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Treatment approaches for relapsed ovarian cancer have evolved over the past decade from a calendar-based decision tree to a patient-oriented biologically driven algorithm. Nowadays, platinum-based chemotherapy should be offered to all patients with a reasonable chance of responding to this therapy. The treatment-free interval for platinum is only one of many factors affecting patients' eligibility for platinum re-treatment. Bevacizumab increases the response to chemotherapy irrespective of the cytotoxic regimen and can be valuable in patients with an urgent need for symptom relief (e.g. pleural effusion, ascites). For patients with recurrent high-grade ovarian cancer, which responds to platinum-based treatment, maintenance therapy with a poly(ADP-ribose) polymerase inhibitor can be offered, regardless of the BRCA mutation status. Here we review contemporary decision-making processes in the systemic treatment of relapsed ovarian cancer.

Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10–8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15–1.34; P = 1.47 × 10–8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options. See related commentary by Peres and Monteiro, p. 1604

The chemotherapy response score (CRS) is a histopathological tool to evaluate response to neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (OC). We critically evaluated the clinical value of CRS and compared its predictive power to standard serological (CA125) and radiological response. A retrospective analysis of 277 OC patients, who received primary chemotherapy, was performed. CRS, serological, and radiological findings were correlated with progression-free (PFS) and overall survival (OS). CRS could be determined in 172 of 277 patients (62.1%). In patients with CRS3, a longer median PFS and OS was observed compared with CRS1/2 patients (31.2 vs. 18.9, P

OBJECTIVE: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial. METHODS: This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017). RESULTS: Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were

BackgroundThere is limited information about the impact of radical surgery including pelvic and para-aortic lymphadenectomy and subsequent platinum-based chemotherapy on sexuality in patients with advanced ovarian cancer.ObjectiveTo evaluate the impact of radical surgery including pelvic and para-aortic lymphadenectomy and subsequent platinum-based chemotherapy on sexuality in patients with advanced ovarian cancer as a sub-protocol of the prospectively randomized LION trial.MethodsThe Sexual Activity Questionnaire was applied to assess sexual function according to its sub-scales activity, pleasure, and discomfort. The 'orgasm' sub-scale from the Female Sexual Function Index was also added. The questionnaire was administered in combination with the EORTC QLQ-C30 questionnaire at baseline prior surgery, after 6, 12, and 24 months. The primary endpoint was changes in sexual function.ResultsOverall, 495 patients received the questionnaires. 254 (51%) responded at baseline. Of these, 55 (22%) patients were sexually active, 182 (72%) were sexually inactive, and for 17 (7%) patients' data were not available. There was a total of 55/495 (11%) patients at 6 months, 139 (28%) patients at 12 months, and 81 (16%) patients at 24 months. Median age was 60.5 years (range 21.4–75.8). At baseline, sexually active responders were significantly younger (median age 51.5 years,) than sexually inactive responders (median age 61.8 years) and tended to have a better performance status. Discomfort evaluated as dryness of the vagina and pain during sexual intercourse was significantly worse at 12 months than at baseline (pConclusionThe majority of patients were sexually inactive; however, in those who were sexually active, pain during intercourse was worse at 12 months. In addition, the orgasm sub-scale demonstrated worse results in patients who underwent complete lymphadenectomy. The study suggests that surgery in the retroperitoneal space may influence sexual function.

Background BRCA1/2 mutations are the leading cause of hereditary epithelial ovarian cancer (EOC). The German Consortium for Hereditary Breast and Ovarian Cancer has defined inclusion criteria, which are retrievable as a checklist and facilitate genetic counselling/testing for affected persons with a mutation probability of ≥ 10%. Our objective was to evaluate the prevalence of the BRCA1/2 mutation(s) based on the checklist score (CLS). Methods A retrospective data analysis was performed on EOC patients with a primary diagnosis treated between 1/2011 – 5/2019 at the Central Essen Clinics, where a BRCA1/2 genetic analysis result and a CLS was available. Out of 545 cases with a BRCA1/2 result (cohort A), 453 cases additionally had an extended gene panel result (cohort B). Results A BRCA1/2 mutation was identified in 23.3% (127/545) in cohort A, pathogenic mutations in non-BRCA1/2 genes were revealed in a further 6.2% in cohort B. In cohort A, 23.3% (127/545) of patients had a BRCA1 (n = 92) or BRCA2 (n = 35) mutation. Singular EOC (CLS 2) was present in 40.9%. The prevalence for a BRCA1/2 mutation in cohort A was 10.8%, 17.2%, 25.0%, 35.1%, 51.4% and 66.7% for patients with CLS 2, 3, 4, 5, 6 and ≥ 7 respectively. The mutation prevalence in cohort B was 15.9%, 16.4%, 28.2%, 40.4%, 44.8% and 62.5% for patients with CLS 2, 3, 4, 5, 6 and ≥ 7 respectively. Conclusions The BRCA1/2 mutation prevalence in EOC patients positively correlates with a rising checklist score. Already with singular EOC, the prevalence of a BRCA1/2 mutation exceeds the required 10% threshold. Our data support the recommendation of the S3 guidelines Ovarian Cancer of offering genetic testing to all patients with EOC. Optimisation of the checklist with clear identification of the testing indication in this population should therefore be aimed for.

Although thrombocytosis in patients with primary ovarian cancer has been widely investigated, there are only very few data about the role of thrombocytosis in recurrent ovarian cancer. The aim of our study was to investigate the impact of pretreatment thrombocytosis prior to chemotherapy on clinical outcome in patients with recurrent platinum eligible ovarian cancer. In our retrospective analysis we included 300 patients who were treated by AGO Study Group Centers within three prospective, randomized phase-III-trials. All patients included had been treatment-free for at least 6 months after platinum-based chemotherapy. We excluded patients who underwent secondary cytoreductive surgery before randomization to the trial. Thrombocytosis was defined as a platelet count of ≥ 400⋅109/L. Pretreatment thrombocytosis was present in 37 out of 300 (12.3%) patients. Patients with thrombocytosis responded statistically significantly less to chemotherapy (overall response rate 35.3% and 41.6%, P = 0.046). The median progression-free survival (PFS) for patients with thrombocytosis was 6.36 months compared to 9.00 months for patients without thrombocytosis (hazard ratio [HR] = 1.19, 95% confidence interval [CI] = 0.84–1.69, P = 0.336). Median overall survival (OS) of patients with thrombocytosis was 16.33 months compared to 23.92 months of patients with a normal platelet count (HR = 1.46, 95% CI = 1.00–2.14, P = 0.047). The present analysis suggests that pretreatment thrombocytosis is associated with unfavorable outcome with regard to response to chemotherapy and overall survival in recurrent ovarian cancer.

Funder: Funding details are provided in the Supplementary Material, Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, ���select and shrink for summary statistics��� (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28���1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08���1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30���1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

BACKGROUND: Treatment for patients with recurrent ovarian cancer has been mainly based on systemic therapy. The role of secondary cytoreductive surgery is unclear. METHODS: We randomly assigned patients with recurrent ovarian cancer who had a first relapse after a platinum-free interval (an interval during which no platinum-based chemotherapy was used) of 6 months or more to undergo secondary cytoreductive surgery and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Patients were eligible if they presented with a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score, defined as an Eastern Cooperative Oncology Group performance-status score of 0 (on a 5-point scale, with higher scores indicating greater disability), ascites of less than 500 ml, and complete resection at initial surgery. A positive AGO score is used to identify patients in whom a complete resection might be achieved. The primary end point was overall survival. We also assessed quality of life and prognostic factors for survival. RESULTS: A total of 407 patients underwent randomization: 206 were assigned to cytoreductive surgery and chemotherapy, and 201 to chemotherapy alone. A complete resection was achieved in 75.5% of the patients in the surgery group who underwent the procedure. The median overall survival was 53.7 months in the surgery group and 46.0 months in the no-surgery group (hazard ratio for death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.02). Patients with a complete resection had the most favorable outcome, with a median overall survival of 61.9 months. A benefit from surgery was seen in all analyses in subgroups according to prognostic factors. Quality-of-life measures through 1 year of follow-up did not differ between the two groups, and we observed no perioperative mortality within 30 days after surgery. CONCLUSIONS: In women with recurrent ovarian cancer, cytoreductive surgery followed by chemotherapy resulted in longer overall survival than chemotherapy alone. (Funded by the AGO Study Group and others; DESKTOP III ClinicalTrials.gov number, NCT01166737.).

Introduction/Background* The detection of gBRCA1/2 mutations in patients (pts) with epithelial ovarian cancer (EOC) provides information regarding family risk and influences clinical management, e.g. use of PARP inhibitors. The availability of next generation sequencing (NGS) allows for simultaneous sequencing of multiple cancer risk genes including BRCA1/2. Our aim was to evaluate the prevalence and clinical outcome of deleterious germline mutations in EOC patients. Methodology EOC patients treated between 2011 and 2020 at our institution and with germline TruRisk® gene panel testing were included in this retrospective analysis. Based on the genetic test result three cohorts were considered: A) no mutation, B) gBRCA1/2, and C) mutations in other risk genes. Demographic and clinicopathological characteristic were retrieved from the prospective database. To evaluate survival outcome in FIGO III/IV EOC univariate and multivariate logistic regression was performed. Result(s)* In total 702 EOC pts underwent germline panel testing. Median age was 59 years, 74.5% underwent primary debulking surgery, 83.9% were FIGO III/IV, and complete macroscopic resection was achieved in 74.0%. No mutation was detected in 76.6% (n=538), pathogenic gBRCA1/2 mutations in 17.4% (n=122), and mutations in other risk genes in 6.0% (n=42), respectively (tbl.1). Significant differences between the cohorts were detected for age, pervious history of malignancies, personal/familial breast/ovarian cancer history, and histology. For FIGO III/IV patients median PFS was significantly different for cohort A, B, and C with 23, 37, and 34 months (p=0.059/multivariate 0.015), respectively. 3-years-OS was 70%, 83%, and 87% for cohorts A, B, and C (p=0.003), respectively. In multivariate analysis type of surgery (IDS: HR 2.79(1.86-4.19), p 500mL (HR 1.75(1.14-2.68), p=0.010), and residual disease (RD>0mm: HR 2.87(1.99-4.14), p Conclusion* The detection rate of germline mutations in EOC is 23.4%. Our findings underline the necessity to offer germline panel testing in EOC to identify families at risk. Further, our findings underscore the prognostic value of germline mutations towards a better prognosis.

Introduction/Background* Debulking surgery is the mainstay of treatment for patients (pts) with advanced epithelial ovarian cancer (EOC). Upfront surgery (PDS) with complete macroscopic resection (TR0) is associated with best survival while PDS to small residual disease (TR1-10) provides moderate benefit in high grade serous OC. The impact of resection status in other histological subtypes so far has not been defined and especially the role of TR1-10 is under debate. This analysis should help to better understand the interplay between histological subtype, surgical outcome, and prognosis. Methodology Data of patients (>FIGO IIIB) from 7 AGO-Studygroup led phase III multicentre trials (AGO-OVAR 3,5,7,9,11,12,15), (1995–2011) were pooled and analysed with focus on PDS resection status on overall survival (OS) in different histological subtypes: low grade (low grade serous or endometrioid), mucinous, clear cell, and high-grade (e.g. serous, endometrioid, undifferentiated histology). Multiple logistic regression of achieving TR0 in the full population and multiple Cox-regression of OS separately in each histological subpopulation adjusting potential confounders (treatment arm within each study, ECOG performance status, age, FIGO stage) were undertaken. Result(s)* 5,745 pts were eligible (5,156 high grade, 299 low grade, 219 mucinous, 71 clear cell). Differences in resection rates between histological subtypes are displayed in the table 1. Adjusted odds ratios showed significantly higher odds for achieving TR0 for low grade and clear cell compared to high-grade, (table 1). Median follow-up was 60.7 months. The figure shows OS within tumour types according to resection status. Hazard ratios between TR0, TR1-10 and TR>10 obtained from multiple Cox regression of OS are shown in the table 1. Conclusion* Our analysis confirmed the value of complete resection in all subtypes of ovarian cancer. The role of largely resection (TR1-10mm) seemed to be relevant in low grade OC, but marginal although significant in HGSOC and inconclusive in mucinous and clear cell OC. Larger databases are necessary to gain more reliable data in these subgroups.

Introduction/Background* There is poor evidence from mostly retrospective series whether co-medication with metformin, statin or beta-blocker have an impact on survival in patients with primary ovarian cancer. The aim of this study was to investigate the association of these medications with survival. Methodology Individual data from 3 prospective phase III randomized controlled trials (AGO-OVAR 11/ICON 7, 12, 16) and one phase II trial (AGO-OVAR 15) were pooled and analyzed. Patients were either classified as “ever-user” if the specific co-medication was documented at least once during the trial. In. contrast, “never-users” served as controls. Data were adjusted for potential confounders (age, FIGO stage, histology, residual tumor after surgery, ECOG performance status, BMI, Charlson Comorbidity Index and assigned treatment within the trial) in multivariate Cox regression analyses. Result(s)* Overall, 2.857 patients were included in the analyses. “Ever-users” were: N=100 patients received metformin (3.5%), N=226 received statins (7.9%), and N=475 (16.6%) received beta-blockers (BB) (N=391 selective (sBB); N=84 non-selective (nsBB)) as co-medication. There were no significant differences regarding the baseline characteristics (histology, FIGO stage, residual tumor after surgery, and chemotherapy-schedule) between “ever- and never-users” except that “ever-users” were significantly older and more obese, compared to controls. Median progression-free (PFS) and overall survival (OS) for the entire cohort was 18.7 months and 60.1 months, respectively Multivariate analyses for PFS and OS including age, BMI, Histology, FIGO stage, residual tumor after surgery, ECOG performance status and CCI revealed neither a significant impact of metformin on survival of “ever-users”, compared to “never-users” (PFS HR 0.94 95%-CI 0.69-1.29, p=0.7; OS HR 0.82 95%-CI 0.58-1.17, p=0.28), nor for statins (PFS HR 0.98 95%-CI 0.82-1.18, p=0.87; OS HR 0.91 95%-CI 0.74-1.12, p=0.37), respectively. In contrast, “ever-users” of sBB had a significantly elevated risk for recurrence and death in multivariate analysis (PFS HR 1.22 95%-CI 1.05-1.41, p=0.009; OS HR 1.25 95%-CI 1.06-1.47, p=0.009). Conclusion* In this large pooled analysis neither a co-medication with metformin nor with statins had a significant impact on survival in patients with primary ovarian cancer. In contrast, co-medication with a beta-blocker was associated with worse survival. Further studies are warranted to confirm this observation.

Introduction/Background* Recent and detailed data regarding treatment quality and outcome of patients with high grade AOC on a nationwide basis are largely unknown in Germany. Methodology All German hospitals treating patients with ovarian cancer were asked to document all patients with first diagnosis in the third quarter in 2012 and 2016. Details of tumor, treatment and outcome were documented. This analysis is focusing on patients with AOC FIGO III/IV and the endpoint PFS (progression free survival) (OS data immature for 2016 cohort). As response rates were not documented, we defined a subcohort of patients without progressive disease within 3 months after end of chemotherapy as potential candidates for an additional maintenance therapy. Result(s)* In total, 1010 patients with high grade AOC with a median age of 65 years were documented. 774/1010 (76.6%) were diagnosed with FIGO III disease and 947/1010 (93.8%) had high-grade serous histologic subtype. 915/1010 (90.6%) had primary cytoreductive surgery. Complete resection was achieved in 434/1010 (43.0%) at primary surgery and in 54/1010 (5.3%) at interval debulking surgery. Carboplatin/paclitaxel/bevacizumab (TCB) was the primary systemic therapy in 627/1010 (62.1%) and carboplatin/paclitaxel (TC) in 292/1010 (28.9%). Median PFS in patients with primary surgery and complete resection was 29.7 months (95% CI 27.4-34.2) compared to 17.2 months (95% CI 15.7-18.9) in all other patients (p Conclusion* Most patients in Germany with high grade AOC are treated with primary surgery followed by carboplatin/paclitaxel/bevacizumab. Depending on biomarker status most patients are potential candidates for a PARP-inhibitor maintenance therapy.

Introduction/Background* Adult granulosa cell tumors (aGCT) represent less than 5% of all ovarian malignancies. The aim of this study was to analyze clinical and histopathological parameters and their impact on recurrence, progression-free- (PFS) and overall survival (OS). Methodology Patients diagnosed with primary aGCT and treated in three international referral centers were included in the study. The following variables were anonymously exported from the prospective database of each clinic for further analysis: patient’s age at diagnosis, stage, chemo-, radiation, or hormonal therapy, surgery for primary site, type of restaging surgery, lymph nodes dissected, follow-up months, PFS, and OS. Descriptive statistical analysis regarding tumor and treatment characteristics was performed. Survival analyses included Kaplan-Meier functions and Cox proportional hazard ratios (HR). Result(s)* The total study cohort included 168 patients with primary aGCT, which were treated surgically. Median age was 50 years (range 13-82). 54.2% (n=91) of patients had FIGO stage IA, 26.8% (n=45) were stage IC, and 17.8% (n=32) had FIGO stage II-IV. In total 66.7% (n=112) of patients underwent surgical restaging procedure of whom 11.9% (n=20) were up-staged. A median laparotomy was performed in 70.8% (n=119) of patients. Adjuvant chemotherapy was administered to 11.3% of patients (n=19) and one patient received endocrine therapy. After a median follow-up of 61 months, 10.7% (n=18) had recurrent disease and 4.8% (n=8) of patients died from the disease. Overall five-year PFS was 86.1% and estimated OS was 95.7%. Survival was worse for patients with advanced stages (FIGO IA/B vs. IC, HR = 5.09; 95% confidence interval [CI]: 1.53-16.9; FIGO IA/B vs. II-IV, HR=5.62; 95% CI: 1.58-19.9) and for patients who underwent adjuvant chemotherapy (HR=9.15; 95% CI: 3.62-23.1). Conclusion* Prognosis of patients with primary aGCT is mainly determined by FIGO-Stage. The outcome of FIGO stage IC is comparable to advanced stages and a significant number of patients were up-staged. The role of adjuvant chemotherapy remains unclear and should be investigated in future studies.

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan–Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81–0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36–0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.

Purpose: Predicting surgical outcome could improve individualizing treatment strategies for patients with advanced ovarian cancer. It has been suggested earlier that gene expression signatures (GES) might harbor the potential to predict surgical outcome. Experimental Design: Data derived from high-grade serous tumor tissue of FIGO stage IIIC/IV patients of AGO-OVAR11 trial were used to generate a transcriptome profiling. Previously identified molecular signatures were tested. A theoretical model was implemented to evaluate the impact of medically associated factors for residual disease (RD) on the performance of GES that predicts RD status. Results: A total of 266 patients met inclusion criteria, of those, 39.1% underwent complete resection. Previously reported GES did not predict RD in this cohort. Similarly, The Cancer Genome Atlas molecular subtypes, an independent de novo signature and the total gene expression dataset using all 21,000 genes were not able to predict RD status. Medical reasons for RD were identified as potential limiting factors that impact the ability to use GES to predict RD. In a center with high complete resection rates, a GES which would perfectly predict tumor biological RD would have a performance of only AUC 0.83, due to reasons other than tumor biology. Conclusions: Previously identified GES cannot be generalized. Medically associated factors for RD may be the main obstacle to predict surgical outcome in an all-comer population of patients with advanced ovarian cancer. If biomarkers derived from tumor tissue are used to predict outcome of patients with cancer, selection bias should be focused on to prevent overestimation of the power of such a biomarker. See related commentary by Handley and Sood, p. 9

Due to advances in anticancer treatment and supportive care, patients increasingly complained about nonphysical side effects of chemotherapy and targeted therapy in recent years. Therefore, continuous assessment of side effects and patients’ perceptions is important. The aim of this study was to evaluate the identification and severity of side effects perceived by ovarian cancer (OC) and breast cancer (BC) patients undergoing contemporary anticancer therapy. Between 2015 and 2017, consecutive chemo-naive OC and BC patients were enrolled in this prospective cohort study. Interviews were performed 12 ± 3 weeks after start of anticancer therapy, and patients were asked to select and rank, according to severity, 72 physical or nonphysical symptoms potentially related to their treatment. Data were analyzed with descriptive statistics. Forty-five OC patients and 98 BC patients completed the interview. Sleeping difficulties were ranked as the most troublesome symptom, followed by concerns about family or partner, and loss of hair. Alopecia was the most predominant side effect for BC patients, whereas OC patients were highly afflicted by numbness in limbs. Chemotherapy alone or in combination with targeted therapy caused pronounced sleep disturbances. Prolonged taxane treatment led to shortness of breath and numbness in limbs. Vomiting was ranked by one and nausea by eight women among the five most bothersome symptoms. Sleep disturbances have lately emerged as the most severe problem in women with OC or BC receiving anticancer therapy. Concerns about family and partner were ranked second in the current study and first in previous investigations.

The indication for staging lymphadenectomy in patients with ovarian cancer (both early- and late-stage disease) has been a major topic of debate in the last decades. Because the Lymphadenectomy in Ovarian Neoplasms (LION) study has recently demonstrated that systematic lymphadenectomy is not beneficial to patients with advanced ovarian cancer, the discussion has become more complex for patients with early-stage ovarian cancer. Further factors, such as differences in the lymph node metastasis rates of different histologic subtypes, which were not known in the past, need to be taken into account. This review is focused on the available evidence concerning lymphadenectomy in patients with newly diagnosed ovarian cancer.

Purpose: Regarding cancer antigen 125 (CA-125) longitudinal kinetics during chemotherapy, the actual predictive value of the Gynecologic Cancer Intergroup (GCIG) CA-125 response criterion is questioned. The modeled CA-125 elimination rate constant KELIM exhibited higher prognostic value in patients with recurrent ovarian cancer enrolled in the CALYPSO trial. The objective was to validate the higher predictive and prognostic values of KELIM during first-line treatments. Experimental Design: Data from three large phase III trials were analyzed: AGO OVAR 9 [learning set: carboplatin-paclitaxel (CP) ± gemcitabine; n = 1,288]; AGO OVAR 7 (validation set: CP ± topotecan; n = 192); and ICON7 (validation set: CP ± bevacizumab; n = 1,388). The CA-125 profiles were fit with a nonlinear mixed-effect model during the first 100 days, and the individual KELIM were calculated. KELIM prognostic and predictive values for survival were assessed against GCIG criterion and other prognostic factors in univariate/multivariate analyses. Results: The GCIG CA-125 endpoint provided no meaningful predictive/prognostic information. C-index analyses confirmed the higher predictive value of KELIM compared with GCIG criterion for progression-free survival and overall survival (OS). KELIM provided reproducible prognostic information. Patients with favorable KELIM ≥ upper tercile (0.0711 per days) consistently experienced better OS, with HRs between 0.44 and 0.58 (e.g., median OS >65 months vs. Conclusions: Modeled KELIM provides higher predictive and prognostic information based on CA-125 longitudinal kinetics compared with GCIG response criteria during first-line chemotherapy. Integration of this endpoint in guidelines may be considered. Individual KELIM and survival simulations can be calculated at http://www.biomarker-kinetics.org/. Further assessment of the surrogate value of KELIM treatment–related variations in a GCIG meta-analysis is warranted. See related commentary by Maitland et al., p. 5182

ObjectivesAdult primary cervical rhabdomyosarcoma is a very rare disease and data regarding treatment are sparce. The goal of this study was to report on our experience with the management of this rare entity, along with an evaluation of the literature.MethodsWe conducted a review of the medical records at four centers from January 1990 to December 2017. We reviewed clinical characteristics including age at diagnosis, BMI, medical history and tumor stage, as well as treatment in the primary and recurrent settings and follow-up data. We reclassified tumors according to the Intergroup Rhabdomyosarcoma Study (IRS) clinical group.ResultsA total of 15 patients were included in the analysis. Median age at diagnosis was 35 years (range 17–55). Median tumor size at presentation was 5 cm (range 3–10). Eleven patients had the embryonal variant, including five showing the botryoid subtype. Four patients had a pleomorphic rhabdomyosarcoma. Eleven patients had disease classified as IRS Clinical Group I, while the remaining four fell into groups II or III. Fertility-sparing treatment was offered to five patients. Primary treatment types were: surgery alone in eight patients, surgery followed by adjuvant chemotherapy in six patients, and neoadjuvant chemotherapy in two patients. The main risk factors for relapse were: IRS clinical group greater than I, tumor size greater than 5 cm, lymph nodal involvement, and non-embryonal histology. At a median follow-up of 35 months (range 3–282), we observed a 5-year overall survival rate of 78.2% and a progression-free survival of 58.2%. No patient in the IRS I group died of the disease. Three out of four patients in the IRS II-III group died of the disease (survival range 5–16 months following treatment).ConclusionOur data show that cervical rhabdomyosarcomas account for at least two prognostic groups, demonstrating the existence of low-risk and high-risk patterns. The best predictor of prognosis appearsd to be the IRS clinical group classification system. IRS Group I tumors had an overall good prognosis and rarely recurred; when they did recur they were mainly local, following conservative treatment.

Simple Summary Most ovarian cancer patients initially show a response to primary treatments, but the development of refractory disease is a major problem. Currently, there are no blood-based prognostic biomarkers, and the prognosis of a patient is determined by the International Federation of Gynecology and Obstetrics (FIGO) stage and residual disease after cytoreductive surgery. In this study, we developed and validated a novel test based on the ratio of two circulatory lipids that enables the prognostic stratification of ovarian cancer patients at the time of diagnosis, prior to any oncological treatments. The translational relevance of this test is to find those patients with poor prognosis early on, and to identify patients that are at high risk of recurrence despite complete cytoreduction. Thus, the test enables the early direction of novel targeted therapies to those ovarian cancer patients at greatest risk of recurrence and death. Epithelial ovarian cancer (EOC) generally responds well to oncological treatments, but the eventual development of a refractory disease is a major clinical problem. Presently, there are no prognostic blood-based biomarkers for the stratification of EOC patients at the time of diagnosis. We set out to assess and validate the prognostic utility of a novel two-lipid signature, as the lipidome is known to be markedly aberrant in EOC patients. The study consisted of 499 women with histologically confirmed EOC that were prospectively recruited at the university hospitals in Turku (Finland) and Charite (Berlin, Germany). Lipidomic screening by tandem liquid chromatography-mass spectrometry (LC-MS/MS) was performed for all baseline serum samples of these patients, and additionally for 20 patients of the Turku cohort at various timepoints. A two-lipid signature, based on the ratio of the ceramide Cer(d18:1/18:0) and phosphatidylcholine PC(O-38:4), showed consistent prognostic performance in all investigated study cohorts. In the Turku cohort, the unadjusted hazard ratios (HRs) per standard deviation (SD) (95% confidence interval) were 1.79 (1.40, 2.29) for overall and 1.40 (1.14, 1.71) for progression-free survival. In a Charite cohort incorporating only stage III completely resected patients, the corresponding HRs were 1.59 (1.08, 2.35) and 1.53 (1.02, 2.30). In linear-mixed models predicting progression of the disease, the two-lipid signature showed higher performance (beta per SD increase 1.99 (1.38, 2.97)) than cancer antigen 125 (CA-125, 1.78 (1.13, 2.87)). The two-lipid signature was able to identify EOC patients with an especially poor prognosis at the time of diagnosis, and also showed promise for the detection of disease relapse.

We evaluated the clinical impact of germline (g)BRCA1/2-mutation on initial disease presentation, surgical implications, surgical morbidity and survival in patients with advanced epithelial ovarian cancer (EOC) undergoing debulking surgery (DS).Data of all consecutive EOC patients with stage III/IV, high-grade serous disease and known gBRCA1/2 status (gBRCA; non-gBRCA), who underwent DS at our department between 01/2011 and 06/2019 were analyzed. Associations between gBRCA-status and severe postoperative complications and survival were analyzed.gBRCA-status was determined in 50.1% (612/1221) of all patients. gBRCA was present in 21.9% (134/612). Significant differences were observed in terms of median age (p = 0.001) and histology (high-grade serous histology gBRCA: 98.5%, non-gBRCA 76.2%; p 0.001). gBRCA-status had no impact on intraoperative disease presentation, surgical complexity or complete resection rate (gBRCA: 74.4%, non-gBRCA: 69.0%; p = 0.274). gBRCA-status was not predictive for severe postoperative complication (gBRCA: 12.0%, non-gBRCA: 19.1%; p = 0.082). Median PFS and OS was 31/22 and 71/53 months in patients with/without gBRCA-mutation, respectively. gBRCA was a significant prognostic factor for PFS (HR 0.57 p 0.001) and for OS (HR 0.64, p = 0.048) after adjusting for established prognostic factors.gBRCA-status had no impact on initial disease presentation, surgical results or postoperative complications. gBRCA patients have a significantly longer PFS but the impact on the long term prognosis is unclear. Complete resection remains the most important prognostic factor in patients with EOC independent of gBRCA-status.

Introduction: Tumor biological factors of breast cancer (BC) such as hormone receptor (HR) status, HER2 status, and grade can differ in the metastatic cascade from primary to lymph node (LN) metastasis and to distant metastatic tissue. Systematic data regarding therapeutic consequences are yet limited. Methods: We conducted a prospectively planned, retrospective cohort study comparing BC phenotype in tissue from primary tumors (PTs), locoregional LN metastases, and disease recurrence (DR). HR and HER2 as well as tumor grade in PTs and DR were obtained by a database search. No centralized biomarker testing was performed. The impact of changes in tumor biological factors on post-recurrence survival (PRS) and overall survival was analyzed. Results: PriMet comprises 635 patients (LN tissue in 142 patients). Discrepancies for HR or HER2 status between PT and DR were observed in 18.7 and 21.6% of cases, respectively. For HR status, positivity of PT and negativity of DR was seen more often (13.2%) than vice versa (5.5%). For HER2 status, negativity of the primary and positivity of DR was seen more often (14.9%) than vice versa (6.7%). Discordance was more often observed between PT and LN metastasis compared to LN versus DR. However, numbers were small. Compared to concordant non-triple-negative (TN) disease, concordant TN disease showed significantly inferior PRS. Conclusion: We demonstrate receptor discordance to occur relatively frequently between PT, LN metastasis, and DR and to impact patient prognosis. However, clinical consequences of receptor discordance need to be drawn with caution considering clinical aspects as well as tumor biology.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

Introduction/Background The 3-Tier Chemotherapy Response Score (CRS) was developed to quantify the response after neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer patients undergoing interval debulking surgery. CRS3 (optimal response) identifies patients with a longer progression-free (PFS) and overall survival (OS) compared to patients with a CRS1/2 (no or minimal response/partial response). We critically evaluated the clinical value of CRS and compared its predictive power to standard serological (CA125) and radiological response in patients with advanced epithelial ovarian cancer. Methodology A retrospective analysis of 277 patients, who received primary chemotherapy for advanced epithelial ovarian cancer was performed. CRS, serological, and radiological findings, and pathological complete remission (pCR) were correlated to PFS and OS. Results Only 62.1% (172/277) patients treated with NACT could be assessed by CRS, as the CRS score can only be determined in patients that undergo interval debulking surgery, have a representative biopsy of the omentum, and have tumours with a high-grade serous histology. In patients with CRS3 (n=50) a longer median PFS and OS was observed compared to patients with CRS1/2 (n=122) (31.2 vs. 18.9, P In the total study cohort, serological and radiological complete response was better at predicting PFS (hazard ratio 2.23 and 2.77). Radiological complete response was better at predicting OS (hazard ratio 2.34). Conclusion In this study, evaluation of response to chemotherapy by CRS was not superior to conventional methods (CA125 or radiology). Independent of the used evaluation method, response to NACT was predictive of PFS and OS. Conventional methods should even be considered more clinically relevant, as these can be applied to all ovarian cancer patients receiving upfront chemotherapy, while only 62% of patients in our cohort could be assessed by CRS. Conventional response assessment, based on radiology and/or CA125, is used to evaluate whether a patient should be offered IDS and can, similar to CRS, be used to predict PFS and OS. As CRS has no influence on the treatment of patients undergoing NACT for ovarian cancer, the added value of response assessment using CRS is negligible. Disclosures JPR has no conflict of interest to declare. TB has been an advisor for Tesaro and received research grant from Amgen, non-financial support from Amgen, MSD, Roche, and Tesaro, outside the submitted work. MLM, AT, KUW, SH have no conflict of interest to declare. PH reports grants and personal fees from Astra Zeneca and Roche, personal fees from Sotio, grants and personal fees from Tesaro and GSK, personal fees from Stryker, Zai Lab, and MSD, grants from Public funding (DKH, DFG, EU), personal fees from Clovis, and Immunogen, grants from Boehringer Ingelheim, Medac, and Genmab, outside the submitted work. AdB reports personal fees from Roche, Astra Zeneca, Tesaro, Clovis, Pfizer, Genmab, Pharmar, and Biocad, outside the submitted work.

Most women with advanced ovarian cancer respond to initial treatment, consisting of surgical resection and ≈6 cycles of platinum-based chemotherapy. However, disease recurrence occurs in most patients, and subsequent therapies become necessary. Historically, close monitoring following treatment (active surveillance) was the only available option, as continued maintenance chemotherapy treatment led to increased toxicity without providing any meaningful clinical benefit. Recently, targeted therapy with the angiogenesis inhibitor bevacizumab and the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib, niraparib, and rucaparib have demonstrated significant clinical benefits as maintenance treatment for recurrent disease. Despite consensus guidelines recommending their use, maintenance treatments are currently underutilized. Here, we review evidence from pivotal clinical trials of approved second-line maintenance treatments demonstrating efficacy in terms of progression-free survival and postprogression efficacy outcomes for patients with recurrent ovarian cancer. Adverse events frequently associated with bevacizumab include hypertension, proteinuria, and non-central nervous system bleeding, whereas PARP inhibitors are associated with nausea, vomiting, fatigue, and anemia. Patient-centered outcomes analyses show that PARP inhibitors provide significant benefits to patient health status, even when accounting for the toxicities associated with treatment. Many factors influence the selection of second-line maintenance treatment for patients with recurrent ovarian cancer, including the maintenance treatment received in the first-line setting. Overall, targeted maintenance treatment represents a new standard of care for patients with ovarian cancer, and we recommend that maintenance treatment should be offered to all eligible patients with recurrent ovarian cancer.

We report a meta-analysis of breast, prostate, ovarian, and endometrial cancer genome-wide association data (effective sample size: 237,483 cases/317,006 controls). This identified 465 independent lead variants (P−8) across 192 genomic regions. Four lead variants were >1Mb from previously identified risk loci for the four cancers and an additional 23 lead variant-cancer associations were novel for one of the cancers. Bayesian models supported pleiotropic effects involving at least two cancers at 222/465 lead variants in 118/192 regions. Gene-level association analysis identified 13 shared susceptibility genes (P−6) in 13 regions not previously implicated in any of the four cancers and not uncovered by our variant-level meta-analysis. Several lead variants had opposite effects across cancers, including a cluster of such variants in the TP53 pathway. Fifty-four lead variants were associated with blood cell traits and suggested genetic overlaps with clonal hematopoiesis. Our study highlights the remarkable pervasiveness of pleiotropy across hormone-related cancers, further illuminating their shared genetic and mechanistic origins at variant- and gene-level resolution.

6000 Background: The role of secondary cytoreductive surgery in recurrent ovarian cancer (ROC) has been under debate for decades. A recent trial in unselected patients (pts) failed to show an OS benefit. Methods: Pts with ROC and 1st relapse after 6+ months (mos) platinum-free interval (TFIp) were eligible if they presented with a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery) and were prospectively randomized to second-line chemotherapy alone vs. cytoreductive surgery followed by the same chemotherapy; platinum combination therapy was recommended. OS was primary endpoint in this superiority trial. Results: 407pts were randomized 2010-2014. The TFIp exceeded 12 mos in 75% of pts. 206 pts were allocated to the surgery arm of whom finally 187 (91%) were operated. A complete resection was achieved in 75%; almost 90% in both arms received a platinum-containing second-line chemo. Primary endpoint analysis showed median OS of 53.7 mos with and 46.2 mos without surgery (HR 0.76, 95%CI 0.59-0.97, p=0.03); median PFS was 18.4 and 14 mos (HR: 0.66, 95%CI 0.54-0.82, p

Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For example, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P < 5 × 10−7). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.

Background:\ud State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin–paclitaxel or carboplatin–gemcitabine) or the most active non-bevacizumab regimen: carboplatin–pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin–pegylated liposomal doxorubicin combined with bevacizumab.\ud Methods:\ud This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m 2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m 2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251.\ud Findings:\ud Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin–pegylated liposomal doxorubicin–bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin–gemcitabine–bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3–21·7) in the experimental group and 11·3 months (8·0–18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7–14·2) in the experimental group versus 11·6 months (11·0–12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68–0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (

Purpose: Endometrioid ovarian carcinoma (ENOC) is generally associated with a more favorable prognosis compared with other ovarian carcinomas. Nonetheless, current patient treatment continues to follow a “one-size-fits-all” approach. Even though tumor staging offers stratification, personalized treatments remain elusive. As ENOC shares many clinical and molecular features with its endometrial counterpart, we sought to investigate The Cancer Genome Atlas–inspired endometrial carcinoma (EC) molecular subtyping in a cohort of ENOC. Experimental Design: IHC and mutation biomarkers were used to segregate 511 ENOC tumors into four EC-inspired molecular subtypes: low-risk POLE mutant (POLEmut), moderate-risk mismatch repair deficient (MMRd), high-risk p53 abnormal (p53abn), and moderate-risk with no specific molecular profile (NSMP). Survival analysis with established clinicopathologic and subtype-specific features was performed. Results: A total of 3.5% of cases were POLEmut, 13.7% MMRd, 9.6% p53abn, and 73.2% NSMP, each showing distinct outcomes (P < 0.001) and survival similar to observations in EC. Median OS was 18.1 years in NSMP, 12.3 years in MMRd, 4.7 years in p53abn, and not reached for POLEmut cases. Subtypes were independent of stage, grade, and residual disease in multivariate analysis. Conclusions: EC-inspired molecular classification provides independent prognostic information in ENOC. Our findings support investigating molecular subtype–specific management recommendations for patients with ENOC; for example, subtypes may provide guidance when fertility-sparing treatment is desired. Similarities between ENOC and EC suggest that patients with ENOC may benefit from management strategies applied to EC and the opportunity to study those in umbrella trials.

Background and importance Closed femoral neck fractures after low impact trauma in the elderly are often treated with hemiarthroplasty. In this setting, the literature with respect to prosthetic joint infection (PJI) is scarce. Aim and objectives The objectives of this study were to investigate the incidence of PJI and the impact of the number of perioperative antimicrobial prophylaxis (PAP) administrations. Furthermore, in this population, risk factors for PJI were identified. Material and methods In this retrospective monocentric study, medical files of elderly (≥75 years) trauma patients with closed femoral neck fractures and treated with a hemiarthroplasty, admitted between January 2006 and July 2017, were evaluated. Patient follow-up was 90 days. A Cox proportional hazards regression analysis with forward step was applied. Results were considered statistically significant if p Results A consecutive series of 745 patients (mean age 85±5 years, 221 (29.7%) men) were treated with a hemiarthroplasty. Within 90 postoperative days, 13 (1.7%) patients developed a PJI and 120 (16.1%) died due to reasons other than infection. The applied PAP regimens consisted of intravenous cefazoline or clindamycin. Single and repeated PAP administrations (every 8 hours) were observed. Patients who developed a PJI received a median of 1 (IQR 1–2) PAP administration, which was not significantly different compared with PAP administrations in patients that did not develop a PJI (1 (IQR 1–3)) (HR=0.236 (95% CI 0.032 – 1.745); p=0.157). Higher body weight (HR=1.05 (95% CI 1.008–1.094); p=0.020), systemic corticoid use (HR=4.790 (95% CI 1.275–17.997; p=0.020) and the need for transfer to the intensive care unit (ICU) for reasons other than infection (HR=8.692 (95% CI 2.353–32.106; p=0.001) were independently associated with the development of a PJI within 90 days. Conclusion and relevance In this fragile trauma population, the observed 1.7% PJI incidence within 90 days was low compared with the incidence rate of 3.4–4.5% in the literature. Our preliminary data showed that the number of PAP administrations did not influence the risk of PJI. Patients with a higher body weight, with systemic corticoid use or with postoperative ICU transfer should be monitored closely for infection. References and/or acknowledgements No conflict of interest.

BACKGROUND: In Study 19, maintenance monotherapy with olaparib significantly prolonged progression-free survival vs placebo in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer. METHODS: Study 19 was a randomised, placebo-controlled, Phase II trial enrolling 265 patients who had received at least two platinum-based chemotherapy regimens and were in complete or partial response to their most recent regimen. Patients were randomised to olaparib (capsules; 400 mg bid) or placebo. We present long-term safety and final mature overall survival (OS; 79% maturity) data, from the last data cut-off (9 May 2016). RESULTS: Thirty-two patients (24%) received maintenance olaparib for over 2 years; 15 (11%) did so for over 6 years. No new tolerability signals were identified with long-term treatment and adverse events were generally low grade. The incidence of discontinuations due to adverse events was low (6%). An apparent OS advantage was observed with olaparib vs placebo (hazard ratio 0.73, 95% confidence interval 0.55‒0.95, P = 0.02138) irrespective of BRCA1/2 mutation status, although the predefined threshold for statistical significance was not met. CONCLUSIONS: Study 19 showed a favourable final OS result irrespective of BRCA1/2 mutation status and unprecedented long-term benefit with maintenance olaparib for a subset of platinum-sensitive, recurrent ovarian cancer patients. ispartof: BRITISH JOURNAL OF CANCER vol:119 issue:9 pages:1075-1085 ispartof: location:England status: published

Aims Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets. Methods A randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48 h was conducted at two occasions 14 days apart in each participant after administration of 400 mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed-effects modelling. A questionnaire was used to assess palatability and acceptability. Results There was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94-108% of that of whole bedaquiline tablets; hence, the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell. Conclusions The bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat multidrug-resistant tuberculosis in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.

Backround The primary aim of this study was to investigate information needs and treatment preferences of patients with ovarian cancer, focusing especially on physician–patient relationship and treatment. Patients and methods A questionnaire was developed based on the experiences of the national German survey ‘Expression II’, and was provided to patients with ovarian cancer either at initial diagnosis or with recurrent disease via Internet (online-version) or as print-out-version. Results From December 2009 to October 2012, a total of 1830 patients with ovarian cancer from eight European countries (Austria, Belgium, France, Germany, Italy, Poland, Romania, Spain) participated, 902 (49.3%) after initial diagnosis and 731 (39.9%) with recurrent ovarian cancer. The median age was 58 years (range 17–89). Nearly all patients (96.2%) had experienced upfront surgery followed by first-line chemotherapy (91.8%). The majority of patients were satisfied with the completeness and comprehensibility of the explanation about the diagnosis and treatment options. The three most important aspects, identified by patients to improve the treatment for ovarian cancer included: ‘the therapy should not induce alopecia’ (42%), ‘there must be more done to counter fatigue’ (34.5%) and ‘the therapy should be more effective’ (29.7%). Out of 659 (36%) patients, who were offered participation in a clinical trial, 476 (26%) were included. Conclusion This study underlines the high need of patients with ovarian cancer for all details concerning treatment options irrespective of their cultural background, the stage of disease and the patient’s age. Increased information requirements regarding potential side effects and treatment alternatives were recorded. Besides the need for more effective therapy, alopecia and fatigue are the most important side effects of concern to patients.

Background: Health-related quality of life (HRQoL) was a secondary end point in AGO-OVAR 16, which randomized 940 patients with EOC after first-line chemotherapy to maintenance pazopanib (PZ) or placebo (P). Additional post hoc analyses were carried out to investigate additional patient-centered end points. Patients and methods: HRQoL was measured with EORTC-QLQ-C30, QLQ-OV28 and EQ-5D-3L. Pre-specified end points included mean differences in HRQoL between treatment arms. Exploratory analyses included quality-adjusted progression-free survival (QAPFS), impact of specific symptoms and progressive disease (PD) on HRQoL and time to second-line chemotherapy. The objective was to provide clinical perspective to the significant median PFS gain of 5.6 months with PZ. Results: There were statistically significant differences between PZ and P in QLQ-C30 global health status [5.5 points; 95% confidence interval (CI), 0.7-10.4, P = 0.024] from baseline to 25 months, but not EQ-5D-3L (0.018 points; 95% CI-0.033 to 0.069, P = 0.485). The impact of diarrhea was captured in QLQ-OV28 Abdominal/GI-Symptoms scale (8.1 points; 95% CI 3.6-12.5, P = 0.001). QAPFS was 386 days (95% CI 366-404 days) with PZ versus 359 days (95% CI 338-379 days) with placebo (P = 0.052). PD was associated with a decline in HRQoL (P

Objectives: In the Phase III PAOLA-1/ENGOT-ov25 (NCT02477644) trial, the addition of the PARP inhibitor olaparib to bevacizumab maintenance therapy led to a significant progression-free survival (PFS) benefit in patients with newly diagnosed advanced ovarian cancer (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.49-0.72), particularly in patients who were homologous recombination deficiency (HRD) positive, both including patients with BRCA1 and/or BRCA2 mutations (BRCAm; HR 0.33; 95% CI 0.25-0.45) and patients without a BRCAm (HR 0.43; 95% CI 0.28-0.66; Ray-Coquard et al. NEJM 2019). We explored the role of mutations in genes involved in homologous recombination repair (HRRm) excluding BRCAm as a predictive biomarker in patients with newly diagnosed advanced ovarian cancer who received olaparib + bevacizumab maintenance therapy in PAOLA-1. Methods: Patients with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer were randomized (2:1) to olaparib + bevacizumab maintenance or placebo + bevacizumab maintenance following response to platinum-based chemotherapy + bevacizumab. In an exploratory analysis, PFS was assessed in patients harboring a tumor mutation in a wide range of HRR gene panels (excluding tumor BRCAm [tBRCAm]): a panel with 13 pre-defined genes involved in HRR, an expanded panel with five additional genes involved in HRR, a restricted panel using five selected genes with the highest median genomic instability scores, and three published panels (Table). Tumors were analyzed using the Myriad myChoice HRD plus assay. Results: Of the 806 patients randomized in PAOLA-1, 235/806 (29.2%) had a tBRCAm. The percentage of patients harboring deleterious mutations involved in HRR excluding tBRCAm ranged from 3.7% to 9.8% depending on the HRR gene panel (Table). For each gene panel, the number of patients with an HRRm in each treatment arm and HRD status are shown in the Table. PFS using different gene panels for HRRm is summarized in the Table; using the 13-gene panel, in patients with an HRRm excluding tBRCAm (n=54), the HR for PFS was 0.95 (95% CI 0.49-1.94). Expansion of this panel to include five other genes (n=72) demonstrated an HR (95% CI) for PFS of 1.01 (0.55-1.95). Consistent results were seen in patients with HRRm excluding tBRCAm using the three other published HRR gene panels (Table). Conclusions: Acknowledging limitations of small subgroup sizes, HRRm (excluding tBRCAm) was not predictive of PFS benefit with maintenance olaparib in combination with bevacizumab, compared with bevacizumab alone, in PAOLA-1, regardless of the gene panel used. Mutation analysis using HRRm gene panels did not have utility beyond tBRCAm for selecting patients who may benefit from maintenance olaparib plus bevacizumab in PAOLA-1 and should not be considered a substitute for HRD determined by BRCA and/or genomic instability testing. Download : Download high-res image (309KB) Download : Download full-size image

Background Primary breast cancer (BC) patients with extensive axillary lymph-node involvement have a limited prognosis. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) trial compared intense dose-dense (idd) adjuvant chemotherapy with conventionally scheduled chemotherapy in high-risk BC patients. Here we report the final, 10-year follow-up analysis. Patients and methods Enrolment took place between December 1998 and April 2003. A total of 1284 patients with 4 or more involved axillary lymph nodes were randomly assigned to receive 3 courses each of idd sequential epirubicin, paclitaxel and cyclophosphamide (iddEPC) q2w or standard epirubicin/cyclophosphamide followed by paclitaxel (EC → P) q3w. Event-free survival (EFS) was the primary end point. Results A total of 658 patients were assigned to receive iddEPC and 626 patients were assigned to receive EC →P. The median duration of follow-up was 122 months. EFS was 47% (95% CI 43% to 52%) in the standard group and 56% (95% CI 52% to 60%) in the iddEPC group [hazard ratio (HR) 0.74, 95% CI 0.63–0.87; log-rank P = 0.00014, one-sided]. This benefit was independent of menopausal, hormone receptor or HER2 status. Ten-year overall survival (OS) was 59% (95% CI 55% to 63%) for patients in the standard group and 69% (95% CI 65% to 73%) for patients in the iddEPC group (HR = 0.72, 95% CI 0.60–0.87; log-rank P = 0.0007, two-sided). Nine versus two cases of secondary myeloid leukemia/myelodysplastic syndrome were observed in the iddEPC and the EC → P arm, respectively. Conclusion The previously reported OS benefit of iddEPC in comparison to conventionally dosed EC → P has been further increased and achieved an absolute difference of 10% after 10 years of follow-up.

We evaluated the prognostic impact of the age-adjusted Charlson Comorbidity Index (ACCI) on both postoperative morbidity and overall survival (OS) in patients with advanced epithelial ovarian cancer (EOC) treated at a tertiary gynecologic cancer center. Exploratory analysis of our prospectively documented tumor registry was performed. Data of all consecutive patients with stage IIIB–IV ovarian cancer who underwent primary cytoreductive surgery (PDS) from January 2000 to June 2016 were analyzed. Patients were divided into three groups, based on their ACCI: low (0–1), intermediate (2–3), and high (≥4), and postoperative surgical complications were graded according to the Clavien–Dindo classification (CDC). The Fisher’s exact test, log-rank test, and Cox regression models were used to investigate the predictive value of the ACCI on postoperative complications and OS. Overall, 793 consecutive patients were identified; 328 (41.4%) patients were categorized as low ACCI, 342 (43.1%) as intermediate ACCI, and 123 (15.5%) as high ACCI. A high ACCI was significantly associated with severe postoperative complications (CDC 3–5; odds ratio 3.27, 95% confidence interval 1.97–5.43, p

Background The effect of adherence to cardiac rehabilitation (CR) on outcome is not clear. Therefore, we aimed to assess the impact of drop-out for non-medical reasons of CR on event-free survival in coronary artery disease (CAD). Methods A total of 876 patients who attended CR after acute coronary syndrome (ACS), percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) were included. Drop-out was defined as attending ≤50% of the training sessions. A combined endpoint of all-cause mortality and rehospitalization for a cardiovascular event was used to specify event-free survival. Differences in clinical characteristics were assessed and parameters with p Results A total of 15% died or had a cardiovascular event during a median follow-up period of 33 months (interquartile range 24, 51). Overall, 17% dropped out before finishing half of the program. Patients who withdrew prematurely had a risk twice as high for a cardiovascular event or death (hazard ratio 1.92, 95% confidence interval 1.28–2.90) than those who attended more than half of the sessions. Both ACS (2.36, 1.47–3.58) and PCI (2.20, 1.22–3.96), as primary indicators for CR, were associated with an adverse outcome and also a prior history of chronic heart failure (CHF) remained negatively associated with event-free survival (3.67, 1.24–10.91). Finally, the presence of hyperlipidemia was independently related to a worse outcome (1.48, 1.02–2.16). Conclusions Drop-out for non-medical reasons was independently associated with a negative outcome in CAD. Therefore, underlying factors for drop-out should gain more attention in future research and should be taken into account when organizing CR.

This manuscript reports the consensus statements regarding recurrent ovarian cancer (ROC), reached at the fifth Ovarian Cancer Consensus Conference (OCCC), which was held in Tokyo, Japan, in November 2015. Three important questions were identified: (i) What are the subgroups for clinical trials in ROC? The historical definition of using platinum-free interval (PFI) to categorise patients as having platinum-sensitive/resistant disease was replaced by therapy-free interval (TFI). TFI can be broken down into TFIp (PFI), TFInp (non-PFI) and TFIb (biological agent-free interval). Additional criteria to consider include histology, BRCA mutation status, number/type of previous therapies, outcome of prior surgery and patient reported symptoms. (ii) What are the control arms for clinical trials in ROC? When platinum is considered the best option, the control arm should be a platinum-based therapy with or without an anti-angiogenic agent or a poly (ADP-ribose) polymerase (PARP) inhibitor. If platinum is not considered the best option, the control arm could include a non-platinum drug, either as single agent or in combination. (iii) What are the endpoints for clinical trials in ROC? Overall survival (OS) is the preferred endpoint for patient cohorts with an expected median OS < or = 12 months. Progression-free survival (PFS) is an alternative, and it is the preferred endpoint when the expected median OS is > 12 months. However, PFS alone should not be the only endpoint and must be supported by additional endpoints including pre-defined patient reported outcomes (PROs), time to second subsequent therapy (TSST), or time until definitive deterioration of quality of life (TUDD).

PURPOSE OF REVIEW: This review provides an overview of the current clinical standard in low-grade serous ovarian cancer (LGSOC). The available evidence for surgery and standard treatments is elaborated. In addition, we discuss recent findings and novel treatments for LGSOC. RECENT FINDINGS: Two large multicenter trials studying MEK inhibitors in LGSOC have been presented in the last year. Binimetinib demonstrated an activity in LGSOC, especially in KRAS-mutated disease. Trametinib was associated with an improved progression-free survival in relapsed LGSOC. Based on the current results, MEK inhibitors could be an alternative treatment for LGSOC. Surgery is an important step in the treatment of LGSOC. Hormonal therapy and bevacizumab can be beneficial, next to chemotherapy. Targeted treatments, such as the MEK-inhibitor trametinib, seem to be efficient and should be introduced into clinical practice. ispartof: CURRENT ONCOLOGY REPORTS vol:22 issue:1 ispartof: location:United States status: published

Background The second decade of 2000s is witnessing a new ovarian cancer (OC) paradigm shift thanks to the results recently obtained by a new class of targeted agents: the Poly(ADP-ribose)polymerase (PARP)-Inhibitors (PARPi). Aim of this meta-analysis is to analyze available results obtained with PARPi, administered alone or in combination with chemo- and/or target-therapies in terms of efficacy and safety for the treatment of recurrent and primary advanced OC. Methods On December 2019, all published phase II/III randomized clinical studies were systematically searched using the terms “[Parp-Inhibitor] AND [ovar*]”. Twelve phase II/III randomized controlled trials were identified, with a total number of 5171 patients included. Results Results demonstrated that PARPi account for a significant improvement of PFS in both recurrent and primary OC setting, independently from their administration schedule and independently from patients’ BRCA mutational status. Moreover, patients harboring a Homologous Recombination Deficiency (HRD) positive testing primary or recurrent OC progress significantly later after PARPi administration/association. Results also reported that PARPi increase the occurrence of severe (G3-G4) anemia. Furthermore, severe fatigue occurred more frequently among patients subjected to PARPi combined with chemotherapy and to PARPi plus Bevacizumab. Finally, a significant increase in severe high blood pressure occurrence was observed when PARPi was added to antiangiogenetics, compared to PARPi alone but a significant decrease in G3-G4 hypertension occurrence was found in PARPi plus bevacizumab users compared to Bevacizumab alone. Conclusions PARPi are a valid option for the treatment of both primary and relapsed OC patients, with a relative low incidence of severe side effects.

Background Borderline ovarian tumors (BOT) are considered a biological category with increased epithelial proliferation and cellular atypia in the absence of invasive growth. Since BOT occur often in young patients fertility sparing surgery (FSS) is an important issue. With this study we aimed to evaluate risk factors for relapses and fertility of patients after FSS. Methods Patients diagnosed with BOT and treated between 2000 and 2018 were included. External pathological review was done in all patients. FSS was performed after individual discussion and a complete surgical staging according to FIGO, without lymphadenectomy and with a waiver for preservation of uterus and one ovary. Results Among 352 Patients 80.2% had FIGO I and 63.9% had a serous BOT. Eighteen patients (5.1%) relapsed and 4 cases of malignant transformation were reported (1.1%). One patient of the latter died, all others have no evidence of disease. The overall recurrence-rate was 1.1% in FIGO-Stage I and 25.5% in FIGO III-IV (HR = 27; 95%-CI 7.7–95; p ≤.001). 95 patients underwent FSS. Thirteen (13.7%) of these patients relapsed, all as BOT. In multivariate analysis FIGO stages II-IV (HR = 27; 95%-CI: 8.1–102; p ≤.001) and FSS (HR = 12; 95%-CI: 2.9–47; p = .001) remained significant risk factors for recurrent disease. Pregnancy rate among forty-one patients attempting to conceive was 82.9%. 29 patients experienced at least one life-birth, in total 38 life-births were reported. Conclusion FSS in stage I is a safe procedure and life-birth-rates after FSS are high. More advanced FIGO stages have to be discussed individually and relapse rates have to be weighed against FSS. A central review of pathology, as we performed routinely, is mandatory and may have contributed to our low rate of invasive relapses.

Introduction/Background Predicting surgical outcome could improve individualizing treatment strategies for pts with AOC. Several earlier papers have proposed that debulking signatures using RNA expression analyses might help in this regard. Methodology FFPE tumor tissue of FIGO stage IIIC/IV pts of AGO-OVAR 11 were used to generate whole-exome data. Previously identified molecular signatures (MS), including TCGA molecular subtype and three other published MPG, were tested. We used state-of the art biostatistical approaches for analyses. A theoretical model using data of a tertiary gynecologic cancer center was implemented to evaluate the impact of predictive factors for RD not directly related to tumor biology on the performance of a debulking signature model that predicts RD status (RD0 and RD Results Of the 266 pts that met inclusion criteria, 104 (39.1%) underwent complete resection. Previously reported MPG did not predict RD in this cohort. Best Area under the Curve (AUC) was generated using LR: 0.53±0.04. Similarly, TCGA molecular subtypes (AUC=0.56±0.04), an independent de novo signature (AUC=0.51±0.04), and the total gene expression data set using all 21,000 genes (AUC=0.55±0.03) were not able to predict RD status. We identified reasons unrelated to tumor biology that serve as potential limiting factors in the ability to use MS for predicting RD. Even in a centre with a complete resection rate higher than 65% in all comers, a debulking signature which perfectly predicts RD (100%) would have a predictive performance of only AUC 0.83, due to UTB. Conclusion Previously identified MPG cannot be generalized. Our theoretical model showed that factors unrelated to tumor biology limit the ability to identify a molecular debulking signature for RD. UTB may be the main obstacle to predict surgical outcome in an all comer Population. Disclosure FH: Advisory board: Roche, Tesaro, Honoraria: AstraZeneca, Roche, Tesaro, Clovis, travel/accommodation expenses: PharmaMar; Tesaro; SK: none ; RT: none; AG: none; LU: none; CA: none; AB:none; CW: none; UC: Advisory board/honoraria: Roche, Astra Zeneca; JW:none; AB: none; SP: none; LH:none; SM: none; BA: Advisory board: Roche, Tesaro, Amgen; honoraria: Celgene, Clovis, Astra Zeneca; travel/accommodation expenses: PharmaMar; FH: Honoraria: Roche, Tesaro, Clovis, Astra Zeneca, PharmaMar travel/accommodations/expenses: Astra Zeneca, Pharmamar; SS: none; JS:; RK: Advisory Role: Medtronic, Roche, Teva; Honoraria: AstraZeneca, Intuitive Surgical, Prostrakan, RIEMSER; travel/accommodations/expenses: Cambridge Medical Robotics; CK: none; BS: none; IB: Honoraria: Roche Pharma, CLOVIS, Tesaro, AstraZeneca, Seattle Genetics, Amgen; PH: Advisory Board: Astra Zeneca, Roche, Tesaro, Lilly, Clovis, Immunogen, MSD/Merck; Honoraria: Astra Zeneca, Roche, Sotio, Tesaro, Stryker, ASCO, Zai Lab, MSD; Research funding (Inst): Astra Zeneca, Roche, GSK, Boehringer Ingelheim, Medac, DFG, European Union, DKH, Tesaro, Genmab; SD: none; BW: none; JP: Advisory board: Clovis, Roche, AstraZeneca, Tesaro; Honoraria: Roche, AstraZeneca, Tesaro, Amgen, Clovis, MSD; travel/accommodations/expenses: Roche, Tesaro; AdB: advisory board: Roche, Astra Zeneca, Tesaro, Clovis, Pfizer, Biocad, Genmab, Seattle Genetics, MSD; Honoraria: Roche, Astra Zeneca, Tesaro, Clovis, Pfizer, Biocad, Genmab, Seattle Genetics, MSD.

Introduction/Background The KEYNOTE-021 trial showed a beneficial effect of the combination of chemotherapy and immunotherapy in non-small-cell lung cancer, since then multiple trials have studied combination of chemotherapy and immunotherapy. However, not all combinations yield positive results, as we learned from the JAVELIN Ovarian 200 trial. Therefore, we need to gain insight into the effect of chemotherapy on the immune system in vivo. In the current study, we investigated the influence of first-line treatment for ovarian cancer on the immune system. Methodology Tumour biopsies and peripheral blood mononuclear cells were collected prospectively in 43 patients with epithelial ovarian cancer. Samples were taken at diagnosis, after cytoreductive surgery, after three courses of (neo-)adjuvant chemotherapy and at the end of their primary treatment. Immunostimulatory cells (Thelper cells (Th), Tcytotoxic cells (Tc), natural killer cells (NK)) and immunosuppressive cells (regulatory T cells (Treg), mMDSC (monocytic myeloid-derived suppressor cells), gMDSC (granulocytic MDSC)) were measured in blood using fluorescence activated cell sorting. Additionally, we checked for the expression of activation markes and immune checkpoint molecules on immune cells. On tumour biopsies, we performed immunohistochemistry for Tc and Treg. Results First-line treatment led to a significant increase in Tc in circulation (p Conclusion We observed a clear change in the immune phenotype of patients during first-line treatment for epithelial ovarian cancer. Chemotherapy led to an increase in the expression of immune checkpoint markers on Th, Tc and Treg in blood. Disclosure TB has reported research grant from Amgen, travel expenses from Amgen and Roche as well as advisory board membership for Tesaro. IV has performed contracted research for Oncoinvent AS and Genmab, received research grants from Amgen, Roche, Stichting tegen Kanker, received travel expenses from Takeda Oncology, Pharma Mar, Genmab, Roche, Astrazeneca, Tesaro, Clovis, Immunogen and is a advisory board member for Advaxis, Inc., Eisai Inc., MSD Belgium, Roche NV, Genmab, F. Hoffmann-La Roche Ltd, Pharmamar, Millennium Pharmaceuticals, Clovis Oncology Inc., AstraZeneca NV, Tesaro, Oncoinvent AS, Immunogen Inc and Sotio. CL, JC, GT, AVH, TV, A-SVR, AdB, DT and AC have no disclosures concerning this abstract.