvement in cytoreduction.

Background Disease relapse is the primary cause of death from ovarian carcinoma. Isolated lymph node relapse is a rare pattern of ovarian carcinoma recurrence, with a reported median postrelapse survival of 2.5 to 4 years. To date, investigations have not compared isolated lymph node relapse ovarian carcinoma directly to a matched extranodal relapse cohort or performed molecular characterization of cases that subsequently experience isolated lymph node relapse. Objective Here we seek to compare the clinical outcome, tumor-infiltrating lymphocyte burden, and frequency of known prognostic genomic events in isolated lymph node relapse ovarian carcinoma vs extranodal relapse ovarian carcinoma. Study Design Forty-nine isolated lymph node relapse ovarian carcinoma patients were identified and matched to 49 extranodal relapse cases using the Edinburgh Ovarian Cancer Database, from which the clinical data for identified patients were retrieved. Matching criteria were disease stage, histologic subtype and grade, extent of residual disease following surgical debulking, and age at diagnosis. Clinicopathologic factors and survival data were compared between the isolated lymph node relapse and extranodal relapse cohorts. Genomic characterization of tumor material from diagnosis was performed using panel-based high-throughput sequencing and tumor-infiltrating T cell burden was assessed using immunohistochemistry for CD3+ and CD8+ cells. Results Isolated lymph node relapse cases demonstrated significantly prolonged postrelapse survival and overall survival vs extranodal relapse upon multivariable analysis (HRmulti = 0.52 [0.33–0.84] and 0.51 [0.31–0.84]). Diagnostic specimens from high-grade serous ovarian carcinomas that subsequently displayed isolated lymph node relapse harbored significantly greater CD3+ and CD8+ cell infiltration compared to extranodal relapse cases (P = .001 and P = .009, Bonferroni-adjusted P = .003 and P = .019). Isolated lymph node relapse high-grade serous ovarian carcinoma cases did not show marked enrichment or depletion of cases with BRCA1/2 mutation or CCNE1 copy number gain when compared to their extranodal relapse counterparts (24.4% vs 19.4% and 18.2% vs 22.6%, P = .865 and P = .900). Conclusion Isolated lymph node relapse ovarian carcinoma represents a distinct clinical entity with favorable outcome compared to extranodal relapse. There was no clear enrichment or depletion of BRCA1/2 mutation or CCNE1 gain in the isolated lymph node relapse ovarian carcinoma cohort compared with extranodal relapse cases, suggesting that these known prognostic genomically defined subtypes of disease do not display markedly altered propensity for isolated lymph node relapse. Diagnostic tumor material from isolated lymph node relapse patients demonstrated greater CD3+ and CD8+ cell infiltration, indicating stronger tumor engagement by T cell populations, which may contribute to the more indolent disease course of isolated lymph node relapse.

Endometrioid ovarian carcinomas (EnOCs) account for 10% of OC diagnoses, representing distinct biological and clinical entities compared to other OC subtypes. We recently reported two molecular subgrouping studies using >100 WT1-negative EnOCs: the first identified molecular subgroups of disease by unsupervised analysis of hormone receptor expression patterns, reporting favorable disease-specific survival (DSS) in the PR-high subgroups (PR+/ER+, PR+/ER- vs PR-/ER+, PR-/ER-). The latter study performed whole exome sequencing, identifying genomic events associated with differential DSS, including TP53 mutation (TP53m) and CTNNB1m. Here, we perform integrated analysis of these data to investigate the overlap between these molecular subgrouping layers. The PR-high subgroups demonstrated low TP53m rate (5% vs 26%, P=0.035) and frequent CTNNB1m (75% vs 26%, P There was no significant difference in tumor mutational burden, microsatellite instability or tumor heterogeneity as defined by Mutant Allele Tumour Heterogeneity (MATH) score between the hormone-receptor-based subgroups. These groups also demonstrated no significant difference in mutation rate of mismatch repair protein-encoding genes. Multivariable analysis identified only FIGO stage at diagnosis (P=0.002), optimal surgical debulking (P=0.035) and hormone receptor subgroup (P=0.004) as independently associated with DSS. TP53m and CTNNB1m were not independently associated with DSS (P=0.187 and P=0.166), though CTNNB1m demonstrated a trend for association in a corresponding model for relapse-free survival (RFS) (HR=0.26, P=0.064). Within PR-high cases, specific genomic events were not associated with significantly differential survival. Conversely, TP53m was associated with inferior outcome specifically in PR-low cases (P=0.010 for RFS; P=0.066 for DSS). Collectively, these data represent the first depiction of the overlay and interplay between recently identified EnOC subgroups defined by WES and hormone receptor expression patterns. They demonstrate that PR-high cases frequently harbor CTNNB1m, while TP53m is rare in this context. Moreover, they suggest that PR-high cases experience favorable outcome irrespective of genomic profile, while TP53m represents an important marker of prognosis in PR-low EnOC. Moreover, given the high expression of ER and PR in the CTNNB1m population, assessment of the potential efficacy of endocrine therapy in this population may now warrant investigation. Citation Format: Robert L. Hollis, John Thomson, Barbara Stanley, Alison M. Meynert, Michael Churchman, Tzyvia Rye, C. Simon Herrington, Charlie Gourley. Integrated analysis of whole exome sequencing and hormone receptor expression data in endometrioid ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4161.

Objectives. The role of endocrine therapy (ET) in high grade serous ovarian carcinoma (HGSOC) is poorly defined due to the lack of phase III data and significant heterogeneity of clinical trials performed. In this study, we sought to identify predictive factors of endocrine sensitivity in HGSOC. Methods. HGSOC patients who received at least four weeks of ET for relapsed disease following one line of chemotherapy at the Edinburgh Cancer Centre were identified. Exclusion criteria were use of endocrine therapy as maintenance therapy or of unknown duration. Duration of therapy and best CA125 response as per modified GCIG criteria were recorded. Oestrogen receptor (ER) histoscore, treatment free interval, prior lines of chemotherapy, and type of ET were evaluated as predictive factors. Results. Of 431 patients identified, 269 were eligible (77.0 % letrozole, 18.6% tamoxifen, 2.2% megesterol acetate, 2.2% other). The median duration of therapy was 126 days (range 28-1427 days). 32.7% remained on ET for ≥180 days and 14.1% for ≥365 days. The CA125 response and clinical benefit rates (response or stable disease) were 8.1% and 40.1% respectively. ER histoscore >200 (P=0.0016) and a treatment free interval of ≥180 days (P200 and a treatment free interval of ≥180 days are most likely to derive benefit.

Background Approximately half of high‐grade serous ovarian carcinomas (HGSOCs) demonstrate homologous recombination repair (HR) pathway defects, resulting in a distinct clinical phenotype comprising hypersensitivity to platinum, superior clinical outcome, and greater sensitivity to poly(adenosine diphosphate‐ribose) polymerase (PARP) inhibitors. EMSY, which is known to be amplified in breast and ovarian cancers, encodes a protein reported to bind and inactivate BRCA2. Thus, EMSY overexpression may mimic BRCA2 mutation, resulting in HR deficiency. However, to our knowledge, the phenotypic consequences of EMSY overexpression in HGSOC patients has not been explored. Methods Here we investigate the impact of EMSY expression on clinical outcome and sensitivity to platinum‐based chemotherapy using available data from transcriptomically characterized HGSOC cohorts. Results High EMSY expression was associated with better clinical outcome in a cohort of 265 patients with HGSOC from Edinburgh (overall survival multivariable hazard ratio, 0.58 [95% CI, 0.38‐0.88; P = .011] and progression‐free survival multivariable hazard ratio, 0.62 [95% CI, 0.40‐0.96; P = .030]). Superior outcome also was demonstrated in the Medical Research Council ICON7 clinical trial and multiple publicly available data sets. Patients within the Edinburgh cohort who had high EMSY expression were found to demonstrate greater rates of complete response to multiple platinum‐containing chemotherapy regimens (radiological complete response rate of 44.4% vs 12.5% at second exposure; P = .035) and corresponding prolonged time to disease progression (median, 151.5 days vs 60.5 days after third platinum exposure; P = .004). Conclusions Patients with HGSOCs demonstrating high EMSY expression appear to experience prolonged survival and greater platinum sensitivity, reminiscent of BRCA‐mutant cases. These data are consistent with the notion that EMSY overexpression may render HGSOCs HR deficient., Patients with high‐grade serous ovarian carcinomas demonstrating high expression levels of EMSY appear to experience prolonged survival and hypersensitivity to multiple lines of platinum‐based chemotherapy. These data support the notion that overexpression of the gene product of EMSY, which is reported to bind and inactivate BRCA2, may mimic the phenotype conferred by BRCA mutation.

Background Approximately 10–15% of ovarian carcinomas (OC) are attributed to inherited susceptibility, the majority of which are due to mutations in BRCA1 or BRCA2 (BRCA1/2). These patients display superior clinical outcome, including enhanced sensitivity to platinum-based chemotherapy. Here, we seek to investigate whether BRCA1/2 status influences the response rate to single-agent pegylated liposomal doxorubicin (PLD) in high grade serous (HGS) OC. Methods One hundred and forty-eight patients treated with single-agent PLD were identified retrospectively from the Edinburgh Ovarian Cancer Database. DNA was extracted from formalin-fixed paraffin-embedded (FFPE) archival tumour material and sequenced using the Ion Ampliseq BRCA1 and BRCA2 panel. A minimum variant allele frequency threshold was applied to correct for sequencing artefacts associated with formalin fixation. Results A superior response rate to PLD was observed in patients with HGS OC who harboured variants likely to affect BRCA1 or BRCA2 function compared to the BRCA1/2 wild-type population (36%, 9 of 25 patients versus 12.1%, 7 of 58 patients; p = 0.016). An enhanced response rate was also seen in patients harbouring only the BRCA1 SNP rs1799950, predicted to be detrimental to BRCA1 function (50%, 3 of 6 patients versus 12.1%, 7 of 58 patients; p = 0.044). Conclusions These data demonstrate that HGS OC patients with BRCA1/2 variants predicted damaging to protein function experience superior sensitivity to PLD, consistent with impaired DNA repair. Further characterisation of rs1799950 is now warranted in relation to chemosensitivity and susceptibility to developing ovarian carcinoma. Electronic supplementary material The online version of this article (10.1186/s12885-017-3981-2) contains supplementary material, which is available to authorized users.

Figure S1. Growth response curves of PE01 and PE04 ovarian cancer cells treated with combinations of glycolysis inhibitors with chemotherapy or metformin. A. 3PO with cisplatin. 3PO concentrations between 0.5-30μΜ alone (blue line) or combined with a constant concentration of cisplatin (red line) were evaluated. In green the effect of 0.5μΜ (PE01) or 1μΜ (PE04) cisplatin on cell viability is presented. B. 3PO with paclitaxel. 3PO concentrations between 0.5-30μΜ alone (blue line) or combined with a constant concentration of paclitaxel (red line) were evaluated. In green the effect of 2μΜ paclitaxel (both PE01 and PE04) on cell viability is presented. C. Oxamic acid with metformin. Concentration response curves of PE01 and PE04 ovarian cancer cells treated with oxamic acid concentrations between 1.56-100mΜ alone (blue line) or combined with 2 mM (PE01) or 0.5 mM (PE04) metformin (red line). In green the effect of 2 mM (PE01) or 0.5 mM (PE04) mM metformin on cell viability is presented. Cell viability was determined by an SRB assay after a 3-day treatment. Mean results of 6 replicates are reported and error bars represent standard deviations. Values are shown as a percentage of control. Asterisks indicate synergistic combination points with * CI value lower than 0.8 and ** CI value lower than 0.3. (PPTX 1444 kb)

Table S2. Spearman correlation of the expression of four glycolytic enzymes in a cohort of 380 ovarian cancers. Spearman rho correlation values (top value) along with the respective adjusted P value (bottom value) of statistically significant correlations thresholded at FDR Pâ

Table S1. Number of ovarian cancer samples analysed by histology and stage. (DOCX 21 kb)

Background: Novel therapeutic approaches are required to treat ovarian cancer and dependency on glycolysis may provide new targets for treatment. This study sought to investigate the variation of expression of molecular components (GLUT1, HKII, PKM2, LDHA) of the glycolytic pathway in ovarian cancers and the effectiveness of targeting this pathway in ovarian cancer cell lines with inhibitors.Methods: Expression of GLUT1, HKII, PKM2, LDHA were analysed by quantitative immunofluorescence in a tissue microarray (TMA) analysis of 380 ovarian cancers and associations with clinicopathological features were sought. The effect of glycolysis pathway inhibitors on the growth of a panel of ovarian cancer cell lines was assessed by use of the SRB proliferation assay. Combination studies were undertaken combining these inhibitors with cytotoxic agents.Results: Mean expression levels of GLUT1 and HKII were higher in high grade serous ovarian cancer (HGSOC), the most frequently occurring subtype, than in non-HGSOC. GLUT1 expression was also significantly higher in advanced stage (III/IV) ovarian cancer than early stage (I/II) disease. Growth dependency of ovarian cancer cells on glucose was demonstrated in a panel of ovarian cancer cell lines. Inhibitors of the glycolytic pathway (STF31, IOM-1190, 3PO and oxamic acid) attenuated cell proliferation in platinum-sensitive and platinum-resistant HGSOC cell line models in a concentration dependent manner. In combination with either cisplatin or paclitaxel, 3PO (a novel PFKFB3 inhibitor) enhanced the cytotoxic effect in both platinum sensitive and platinum resistant ovarian cancer cells. Furthermore, synergy was identified between STF31 (a novel GLUT1 inhibitor) or oxamic acid (an LDH inhibitor) when combined with metformin, an inhibitor of oxidative phosphorylation, resulting in marked inhibition of ovarian cancer cell growth. Conclusions: The findings of this study provide further support for targeting the glycolytic pathway in ovarian cancer and several useful combinations were identified.

// Saeed Rafii 1 , Charlie Gourley 2 , Rajiv Kumar 1 , Elena Geuna 1 , Joo Ern Ang 1 , Tzyvia Rye 2 , Lee-May Chen 3 , Ronnie Shapira-Frommer 4 , Michael Friedlander 5 , Ursula Matulonis 6 , Jacques De Greve 7 , Amit M. Oza 8 , Susana Banerjee 9 , L. Rhoda Molife 1 , Martin E. Gore 9 , Stan B. Kaye 1 and Timothy A. Yap 1 1 Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK 2 University of Edinburgh Cancer Research UK Centre, Edinburgh, UK 3 University of California San Francisco, San Francisco, CA, USA 4 Sheba Medical Centre, Ramat Gan, Israel 5 Prince of Wales Cancer Centre, Randwick, Australia 6 Dana-Farber Cancer Institute, Boston, MA, USA 7 Oncologisch Centrum UZ Brussel, Brussels, Belgium 8 Princess Margaret Cancer Centre, University Health Network, Toronto, Canada 9 Gynae-Oncology Unit, Royal Marsden Hospital, London, UK Correspondence to: Timothy A. Yap, email: tyap@mdanderson.org Keywords: PARP inhibitor, olaparib, BRCA, ovarian cancer, predictive biomarkers Received: October 25, 2016 Accepted: February 22, 2017 Published: April 10, 2017 ABSTRACT Background: The PARP inhibitor olaparib was recently granted Food and Drug Administration (FDA) accelerated approval in patients with advanced BRCA1/2 mutation ovarian cancer. However, antitumor responses are observed in only approximately 40% of patients and the impact of baseline clinical factors on response to treatment remains unclear. Although platinum sensitivity has been suggested as a marker of response to PARP inhibitors, patients with platinum-resistant disease still respond to olaparib. Results: 108 patients with advanced BRCA1/2 mutation ovarian cancers were included. The interval between the end of the most recent platinum chemotherapy and PARPi (PTPI) was used to predict response to olaparib independent of conventional definition of platinum sensitivity. RECIST complete response (CR) and partial response (PR) rates were 35% in patients with platinum-sensitive versus 13% in platinum-resistant (p

High grade serous ovarian carcinomas (HGSOCs) are molecularly and clinically heterogeneous malignancies. Currently, molecular stratification of patient care is limited to tumors rendered homologous recombination deficient (HRD) by BRCA1/2 mutation (BRCAm). Here we explore the overlap, interplay and clinical impact of molecular subgrouping layers in a cohort of 362 FFPE HGSOCs. We overlay genomic subgrouping and tumor-infiltrating lymphocyte (TIL) burden with the three transcriptionally-defined subtypes (Immune, Angio and AngioImmune) we have previously reported as associated with survival and bevacizumab sensitivity. The BRCAm group, the Immune subtype and those with high CD8+ TIL burden demonstrated prolonged overall survival (OS) as previously reported. The OS benefit of CD8+ TILs was abrogated in the context of gross residual disease following debulking [multivariable hazard ratio (mHR)=0.51 (0.34-0.78) vs 0.93 (0.76-1.52)]. BRCAwild-type patients demonstrating high expression of EMSY, encoding the BRCA2-binding protein EMSY, demonstrated prolonged OS [mHR=0.48 (0.29-0.79)]. BRCA2m and high-EMSY patients displayed greater chemosensitivity (first-line CA125-CR 94.4% and 81.3% vs 48.2%, P There was significant enrichment and depletion of BRCAm and CCNE1-gain (CCNE1g) in the Immune subtype (28.9% vs 6.3%, P=0.001 and 9.1% vs 17.4%, P=0.050). The Angio subtype harboured far fewer CD8+ TILs compared to the Immune and AngioImmune subtypes (P The clinical impact of CCNE1g was modulated by transcriptomic subtype: in the Immune group, CCNE1g was associated with poor OS [mHR=3.32 (1.49-7.41)], while in the Angio group CCNE1g cases had favourable outcome [PFS mHR=0.26 (0.10-0.68)]. CD8+ TIL burden was not associated with outcome in CCNE1g cases. Missense TP53 mutation was associated with better outcome versus TP53-null mutations in BRCAm patients [PFS mHR=0.43 (0.14-0.82)], but not in the context of HR proficiency [mHR=0.90 (0.67-1.22)]. Integrated classification using the consensus of favourable and unfavourable HR-centric (HRD favourable, HR-proficient unfavourable) and transcriptomic (Immune favourable, Angio/AngioImmune unfavourable) subgrouping yielded three groups with distinct OS [favourable vs unfavourable mHR=0.49 (0.34-0.74); favourable vs no-consensus mHR=0.64 (0.42-0.98); unfavourable vs no-consensus mHR=1.31 (1.00-1.70)]. Together, these data paint a more granular picture of the clinical impact of HGSOC subgroups and demonstrate novel candidate interactions between subgrouping layers. The poorest outcome groups represent those with most to gain from trials of novel treatment regimens. Citation Format: Robert L. Hollis, Alison M. Meynert, Michael Churchman, Tzyvia Rye, Patricia Roxburgh, Daniel Stetson, Athena Matakidou, Brian Dougherty, J. Carl Barrett, Ruth E. March, Colin A. Semple, C. Simon Herrington, Charlie Gourley. Multi-layer molecular characterization of high grade serous ovarian carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 749.

5553 Background: Endometrioid ovarian carcinomas (EC) have been historically under-investigated. We sought to determine the molecular landscape of contemporarily defined EC using whole exome sequencing (WES). Methods: Tumours diagnosed as EC between May 1980 and December 2013 were identified through the Edinburgh Ovarian Cancer Database. Pathology review was performed according to WHO 2014. Other pathologies including WT1 positive HGSOC were excluded. A selected cohort underwent WES and were analysed for single nucleotide and copy number variants across a panel of genes previously reported as mutated in endometrial, ovarian or pan cancer studies. Tissue microarrays were stained for ER, PR and AR. Multivariable analysis for disease specific survival (DSS) was performed. Results: 125 tumours were included. 61 tumours of all grades underwent WES. 5 molecular groups were identified based on the presence of TP53 mutations (45.9%); or an EClike profile (one or more mutations in ARID1A (41.0%); CTNNB1 (31.1%), PTEN (24.6%) or PIK3CA (23.0%)). Tumours with no mutations in EClike genes were termed ECnull. Each group demonstrated differential DSS (table). Some ECnull: TP53mut tumours also displayed mutations in KRAS, APC and mismatch repair genes. Unsupervised clustering analysis based on the top 100 differentially mutated genes across the dataset validated these groups. Somatic copy number alterations were significantly higher in the TP53mu t groups than the TP53wt groups (Plike genes in the ECnull groups. A PR histoscore of >150, but not ER or AR, was more frequent in the TP53wt group compared to the TP53mut groups (P=0.003). TP53mut status (P=0.0182) and PR histoscore ≤150 (P=0.0115) were independently associated with DSS. Conclusions: EC is a heterogeneous disease comprising 5 molecular subgroups each demonstrating differential clinical outcome. TP53 mutations and PR histoscore ≤150 are independently associated with poor prognosis. [Table: see text]

EMSY, encoding a BRCA2-binding protein, is reportedly amplified in 6-18% of high grade serous ovarian carcinomas (HGSOCs). As a negative regulator of BRCA2, HGSOCs with EMSY overexpression may mimic BRCA-mutant patients, who experience superior clinical outcome and hypersensitivity to platinum chemotherapy and PARP inhibition by virtue of homologous recombination deficiency (HRD). Here we investigate the impact of EMSY expression, extracted from local and publicly available transcriptomic data, on the outcome and platinum sensitivity of HGSOCs. Platinum response data were collected from the Edinburgh Ovarian Cancer Database. Overall survival (OS) and progression-free survival (PFS) differences were assessed using multivariate cox regression accounting for age, stage at diagnosis and debulking status. Within the Edinburgh cohort, high EMSY expression was associated with superior OS and PFS (table 1). Datasets from the MRC ICON7 trial control arm, Tothill et al, Mateescu et al, Pils et al, and TCGA cohorts demonstrated similar benefit for high-EMSY patients. Within the Edinburgh cohort, high-EMSY patients displayed significantly superior complete response (CR) rate to platinum at second (radio CR 44.4% vs 12.5%, P = 0.035; CA125 CR 88.0% vs 55.0%, P = 0.002) and third exposure (radio CR 50.0% vs 5.9%, P = 0.080; CA125 CR 53.3% vs 21.3%, P = 0.021), with prolonged time to progression (median 127 vs 83.5 days from second platinum, P = 0.084; median 151.5 vs 60.5 days from third platinum, P = 0.004). Within high-risk (advanced stage suboptimally debulked) HGSOCs, more high-EMSY patients remained recurrence-free 5 and 10 years from diagnosis (17.6% vs 2.7%, P = 0.031; 12.5% vs 0.9%, P = 0.041). Together these data demonstrate a subgroup of HGSOCs defined by high EMSY expression experience superior clinical outcome and platinum sensitivity, consistent with HRD. This subgroup may therefore represent HGSOCs that are also sensitive to PARP inhibition. DatasetEventMulti HR95% CIPEdinburghOS0.590.39 – 0.900.013PFS0.600.38 – 0.930.022MRC ICON7 control armOS0.210.07 – 0.680.009Tothill (primary tumour masses)OS0.280.09 – 0.900.032MateescuOS0.430.18 – 0.990.048PilsOS0.270.08 – 0.870.028TCGA advanced stage patientsPFS0.690.45 – 1.050.081 Citation Format: Robert L. Hollis, Michael Churchman, Tzyvia Rye, Andrena M. McCavigan, Laura A. Knight, Richard Kennedy, C. Simon Herrington, Charlie Gourley. High EMSY expression defines a BRCA-like subgroup of high-grade serous ovarian carcinoma with superior survival and platinum sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 322.

BACKGROUND. Clinicopathological features and outcome of women with endo-metrioid and serous ovarian adenocarcinoma were compared. METHODS. Between 1984 and 2004, baseline and follow-up data were prospectively recorded on 1545 patients with ovarian cancer. Of these, 270 had pure endometrioid tumors; 659 had pure serous adenocarcinoma of the ovary. Response to platinum-based chemotherapy (PBC) overall survival, stage-for-stage median progression-free survival (PFS), and cause-specific median survival were compared. Independent predictors of survival were examined by using multivariate analyses. RESULTS. Median age of diagnosis for patients with endometrioid tumors was younger than those with serous adenocarcinoma of the ovary (60 years vs 62 years; P =.013). They presented more often with early disease (stage I and 11; 50% vs 17%; P

Purpose: To evaluate the efficacy of the aromatase inhibitor letrozole in preselected estrogen receptor (ER)–positive relapsed epithelial ovarian cancer patients and to identify markers that predict endocrine-sensitive disease. Experimental Design: This was a phase II study of letrozole 2.5 mg daily until clinical or marker evidence of disease progression in previously treated ER-positive ovarian cancer patients with a rising CA125 that had progressed according to Rustin's criteria. The primary end point was response according to CA125 and response evaluation criteria in solid tumors (RECIST) criteria. Marker expression was measured by semiquantitative immunohistochemistry in sections from the primary tumor. Results: Of 42 patients evaluable for CA125 response, 7 (17%) had a response (decrease of >50%), and 11 (26%) patients had not progressed (doubling of CA125) following 6 months on treatment. The median time taken to achieve the CA125 nadir was 13 weeks (range 10-36). Of 33 patients evaluable for radiological response, 3 (9%) had a partial remission, and 14 (42%) had stable disease at 12 weeks. Eleven patients (26%) had a PFS of >6 months. Subgroup analysis according to ER revealed CA125 response rates of 0% (immunoscore, 150-199), 12% (200-249), and 33% (250-300); P = 0.028, χ2 for trend. Expression levels of HER2, insulin-like growth factor binding protein 5, trefoil factor 1, and vimentin were associated with CA125 changes on treatment. Conclusions: This is the first study of a hormonal agent in a preselected group of ER-positive ovarian cancer patients. A signature of predictive markers, including low HER2 expression, predicts response.

BACKGROUND A review of clinicopathologic features and outcome in women with carcinosarcoma of the ovary (also known as malignant mixed mesodermal tumor [MMMT]) compared with a group of women with serous adenocarcinoma (SAC) of the ovary was conducted. METHODS Between 1984 and 2002, 1568 patients with epithelial ovarian carcinoma and 70 patients with ovarian carcinosarcoma underwent treatment at the Edinburgh Cancer Centre. Analysis was performed on 65 patients with MMMT, and 746 patients with SAC were selected as a group for comparison. Baseline variables were recorded prospectively and response to chemotherapy and progression-free and cause-specific survival between the groups were compared. RESULTS Patients with carcinosarcoma had a mean age of 66.6 years, which is significantly older than those with SAC (62.0 years) (P < 0.001). The objective response rate to platinum-based chemotherapy was found to be significantly lower in patients with carcinosarcoma (25% vs. 60%; P = 0.02). Cause-specific survival in the carcinosarcoma group was poor and significantly shorter than that observed in the SAC group (median survival of 8.2 months vs. 20.7 months; P < 0.0001). Progression-free survival in patients with carcinosarcoma also was found to be significantly shorter compared with patients with SAC (median progression-free survival of 6.4 months vs. 12.1 months; P < 0.001). Achieving optimal debulking at the time of initial surgery was found to be a highly significant factor in patients with carcinosarcoma with regard to determining outcome (median survival of 14.8 months for patients with optimally debulked International Federation of Gynecology and Obstetrics Stage III disease vs. 3.1 months for patients with suboptimally/nondebulked Stage III disease; P < 0.001). CONCLUSIONS Ovarian carcinosarcoma is a distinct entity with a poor prognosis. Patients with carcinosarcoma differ from those with SAC with regard to having an older mean age of onset, an inferior response to platinum-based chemotherapy, and worse progression-free and cause-specific survival. The extent of benefit from chemotherapy is unclear. Cancer 2004. © 2004 American Cancer Society.

The pathogenesis of brain metastasis as a relatively rare complication of epithelial ovarian cancer is poorly understood. Some observations suggest that brain metastases from ovarian cancer are becoming more common and that ovarian cancers, which metastasize to the brain, may have a different biological pattern.Data were extracted from the Edinburgh Ovarian Cancer Database on a cohort of patients managed at the Edinburgh Cancer Centre (UK) between 1998 and 2004. The incidence of brain metastases was compared between patients with previous treatment for early breast cancer and patients without previous treatment for early breast cancer. Baseline characteristics, the time to cancer antigen 125 relapse, the time to brain metastasis, and the radiological pattern of relapse were also compared between these patients.We demonstrate a higher incidence of serous histology (P = 0.02) in patients in remission from early breast cancer and that the incidence of brain metastases in this group is 11.6% compared with 1.1% in patients without prior breast cancer (relative risk = 10.5, P0.001). Brain metastases were clinically evident after 45.6 months in patients with previous breast cancer compared with 21 months in patients without previous breast cancer (P = 0.008). Among the patients who developed brain metastases, isolated retroperitoneal lymph node recurrence was noticed in patients in remission from early breast cancer but rarely in other patients.Ovarian cancer patients with a history of early breast cancer have a higher incidence of brain metastases and a different pattern of disease recurrence. We speculate that a higher incidence of breast cancer early onset mutations in patients with previous early breast cancer underlies these observed differences.

Purpose To compare the frequency of visceral relapse of BRCA1/2-deficient ovarian cancer to that of nonhereditary controls. Patients and Methods All patients diagnosed in Scotland with epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) and a germline BRCA1/2 mutation were identified. Those with previous malignancy were excluded. Each remaining patient who experienced relapse was matched with two nonhereditary controls. Results Seventy-nine patients with EOC/PPC and germline BRCA1/2 mutations were identified. Fifteen had inadequate clinical data, two had carcinosarcoma, 27 had previous breast cancer, and 16 were in remission. Of the remaining 19 patients who were BRCA1/2 deficient, 14 patients (74%) developed visceral metastases compared with six (16%) of 38 patients in the control group. The percentages of liver, lung, and splenic metastases were 53%, 32%, and 32%, respectively, in the patients compared with 5%, 3%, and 5%, respectively, in the controls. When events occurring outside the matched follow-up period were omitted, the percentages of visceral, liver, lung, and splenic metastases were 58%, 42%, 16%, and 32% in the patients compared with 5%, 0%, 0%, and 3% in controls (P < .001, P < .001, P = .066, and P = .011, respectively). In an independent validation set, the corresponding percentages of visceral, liver, lung, and splenic metastases were 63%, 46%, 13%, and 17% in the patients compared with 11%, 4%, 2%, and 2% in controls (P < .001, P < .001, P = .153, and P = .052, respectively). Conclusion Although sporadic EOC commonly remains confined to the peritoneum, BRCA1/2-deficient ovarian cancer frequently metastasizes to viscera. These data extend the ovarian BRCAness phenotype, imply BRCA1/2-deficient ovarian cancer is biologically distinct, and suggest that patients with visceral metastases should be considered for BRCA1/2 sequencing.

Background: The PARPi olaparib (Ola) was recently granted FDA accelerated approval in advanced BMOC. Despite impressive clinical activity in BMOC, the impact of baseline pt factors remains unclear. We hypothesized that the platinum chemotherapy (Plt chemo) to PARPi interval (PTPI) can be used to refine the conventional prediction of response to PARPi based on the clinical categorization of pts into Plt sensitive (Plt-S) and Plt resistant (Plt-R). Methods: Retrospective study of pt with advanced BMOC treated in relapsed setting with ≥ 200 mg bid Ola between 4/2006 – 8/2013 in multiple centers. Pearson Chi2, odds ratios (OR) and Fisher’s exact probability tests were used for statistical analyses. Results: 108 advanced BMOC pts were assessed; median age 55y (range 38-79); 83 (77%) pts had high grade serous carcinoma. BRCA1:BRCA2 mutations ratio 71:29. Median prior lines of chemo: 3 (range 1-10). 41 (38%) pts had prior breast cancer (BC). 64% had Plt-S disease and 36% had Plt-R disease prior to Ola. Median PTPI was 53 weeks (w) (range 4-244). Median PTPI was 68.7w for Plt-S pts versus (vs) 25.9w for Plt-R pts (p < 0.0001). RECIST complete or partial responses (CR/PR) were observed in 23/65 (35%) Plt-S pts vs 5/38 (13%) Plt-R pts (p < 0.02). Pts with > 52w PTPI had higher CR/PR rates than those with < 52w PTPI independent of their Plt status (37% vs 18%, respectively, p = 0.053). Pts who had only 1 prior line of chemo had higher CR/PR rates vs pts who had > 1 prior line (p < 0.005). No differences in CR/PR rates were noted between pts with BRCA1 vs pts with BRCA2 mutations, pts with prior BC vs pts without, or use of chemo for BC vs none. Median progression-free survival was 70w for pts with PR/CR vs 28w for pts without (log-rank, p = 0.0004). Median survival was 161w for pts with CR/PR and 64w for pts without (log-rank, p = 0.0005). Conclusions: These data suggest that prediction of response to PARPi in advanced BMOC based on conventional Plt-S/Plt-R categorization may be refined by PTPI. Treatment of Plt-R BMOC pts with a non-Plt agent prior to Ola in order to prolong PTPI may be an appropriate clinical strategy. These findings should be validated prospectively in a larger data set.

Aim: Optimum management of OCCCs following primary surgery remains unclear. While adjuvant WAPRT has been shown to improve disease free survival in OCCCs, its effect on overall survival (OS) is unknown. Scant data also exists regarding the benefit of adjuvant chemotherapy in OCCCs. The aim of this study is to evaluate the response rates (RR = PR/CR), progression free (PFS) and overall survival (OS) following adjuvant chemotherapy +/- WAPRT for OCCC. Methods: We conducted a retrospective review of patients with OCCC treated at Princess Margaret Cancer Centre and Edinburgh Cancer Centre to evaluate RR (RECIST criteria), PFS (time from diagnosis to RECIST or clinical PD) and OS (time from diagnosis to death) following completion of chemotherapy +/- WAPRT. Adjuvant whole abdomen/ pelvic RT (WAPRT) was administered using 45Gy in 25 fractions to the pelvis +/- 23Gy in 23 fractions to the abdomen. Survival differences were analysed by log-rank analysis and multivariate cox regression analyses. Results: A total of 256 patients with primary OCCC were identified. In 53 patients with measurable disease, an overall response rate of 30% (6CRs and 10PRs) was observed following adjuvant platinum-based chemotherapy. Forty women with FIGO stage 1 to 3 disease (stage 1 = 24, stage 2 = 10, stage 3 = 6) received adjuvant WAPRT. Median PFS and OS for all patients was 147 weeks (95% CI 94, 200) and 70mths (95% CI 32, 108) respectively. Compared with patients who did not receive WAPRT, adjuvant WAPRT was associated with significantly superior median PFS (median PFS not reached vs 133 weeks [95% CI 100,166]; p 2cm (HR = 3, p = 0.0001). Independent predictors of improved PFS included adjuvant treatment with WAPRT (HR 0.37, p = 0.001), and chemotherapy (HR 0.4, p = 0.0001). Likewise for OS, adjuvant WAPRT (HR = 0.35, p = 0.014) and chemotherapy (HR 0.35, p= 0.0001), Stage 1 OCCC (HR = 0.26, p = 0.0001) and residual disease Conclusions: Our data suggests that a combined adjuvant strategy of chemotherapy and WAPRT is associated with significantly improved PFS and OS in the treatment of OCCC. Disclosure: All authors have declared no conflicts of interest.

5548 Background: Advanced stage primary OCCC is associated with a poor prognosis following primary surgery and chemotherapy, but scant data exists regarding response rates (RR = RECIST PR/CR), prog...

5571 Background: Ovarian cancer patients with germline BRCA1 or BRCA2 (gBRCA1/2) mutations frequently respond to multiple lines of chemotherapy. Having noticed significant myelosuppression during chemotherapy in gBRCA1/2 patients we wished to determine whether this was a chance finding or related to a heterozygous gene dosage effect in the bone marrow. Methods: gBRCA1/2 ovarian cancer patients from Edinburgh, Glasgow and Dundee were identified and matched for chemotherapy regimen, dose and age to controls from the Edinburgh Ovarian Cancer Database. Case notes and transfusion service records were analysed for chemotherapy details, haematology results, G-CSF use, red cell and platelet transfusions during first line chemotherapy. Results: Of 91 gBRCA1/2 patients, 35 patients were excluded who had previously received cytotoxic chemotherapy (mostly for breast cancer) or unusual chemotherapy regimens unable to be matched to controls. 56 were matched to controls. Baseline haematological indices were similar. There was a significant difference in the fall in haemoglobin levels from baseline to cycle 4 in gBRCA1/2 patients compared to controls (12.23% v 5.14%, p = 0.0005) and gBRCA1/2 patients had longer delays during their chemotherapy (mean 7.73 v 4.51 days, p = 0.0375) and more dose reductions for haemotoxicity (14 v 4 p = 0.0011). gBRCA1/2 were more likely to have a red cell transfusion (19 v 11, p = 0.099), and received more red cells (69 v 31 units, p = 0.0318). G-CSF was required in 3 BRCA patients versus 0 controls. Differences in platelet and white cell counts at cycle 4 were not significant. Conclusions: Patients with ovarian cancer and germline BRCA1/2 mutations were more likely to have significant falls in haemoglobin levels and require red cell transfusions and to experience delays during chemotherapy. This susceptibility to anaemia may be a hemizygous BRCA1/2 gene dosage effect manifest in the bone marrow and may have implications for the optimisation of cytotoxic and PARP inhibitor therapy in this patient group.

5055 Background: Pre-chemotherapy identification of platinum-resistant EOC would facilitate use of alternative treatment strategies. Small studies have proposed ERCC1 as a platinum resistance marke...

5564 Background: The excision repair cross-complementation group 1 (ERCC1) enzyme is a crucial component of the nucleotide excision repair pathway which removes cisplatin-induced DNA adducts. High ...

5025 Background: Letrozole is a potent oral aromatase inhibitor which rapidly suppresses circulating estrogen levels by 99% in postmenopausal women. By comparison with cytotoxic agents it is very well tolerated. We previously demonstrated an ‘endocrine sensitive’ subgroup of ovarian cancer patients with ER histoscore cutoff of ≥150 (Bowman et al, Clin Can Res 2002). Methods: This was a phase II study with a planned sample size of 33 patients. Eligible patients had relapsed EOC or primary peritoneal cancer with an ER histoscore of ≥150 and a rising CA125 that had progressed according to Rustin’s criteria. Patients were treated with letrozole 2.5mg daily until clinical or marker evidence of disease progression. The primary endpoint was response according to CA125 and RECIST criteria. Biomarker analysis by tissue microarray is also being performed. Results: 46 patients were accrued, 45 of whom were eligible. The median age was 61 (range 39–81). 24, 10 and 10 patients had received 1,2 and >2 previous lines of chemotherapy respectively. Of 43 patients evaluable for CA125 response, 7 (16%) had a response (decrease of >50%) and 16 (37%) patients had not progressed (doubling of CA125) following 12 weeks on treatment. In the CA125 responders, the nadir CA125 ranged from 0.7–49% of baseline (actual % of baseline: 0.7, 2.6, 11.1, 17.6, 23.6, 42.6, 49). Of the 7 responding patients, 5 had received only one previous line of chemotherapy. The time taken to achieve the nadir CA125 value ranged from 10 to 36 weeks, with a median of 13 weeks. Of 33 patients evaluable for radiological response, 3 (9%) had a PR and 14 (42%) had stable disease at 12 weeks. Overall, 11 patients (26%) had a PFS of >6 months and 2 patients (5%) had a PFS of ≥2 years. Conclusions: To our knowledge this is the first study of a hormonal agent in a selected ER +ve population of ovarian cancer patients. Promising efficacy of the agent is demonstrated in this population of pre-treated patients, many with a considerable bulk of disease. Given the median time of 13 weeks to response, we suggest that this strategy should be tested in ER+ve ovarian cancer patients in the adjuvant setting following first line chemotherapy No significant financial relationships to disclose.

Recurrently called variants confirmed as sequencing errors by Sanger sequencing. (DOCX 11 kb)

Sum of squares differences (SSD) between our SNV spectrum and the fresh frozen TCGA SNV spectrum at various allele frequency threshold for variant filtering. (DOCX 53 kb)

Recurrently called variants confirmed as sequencing errors by Sanger sequencing. (DOCX 11 kb)