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Mihaela Asp,1 Ingrida Mockute,1 Anna Måsbäck,2 Karina Liuba,1 Päivi Kannisto,1 Susanne Malander3 1Department of Obstetrics and Gynecology, Department of Clinical Science, Skåne University Hospital, Lund University, Lund, Sweden; 2Department of Clinical Genetics and Pathology, Department of Clinical Science, Skåne University Hospital, Lund University, Lund, Sweden; 3Department of Oncology and Pathology, Department of Clinical Science, Skåne University Hospital, Lund University, Lund, SwedenCorrespondence: Mihaela Asp, Department of Obstetrics and Gynecology, Department of Clinical Science, Skåne University Hospital, Lund University, Klinikgatan 12, Lund, 221 85, Sweden, Tel +46722434109, Email mihaela.asp@med.lu.sePurpose: Tru-cut biopsy is a minimally invasive technique used to obtain tissue samples for the diagnosis of tumors, especially in patients where primary surgery is not indicated. The aim of this study was to assess the adequacy, accuracy and safety of the tru-cut biopsy for diagnosis in gynecological cancer.Methods: A retrospective population-based review of 328 biopsies was conducted. The indications for tru-cut biopsies were diagnosis of primary tumors, metastases of gynecological and non-gynecological tumors, and suspected recurrences. A tissue sample was considered adequate when the quality/quality was sufficient to identify the subtype/origin of the tumor. Potential factors affecting adequacy were analyzed using logistic regressions analyses. Accuracy was defined as agreement between the diagnosis of the tru-cut biopsy and the postoperative histology. The therapy plan was registered, and the clinical applicability of the tru-cut biopsy was investigated. Complications within 30 days after the biopsy procedure were registered.Results: In total, 300 biopsies were identified as tru-cut biopsies. The overall adequacy was 86.3%, varying between 80.8% and 93.5%, respectively, when performed by a gynecological oncologist or a gynecologist with a subspecialty in ultrasound diagnosis. Sampling of a pelvic mass had a lower adequacy (81.6%) compared with sampling of the omentum (93.9%) or carcinomatosis (91.5%). The accuracy was 97.5%, and the complication rate was 1.3%.Conclusion: The tru-cut biopsy is a safe and reliable diagnostic method with a high accuracy and a good adequacy, depending on the site of the tissue sample, indications for the biopsy and the experience of the operator.Keywords: tru-cut biopsy, gynecological malignancy, ultrasound, adequacy, accuracy

Anna Norbeck,1,2 Mihaela Asp,1,2 Tobias Carlsson,3 Päivi Kannisto,1,2 Susanne Malander4,5 1Department of Obstetrics and Gynecology, Skåne University Hospital, Lund, Sweden; 2Department of Clinical Sciences, Division of Obstetrics and Gynecology, Lund University, Lund, Sweden; 3Regional Cancer Centre South, Region Skåne, Lund, Sweden; 4Department of Oncology, Skåne University Hospital, Lund, Sweden; 5Department of Clinical Sciences, Division of Oncology, Lund University, Lund, SwedenCorrespondence: Anna Norbeck, Kvinnoklinken Skånes Universitetessjukhus, Klinikgatan 12, Lund, 221 85, Sweden, Tel +4646172106, Email anna.norbeck@med.lu.sePurpose: The majority of women with ovarian cancer are diagnosed in late stages. Most women do have symptoms prior to diagnosis, sometimes several months before the diagnosis. The aim of this study was to evaluate the timeline from the first presentation of symptoms to a physician until there is a reasonable suspicion of cancer, among women diagnosed with advanced stage ovarian cancer. We wanted to investigate which symptoms were the most common and whether there are other factors affecting the time interval before the suspicion of cancer was confirmed.Patients and Methods: This was a retrospective population-based cohort study of women diagnosed with advanced ovarian cancer between January 1, 2017 and December 31, 2019 who were referred to Skane University Hospital Lund, Sweden. Data were collected from electronic medical records at Skane University Hospital. The time interval was recorded as the time from first physician consultation with predefined symptoms to the date when there was a reasonable suspicion of ovarian cancer. Data processing and statistical analysis were performed with the statistical software R.Results: Among the 249 patients included in this study, the median time interval from the first consultation to the reasonable suspicion of cancer was 24 days. The first consultation in specialized care had a 70% decrease in delay compared to primary care. Emergency consultations had a 52.2% decrease in time delay compared to planned consultations. Older age was associated with an increase in the geometric mean by 54.7%, comparing the first to the third quartile. The most common symptom was abdominal pain.Conclusion: The length of time interval from first presentation with symptoms relating to ovarian cancer to reasonable suspicion of cancer was associated with whether the consultation was in primary or specialized care, emergency or planned visit and the patient’s age.Keywords: epithelial ovarian cancer, routes to diagnosis, cancer patient pathway, time to diagnosis

Purpose Epithelial ovarian cancer is usually diagnosed in the advanced stages. To choose the best therapeutic approach, an accurate preoperative assessment of the tumour extent is crucial. This study aimed to determine whether the peritoneal cancer index (PCI), the amount of ascites, and the presence of cardiophrenic nodes (CPLNs) visualized by computed tomography (CT) can assess the tumour extent (S-PCI) and residual disease (RD) for advanced ovarian cancer (AOC) patients treated with upfront surgery. Methods In total, 118 AOC cases were included between January 2016 and December 2018 at Skåne University Hospital, Lund, Sweden. Linear regression and interclass correlation (ICC) analyses were used to determine the relationship between CT-PCI and S-PCI. The patients were stratified in complete cytoreductive surgery (CCS) with no RD or to non-CCS with RD of any size. The amount of ascites on CT (CT-ascites), CA-125 and the presence of radiological enlarged CPLNs (CT-CPLN) were analysed to evaluate their impact on estimating RD. Results CT-PCI correlated well with S-PCI (0.397; 95% CI 0.252–0.541; p p p = 0.000). The sensitivity, specificity, positive predictive value and negative predictive value were 58.5, 70.3, 52.2 and 75.4%, respectively. CT-ascites above 1000 ml predicted RD (OR 3.510 (1.298–9.491) p Conclusion CT is a reliable tool to assess the extent of the disease in advanced ovarian cancer. Higher CT-PCI scores and large volumes of ascites estimated on CT predicted RD of any size.

Objective Pre-clinical studies have identified marker- and tumor compartment-defined functionally distinct macrophage subsets. Our study analyzes marker-defined macrophage subsets in different tumor compartments of high-grade serous ovarian cancer (HGSC). Methods A discovery cohort (N = 113) was subjected to immunohistochemistry (IHC) analyses. CD68-positivity was confirmed for CD11c-, CD80- and CD163-positive cells. Subset-marker-positive cells were scored in the total tumor and in four tumor compartments. Correlation analyses investigated co-expression of subsets, relationship to CD8+ cells and survival associations. A validation cohort (N = 121) was used to confirm selected findings from the discovery cohort. Results CD163-positve cells was the most abundant subtype in all compartments. CD11c and CD163 subsets were strongly correlated with each other in stroma and epithelial areas, whereas CD80 and CD163 were correlated in epithelial areas. CD80 and CD11c in perivascular areas showed low correlations. Strong associations were detected between CD8 and CD80 in the tumor epithelium-dominated areas, and between CD8 and CD11c in stroma areas. High stromal CD11c density was associated with a longer median overall survival in the discovery cohort (HR 0.39; CI 95%, 0.23–0.68; p = 0.001) and in the validation cohort (HR 0.46; CI 95%, 0.22–0.93; p = 0.03). Conclusions Our study supports the existence of clinically relevant marker- and localization defined macrophage subsets in HGSC, which are independently regulated. Moreover, it suggests stromal CD11c as a novel prognostic marker in HGSC.

Ovarian Cancer (OC) constitute the eighth most common cancers among women worldwide. Surgery remains the cornerstone in the management of OC. Intraoperative frozen section (FS) diagnosis is widely used to decide the surgery course. We aimed to assess the reliability of intraoperative FS diagnosis for treatment planning of patients with suspected OC from a multidisciplinary perspective. The clinical consequences of reclassification and the multidisciplinary management of the therapy plan, is the secondary aim of this study. To our knowledge, this information is sparely investigated.A single-center, retrospective population-based study of patients who underwent surgery for suspected OC between 2018 and 2020. Histopathological outcomes were classified as benign, borderline, or malignant. The FS diagnosis was the diagnostic test, and the final histopathology report was the gold standard. Diagnostic capability for treatment planning was assessed, and modifications made possible by overall clinical knowledge were discussed.A total of 358 patients were identified, of whom 187 were included in the FS group. Overall accuracy was 89.8%, and 19 patients were reclassified; the malignancy grade of 15 tumors was underestimated. Prevalence, sensitivity, specificity, positive predictive value, and negative predictive value for invasive malignancies on FS were 54.0% (CI 46.6-61.3%), 88.1% (CI 80.2-93.7%), 98.8% (CI 93.7-99.9%), 98.9% (CI 92.7-99.8%), and 87.6% (CI 80.6-92.4%), respectively. Tumors incorrectly graded by FS tended to be of borderline-related.The reliability of the FS methodology was an accurate test to help perform appropriate surgery and plan swift oncological treatment. FS is a reliable method to diagnose invasive malignancies and benign pathology. The communication between the pathologist, surgeon, and medical oncologist is highly important for both intraoperative decision-making and postoperative patient care.

Residual disease (RD) after primary debulking surgery (PDS) is a prognostic factor for survival in advanced ovarian cancer (AOC). This study aimed to examine whether the tumor extent affects overall survival (OS) and progression-free survival (PFS) in AOC patients treated with PDS.A total of 118 patients treated with PDS were included. Age, ECOG score, AOC International Federation of Gynecology and Obstetrics (FIGO) stage, CA-125, RD, peritoneal cancer index (PCI), preoperative imaging (CT-PCI) and macroscopic visualization at the surgery start (S-PCI) were analyzed. Tumor extent was quantified using the PCI, and by CT-PCI and S-PCI. Cox regression, Kaplan-Meier and receiver operating curves (ROC) were performed for survival analyses.S-PCI correlated with both OS (1.067, 95%CI=1.018-1.119, p0.007) and PFS. Patients exhibiting S-PCI≥18.5, adjusted to age, performance status, and RD, had a two-fold risk of dying (HR=2.070, 95%CI=1.061-4.038, p=0.033) compared those with PCI18.5. CT-PCI correlated with OS in crude data (1.037, 95%CI=1.005-1.071, p=0.025), but this was not sustained in multivariate analyses. RD of any size doubled the risk of dying (2.177, 95%CI=1.235-3.838, p=0.007).The tumor extent at the beginning of surgery seemed to affect OS in patients with AOC, regardless of the extent of RD at the end of the surgery. PCI above 18.5 doubled the risk of dying of the disease. No difference in major complications was noted in the two groups of patients. CT-PCI seemed to play a prognostic role for PFS; however, it is still to be investigated as a prognostic factor for OS.

High-grade serous ovarian cancer (HGSOC) is the most common subtype of epithelial ovarian cancer and early detection is challenging. TP53 mutations are a hallmark of HGSOC and detection of these mutations in liquid-based Pap samples could provide a method for early diagnosis. Here we evaluate the use of IBSAFE, an ultra-sensitive droplet digital PCR (ddPCR) method, for detecting TP53 mutations in liquid-based Pap samples collected from fifteen women at the time of diagnosis (diagnostic samples) and/or up to seven years prior to diagnosis (archival samples). We analysed tumours for somatic TP53 mutations with next generation sequencing and were able to detect the corresponding mutations in diagnostic samples from six of eight women, while one patient harboured a germline mutation. We further detected a mutation in an archival sample obtained 20 months prior to the ovarian cancer diagnosis. The custom designed IBSAFE assays detected minor allele frequencies (MAFs) with very high assay sensitivity (MAF = 0.0068%) and were successful despite low DNA abundance (0.17–206.14 ng, median: 17.27 ng). These results provide support for further evaluation of archival liquid-based Pap samples for diagnostic purposes and demonstrate that ultra-sensitive ddPCR should be evaluated for ovarian cancer screening in high-risk groups or in the recurrent setting.

Overexpression of the receptor tyrosine kinase MET has been linked to poor survival in several cancer types, and MET has been suggested to interact with stem cell networks. In vitro studies have further suggested a possible benefit of a combined treatment using PARP and MET inhibitors. We used a tissue microarray (TMA) with 130 samples of advanced-stage high-grade serous fallopian tube/ovarian cancer (HGSC) to investigate the prognostic value of MET protein expression alone and in combination with the stem cell factor SOX2. The possible synergistic effects of a PARP and MET inhibitor treatment were evaluated in two cell lines with BRCA1 or BRCA2 deficiency and in their BRCA1/2-proficient counterparts. Patients with tumors positive for MET had worse overall survival (log-rank test, p = 0.015) compared to patients with MET-negative tumors. The prognostic role of MET was even more prominent in the subgroup of patients with SOX2-negative tumors (p = 0.0081). No synergistic effects of the combined treatment with PARP and MET inhibitors were found in the cell lines examined. We conclude that MET expression could be used as a marker for OS in HGSC and that stemness should be taken into consideration when evaluating the mechanisms of this effect.

6012 Background: We previously reported significantly improved progression-free survival (PFS) with the chemotherapy-free regimen of niraparib and bevacizumab compared to niraparib alone, in women with platinum-sensitive relapsed ovarian cancer (PSROC), regardless of homologous recombination deficiency (HRD) status (MyChoice HRD), duration of chemotherapy-free interval (CFI) and number of previous lines of therapy (Mirza MR et al, Lancet Oncol 2019). We now present the updated PFS, overall survival (OS) and other efficacy and safety endpoints. Methods: In this randomized, open-label, phase 2 study, women with measurable/evaluable, high-grade serous or endometrioid PSROC were randomized to niraparib 300mg once daily or the combination of niraparib 300mg once daily and bevacizumab 15mg/kg IV every 3 weeks until disease progression (1:1 randomization). The primary endpoint was PFS. Stratification was according to HRD status and CFI (6-12months (mo) vs. > 12mo). First-line maintenance bevacizumab was permitted. Results: Of 97 enrolled patients, 48 were randomized to niraparib monotherapy and 49 to the chemotherapy-free combination. The combined treatment significantly improved PFS compared to niraparib alone: updated median PFS 12.5 mo vs. 5.5 mo; hazard ratio (HR) adjusted for stratification factors 0.34; 95% confidence interval (CI) [0.21 to 0.55]; P < 0.0001. Preplanned exploratory subgroup analyses: patients with HRD-positive tumors (n = 54) HR 0.41 (CI, 0.23-0.76); HRD-negative disease (n = 43) HR, 0.40 (CI, 0.20-0.79); Time to First Subsequent Therapy (TFST) (n=97) HR, 0.4 (CI, 0.25-0.64); PFS2 (n=97) HR 0.55 (CI, 0.35-0.88); Time to Second Subsequent Therapy (TSST) (n=97) HR, 0.56 (CI, 0.35-0.90); OS (49 events only) HR, 0.77 (CI, 0.42-1.41). There was no difference in treatment-emergent grade 3-4 adverse events except for the rate of hypertension (22.9% vs. 0%) and neutropenia (8.3% vs. 2.0%). Patient-reported outcomes measured using EORTC QLQ-C30 and OV28 were similar for both treatment arms. Conclusions: Updated PFS consistently demonstrates that the niraparib-bevacizumab combination had clinically and statistically meaningful activity in PSROC. This phase 2 study was not powered to detect differences in OS or any other efficacy endpoints however TFST, PFS2 & TSST are significantly improved while there is a trend towards OS improvement with niraparib-bevacizumab combination. Clinical trial information: NCT02354131.

Summary Cancer is mostly incurable when diagnosed at a metastatic stage, making its early detection via blood proteins of immense clinical interest. Proteomic changes in tumor tissue may lead to changes detectable in the protein composition of circulating blood plasma. Using a proteomic workflow combining N-glycosite enrichment and SWATH mass spectrometry, we generate a data resource of 284 blood samples derived from patients with different types of localized-stage carcinomas and from matched controls. We observe whether the changes in the patient's plasma are specific to a particular carcinoma or represent a generic signature of proteins modified uniformly in a common, systemic response to many cancers. A quantitative comparison of the resulting N-glycosite profiles discovers that proteins related to blood platelets are common to several cancers (e.g., THBS1), whereas others are highly cancer-type specific. Available proteomics data, including a SWATH library to study N-glycoproteins, will facilitate follow-up biomarker research into early cancer detection.

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

PURPOSE In the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274 ), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer who had a response to their last platinum-based chemotherapy. The objective of the study was to assess the clinical benefit and patient-reported outcomes in patients who had a partial response (PR) and complete response (CR) to their last platinum-based therapy. PATIENTS AND METHODS A total of 553 patients were enrolled in the trial. Of 203 patients with a germline BRCA mutation (g BRCAmut), 99 had a PR and 104 had a CR to their last platinum-based therapy; of 350 patients without a confirmed g BRCAmut (non–g BRCAmut), 173 had a PR and 177 had a CR. Post hoc analyses were carried out to evaluate safety and the risk of progression in these patients according to g BRCAmut status and response to their last platinum-based therapy. Ovarian cancer–specific symptoms and quality of life were assessed using the Functional Assessment of Cancer Therapy–Ovarian Symptom Index. RESULTS Progression-free survival was improved in patients treated with niraparib compared with placebo in both the g BRCAmut cohort (PR: hazard ratio [HR], 0.24; 95% CI, 0.131 to 0.441; P < .0001; CR: HR, 0.30; 95% CI, 0.160 to 0.546; P < .0001) and the non–g BRCAmut cohort (PR: HR, 0.35; 95% CI, 0.230 to 0.532; P < .0001; CR: HR, 0.58; 95% CI, 0.383 to 0.868; P = .0082). The incidence of any-grade and grade 3 or greater adverse events was manageable. No meaningful differences were observed between niraparib and placebo in PR and CR subgroups with respect to patient-reported outcomes. CONCLUSION Patients achieved clinical benefit from maintenance treatment with niraparib regardless of response to the last platinum-based therapy.

The response rate to checkpoint inhibitors for women with high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum (HGSC) is modest, and development of predictive biomarkers is needed. The main focus has been on tumor cell PD-L1 expression, but its assessment alone is insufficient for patient selection in most malignancies. We mapped the presence of macrophages (CD68 and CD163) and lymphocytes (CD3) located within the tumor epithelium, the cell type–specific expression of PD-L1 and PD-1, and their impact on 5-year overall survival (OS) in a consecutive cohort of 130 women diagnosed with advanced HGSC between 2011 and 2015. PD-L1 was expressed mainly by macrophages (not by tumor cells) and PD-1 by lymphocytes. Women with higher CD3, PD-L1, and PD-1 expression had improved OS (P = 0.03,P = 0.007, andP = 0.02, respectively). In the external data set (203 women), high expression ofCD274(encoding PD-L1) was associated with improved OS (P = 0.03), in accordance with our results. Furthermore, higher CD163 expression was associated with better outcome in women with no residual tumor after primary surgery (P = 0.02). Thus, women with greater lymphocyte tumor infiltration had better outcome and PD-L1/PD-1 expression, regardless of PD-1/PD-L1 being markers for immune suppressive pathways, conferred a survival benefit in our cohort. Our results highlight that tumor immunity may be harnessed in subsets of HGSC.

BACKGROUND: Platinum-based chemotherapy is the foundation of treatment for platinum-sensitive recurrent ovarian cancer, but has substantial toxicity. Bevacizumab and maintenance poly(ADP-ribose) polymerase (PARP) inhibitors both significantly improve efficacy versus standard therapy, primarily in terms of progression-free survival, and offer the potential for chemotherapy-free treatment. AVANOVA2 compared niraparib and bevacizumab versus niraparib alone as definitive treatment for platinum-sensitive recurrent ovarian cancer.METHODS: This open-label, randomised, phase 2, superiority trial in 15 university hospitals in Denmark, Sweden, Finland, Norway, and the USA enrolled women aged 18 years or older with measurable or evaluable high-grade serous or endometrioid platinum-sensitive recurrent ovarian cancer. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, and had to have previously received platinum-containing therapy for primary disease but ≤1 prior non-platinum-containing regimen for recurrent disease. Previous treatment with bevacizumab or first-line maintenance PARP inhibitors was permitted. Eligible patients were randomly assigned 1:1 (by random permuted blocks with block sizes of two and four, no masking), stratified by homologous recombination deficiency status and chemotherapy-free interval, to receive once-daily oral niraparib 300 mg alone or with intravenous bevacizumab 15 mg/kg once every 3 weeks until disease progression. The primary endpoint was progression-free survival, assessed by the investigators in the intention-to-treat population after events in at least 62 patients. Safety was analysed in all patients who received at least one dose of study drug. This ongoing trial is registered with ClinicalTrials.gov, number NCT02354131.FINDINGS: Between May 23, 2016, and March 6, 2017, 97 patients were enrolled and randomly assigned: 48 to niraparib plus bevacizumab and 49 to single-agent niraparib. Median follow-up was 16·9 months (IQR 15·4-20·9). Niraparib plus bevacizumab significantly improved progression-free survival compared with niraparib alone (median progression-free survival 11·9 months [95% CI 8·5-16·7] vs 5·5 months [3·8-6·3], respectively; adjusted hazard ratio [HR] 0·35 [95% CI 0·21-0·57], pINTERPRETATION: The efficacy observed with this chemotherapy-free combination of approved agents in women with platinum-sensitive recurrent ovarian cancer warrants further evaluation. A randomised phase 3 trial investigating niraparib plus bevacizumab versus chemotherapy plus bevacizumab in platinum-sensitive recurrent ovarian cancer is planned.FUNDING: Nordic Society of Gynaecological Oncology and Tesaro.

BACKGROUND: Combining poly(ADP-ribose) polymerase (PARP) inhibitors with antiangiogenic agents appeared to enhance activity vs PARP inhibitors alone in a randomized phase II trial.MATERIALS AND METHODS: In AVANOVA (NCT02354131) part 1, patients with measurable/evaluable high-grade serous/endometrioid platinum-sensitive ovarian cancer received bevacizumab 15 mg/kg every 21 days with escalating doses of niraparib capsules (100, 200, or 300 mg daily) in a 3 + 3 dose-escalation design. Primary objectives were to evaluate safety and tolerability and to determine the recommended phase II dose (RP2D).RESULTS: Three of 12 enrolled patients had germline BRCA2 mutations. In cycle 1, nine patients experienced grade 3 toxicities: five with hypertension, three with anemia, and one with thrombocytopenia. There was one dose-limiting toxicity (grade 4 thrombocytopenia with niraparib 300 mg), thus the RP2D was bevacizumab 15 mg/kg with niraparib 300 mg. The response rate was 50%; disease was stabilized in a further 42%. Median progression-free survival was 11.6 (95% confidence interval 8.4-20.1) months. Niraparib pharmacokinetics were consistent with historical single-agent data. Overlapping exposure was observed across the dose ranges tested on days 1 and 21.CONCLUSIONS: There was one dose-limiting toxicity; other adverse events were typical PARP inhibitor and antiangiogenic class effects. Niraparib-bevacizumab showed promising activity; Part 2 (vs bevacizumab) was recently reported and phase III comparison with standard-of-care therapy is planned.

Protein biomarkers for epithelial ovarian cancer are critical for the early detection of the cancer to improve patient prognosis and for the clinical management of the disease to monitor treatment response and to detect recurrences. Unfortunately, the discovery of protein biomarkers is hampered by the limited availability of reliable and sensitive assays needed for the reproducible quantification of proteins in complex biological matrices such as blood plasma. In recent years, targeted mass spectrometry, exemplified by selected reaction monitoring (SRM) has emerged as a method, capable of overcoming this limitation. Here, we present a comprehensive SRM-based strategy for developing plasma-based protein biomarkers for epithelial ovarian cancer and illustrate how the SRM platform, when combined with rigorous experimental design and statistical analysis, can result in detection of predictive analytes. Our biomarker development strategy first involved a discovery-driven proteomic effort to derive potential N-glycoprotein biomarker candidates for plasma-based detection of human ovarian cancer from a genetically engineered mouse model of endometrioid ovarian cancer, which accurately recapitulates the human disease. Next, 65 candidate markers selected from proteins of different abundance in the discovery dataset were reproducibly quantified with SRM assays across a large cohort of over 200 plasma samples from ovarian cancer patients and healthy controls. Finally, these measurements were used to derive a 5-protein signature for distinguishing individuals with epithelial ovarian cancer from healthy controls. The sensitivity of the candidate biomarker signature in combination with CA125 ELISA-based measurements currently used in clinic, exceeded that of CA125 ELISA-based measurements alone. The SRM-based strategy in this study is broadly applicable. It can be used in any study that requires accurate and reproducible quantification of selected proteins in a high-throughput and multiplexed fashion.

Aim of the study: Endocrine treatment (ET) is an alternative as salvage therapy in epithelial ovarian cancer (EOC) but the usage in routine care is unknown. We evaluated the treatment patterns and outcome of patients receiving ET for EOC in the Southeast medical region in Sweden. Method: Patients were identified through the population-based Southeast Quality Registry for gynaecological cancer. Inclusion criteria were: age ≥18 years, histologically verified EOC diagnosed 2000–2013, ET for ≥4 weeks. Coverage compared with the Swedish National Cancer Registry was 100%. Data extracted from medical records was collected by means of a study-specific Case Report Form. Last date of follow-up was February 1st, 2018. All statistics were descriptive. Results: Altogether 248 (18%) of 1414 patients were treated with ET. Most (49%) had received only one, and 34% two previous lines of chemotherapy. Time from last chemotherapy to ET was 4 months, range 0–55months. The reason for initiating ET was tumor progression (66%), chemotherapy related toxicity (29%) and maintenance (4%). Tamoxifen was prescribed in 94% of cases. Best response was partial (< 5%) and stable disease (50%). No patient had a complete response. 194 (78%) patients received subsequent chemotherapy, of these 27% had 3–7 lines of chemotherapy. Duration of ET was a median 4 months (range 1–80 months). Median time from ET to subsequent chemotherapy was 5 months (range 0–79). The median overall survival was 45 months (range 9–173). Conclusion: In the Southeast region of Sweden, endocrine treatment for EOC was prescribed inconsistently and in various settings, usually initiated by a rising CA-125 level. Poorer documentation and irregular tumor response assessment were observed for endocrine treatment compared to chemotherapy.

Summary Background Quality of life (QOL) has become an important complementary endpoint in cancer clinical studies alongside more traditional assessments (eg, tumour response, progression-free survival, overall survival). Niraparib maintenance treatment has been shown to significantly improve progression-free survival in patients with recurrent ovarian cancer. We aimed to assess whether the benefits of extending progression-free survival are offset by treatment-associated toxic effects that affect QOL. Methods The ENGOT-OV16/NOVA trial was a multicentre, double-blind, phase 3, randomised controlled trial done in 107 study sites in the USA, Canada, Europe, and Israel. Patients with recurrent ovarian cancer who were in response to their last platinum-based chemotherapy were randomly assigned (2:1) to receive either niraparib (300 mg once daily) as a maintenance treatment or placebo. Randomisation was stratified based on time to progression after the penultimate platinum-based regimen, previous use of bevacizumab, and best response (complete or partial) to the last platinum-based regimen with permuted-block randomisation (six in each block) using an interactive web response system. The trial enrolled two independent cohorts on the basis of germline BRCA (g BRCA ) mutation status (determined by BRAC Analysis Testing, Myriad Genetics, Salt Lake City, UT, USA). The primary endpoint of the trial was progression-free survival, and has already been reported. In this study, we assessed patient-reported outcomes (PROs) in the intention-to-treat population using the Functional Assessment of Cancer Therapy–Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L). We collected PROs from trial entry every 8 weeks for the first 14 cycles and every 12 weeks thereafter. If a patient discontinued, we collected PROs at discontinuation and during a postprogression visit 8 weeks (plus or minus 2 weeks) later. We assessed the effect of haematological toxic effects on QOL with disutility analyses of the most common grade 3–4 adverse events (thrombocytopenia, anaemia, and neutropenia) using a mixed model with histology, region, previous treatment, age, planned treatment, and baseline score as covariates. This study is registered with ClinicalTrials.gov, number NCT01847274. Findings Between Aug 28, 2013, and June 1, 2015, 553 patients were enrolled and randomly assigned to receive niraparib (n=138 in the g BRCA mut cohort, n=234 in the non-g BRCA mut cohort) or placebo (n=65 in the g BRCA mut cohort, n=116 in the non-g BRCA mut cohort). The mean FOSI score at baseline was similar between the two groups (range between 25·0–25·6 in the two groups). Overall QOL scores remained stable during the treatment and preprogression period in the niraparib group; no significant differences were observed between the niraparib and placebo group, and preprogression EQ-5D-5L scores were similar between the two groups in both cohorts (0·838 [0·0097] in the niraparib group vs 0·834 [0·0173] in the placebo group in the g BRCA mut cohort; and 0·833 [0·0077] in the niraparib group vs 0·815 [0·0122] in the placebo group in the non-g BRCA mut cohort). The most common adverse events reported at screening (baseline) were lack of energy (425 [79%]; 97 [18%] reporting severe lack of energy), pain (236 [44%]), and nausea (118 [22%]). All symptoms, except nausea, either remained stable or improved over time in the niraparib group. The most common grade 3 or 4 toxicities observed in the niraparib group were haematological in nature: thrombocytopenia (124 [34%] of 367 patients), anaemia (93 [25%]), and neutropenia (72 [20%]); disutility analyses showed no significant QOL impairment associated with these toxic effects. Interpretation These PRO data suggest that women who receive niraparib as maintenance treatment for recurrent ovarian cancer after responding to platinum treatment are able to maintain QOL during their treatment when compared with placebo. Funding TESARO.

Background and Aims: Although most ovarian cancers express estrogen (ER), progesterone (PR), and androgen (AR) receptors, they are currently not applied in clinical decision making. We explored the prognostic impact of sex steroid hormone receptor protein and mRNA expression on survival in epithelial ovarian cancer. Methods: Immunohistochemical stainings for ERα, ERβ, PR, and AR were assessed in relation to survival in 118 serous and endometrioid ovarian cancers. Expression of the genes encoding the four receptors was studied in relation to prognosis in the molecular subtypes of ovarian cancer in an independent data set, hypothesizing that the expression levels and prognostic impact may differ between the subtypes. Results: Expression of PR or AR protein was associated with improved 5-year progression-free (P=.001 for both) and overall survival (P

Supplemental Digital Content is available in the text., The tight junction protein claudin-4 has been reported to be overexpressed in advanced ovarian cancer. We investigated the prognostic significance of claudin-4 overexpression and whether claudin-4 expression could predict platinum response in primary ovarian carcinoma (OC). Claudin-4 expression was evaluated by immunohistochemistry in a tissue microarray of 140 OCs. Multivariable Cox-regression models were used to assess the effect of claudin-4 overexpression on progression-free survival and overall survival (OS). Kaplan-Meier survival analyses and the logrank test were performed comparing claudin-4 high and low groups. The association between claudin-4 expression and platinum resistance was assessed using risk ratios and the Pearson χ2 test. A dataset of >1500 epithelial ovarian cancers was used to study the association between CLDN4 mRNA and survival. Of 140 evaluable cases, 71 (51%) displayed high claudin-4 expression. Claudin-4 overexpression predicted shorter 5-yr progression-free survival and OS in univariable analyses [hazard ratio (HR)=1.6 (1.1–2.5), P=0.020 and HR=1.6 (1.0–2.4), P=0.041, respectively]. Hazard of relapse was similar [HR=1.5 (1.0–2.4)] after adjustment for age, stage, type, and BRCA1/2 status in a multivariable analysis, but the evidence was slightly weaker (P=0.076). Validation in an external cohort confirmed the association between high expression of CLDN4 and poor 10-yr OS [HR=1.3 (1.1–1.5), P

Ovarian cancer develops due to a complex interplay between hereditary and environmental factors. Although often described as one disease, ovarian cancer is actually a group of distinct tumor types. Recent research has indicated that a large percentage of ovarian cancers may originate from the fallopian tube epithelium. Although most cancers develop in patients without a known hereditary syndrome, it is clear that the number of familial cancers is larger than previously supposed. The two most common hereditary syndromes where ovarian cancer can develop are hereditary breast ovarian cancer syndrome (HBOC) and Lynch syndrome.

At least one of ten patients with ovarian cancer is estimated to develop their tumor because of heredity with the breast and ovarian cancer syndrome due to mutations in the BRCA1 and BRCA2 genes and hereditary nonpolyposis colorectal cancer (HNPCC) being the major genetic causes. Cancer at young age is a hallmark of heredity, and ovarian cancers associated with HNPCC have been demonstrated to develop at a particularly early age. We used the Swedish Cancer Registry to identify a population-based series of 98 invasive epithelial ovarian cancers that developed before 40 years. Mucinous and endometrioid cancers were overrepresented and were diagnosed in 27% and 16% of the tumors, respectively. Immunostaining using antibodies against MLH1, PMS2, MSH2, and MSH6 was used to assess the mismatch-repair status and revealed loss of expression of MLH1/PMS2 in two cases, loss of MSH2/MSH6 in one case, and loss of MSH6 only in three tumors. A microsatellite instability-high phenotype was verified in five of six tumors. Based on the identified mutations and family history of cancer, several of these individuals are likely to be affected by HNPCC. We conclude that although the causes of the vast majority of epithelial ovarian cancer at young age are unknown, HNPCC should be considered because of the high risk of metachronous colorectal cancer in the individual and the possibility of preventing additional cancers in the family through control programs.

Objective. Ovarian cancer has one of the highest fractions of hereditary cases. The hereditary breast and ovarian cancer syndrome, primarily due to mutations in BRCA1 and BRCA2, is the main cause of heredity, but also the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome confers an increased risk of ovarian cancer. In order to clarify the contribution of HNPCC to the development of ovarian cancer, we collected data on family history of cancer and characterized MMR function in a consecutive series of 128 tumors unselected for age at diagnosis and previously characterized for BRCA gene mutations. Methods. Expression of the MMR proteins MLH1 PMS2, MSH2, and MSH6 was analyzed by immunohistochemistry using tissue microarray sections. Tumors with reduced staining or loss of staining were also analyzed for microsatellite instability (MSI). Results. Loss of MMR protein expression was identified in 3 ovarian cancers, all of which had a MSI-high phenotype. DNA sequence analysis revealed disease-causing germline mutations (deletions of exons 4-6 in MLHI and a 1-nucleotide deletion in exon 5 of MSH6) in two patients diagnosed at ages 40 and 49 years, both of whom had family histories suggestive of HNPCC. The genetic defect in the third case, which was a 47-year old woman without knowledge about her family history with loss of MLH1/PMS2 expression in the tumor tissue, remains elusive. A family history suggestive of HNPCC was identified in an additional case, but this tumor showed normal, retained MMR protein expression and a microsatellite stable phenotype. Conclusions. About 2% of ovarian cancer is caused by germline mutations in the MMR-genes, a minor proportion as compared to the contribution of the BRCA-genes (11% in the present series). However, identification of HNPCC patients is important since it allows inclusion of high-risk individuals into control programs aimed at preventing the more frequent colorectal and endometrial cancers. Tumors within the HNPCC-spectrum should therefore be included when recording a family history of cancer among patients diagnosed with ovarian cancer. (c) 2005 Elsevier Inc. All rights reserved. (Less)

At least 10% of all ovarian cancers are estimated to have a hereditary background. Hereditary breast-ovarian cancer (HBOC) due to mutations in the BRCA genes is a major cause of hereditary ovarian cancer, although its frequency and relationship to age and family history in unselected series of ovarian cancers is not completely known. We report here the results of a full mutational screening analysis for germ line BRCA1 and BRCA2 mutations in 161 patients with invasive epithelial ovarian carcinomas. Age at diagnosis ranged from 22 to 82 years (mean 59 years). Deleterious (frame-shift, nonsense and missense) mutations were detected in 13/161 (8%) of the patients and affected BRCA1 in 12 cases and BRCA2 in one case. Four additional missense variants (one in BRCA1 and three in BRCA2) with a possible association with an increased risk ovarian cancer were revealed, resulting in a total frequency of BRCA gene alterations of 17/161 (11%). The 13 patients with deleterious mutations had a mean age of 57 years (range 41-76 years) and only three of these patients were below 50 years of age. A family history of at least one breast cancer and/or ovarian cancer was reported in all but 1 of the patients with BRCA mutations compared with only 24% of patients without mutations. Our findings in this prospective study confirm approximately 1 in 10 patients with ovarian cancer carry a germ line BRCA gene mutation associated with HBOC, and also indicate that a large number of these patients are over 50 years of age at diagnosis.

Background: We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma.Methods: We performed an open-label one-arm, two-stage, phase II study of 25 mg of oral exemestane in 51 patients with advanced (FIGO stage III-IV) or relapsed endometrioid endometrial cancer. Patients were stratified into subsets of estrogen receptor (ER) positive and ER negative patients.Results: Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual. In the ER positive patients, we observed an overall response rate of 10%, and a lack of progression after 6 months in 35% of the patients. No responses were registered in the ER negative patients, and all had progressive disease within 6 months. For the total group of patients, the median progression free survival (PFS) was 3.1 months (95% CI: 2.0-4.1). In the ER positive patients the median PFS was 3.8 months (95% CI: 0.7-6.9) and in the ER negative patients it was 2.6 months (95% CI: 2.1-3-1). In the ER positive patients the median overall survival (OS) time was 13.3 months (95% CI: 7.7-18.9), in the ER negative patients the corresponding numbers were 6.1 months (95% CI: 4.1-8.2). Treatment with exemestane was well tolerated.Conclusion: Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and lack of progression after 6 months in 35% of the patients. Trial registration: Trial identification number (Clinical Trials.gov): NCT01965080.Nordic Society of Gynecological Oncology: NSGO-EC-0302.EudraCT number: 2004-001103-35.

ObjectiveTranscriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer.MethodsGlobal gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset.Results5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged.ConclusionsThese data link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, and suggest that biomarkers and targeted therapies may overlap between these tumor subsets. The link between benign and borderline ovarian cancer and luminal breast cancer may indicate endocrine responsiveness in a subset of ovarian cancers.

Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic ovarian cancers point to alternative preferred tumorigenic routes and suggest that genetic discriminators may be relevant for molecular diagnostics and targeted therapeutics. Electronic supplementary material The online version of this article (doi:10.1007/s10689-014-9728-1) contains supplementary material, which is available to authorized users.

Background. Cerebral metastasis secondary to ovarian cancer is a rare phenomenon. While no clear relationship to known prognostic factors is found, others suggest this as a biologically diverse behavior of ovarian cancer. Cases. In a pilot study, 37 invasive epithelial ovarian cancer samples were analyzed to detect the frequency of BRCA1/BRCA2 mutations in the south of Sweden (results published). A retrospective follow-up revealed that 2 of these (2/37; 5.4%) patients developed central nervous system metastases during the course of their disease. Both patients had advanced surgical stage disease at the time of diagnosis, with histopathological serous type tumors that were negative for estrogen and progesterone receptors. One of these patients carried a germline BRCA1 mutation, whereas a somatic BRCA1 mutation was identified in the other patient. Conclusions. To the best of our knowledge the molecular genetic profile of these tumors is not found in the literature and it is suggested that such analyses could provide some insight for a better understanding of this rare phenomenon.

Pre-neoplastic p53 signature containing lesions, termed serous tubal intraepithelial carcinomas (STICs), have been identified in the fimbriae of women predisposed to ovarian cancer and in patients with sporadic high grade serous ovarian cancer (HGSOC). These findings instigated the theory that HGSOC originates from fallopian tube epithelium (FTE) and not from ovarian surface epithelium (OSE), and has now become an accepted paradigm for HGSOC genesis. However, only few studies have investigated the stem cell niche in the human fallopian tube. Instead, most research on ovarian cancer stem cells has focused on cells isolated from primary ovarian tumors or cell lines. In this study we performed immunohistochemistry to explore the presence of putative ovarian cancer stem cells in fallopian tubes from women who had undergone a risk reducing salpingo-oophorectomy (RRSO) due to a germline BRCA1/2 mutation and/or strong family history. Sections of frozen tissue from 14 RRSO patients (10 BRCA1/2 mutation carriers, 4 tested negative for BRCA1/2 mutations) were used in immunohistochemistry for p53 and the proposed cancer stem cell markers ALDH1, CD44, CD117, CD133, LGR5 and SOX2. Presence of a p53 signature (>12 consecutive cell nuclei in normal appearing FTE) was observed in 1 of 10 BRCA1/2 mutation carriers and none of the non-carriers. ALDH1 and CD44 positive staining of varying intensity was found in both FTE cells and stromal cells within the fallopian tube mucosa in all cases. On the other hand, no CD117 positive epithelial cells were observed in any of the samples, though strongly stained CD117+ mast cells were present in all sections. Most FTE cells were weakly positive for CD133 in all sections, while only one case showed positive LGR5 staining of FTE cells. Finally, SOX2 positive FTE cells were found in all samples. In most cases, the fimbriated end of the fallopian tube harbored more SOX2 positive cells than the more proximal end. This is an initial attempt at visualizing proposed ovarian cancer stem cells in the fallopian tubes of women predisposed to developing HGSOC. Further research is needed to validate the significance of these findings, including investigating additional markers, testing different antibodies and performing multiple labeling experiments. Based on the currently prevailing theory that HGSOC originates from STICs in the fimbriated end of the fallopian tube, we find SOX2 to be the most promising candidate for further investigations, since SOX2 was the only marker found to be differentially expressed throughout the fallopian tube. Elucidating the cell of origin and etiology of HGSOC has important implications for early detection and preventive therapeutic approaches. Citation Format: Anna Ebbesson, Susanne Malander, Päivi Kannisto, Anita Ringberg, Anna Måsbäck, Ingrid A. Hedenfalk. Expression of putative cancer stem cell markers in fallopian tube epithelium from women at increased risk of developing high-grade serous ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3348.

Objective: Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype. Despite relatively clear clinical features, OCCCs can be difficult to distinguish morphologically from other epithelial ovarian cancers. OCCC gene expression signatures capturing not only the morphology but also the biology of this tumor subtype have been described, and a previous study using comparative genomic hybridization showed that OCCCs are indeed heterogeneous. Still, only a few genes have been analyzed using gene sequencing techniques. In the present study we aimed to further characterize OCCCs and their histotype specific genetic changes using targeted sequencing of 60 well-established cancer genes. Increased knowledge about genetic aberrations in OCCCs may help to guide future development of targeted treatments and improve the outcome for these patients. Methods: Formalin fixed, paraffin-embedded (FFPE) tumor tissue was collected from 11 primary OCCCs, diagnosed at the Skane University Hospital, Lund, Sweden (1998-2013). One sample was excluded due to poor DNA quality. For the remaining 10 samples, 600 ng genomic DNA/sample was used for single strand targeted DNA sequencing using the SureSeq™ solid tumor panel consisting of 60 key genes involved in cancer evolution, including ovarian cancer. The panel covers all coding exons in the included genes, and is validated for research use on FFPE samples. The publicly available ENSEMBL database was used to classify the mutations according to severity across the genes. Serious mutations, defined as major non-conservative amino acid changes, splice or frameshift variants or changes in stop codons, affecting single nucleotide variations (SNVs) or insertions or deletions of DNA bases (indels) were used for further analyses. The mutation call cut-off was set to 20% and the reading depth ≥300x, and unsupervised hierarchical clustering of the tumor samples was performed. Results: >99% of the target bases had a 30x coverage across all samples, and the mean target coverage was 534x. Using the 20% cut-off, approximately 300 mutations were detected in the 60 genes across the 10 tumor samples. Unsupervised hierarchical clustering revealed two distinct clusters related to mutational load. Mutations in genes previously reported to be affected in OCCCs, such as ARID1A and ERBB2, were identified. Whereas ARID1A was mainly affected in one cluster, mutations in genes signifying a highly malignant phenotype, such as BRCA1 and BRCA2 dominated in the other. Genes in signaling pathways often affected in malignant tumors, as e.g. the RAS pathway, however, were unaffected. Other mutations detected in this dataset were ZFHX3 and KMT2C. KMT2C was the only highly mutated gene across both clusters. The clustering pattern was not related to age of FFPE blocks or tumor cell content. Conclusions: In the present study we show that OCCCs are genetically heterogeneous. The variation in mutation rate is in line with a previous publication, and points to differences in tumor biology that may be important for tumor behavior and thus patient outcome. The highly mutated genes may help in guiding trials of targeted treatments; the methyl transferase gene KMT2C, also known as MLL3, may potentially be one such target. Rearrangements of this gene are well-described in acute leukemias. Interestingly, KMT2C/MLL3 is also reported to be a mutational cancer driver gene in renal clear cell carcinomas according to the TCGA. Likewise, ZFHX3 has recently been reported in endometrial clear cell carcinomas. Despite the small size of this study it points to the well-established fact that ovarian cancer is not one single disease, and also confirms that even the rare OCCCs seem to harbor different biological features which may be of potential clinical importance. Citation Format: Jenny-Maria Jönsson, Nicolai Skovbjerg Arildsen, Anna Ebbesson, Sofia Westbom-Fremer, Anna Måsbäck, Susanne Malander, Mef Nilbert, Ingrid Hedenfalk. Targeted sequencing of ovarian clear cell carcinomas reveals intertumor heterogeneity and distinct clustering related to mutational load. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B12.

Objective Heredity is a major cause of ovarian cancer and during recent years the contribution from germline mismatch repair (MMR) gene mutations linked to Lynch syndrome has gradually been recognized. Methods We characterized clinical features, tumor morphology and mismatch repair defects in all ovarian cancers identified in Swedish and Danish Lynch syndrome families. Results In total, 63 epithelial ovarian cancers developed at mean 48 (range 30–79) years of age with 47% being early stage (FIGO stage I). Histologically, endometrioid (35%) and clear cell (17%) tumors were overrepresented. The underlying MMR gene mutations in these families affected MSH2 in 49%, MSH6 in 33% and MLH1 in 17%. Immunohistochemical loss of the corresponding MMR protein was demonstrated in 33/36 (92%) tumors analyzed. Conclusion The combined data from our cohorts demonstrate that ovarian cancer associated with Lynch syndrome typically presents at young age as early-stage, non-serous tumors, which implicates that a family history of colorectal and endometrial cancer should be specifically considered in such cases.

Heredity represents the strongest risk factor for ovarian cancer with disease predisposing mutations identified in 15% of the tumors. With the aim to identify genetic classifiers for hereditary ovarian cancer, we profiled hereditary ovarian cancers linked to the hereditary breast and ovarian cancer (HBOC) syndrome and the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Genome-wide array comparative genomic hybridization was applied to 12 HBOC associated tumors with BRCA1 mutations and 8 HNPCC associated tumors with mismatch repair gene mutations with 24 sporadic ovarian cancers as a control group. Unsupervised cluster analysis identified two distinct subgroups related to genetic complexity. Sporadic and HBOC associated tumors had complex genetic profiles with an average 41% of the genome altered, whereas the mismatch repair defective tumors had stable genetic profiles, with an average 18% of the genome altered. Losses of 4q34, 13q12-q32 and 19p13 were overrepresented in the HBOC subset. Discriminating genes within these regions include BRCA2, FOXO1A and RB1. Gains on chromosomes 17 and 19 characterized the HNPCC tumors, but target genes herein are unknown. The results indicate that HBOC and HNPCC associated ovarian cancer develop along distinct genetic pathways and genetic profiles can thus be applied to distinguish between different types of hereditary ovarian cancer.

Background and aims: Influence of sex hormones in ovarian cancer is of great interest, but study results are inconclusive. A majority of all ovarian cancers display high expression of sex hormone receptors, but the effect of endocrine treatment is limited. We assessed estrogen (ER) α and β, progesterone (PR), and androgen (AR) receptor expression in an ovarian cancer cohort in order to study the potential correlation between receptor expression and disease free survival. Expression of the genes encoding the respective receptors (ESR1, ESR2, PGR and AR), was further explored in molecular ovarian cancer subtypes. Methods: 140 ovarian cancers were collected in Sweden 1998-2000. A majority of the tumors were serous, high-grade and advanced stage. Immunohistochemical stainings for the receptors were evaluated on a tissue microarray, and dichotomized as either negative (10% stained cells). The 5-year disease free survival (DFS) was estimated and Cox regression was used for multivariable modelling. ESR1, ESR2, PGR and AR were analyzed using an independent dataset (n = 285 tumors). Progression free (PFS) and overall survival (OS) for high versus low gene expression was analyzed in the six molecular ovarian cancer subtypes, using the median as cut-off. Results: Immunohistochemical expression of PR and AR were both associated with increased 5-year DFS (p Gene expression analyses revealed higher mRNA levels of PGR in the molecular subtypes constituted of borderline and endometrioid tumors respectively (p Conclusions: This study indicates that PR and AR may serve as independent prognostic markers in subsets of ovarian cancer, with the best 5-year disease free survival seen with combined PR/AR positivity. Gene expression analysis of the corresponding genes revealed differences among the subtypes of ovarian cancer. This underlines the importance of stratifying tumors also based on molecular features when investigating prognostic markers. Larger, well defined study cohorts are needed to identify the best markers and to elucidate in which specific subtypes of ovarian cancer endocrine treatment may have a role. Citation Format: Jenny-Maria Jönsson, Nicolai Arildsen, Susanne Malander, Anna Måsbäck, Linda Werner Hartman, Mef Nilbert, Ingrid Hedenfalk. Sex hormone receptor expression affects ovarian cancer survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1834. doi:10.1158/1538-7445.AM2015-1834

Ovarian carcinoma is the fourth most common cause of cancer death in women. The cause and pathogenesis of this disease has remained obscure. Galactose, the hydrolyzing product of the milk sugar lactose, has been hypothesized to be toxic to ovarian epithelial cells and consumption of dairy products and lactase persistence has been suggested to be a risk factor for ovarian carcinoma. In adults, downregulation of lactase depends on a variant C/T-13910 at the 5' end of the lactase gene. To explore whether lactase persistence is related to the risk of ovarian carcinoma we determined the C/T-13910 genotype in a cohort of 782 women with ovarian carcinoma. The C/T-13910 genotype was defined by solid phase minisequencing from 327 Finnish, 303 Polish, 152 Swedish patients and 938 Finnish, 296 Polish and 97 Swedish healthy individuals served as controls. Lactase persistence did not associate significantly with increased risk for ovarian carcinoma in the Finnish (odds ratio [OR]=0.77, 95% confidence interval [CI]=0.57-1.05, p=0.097), in the Polish (OR=0.95, 95% CI=0.68-1.33, p=0.75), or in the Swedish populations (OR=1.63, 95% CI=0.65-4.08, p=0.29). Our results do not support the hypothesis that lactase persistence increases the ovarian carcinoma risk. On the contrary, lactase persistence may decrease the ovarian carcinoma risk at least in the Finnish population.

Aim: We previously reported results from AGO-OVAR16 (NCT00866697), a randomized, double-blind, placebo-controlled phase 3 trial that evaluated the efficacy, safety, and tolerability of pazopanib maintenance therapy in patients without disease progression after first-line chemotherapy for AEOC (du Bois et al, ASCO 2013; abstract LBA5503). Patients in the pazopanib arm had longer progression-free survival (PFS) versus those in the placebo arm (HR = 0.766; 95% CI: 0.643, 0.911; P = .0021; medians 17.9 vs 12.3 months, respectively). The first interim analysis for overall survival (OS) after 190 deaths (20% of the study population) revealed no difference between arms (HR = 0.994; 95% CI: 0.747, 1.321). In this report we present updated results from the planned second interim OS analysis after 335 events (36% of the study population; 61% of events required for the final OS analysis, which will be performed after 551 events). Methods: Eligible patients had histologically confirmed AEOC, FIGO stage II-IV, and no evidence of disease progression after surgery and ≥ 5 cycles of platinum-taxane chemotherapy. Patients were randomized 1:1 to receive pazopanib 800 mg once daily or placebo for up to 24 months. The primary endpoint was PFS by RECIST. Secondary endpoints included OS, safety, and quality of life. Results: A total of 940 patients were randomized. At this second interim analysis of OS, 172 patients (36%) in the pazopanib arm and 163 patients (35%) in the placebo arm had died (HR = 1.076; 95% CI: 0.868, 1.333; P = .4985). The majority of deaths in each arm were attributed to the cancer under study. Additional subgroup analyses are ongoing and will be presented. Conclusions: Results from this updated OS analysis are consistent with the first interim analysis. Although maintenance therapy with pazopanib in AEOC significantly prolonged PFS in the overall study population, no difference in OS was observed in the planned second interim OS analysis. Disclosure: J.A. Arranz Arija: I have received honorarium for participating in advisory boards organized by GSK. I have received honorarium for participating as speaker in meetings organized by GSK. I do not have other economic relationships nor interest with GSK; N. Colombo: I have to declare participation in advisory boards; B.J. Monk: I have received honoraria for Advisory Boards. GSK supports research done at my institution and the payments do not go to me; T. Herzog: Consultant via advisory boards: Az, Roche, merk, morphotek No other as no speaker bureaus stock etc; C. Barrett and M. Jobanputra: I am employed by GlaxoSmithKline and hold GSK stock; Q. Wang: I'm a GSK employee and own GSK stocks. I do not have anything else to disclose; A. Du Bois: Consultant/advisor for Roche, Pharmamar, Amgen, and MSD Honoraria received from Roche, Johnson & Johnson, Pharmamar and MSD. All other authors have declared no conflicts of interest.

Background: Niraparib is an oral PARP-1/2 inhibitor with efficacy in both germline BRCA mutated (gBRCA) ovarian cancer (OvCa) and high grade serous OvCa (HGSC) patients (pts) who are non-gBRCA. Phase I data established a RP2D of 300 mg. At the recommended dose, 75% platinum sensitive patients achieved RECIST response in phase 1. Trial design: ENGOT-OV16/NOVA study (n = 360) is a double-blind, 2:1 randomized, placebo controlled phase III study of oral niraparib versus placebo in pts with platinum (plat) sensitive recurrent OvCa. Primary objective is to evaluate efficacy of niraparib as maintenance therapy assessed by the prolongation of progression free survival (PFS). PFS will be independently evaluated in a cohort of gBRCA pts and in HGSC pts who are non-gBRCA. Secondary objectives: overall survival in each cohort; bridge the centralized BRCA mutation test method to the candidate companion diagnostic test; patient-reported outcomes; PFS2; chemotherapy free interval; safety/tolerability; QTc in a subset of niraparib-treated pts. Study eligibility includes: histologically confirmed OvCa, HGSC histology or known gBRCA, plat sensitive recurrence, at least 2 prior courses of plat-containing therapy with no/minimal radiological residual disease, and normal CA125 or decrease by 90% after last plat, PS 0-1, and normal organ function. The study is powered to assess PFS and OS in both cohorts (gBRCA & non-gBRCA). The trial is being conducted in 126 sites in collaboration with European Network of Gynaecological Oncological Trials Groups (NSGO Denmark-Norway-Sweden, AGO Austria, AGO Germany, BGOG Belgium, ISGO Israel, GEICO Spain, GINECO France, MaNGO Italy, MITO Italy, NCRI UK), US, Canada, Hungary & Poland. The pt. enrolment is according to the timelines. ClinicalTrials.gov Identifier: NCT01847274 Disclosure: S. Agarwal: Medical Officer, Tesaro Bio Inc. (sponsor of the trial); R.E. Martell: Chief Medical Officer, Tesaro Bio Inc. (Sponsor of the trial). All other authors have declared no conflicts of interest.

5556^ Background: N is an oral inhibitor of VEGFR, PDGFR, and FGFR. As reported earlier, in the AGO-OVAR12 trial, N compared to placebo (Pl), added to standard chemotherapy, significantly prolonged...