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Background: Parental cancer affects not only the patient, but all family members. Access to psychological support for the entire family is highly relevant, but still scarce. The aim of the present research project was to develop, implement, and evaluate the effectiveness of a short-term counselling intervention for families with parental cancer. Methods: The short-term counselling intervention consisted of six sessions and was developed based on pre-existing evaluated concepts. All participating family members had to complete questionnaires prior and post-intervention. These questionnaires investigated changes in family communication and satisfaction levels, parental anxiety and depression levels, parental partnership quality and self-assessed quality of life of children and adolescents. Furthermore, feasibility of and satisfaction with the intervention was assessed. Results: Acceptability of short-term counselling was high in participating families, although feasibility was limited with regard to the final inclusion rate (n = 10). Comparison of pre and post intervention measures showed a significant increase in family communication and satisfaction levels. Anxiety and depression levels were low, quality of parental partnership within the normal range, and quality of life reported from children was high. These scores remained stable from pre to post intervention. Conclusions: The counselling intervention most likely had positive effects in all family members with either stabilizing or increasing all measured outcomes. Although interpretation of the results is limited due to the small sample size, we believe that integrated in clinical routine of adult care of a hospital, this additional offer might be a valuable benefice to cancer patients and their families. Clinical Trial Registration Number: NCT03097458 (clinicaltrials.gov)

Purpose: Several studies evidenced the potential of L1CAM as a prognostic marker in endometrial cancer. The aim of this study was to investigate whether L1CAM can predict lymph node metastasis and could therefore be used preoperatively to identify patients with low to high-intermediate risk endometrial cancer who would profit from a lymphadenectomy and an adjuvant treatment. To avoid unnecessary morbidity, de-escalating strategies are still required. Methods: Immunohistochemistry for L1CAM was performed on curettage or hysterectomy specimens from 212 patients diagnosed with endometrial cancer who were treated at the University Hospital Basel during 2011-2019. L1CAM expression was correlated with clinicopathological features such as histological subtype, FIGO stage, lymph node metastasis, lymphadenectomy, adjuvant treatment and outcome. Results: Using a cut off ≥10%, L1CAM was positive in 41/212 patients (19.3%) and negative in 171/212 patients (80.7%). L1CAM was associated with high-risk features such as non-endometrioid histology, high tumour grade, and high FIGO stage. There was no significant correlation between L1CAM expression and lymph node metastasis. However, patients with L1CAM positive tumours showed improved disease-specific survival if treated with adjuvant radiotherapy. Conclusion: Although L1CAM expression pointed towards aggressive tumour biology, preoperative L1CAM analysis did not add any substantial predictive information regarding lymph node metastasis in low to high-intermediate risk groups. Therefore, L1CAM status is not suitable to tailor the surgical algorithm for lymph node staging. Nevertheless, our results suggest that L1CAM could be used as a predictive biomarker to select patients who may benefit the most from adjuvant radiotherapy.

BackgroundWe estimated the cost-effectiveness of universal DNA screening for Lynch syndrome (LS) among newly diagnosed patients with colorectal cancer (CRC) followed by cascade screening of relatives from the Swiss healthcare system perspective.MethodsWe integrated decision trees with Markov models to calculate incremental cost per quality-adjusted life-year saved by screening all patients with CRC (alternative strategy) compared with CRC tumour-based testing followed by DNA sequencing (current strategy).ResultsThe alternative strategy has an incremental cost-effectiveness ratio of CHF65 058 compared with the current strategy, which is cost-effective according to Swiss standards. Based on annual incidence of CRC in Switzerland, universal DNA screening correctly identifies all 123 patients with CRC with LS, prevents 17 LS deaths and avoids 19 CRC cases, while the current strategy leads to 32 false negative results and 253 LS cases lost to follow-up. One way and probabilistic sensitivity analyses showed that universal DNA testing is cost-effective in around 80% of scenarios, and that the cost of DNA testing and the number of invited relatives per LS case determine the cost-effectiveness ratio.ConclusionResults can inform policymakers, healthcare providers and insurance companies about the costs and benefits associated with universal screening for LS and cascade genetic testing of relatives.

Introduction/Background* Clinical trials consistently demonstrate the detrimental impact of progressive disease (PD) on patients’ health-related quality of life (HRQoL). Progression-free survival (PFS) is an established regulatory endpoint. However, PFS is often excluded as an efficacy endpoint on the basis that — PFS is not patient relevant — in early benefit assessment by select EU health technology agencies. The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) Phase 3 trial showed niraparib significantly prolongs median PFS vs placebo in patients with AOC responsive to 1L platinum (Pt)-based chemotherapy, (CT), regardless of biomarker status. This post-hoc analysis of PRIMA is the first study to examine the relationship between HRQoL and PD in a broad frontline AOC maintenance treatment setting. Methodology In PRIMA, patients with AOC responsive to 1L Pt CT were randomised 2:1 to once-daily, maintenance niraparib or placebo. Impact of PD on patient HRQoL, irrespective of treatment, was evaluated within the pooled ITT population by comparing HRQoL at the last on-treatment (pre-progression) visit with HRQoL at end of treatment (EOT), +4 weeks, +8w, +12w, and +24w. Assessments included FOSI, EORTC QLQ-C30, EQ-5D-VAS, and EORTC QLQ-OV28 abdominal/GI symptom scale. ANCOVA was applied with treatment as a fixed effect and HRQoL at last on-treatment visit as a continuous covariate. Mixed models for repeated measurements (MMRM) evaluated cumulative HRQoL changes. Result(s)* Significant reductions in HRQoL from pre- to post-progression were observed across all measures. Compared with pre-progression, FOSI scores (Least-squares mean [95% CI]) were lower at EOT+4w (-2.2 [-2.8, -1.6]) and EOT+24w (-1.7 [-2.3, -1.1]); each p Conclusion* These findings demonstrate HRQoL is negatively impacted by PD in AOC. Preservation of HRQoL, an important therapy goal in the maintenance setting particularly for asymptomatic patients, can be achieved with PFS prolongation. PFS is of significant relevance and clinically important for AOC patients.

Background Malignant mixed Mullerian tumors of endometrial (MMMT-E) and ovarian (MMMT-O) origin are associated with poor prognosis. Suggestively epithelial-driven tumors, their treatment has shifted from anthracycline or ifosfamide-based towards taxane-based chemotherapy. It remains unclear whether this change associates with better outcomes. Patients and methods A conjoined Australian and Swiss patient cohort of MMMT-E (N = 103) and MMMT-O (N = 17) was compared to patients with adenocarcinoma of the endometrium (EC, N = 172) and ovary (OC, N = 189). Clinicopathological characteristics, FIGO stage, first-line treatment, and patient outcomes were analyzed. The generated hypothesis was verified in an US-American cohort with high-grade serous ovarian cancer (HGSOC, N = 1290) and MMMT-O (N = 450) using immunohistochemistry and next-generation sequencing. Results Early stage I/II MMMT-E showed a survival plateau after 2.5 years, with no recurrence or death observed afterwards. Relapse-free survival was significantly worse in MMMT-E treated with platinum/taxanes (P = 0.024) compared to non-taxane regimen. Hypothesizing that also MMMT-O might benefit from an adjuvant non-paclitaxel regimen, a second independent cohort of MMMT-O and HGSOC patients was examined. p53 mutations dominated in both cancers with comparable frequency. PI3KCA and KRAS mutations were less frequent: they were more frequent in MMMT-O than in HGSOC (P = 0.015 and P = 0.018, respectively). MMMT-O responded better to a combination of carboplatin with anthracyclines than with taxanes (73.9% vs. 39.4%). Conclusion Early stage I/II MMMT-E patients have excellent prognosis if no recurrence has appeared within the first 2.5 years. In MMMT-E, platinum/anthracycline or ifosfamide regimen associated with better outcomes than platinum/taxanes regimens. This might also apply to MMMT-O.

Purpose: Inguinofemoral lymphadenectomy (IFLD) is associated with very high morbidity. Fibrin sealant patches are used in various surgical procedures to prevent hematomas and lymphoceles. Here, we report a single-institution experience of fibrin sealants after IFLD in vulvar cancer and give an overview of the current literature. Patients and methods: We retrospectively analyzed outcome data on vulvar cancer patients who underwent bilateral IFLD between November 2014 and June 2016 at the University Hospital Basel. A fibrin sealant patch (Tachosil®) was placed in one groin only. Postsurgical fluid collection and complications were compared between both groins; time courses of lymphocele formation were analyzed using a linear mixed-effects regression model. Results: Postsurgical outcome of 11 consecutive patients with bilateral IFLD for vulvar cancer was assessed for a median follow-up of 32 days (range 12-77). Significantly larger lymphoceles were detected over time in the groin with the fibrin sealant patch (median 20 mL vs 5 mL without patch, p=0.002), and more punctures for symptomatic lymphocele were required on this side. The infection rate did not differ between sides. Conclusion: Fibrin sealant patches should not routinely be used for prevention of lymphoceles after IFLD for vulvar cancer. They do not seem to reduce lymph collection, the need for puncture or the infection risk after lymphadenectomy in our experience and according to a general literature review.

Laparoscopic surgery provides well-known benefits, but it has technological limitations. Depth perception is particularly crucial, with three-dimensional (3D) imaging being superior to two-dimensional (2D) HD imaging. However, with the introduction of 4K resolution monitors, 2D rendering is capable of providing higher-quality visuals. Therefore, this study aimed to compare 3D HD and 2D 4K imaging using a pelvitrainer model. Eight experts and 32 medical students were performing the same four standardized tasks using 2D 4K and 3D HD imaging systems. Task completion time and the number of errors made were recorded. The Wilcoxon test and mixed-effects models were used to analyze the results. Students were significantly faster in all four tasks when using the 3D HD perspective. The median difference ranged from 18 s in task 3 (P P P P P

The application and integration of molecular profiling technologies create novel opportunities for personalized medicine. Here, we introduce the Tumor Profiler Study, an observational trial combining a prospective diagnostic approach to assess the relevance of in-depth tumor profiling to support clinical decision-making with an exploratory approach to improve the biological understanding of the disease.

CD8+ tumor-infiltrating T cells can be regarded as one of the most relevant predictive biomarkers in immune-oncology. Highly infiltrated tumors, referred to as inflamed (clinically “hot”), show the most favorable response to immune checkpoint inhibitors in contrast to tumors with a scarce immune infiltrate called immune desert or excluded (clinically “cold”). Nevertheless, quantitative and reproducible methods examining their prevalence within tumors are lacking. We therefore established a computational diagnostic algorithm to quantitatively measure spatial densities of tumor-infiltrating CD8+ T cells by digital pathology within the three known tumor compartments as recommended by the International Immuno-Oncology Biomarker Working Group in 116 prospective metastatic melanomas of the Swiss Tumor Profiler cohort. Workflow robustness was confirmed in 33 samples of an independent retrospective validation cohort. The introduction of the intratumoral tumor center compartment proved to be most relevant for establishing an immune diagnosis in metastatic disease, independent of metastatic site. Cut-off values for reproducible classification were defined and successfully assigned densities into the respective immune diagnostic category in the validation cohort with high sensitivity, specificity, and precision. We provide a robust diagnostic algorithm based on intratumoral and stromal CD8+ T-cell densities in the tumor center compartment that translates spatial densities of tumor-infiltrating CD8+ T cells into the clinically relevant immune diagnostic categories “inflamed”, “excluded”, and “desert”. The consideration of the intratumoral tumor center compartment allows immune phenotyping in the clinically highly relevant setting of metastatic lesions, even if the invasive margin compartment is not captured in biopsy material., The authors present a robust diagnostic algorithm based on digital pathology and image analysis that quantifies intratumoral and stromal CD8+ T-cell densities in the tumor center and invasive margin compartment in metastatic melanoma. Spatial CD8+ T-cell densities are translated into the clinically relevant immune diagnostic categories “inflamed”, “excluded”, and “desert”. Their approach also allows efficient immune phenotyping of metastatic lesions, on biopsy material or even in the absence of material from the invasive margin.

Main aim of this study is to assess the effect of a structured, interdisciplinary, surgical, team-training protocol in robotic gynecologic surgery, with the gradual integration of an advanced nurse practitioner. Data from all robotic surgical procedures were prospectively acquired. The surgical team consisted of one experienced surgeon and two surgical fellows and the scrub nurse team from three advance nurse practitioners, specialized in robotic surgery. The training was performed in a four-phase manner over 4 years and included theoretical training, hands-on training and team-communication skills enhancement. Scrub nurses increasingly adopted an active role during surgery. For a period of 4 years, 175 patients could be included in the analysis. All of them underwent a robotic gynecologic procedure. Mean docking time decreased from 45.3 to 27.3 min (p p = 0.0071) and costs per case from 17,891 to 14,731 Swiss Francs (p = 0.035). There were no statistically significant changes in perioperative complications and conversions to laparotomy. An interdisciplinary long-term training protocol for high specialized robotic surgery within a “fixed” team with the gradually addition of an advanced study nurse improves the efficacy of the procedure in terms of time and costs. Although the surgery is performed quicker, the same performance and quality of surgical care could be reached.

BackgroundThe costimulatory receptor 4-1BB (CD137, TNFRSF9) plays an important role in sustaining effective T cell immune responses and is investigated as target for cancer therapy. Systemic 4-1BB directed therapies elicit toxicity or low efficacy, which significantly hampered advancement of 4-1BB-based immunotherapy. Therefore, targeted delivery of 4-1BB agonist to the tumor side is needed for eliciting antitumor efficacy while avoiding systemic toxicity.MethodsWe analyzed the immunostimulatory properties of a fibroblast activation protein (FAP)-targeted 4-1BB agonist (FAP-4-1BBL) by assessing tumor-infiltrating lymphocytes’ (TIL) activity from patients with non-small cell lung cancer and epithelial ovarian cancer.ResultsCombination treatment with FAP-4-1BBL and T cell receptor stimulation by either anti-CD3 or T cell bispecific antibodies significantly enhanced TIL activation and effector functions, including T cell proliferation, secretion of proinflammatory cytokines and cytotoxicity. Notably, costimulation with FAP-4-1BBL led to de novo secretion of interleukin (IL)−13. This was associated with cytokine-mediated tumor cell apoptosis, which was partially dependent on IL-13 alpha 1/2 receptors and STAT6 phosphorylation.ConclusionsOur study provides mechanistic insights into T cell stimulation induced by FAP-4-1BBL in primary human tumors and supports the investigation of FAP-4-1BBL compound in early clinical trials.

Background The presence of circulating tumor cells (CTCs) in patients with breast cancer correlates to a bad prognosis. Yet, CTCs are detectable in only a minority of patients with progressive breast cancer, and factors that influence the abundance of CTCs remain elusive. Methods We conducted CTC isolation and enumeration in a selected group of 73 consecutive patients characterized by progressive invasive breast cancer, high tumor load and treatment discontinuation at the time of CTC isolation. CTCs were quantified with the Parsortix microfluidic device. Clinicopathological variables, blood counts at the time of CTC isolation and detailed treatment history prior to blood sampling were evaluated for each patient. Results Among 73 patients, we detected at least one CTC per 7.5 ml of blood in 34 (46%). Of these, 22 (65%) had single CTCs only, whereas 12 (35%) featured both single CTCs and CTC clusters. Treatment with the monoclonal antibody denosumab correlated with the absence of CTCs, both when considering all patients and when considering only those with bone metastasis. We also found that low red blood cell count was associated with the presence of CTCs, whereas high CA 15-3 tumor marker, high mean corpuscular volume, high white blood cell count and high mean platelet volume associated specifically with CTC clusters. Conclusions In addition to blood count correlatives to single and clustered CTCs, we found that denosumab treatment associates with most patients lacking CTCs from their peripheral circulation. Prospective studies will be needed to validate the involvement of denosumab in the prevention of CTC generation. Electronic supplementary material The online version of this article (10.1186/s13058-018-1067-y) contains supplementary material, which is available to authorized users.

Céline Montavon Sartorius,1 Uzma Mirza,1 Andreas Schötzau,2 Gillian Mackay,1 Daniel Fink,3 Neville F Hacker,4 Viola Heinzelmann-Schwarz1,2 1Department of Gynecology and Gynecological Oncology, Hospital for Women, University Hospital Basel, Basel, Switzerland; 2Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland; 3Department of Gynecology, University Hospital Zurich, Zürich, Switzerland; 4Gynecological Cancer Centre, Royal Hospital for Women, School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW, Australia Purpose: The stage of disease is one of the strongest prognostic factors in epithelial ovarian cancer. The International Federation of Gynecology and Obstetrics (FIGO) classification was revised in 2013; stage IC was subdivided into IC1 (intraoperative surgical spill), IC2 (capsule rupture before surgery or tumor on surface), and IC3 (positive peritoneal washing or ascites). Our aim was to compare the outcome of patients in the new FIGO stage I subgroups, as this might influence adjuvant therapy decisions.Patients and methods: Patient databases of three gynecological oncology centers were retrospectively analyzed. Patients with FIGO stage I ovarian cancers were restaged according to the revised classification, based on operative and pathological reports, and determined patient outcomes.Results: We analyzed 128 patients with ovarian cancers. In FIGO IA, we found 11.3% recurrences and 4.2% deaths. In FIGO IC, 21.8% of the patients recurred and 7.3% died. There was a trend toward a shorter time to recurrence when comparing IA to IC (P=0.076). Within all new subgroups of FIGO IC, there was no difference in time to recurrence (P=0.59). There was also no significant difference in survival when FIGO IA was compared to FIGO IC in comparison with the new individual classifications (IA to IC, IA to IC1, 2, or 3; P=0.60, P=0.15, P=0.61, P=0.66, respectively) or within the different subgroups (P=0.56). Platinum-based chemotherapy was given to the majority (82.6%, n=38/46) of the FIGO IC patients compared to 30.9% in FIGO IA (n=17/55). There was no significant difference within the new subgroups of FIGO IC (P=0.88).Conclusion: In our retrospective analysis, the new FIGO staging of IC ovarian cancers did not predict prognosis, but the use of adjuvant chemotherapy in 82.6% of the stage IC patients may have biased the outcome. Keywords: ovarian neoplasm, cancer staging, survival, recurrence

Objectives Endocrine therapy is used as maintenance in estrogen receptor (ER) positive breast cancers and has been proposed in low-grade serous ovarian cancers (LGSOC). Here we examine a rationale for its use as maintenance in high-grade serous ovarian cancers (HGSOC). Methods We accessed the TCGA PANCAN dataset to evaluate the expression of ESR1 . ESR1 expression data on all cancers (n=8901) and HGSOC (n=527) were followed by investigation of ER expression via immunohistochemistry (IHC) (n=4071). The same was performed in an independent cohort for matched primary and recurrent HGSOC (n=80). Finally, newly diagnosed ER+ HGSOC patients were offered a maintenance therapy with Letrozole. Results ESR1 was strongly expressed in similar levels in HGSOC as in breast cancer. We found a strong ER expression via IHC in both the primary and matched recurrent HGSOC, particularly in the Platinum-resistant subgroup. The additional use of Letrozole as maintenance treatment was associated with a significantly prolonged recurrence free interval (after 24months 60% when taking Letrozole versus 38.5% in the control group; p =0.035; RFS: IC 50 reached by one subject versus 13.2months). This effect was also present in patients treated additionally with Bevacizumab; 20.8% of patients had no recurrence after 12months compared to 87.5% when taking Letrozole in addition to Bevacizumab ( p =0.026). Conclusions Primary HGSOC have a slightly higher ESR1 than and a similar ER expression breast cancer where aromatase inhibitor maintenance is routine for decades. Here we demonstrate evidence for the usefulness of Letrozole in HGSOC, particularly in patients with chemotherapy resistance or residual disease.

Background: The clinical presentation of Langerhans cell histiocytosis (LCH) is heterogeneous ranging from single-organ involvement to systemic disease causing substantial morbidity and mortality. We describe an unusual course of severe multisystem LCH with spontaneous remission. Case Presentation: We report on a 45-year-old Caucasian woman with cervical cancer, FIGO stage IVB. Five months after the end of combined radiochemotherapy and brachytherapy, the patient was readmitted because of severe dysuria. Sterile leukocyturia was seen, and cystoscopy revealed only 3 unspecific small mucosal lesions compatible with postradiation cystitis. Incidentally, a computed tomography (CT) scan of the body showed diffuse micronodular and cystic lesions in lungs and hypodense lesions in the liver. Biopsies revealed infiltrations of CD1a and Langerin (CD207)-positive histiocytes in the lung, liver, and bladder. Additionally, positron emission tomography-CT (PET-CT) was compatible with bone involvement. Retrospective analysis revealed that the increase in alkaline phosphatase might have been a surrogate of bone marrow infiltration with osseous activity. Repeated pneumothoraces occurred, and only one course of vinblastine-prednisolone could be applied. Despite ongoing tobacco consumption and without further therapy, PET-CT showed considerable remission 2 months later. However, despite stable remission, documented by serial PET and conventional CT scans, persistent infiltration of the bladder by Langerhans histiocytes could still be demonstrated 17 months later. Unfortunately, cervical cancer recurred and progressed. Conclusion: Multisystem LCH may rapidly occur, may be oligosymptomatic and, even in high-risk cases, remission without specific therapy might occur. Whether alkaline phosphatase might be a surrogate to monitor osseous disease activity has to be further explored.

Peritoneal dissemination is a particular form of metastasis typically observed in ovarian cancer and the major cause for poor patient’s outcome. Identification of the molecular players involved in ovarian cancer dissemination can offer an approach to develop treatment strategies to improve clinical prognosis. Here, we identified mesothelin (MSLN) as a crucial protein in the multistep process of peritoneal dissemination of ovarian cancer. We demonstrated that MSLN is overexpressed in primary and matched peritoneal metastasis of high-grade serous carcinomas (HGSC). Using several genetically engineered ovarian cancer cell lines, resulting in loss or gain of function, we found that MSLN increased cell survival in suspension and invasion of tumor cells through the mesothelial cell layer in vitro. Intraperitoneal xenografts established with MSLNhigh ovarian cancer cell lines showed enhanced tumor burden and spread within the peritoneal cavity. These findings provide strong evidences that MSLN is a key player in ovarian cancer progression by triggering peritoneal dissemination and provide support for further clinical investigation of MSLN as a therapeutic target in HGSC. This work was partly developed at IPATIMUP, an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and I3S. This work was supported by FEDER–Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020–Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT–Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). This research was funded by projects PTDC/MEC-ONC/29503/ 2017 (to L.D.), NORTE 2020 grant numbers NORTE-01-0145-FEDER-000029, NORTE-01-0145-FEDER-000003, Wilhelm Sander Stiftung 2018.010.1 (to F.J.), Swiss Cancer League KLS-3841-02-2016 (to F.J.), and FCT PhD fellowship number SFRH/BD/111885/2015 (to R.C.) We would like to thank Dr. Ronny Drapkin (University of Pennsylvania) for sharing the fallopian tube cell lines.

Background Treatment options for advanced cervical cancer are limited and patients experiencing recurrence after first-line cisplatin-based chemotherapy and bevacizumab have a poor prognosis. A recent phase II study in advanced cervical cancer has demonstrated a disease control rate of 68.4% with the immune checkpoint inhibitor nivolumab. By blocking immune checkpoints, immunotherapy puts the immune system into a state of hyper-activation that can cause immune-related adverse events. We present the clinical, pathological and molecular data of a patient with metastatic cervical cancer and progressive disease after second-line therapy. We report on the therapeutic response under third-line immunotherapy with nivolumab, the immune-related adverse events (IRAE), and their successful management. Case presentation We report the case of a 62-year-old woman who was diagnosed with advanced squamous cell carcinoma of the cervix with paraaortic lymph node metastases. After an initial combined radio-chemotherapy with cisplatin, she developed local and nodal (supraclavicular) recurrence. Second-line chemotherapy with 6 cycles of carboplatin, paclitaxel, and bevacizumab resulted in a partial response for 6 months. Checkpoint inhibition with nivolumab was started due to progression, leading to persistent complete remission. Immunotherapy was well tolerated for 8 months until the patient presented with an immune-related isolated vulvitis, which was successfully managed with topical corticosteroids. Conclusions The persistent complete response after third-line treatment for relapsed chemotherapy-resistant cervical cancer presented in this case highlights the potential of immunotherapy for patients with advanced cervical cancer impressively. To our knowledge, this is the first report of an isolated immune-related vulvitis under nivolumab. This adverse event might be underdiagnosed and mistreated, however, it is of importance due to its impact on quality of life, sexual wellbeing and compliance of patients. Successful IRAE management may enable prolonged immune checkpoint inhibitor therapy. In the future, routine molecular tumour profiling is likely to aid in the stratification of cervical cancer patients for immunotherapy. Here, we provide the methylome data of a case with complete response.

Background Carriers of pathogenic variants in both BRCA1 and BRCA2 genes as a double mutation (BRCA1/2 DM) have been rarely reported in women with epithelial ovarian cancer (EOC). Methods We reviewed the English literature and interrogated three repositories reporting EOC patients carrying BRCA1/2 DM. The clinicopathological parameters of 36 EOC patients carrying germline BRCA1/2 DM were compared to high-grade serous EOC women of the COEUR cohort with known germline BRCA1/BRCA2 mutation carrier status (n = 376 non-carriers, n = 65 BRCA1 and n = 38 BRCA2). Clinicopathological parameters evaluated were age at diagnosis, stage of disease, loss of heterozygosity, type of mutation, immunohistochemistry profile, progression occurrence and survival. Results Median age at diagnosis of BRCA1/2 DM patients was 51.9 years, similar to BRCA1 mutation carriers (49.7 years, p = .58) and younger than BRCA2 mutation carriers (58.1 years, p = .02). Most patients were diagnosed at advanced stage (III-IV; 82%) and were carriers of founder/frequent mutations (69%). Tissue immunostainings revealed no progesterone receptor expression and low intraepithelial inflammation. The 5-year survival rate (60%) was significantly lower than that of BRCA2 mutation carriers (76%, p = .03) but not of BRCA1 mutation carriers (51%, p = .37). Conclusions Our data suggests some co-dominant effect of both mutations but the outcome of these patients more closely resembled that of BRCA1 mutation carriers with poor prognosis factors.

Background Large tumor suppressor (LATS) proteins are putative tumor suppressors and poorly expressed associated with poor outcome in many cancers. A recent immunohistochemistry study showed that LATS protein expression correlated with poor outcome in serous ovarian cancer. Materials and methods We analyzed LATS expression in various ovarian cancer transcriptomic data sets and immunohistochemically assessed LATS protein expression in a Swiss ovarian tumor cohort. Results were compared to clinicopathological characteristics and outcome. We also compared LATS protein expression in serous ovarian cancer cell lines to their EMT status (Western blotting) and drug sensitivity (MTT assay). Results The analysis of 15 different transcriptomic data sets showed that LATS2 was associated with poorer outcome, while LATS1 was irrelevant (HR = 1.19 and HR = 1.00, respectively). The TCGA-RNASeqV2 data set showed that low LATS1 and LATS2 were associated with better survival in serous ovarian carcinoma. Despite heterogeneity among the different data sets, LATS expression is not an indicator of survival in serous ovarian cancer and LATS2 expression may even be tumorigenic. LATS expression was neither associated with survival nor with the stage and grade in the Swiss cohort. It was low in cystadenoma, intermediate in carcinoma, and high in borderline tumors and was higher in serous than mucinous ovarian carcinoma. LATS protein expression extent was comparable in epithelial-, intermediate-, and mesenchymal-type ovarian cancer cells and was not associated with drug sensitivity. Conclusion These results are largely incompatible with a tumor-suppressive function of LATS in ovarian cancer, and LATS protein level is also not an indicator for drug sensitivity and EMT status of ovarian cancer cells.

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.

Ovarian cancer is the most aggressive gynecologic malignancy, with a 5-year survival rate ranging around 40 %. A crucial factor influencing the prognosis is early detection of a suspicious mass and referral to a gynecologic oncology center for further diagnosis, staging and debulking surgery. Here, we present the different imaging methods ultrasound (US), magnetic resonance imaging, computer tomography (CT) and 18F-fluoro-deoxyglucose positron emission tomography (PET)/CT that are used for the characterization, diagnosis, staging and surveillance of ovarian cancer. In this review, we focus on US and discuss in detail the advantages and the limitations, as well as the appropriate indications for each of the individual imaging techniques.

Objective To investigate clinical factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in relapsing epithelial ovarian cancer (EOC) patients with BRCA mutations and receiving olaparib as maintenance therapy in daily practice. Methods Multicenter (8 hospitals) European retrospective study of relapsing EOC patients having germline or somatic mutations of BRCA1/BRCA2 genes and treated with olaparib as maintenance therapy after platinum-based chemotherapy. Results One hundred and fifteen patients were included. Median age was 54 years. There were 90 BRCA1 carriers, 24 BRCA2 carriers and one patient had germline mutation of BRCA1 and BRCA2. Six patients had somatic mutations (all BRCA1) and 109 had germline mutations. Ninety percent had serous carcinomas and were platinum-sensitive. Following ultimate platinum-based chemotherapy, 69% of the patients had normalization of CA-125 levels and 87% had RECIST objective responses, either partial (53%) or complete (34%). After a median follow-up of 21 months, median PFS was 12.7 months and median OS was 35.4 months. In multivariate analysis, factors associated with prolonged PFS under olaparib were: platinum-free interval (PFI) ≥ 12 months, RECIST complete response (CR) or partial response (PR) and normalization of CA-125 upon ultimate platinum-based chemotherapy. Factors associated with prolonged OS were PFI ≥ 12 months, CR and normalization of CA-125. Conclusions Platinum-free interval ≥ 12 months, complete response and normalized CA-125 levels after ultimate platinum-based chemotherapy are associated with prolonged PFS and OS in relapsing BRCA1/BRCA2 mutated ovarian cancer patients who received olaparib as maintenance therapy.

Objectives Pelvic congestion syndrome is defined as chronic pelvic pain due to incompetent (dilated and refluxing) pelvic veins. The aim of this study was to investigate the prevalence of this condition by examining the prevalence of dilated ovarian and para-uterine veins in pre- and postmenopausal female patients, irrespective of their symptoms. We subsequently investigated how many women with dilated veins suffered from chronic pelvic pain. Additionally, we attempted to define diagnostic criteria that may allow for early identification of affected patients. Methods We reassessed 2384 abdomino-pelvic computed tomography scans performed on women at our institution. The maximal diameters of the ovarian and para-uterine veins were measured. Patients with a pathological process in the abdomen or pelvis affecting the veins were excluded. We considered ovarian vein dilation to be 6 mm or more in the axial plane. For patients that met these criteria, we performed a retrospective chart review to evaluate the clinical presentation and/or symptoms of these patients. Results Dilated pelvic veins were present in 293/2384 (12%) patients, 118/559 premenopausal (21%) and 175/1825 postmenopausal (10%). Chronic pelvic pain of unclear etiology had been documented prior to the CT in 54/293 (18%) women with dilated veins—2% of the whole study collective (54/2384); 8% of all premenopausal (44/559) and 0.5% of all postmenopausal (10/1825). It was often accompanied by urological symptoms such as hematuria, dysuria, and urinary frequency, in the absence of infection (p

TPS5598 Background: The prognosis of advanced epithelial ovarian cancer (OC) is poor with a relapse rate of 75% at 5 years. Some 80% of OC express estrogen receptor (ER). This is the first trial that wants to capitalize on this and prospectively evaluates letrozole, a potent aromatase inhibitor, as initial maintenance treatment for high and low grade OC. Methods: Eligible pts have primary OC, FIGO Stage II-IV with low or high grade serous or endometrioid histology, with (interval) debulking surgery, ECOG-status 0-2, Positivity (≥ 1%) for ER expression, and at least 4 cycles of platinum-based chemotherapy (neoadjuvant allowed). Pts are allowed to undergo concurrent maintenance treatment with bevacizumab and PARP inhibitors. Extensive quality of life (QoL) questionnaires via an App and physical activity measurements by a tracking device as well as G8 geriatric score, ESGO surgery questionnaire, and Charleson Comorbidity Index are routinely assessed. Primary objective is to evaluate the efficacy of letrozole maintenance therapy after standard surgical and chemotherapy treatment as measured by Progression Free Survival (PFS) compared to no maintenance therapy (placebo). Primary outcome is PFS, defined as time from date of first letrozole/placebo administration until date of progression or death by any cause. Stratification for high and low grade histologies and ER measurement is performed via a digital centralized pathology review process. Final analysis will be performed for the whole cohort and for the subgroup of low grade ovarian cancers (LOGOS subprotocol). Secondary objectives and outcomes are overall survival (OS), quality adjusted progression free survival (QAPFS), time to first subsequent treatment (TFST), quality adjusted time without symptoms (TWiST), and health related QoL. Study is designed as international, randomized (1:1 ratio), two-arm, multi-centric, double-blinded, placebo-controlled superiority phase III trial. In total, 528 pts will be randomly assigned to letrozole or placebo for 5 yrs or until unacceptable toxicity, progression of underlying disease, or study discontinuation. Final analysis is planned after 5 years without interval analysis and follow-up is collected for up to 10yr and for the low-grade cohort for up to 12yr. Clinical trial information: NCT04111978.

// Reto S. Kohler 1 , Merrina Anugraham 1 , Monica Nunez Lopez 1 , Christina Xiao 1 , Andreas Schoetzau 1 , Timm Hettich 2 , Goetz Schlotterbeck 2 , Andre Fedier 1 , Francis Jacob 1, 3, * , Viola Heinzelmann-Schwarz 1, 4, * 1 Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland 2 School of Life Sciences, University of Applied Sciences and Arts Northwestern Switzerland, Muttenz, Switzerland 3 Glyco-Oncology, Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland 4 Hospital for Women, Department of Gynecology and Gynecological Oncology, University Hospital Basel, Basel, Switzerland * These authors contributed equally to this work Correspondence to: Viola Heinzelmann-Schwarz, email: viola.heinzelmann@usb.ch Keywords: N-glycosylation, DNA methylation, long-time survival, bisecting GlcNAc, ovarian cancer Received: December 18, 2015 Accepted: June 26, 2016 Published: July 12, 2016 ABSTRACT Bisecting GlcNAc on N -glycoproteins is described in E-cadherin-, EGF-, Wnt- and integrin- cancer-associated signaling pathways. However, the mechanisms regulating bisecting GlcNAc expression are not clear. Bisecting GlcNAc is attached to N -glycans through beta 1-4 N -acetylglucosaminyl transferase III (MGAT3), which is encoded by two exons flanked by high-density CpG islands. Despite a recently described correlation of MGAT3 and bisecting GlcNAc in ovarian cancer cells, it remains unknown whether DNA methylation is causative for the presence of bisecting GlcNAc. Here, we narrow down the regulatory genomic region and show that reconstitution of MGAT3 expression with 5-Aza coincides with reduced DNA methylation at the MGAT3 transcription start site. The presence of bisecting GlcNAc on released N -glycans was detected by mass spectrometry (LC-ESI-qTOF-MS/MS) in serous ovarian cancer cells upon DNA methyltransferase inhibition. The regulatory impact of DNA methylation on MGAT3 was further evaluated in 18 TCGA cancer types ( n = 6118 samples) and the results indicate an improved overall survival in patients with reduced MGAT3 expression, thereby identifying long-term survivors of high-grade serous ovarian cancers (HGSOC). Epigenetic activation of MGAT3 was also confirmed in basal-like breast cancers sharing similar molecular and genetic features with HGSOC. These results provide novel insights into the epigenetic regulation of MGAT3 /bisecting GlcNAc and demonstrate the importance of N -glycosylation in cancer progression.

Background: New targets for ovarian cancer treatment are critically needed. The Wnt receptors ROR1 and ROR2 are overexpressed in all subtypes of ovarian cancer and appear to play a role in both the tumor and surrounding microenvironment (1). In vitro studies support the approach of targeting these receptors together to inhibit ovarian cancer migration and invasion (2, 3). Aim: To investigate the role of ROR1 and ROR2 in ovarian cancer progression, survival and chemoresistance, to determine their feasibility as therapeutic targets. Methods: Analysis of RNA-Seq data from publicly available ovarian cancer datasets was performed to determine associations with overall survival and platinum resistance. ROR1 IHC using a recently released monoclonal antibody (4A5, BD Bioscience) was performed on a cohort of ovarian cancer patients. ROR1 and/or ROR2 were silenced in a unique preclinical organotypic model of platinum-resistant ovarian cancer metastasis. Results: There is a significant increase (p=0.01) in ROR1 expression in both primary resistant and acquired resistant (p=0.03) high-grade serous ovarian cancer (HGSOC). ROR2 expression is not significantly associated with chemoresistance. High ROR1 (P=0.002, HR 1.93) or high ROR2 (P=0.004, HR 1.9) expression is associated with a significantly shorter overall survival (OS) in the Tothill cohort (4). Patients expressing both high ROR1 and high ROR2 have the shortest OS (P=0.0003, HR 2.38). ROR1 protein expression was detected in 97% of HGSOC patients via IHC, with 59% of HGSOC expressing “high ROR1” (IHC score 2 or 3). Overall, patients with higher-grade tumors expressed significantly higher ROR1 levels (P=0.001) than patients with low-grade tumors. Silencing ROR1 and ROR2 in combination inhibits adhesion and invasion of platinum resistant ovarian cancer in a 3D organotypic coculture model. Conclusion: Our data support targeting both ROR1 and ROR2 as a new approach to treating ovarian cancer. The development of a number of monoclonal antibodies targeting ROR1 and ROR2 that are currently in phase 1 trials for other tumor types makes this clinically feasible in the future. These data also suggest that this may be most effective in the context of HGSOC with platinum resistance. References: 1. Henry CE et al. Distinct patterns of stromal and tumor expression of ROR1 and ROR2 in histological subtypes of epithelial ovarian cancer. Transl Oncol 2017;10(3):346-56. 2. Henry C, Hacker NF, Ford CE. Silencing ROR1 and ROR2 inhibits invasion and adhesion in an organotypic model of ovarian cancer metastasis. Oncotarget 2017;8(68):112727-38. 3. Henry C et al. ROR1 and ROR2 are upregulated in chemoresistant ovarian cancer and promote migration and invasion. Oncogenesis 2016;5(5):doi: 10.1038/oncsis.2016.32. 4. Tothill RW et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res 2008;14(16):5198-208. Citation Format: Dongli Liu, Miya John, Claire E. Henry, Elizabeth L. Christie, David D.L. Bowtell, Kristina Tang, Viola Heinzelmann-Schwarz, Catherine Kennedy, Jessica Boros, Anna DeFazio, Caroline E. Ford. ROR1 is associated with ovarian cancer progression and chemoresistance [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A41.

12065 Background: Long-term survivors (LTS) with ovarian cancer may be cured from cancer but frequently experience long-term toxicities such as fatigue with a huge impact on quality of life. Aim of this study was to evaluate factors associated with fatigue in LTS. Methods: Within the study “Carolin meets HANNA” ( www.carolinmeetshanna.com ) long-term survivors with ovarian cancer (LTS) were recruited since 11/2016. Long-term survival was defined as an ovarian cancer diagnosis more than eight years ago. Results: Until 12/2019 473 LTS could be recruited. 211 LTS (44.5%) have experienced fatigue. At the time point of recruitment in 23.4% (111 LTS) fatigue was still present. LTS with fatigue were not more frequently under current treatment compared to LTS without fatigue (p = 0.348). LTS with fatigue were not younger at initial diagnosis (50.4 vs. 51.9 years, p = 0.228). 58.6% of LTS with fatigue compared to 41.5% without fatigue have developed recurrent disease (p = 0.002) and LTS had more frequently more than one recurrence (66.1% vs. 51.7%, p = 0.055). Fatigue was associated with worse health status (2.9 vs. 2.2 on a scale from 1-5, p < 0.001). Fatigue was associated with medical complaints in general (82.0% vs. 43.0%, p < 0.001). Symptoms such as nausea and vomiting (p < 0.001), loss of appetite (p < 0.001), constipation (p < 0.001), diarrhea (p < 0.001), weight loss (p = 0.001) and bloating (p < 0.001) were more frequent in LTS with fatigue. This also accounts for cognitive disorders (39.6% vs. 10.5%, p < 0.001), depression (23.4% vs. 7.4%, p < 0.001), polyneuropathy (39.6% vs. 13.2%, p < 0.001) and cardiovascular disease (11.7% vs. 3.6%, p = 0.002). LTS with fatigue regard themselves more frequently as cancer patient (73.9% vs. 40.8%), p < 0.001). Conclusions: Fatigue is still very common in LTS despite the long survival time. Fatigue is associated with worsened health status and other long-term side effects underlining the impact on LTS. There is a high need for survivorship clinics that should ask for and, if necessary, should address still existing side effects such as fatigue.

Objective: The methods used to diagnose and classify ovarian cancer have changed over the past decade. We used hospital registry data to assess the incidence, treatment durations and hospital costs of ovarian cancer in Switzerland. Methods: We carried out a retrospective analysis of a hospital registry covering all inpatient care episodes in Switzerland between 1998 and 2012. Ovarian cancer incidence was assessed by identifying patients with a first ovarian cancer diagnosis as the main reason for hospital stay after an event-free period. We assessed the duration and cost of ovarian cancer treatment sequences as well as the evolution of hospital patient volume over time. Results: The average age-adjusted incidence rate was 14.6 per 100,000 women per year between 2004 and 2012. This rate is substantially higher (+35.5%) than the corresponding rate published by the National Institute for Cancer Epidemiology and Registration (NICER). Hospital patient volume was low in most cases, with more than 40% of patients treated in hospitals with fewer than 20 cases per year. However, the share of patients treated in hospitals with more than 30 cases per year has increased substantially since 2009. Conclusions: We found a substantial difference between the ovarian cancer incidence estimate based on hospital registry data and the corresponding estimate by NICER. The reasons for this substantial difference should be carefully explored. A case-wise comparison could determine whether the difference is due to over- or under-reporting in one of the two registries. The low ovarian cancer patient volume in many hospitals is in conflict with the numbers required for certified specialised cancer centres. The recent increase in patient volume in specialised cancer centres, however, might reflect a growing understanding of the needs and requirements of comprehensive cancer care.

Introduction: Endocrine therapy with tamoxifen and aromatase inhibitors has been used in Estrogen Receptor (ER) positive breast cancer for decades. Epithelial ovarian cancer, in particular serous Low- and High Grade Subtypes (LGSOC, HGSOC), shows a similar high ER expression and represents therefore a potential target for endocrine therapy. Many treatments have been evaluated in phase II clinical trials in heavily pretended patients, but the overall tumor response and agent superiority (tamoxifen vs. aromatase inhibitors) remains unclear. Methods: We present a literature review of endocrine therapy for ovarian cancer and emphasize the role of endocrine maintenance therapy with letrozole after standard of care. Results: Endocrine therapy appears to be an eligible and cost effective treatment option with good quality of life in the adjuvant and recurrent treatment of advanced ovarian cancer. The trend shows the highest effect in histological subtypes with the highest ER expression (LGSOC and HGSOC).

Peritoneal biopsies (PB) and peritoneal washing (PW) are routine measures in abdominal staging of gynecological malignancies and are used particularly for the assessment of occult microscopic tumor spread to the peritoneal surface including the diaphragm. Cytological diaphragmatic smears (DS) have been suggested as a supplemental tool; however, they are not routinely taken and their usefulness is still unclear. The present study retrospectively evaluated whether DS provide an additional benefit over PB and PW for the detection of peritoneal malignancies in patients with gynecological cancer. The data from patients who underwent laparotomy for suspected gynecological cancer and had DS and either PB, PW or ascites were reviewed. Sensitivity and specificity, and the number upstaged patients were determined. A total of 43 patients were excluded due to benign diagnosis (those with negative DS or PW) and 2 out of the remaining had 2 carcinomas simultaneously. Among these 41 malignancies, DS were positive in 12, PW in 18 and PB in 19 cases. No case was DS-positive while negative for both PB and PW. Four cases were missed when only PB and 5 when only PW was performed. Notably, no case of peritoneal disease was identified solely on positive DS, indicating that all 23 positive cases (presence of occult peritoneal disease in 56.1%) were identified by PB and PW together (100% sensitivity; 62% specificity). In addition, none of the cases was upstaged solely on positive DS results. Taken together, these data demonstrated that DS do not present an additional benefit to PW and PB in the detection of peritoneal gynecological disease.

BACKGROUND Breast, colorectal, ovarian, and endometrial cancers constitute approximately 30% of newly diagnosed cancer cases in Switzerland, affecting more than 12,000 individuals annually. Hundreds of these patients are likely to carry germline pathogenic variants associated with hereditary breast ovarian cancer (HBOC) or Lynch syndrome (LS). Genetic services (counseling and testing) for hereditary susceptibility to cancer can prevent many cancer diagnoses and deaths through early identification and risk management. OBJECTIVE Cascade screening is the systematic identification and testing of relatives of a known mutation carrier. It determines whether asymptomatic relatives also carry the known variant, needing management options to reduce future harmful outcomes. Specific aims of the CASCADE study are to (1) survey index cases with HBOC or LS from clinic-based genetic testing records and determine their current cancer status and surveillance practices, needs for coordination of medical care, psychosocial needs, patient-provider and patient-family communication, quality of life, and willingness to serve as advocates for cancer genetic services to blood relatives, (2) survey first- and second-degree relatives and first-cousins identified from pedigrees or family history records of HBOC and LS index cases and determine their current cancer and mutation status, cancer surveillance practices, needs for coordination of medical care, barriers and facilitators to using cancer genetic services, psychosocial needs, patient-provider and patient-family communication, quality of life, and willingness to participate in a study designed to increase use of cancer genetic services, and (3) explore the influence of patient-provider communication about genetic cancer risk on patient-family communication and the acceptability of a family-based communication, coping, and decision support intervention with focus group(s) of mutation carriers and relatives. METHODS CASCADE is a longitudinal study using surveys (online or paper/pencil) and focus groups, designed to elicit factors that enhance cascade genetic testing for HBOC and LS in Switzerland. Repeated observations are the optimal way for assessing these outcomes. Focus groups will examine barriers in patient-provider and patient-family communication, and the acceptability of a family-based communication, coping, and decision-support intervention. The survey will be developed in English, translated into three languages (German, French, and Italian), and back-translated into English, except for scales with validated versions in these languages. RESULTS Descriptive analyses will include calculating means, standard deviations, frequencies, and percentages of variables and participant descriptors. Bivariate analyses (Pearson correlations, chi-square test for differences in proportions, and t test for differences in means) will assess associations between demographics and clinical characteristics. Regression analyses will incorporate generalized estimating equations for pairing index cases with their relatives and explore whether predictors are in direct, mediating, or moderating relationship to an outcome. Focus group data will be transcribed verbatim and analyzed for common themes. CONCLUSIONS Robust evidence from basic science and descriptive population-based studies in Switzerland support the necessity of cascade screening for genetic predisposition to HBOC and LS. CASCADE is designed to address translation of this knowledge into public health interventions. TRIAL REGISTRATION ClinicalTrials.gov NCT03124212; https://clinicaltrials.gov/ct2/show/NCT03124212 (Archived by WebCite at http://www.webcitation.org/6tKZnNDBt).

Background To investigate clinical factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in relapsing epithelial ovarian cancer (EOC) patients with BRCA mutations and receiving olaparib as maintenance therapy in real-world. Methods Multicenter (8 hospitals) European retrospective study of relapsing EOC patients having germline or somatic mutations of BRCA1/BRCA2 genes and treated with olaparib as maintenance therapy after platinum-based chemotherapy. Results One hundred and fifteen patients were included. Median age was 54 years. There were 90 BRCA1 carriers, 24 BRCA2 carriers and one patient had germline mutation of BRCA1 and BRCA2. Six patients had somatic mutations (all BRCA1) and 109 had germline mutations. Ninety percent had serous carcinomas and were platinum-sensitive. Following ultimate platinum-based chemotherapy, 69% of the patients had normalization of CA-125 levels and 87% had RECIST objective responses, either partial (53%) or complete (34%). After a median follow-up of 21 months, median PFS was 12.7 months and median OS was 35.4 months. In multivariate analysis, factors associated with prolonged PFS under olaparib were: platinum-free interval (PFI) ≥ 12 months, RECIST complete response (CR) or partial response (PR) and normalization of CA-125 upon ultimate platinum-based chemotherapy. Factors associated with prolonged OS were PFI ≥ 12 months, CR and normalization of CA-125. Conclusions Platinum-free interval ≥ 12 months, complete response and normalized CA-125 levels after ultimate platinum-based chemotherapy are associated with prolonged PFS and OS in relapsing BRCA mutated ovarian cancer patients who received olaparib as maintenance therapy. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure S.I. Labidi-Galy: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. T. de La Motte Rouge: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. O. Derbel: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. A. Wolfer: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. E. Kalbacher: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. O. Tredan: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. V. Heinzelmann-Schwarz: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. F. Bazan: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. M. Rodrigues: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. I.L. Ray-Coquard: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca. All other authors have declared no conflicts of interest.

Maternal embryonic leucine-zipper kinase (MELK) shows oncogenic properties in basal-like breast cancer, a cancer subtype sharing common molecular features with high-grade serous ovarian cancer. We examined the potential of MELK as a molecular and pharmacological target for treatment of epithelial ovarian cancer (EOC).Bioinformatic analysis was performed on nine OC transcriptomic data sets totaling 1241 patients. Effects of MELK depletion by shRNA or inhibition by OTSSP167 in cell lines were assessed by colony formation and MTT (proliferation) assays, Western blotting (apoptosis), and flow cytometry (cell cycle analysis).Elevated MELK expression was correlated with histological grading (n=6 data sets, p0.05) and progression-free survival (HR 5.73, p0.01) in OC patients and elevated MELK expression in other cancers with disease-free survival (n=3495, HR 1.071, p0.001). Inhibition or depletion of MELK reduced cell proliferation and anchorage-dependent and -independent growth in various OC cell lines through a G2/M cell cycle arrest, eventually resulting in apoptosis. OTSSP167 retained its cytotoxicity in Cisplatin- and Paclitaxel-resistant IGROV1 and TYK-nu OC cells and sensitized OVCAR8 cells to Carboplatin but not Paclitaxel.MELK inhibition by OTSSP167 may thus present a strategy to treat patients with aggressive, progressive, and recurrent ovarian cancer.