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OBJECTIVES: Adding maintenance olaparib to bevacizumab provided a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the randomized, double-blind PAOLA-1/ENGOT-ov25 trial (NCT02477644). We analyzed PFS by clinical risk and biomarker status. METHODS: Patients received olaparib 300 mg twice daily for up to 24 months plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total, or placebo plus bevacizumab. This post hoc exploratory analysis evaluated PFS in patients classified as higher risk (stage III with upfront surgery and residual disease or neoadjuvant chemotherapy; stage IV) or lower risk (stage III with upfront surgery and no residual disease), and by biomarker status. RESULTS: Of 806 randomized patients, 74% were higher risk and 26% were lower risk. After a median 22.9 months of follow-up, PFS favored olaparib plus bevacizumab versus placebo plus bevacizumab in higher-risk patients (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.49-0.74) and lower-risk patients (0.46; 0.30-0.72). Olaparib plus bevacizumab provided a substantial PFS benefit versus bevacizumab alone in the homologous recombination deficiency (HRD)-positive subgroup (higher risk: HR 0.39; 95% CI 0.28-0.54 and lower risk: 0.15; 0.07-0.30), with 24-month PFS rates in lower-risk patients of 90% versus 43%, respectively (Kaplan-Meier estimates). CONCLUSIONS: In PAOLA-1, maintenance olaparib plus bevacizumab provided a substantial PFS benefit in HRD-positive patients with a reduction of risk of progression or death of 61% in the higher-risk group and of 85% in the lower-risk group compared with bevacizumab alone. ispartof: GYNECOLOGIC ONCOLOGY vol:164 issue:2 pages:254-264 ispartof: location:United States status: published

PURPOSE To compare standard versus extended duration of bevacizumab treatment in combination with front-line chemotherapy in women with newly diagnosed stage IIB-IV ovarian cancer. METHODS In this multicenter, open-label, randomized phase III trial (ClinicalTrials.gov identifier: NCT01462890 ), patients with newly diagnosed International Federation of Gynecology and Obstetrics stage IIB-IV epithelial ovarian, fallopian tube, or peritoneal cancer underwent primary cytoreductive surgery followed by six cycles of chemotherapy (paclitaxel 175 mg/m2 plus carboplatin area under the curve 5 once every 3 weeks) and bevacizumab (15 mg/kg once every 3 weeks). Patients were randomly assigned 1:1 to receive bevacizumab for either 15 or 30 months, stratified by International Federation of Gynecology and Obstetrics stage/residual tumor. The primary end point was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary end points included overall survival (OS), safety, and tolerability. RESULTS Between November 11, 2011, and August 6, 2013, 927 women were randomly assigned. There was no difference in PFS between treatment arms (hazard ratio, 0.99; 95% CI, 0.85 to 1.15; unstratified log-rank P = .90). Median PFS was 24.2 versus 26.0 months with standard versus extended duration of bevacizumab, respectively; restricted mean PFS was 39.5 versus 39.3 months, respectively. There was no OS difference between treatment arms (hazard ratio, 1.04; 95% CI, 0.87 to 1.23; P = .68). Serious/nonserious adverse events of special interest occurred in 29% versus 34% of patients in the standard versus experimental arms, respectively, and were consistent with the known safety profile of standard bevacizumab. CONCLUSION Longer treatment duration with bevacizumab for up to 30 months did not improve PFS or OS in patients with primary epithelial ovarian, fallopian tube, or peritoneal cancer. A bevacizumab treatment duration of 15 months remains the standard of care.

Fertility-sparing treatment in patients with cervical cancer should, in principle, follow identical algorithms to that in patients without future reproductive plans. In recent years, a trend towards non-radical procedures such as conization or simple trachelectomy has become apparent in medical literature, because of their associations with better pregnancy outcomes. However, the published reports included small numbers of patients and heterogenous treatment strategies to ascertain safety of such approaches.Our aims were to collect multi-institutional data regarding the oncological outcomes after fertility-sparing treatment in cervical cancer patients and to identify prognostic risk factors, including the influence of the radicality of individual cervical procedures.Patients aged 18-40 years with FIGO 2018 stage IA1 + lymphovascular space invasion or ≥IA2 cervical cancer who underwent any type of fertility-sparing procedure were eligible for this retrospective observational study, regardless of their histotype, tumor grade, and history of neoadjuvant chemotherapy. Associations between disease- and treatment-related characteristics with the risk of recurrence were analyzed.A total of 733 patients from 44 institutions across 13 countries were included in this study. Almost half of the patients had stage IB1 cervical cancer (49%), and two-thirds were nulliparous (66%). After a median follow-up of 72 months, 51 patients (7%) experienced recurrence of whom 19 (2.6%) died due to the disease. The most common sites of recurrence were the cervix (53%) and pelvic nodes (22%). The risk of recurrence was three times higher in patients with tumors2 cm in size than in patients with smaller tumors, irrespective of the treatment radicality (19.4% vs. 5.7%; hazard ratio 2.982, 95% CI 1.383-6.431, P = .005). The recurrence risk in patients with tumors ≤2 cm in size did not differ between patients who underwent radical trachelectomy or non-radical (conization and simple trachelectomy) cervical procedures (P = .957), regardless of tumor size subcategory (1 or 1-2 cm) or lymphovascular space invasion.Fertility-sparing non-radical cervical procedures were not associated with increased risk of recurrence compared with radical procedures in patients with tumors ≤2 cm in size in this large, multicenter retrospective study. The risk of recurrence after any type of fertility-sparing procedure was significantly greater in patients with tumors2 cm in size.

Purpose Sphingosine-kinase-1 (SPHK1) is a key enzyme of sphingolipid metabolism which is involved in ovarian cancer pathogenesis, progression and mechanisms of drug resistance. It is overexpressed in a variety of cancer subtypes. We investigated SPHK1 expression as a prognostic factor in epithelial ovarian cancer patients. Methods Expression analysis of SPHK1 was performed on formalin-fixed paraffin-embedded tissue from 1005 ovarian cancer patients with different histological subtypes using immunohistochemistry. Staining intensity of positive tumor cells was assessed semi-quantitatively, and results were correlated with clinicopathological characteristics and survival. Results In our ovarian cancer collective, high levels of SPHK1 expression correlated significantly with complete surgical tumor resection (p = 0.002) and lower FIGO stage (p = 0.04). Progression-free and overall survival were further significantly longer in patients with high-grade serous ovarian cancer and overexpression of SPHK1 (p = 0.002 and p = 0.006, respectively). Conclusion Our data identify high levels of SPHK1 expression as a potential favorable prognostic marker in ovarian cancer patients.

Variant-specific loss of heterozygosity (LOH) analyses may be useful to classify BRCA1/2 germline variants of unknown significance (VUS). The sensitivity and specificity of this approach, however, remains unknown. We performed comparative next-generation sequencing analyses of the BRCA1/2 genes using blood-derived and tumour-derived DNA of 488 patients with ovarian cancer enrolled in the observational AGO-TR1 trial (NCT02222883). Overall, 94 pathogenic, 90 benign and 24 VUS were identified in the germline. A significantly increased variant fraction (VF) of a germline variant in the tumour indicates loss of the wild-type allele; a decreased VF indicates loss of the variant allele. We demonstrate that significantly increased VFs predict pathogenicity with high sensitivity (0.84, 95% CI 0.77 to 0.91), poor specificity (0.63, 95% CI 0.53 to 0.73) and poor positive predictive value (PPV; 0.71, 95% CI 0.62 to 0.79). Significantly decreased VFs predict benignity with low sensitivity (0.26, 95% CI 0.17 to 0.35), high specificity (1.0, 95% CI 0.96 to 1.00) and PPV (1.0, 95% CI 0.85 to 1.00). Variant classification based on significantly increased VFs results in an unacceptable proportion of false-positive results. A significantly decreased VF in the tumour may be exploited as a reliable predictor for benignity, with no false-negative result observed. When applying the latter approach, VUS identified in four patients can now be considered benign. Trial registration number NCT02222883., publishedVersion

To assess the correlation between fetal head regression and levator ani muscle (LAM) co-activation under Valsalva maneuver.This study was a secondary analysis of a prospective cohort study on the association between the angle of progression (AoP) and labor outcome. We scanned a group of nulliparous women at term before the onset of labor at rest and under maximum Valsalva maneuver. In addition to the previously calculated AoP, in the present study, we measured the anteroposterior diameter of LAM hiatus (APD) on each ultrasound image. LAM co-activation was defined as APD at Valsalva less than that at rest, whereas fetal head regression was defined as AoP at Valsalva less than that at rest. We calculated the correlation between the two phenomena. Finally, we examined various labor outcomes according to the presence, absence, or co-existence of these two phenomena.We included 469 women. A total of 129 (27.5%) women presented LAM co-activation while 50 (10.7%) showed head regression. Only 15 (3.2%) women showed simultaneous head regression and LAM co-activation. Women with coexisting LAM co-activation and head regression had the narrowest AoP at Valsalva in comparison with other study groups (In nulliparous women at term before the onset of labor fetal head regression and LAM co-activation at Valsalva are two distinct phenomena that uncommonly coexist.

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

Acid ceramidase (ASAH1) is a key player in sphingolipid metabolism and signaling. It has prognostic value for several cancers, but histotype-specific analyses of ovarian cancer are not yet available. We used three retrospective TMA cohorts encompassing a total of 1106 ovarian cancers with follow-up data for immunohistochemical analysis of acid ceramidase (ASAH1) expression. Patients with sub-optimal debulking and persistent residual tumor after surgery introduced bias in the prognostic analysis and were excluded from further studies. Overall, we detected an association of ASAH1 expression with better prognosis in ovarian cancer patients. ASAH1 expression differed between histological ovarian cancer histotypes with most frequent expression in endometrioid and clear cell ovarian cancer, which are both associated with good prognosis. Stratified subgroup analyses within these histotypes did not reveal significant survival differences, but the power of the analysis may be limited by smaller sample sizes. In contrast to breast cancer, we found only a modest concordance between estrogen receptor status and ASAH1 expression within the endometrioid ovarian cancer histotype. In an exploratory analysis of estrogen receptor negative endometrioid ovarian cancer, ASAH1 expression was associated with significantly better overall survival (P = 0.007). Acid ceramidase is most frequently expressed in endometrioid and clear cell histotypes and could add independent prognostic value to estrogen receptor in endometrioid ovarian cancer. Modulating sphingolipid metabolism may lead to novel therapeutic intervention strategies for this disease.

Introduction/Background* According to current guidelines fertility-sparing treatment (FST) in cervical cancer patients should follow the same principles as in patients without fertility preservation. The literature from the last years, however, show a trend towards less-radical procedures. Although oncological outcomes are reported to be equal or better than in non-FST, published groups are small, mostly single institutional, inclusion criteria vary, and treatment is not uniform. The aim of this study was to collect retrospective data from multiple institutions across several countries on oncological and reproductive outcomes after FST. Methodology Included were cervical cancer patients between 18–40 years with stages ≥ IA1+LVSI, who underwent any type of FST and completed follow-up of at least 6 months. Patients were eligible irrespective of neoadjuvant chemotherapy, histotype or tumour grade. Result(s)* Altogether 733 patients from 44 centers in 13 countries were eligible for analyses. Median follow-up of the whole cohort was 6 years (1.2–14.5). More than half of the cases had stage IB1 (54.2%; 397/733). Mean age of patients was 32 years and two thirds were nulliparous (484/733). Most common surgical procedure was conization (48%). Repeated cervical surgery was performed in 161 patients (21.9%), most frequently re-conization (57.8%). Less than half of the patients (49.2%; 361/733) attempted to conceive after treatment. Out of them, 138 (38.2%) got pregnant and 100 (27.7%) successfully delivered. Pre-cancer recurrence was diagnosed in 22 (3%) patients, 51 (7%) patients had cancer recurrence and 19 (2.6%) died of disease. Three times higher risk of recurrence was observed in tumours ≥ 2 cm in comparison to smaller tumours (19.4% vs. 5.7%; p Conclusion* Data from the real life practice showed that FST in cervical cancer patients is safe in patients with HPV related tumours smaller than 2 cm. In such tumours conization represents sufficient procedure with satisfactory pregnancy outcomes. Surprisingly less than half of patients attempt to conceive after treatment.

Paclitaxel is a frontline drug for the treatment of epithelial ovarian cancer (EOC). However, following paclitaxel-platinum based chemotherapy, tumor recurrence occurs in most ovarian cancer patients. Chromosomal instability (CIN) is a hallmark of cancer and represents genetic variation fueling tumor adaptation to cytotoxic effects of anticancer drugs. In this study, our Kaplan-Meier analysis including 263 ovarian cancer patients (stages I/II) revealed that high Polo-like kinase (PLK) 1 expression correlates with bad prognosis. To evaluate the role of PLK1 as potential cancer target within a combinatorial trial, we induced strong mitotic arrest in ovarian cancer cell lines by synergistically co-targeting microtubules (paclitaxel) and PLK1 (BI6727) followed by pharmaceutical inhibition of the Anaphase-Promoting Complex (APC/C) using proTAME. In short- and long-term experiments, this triple treatment strongly activated apoptosis in cell lines and primary ovarian cells derived from cancer patients. Mechanistically, BI6727/paclitaxel/proTAME stabilize Cyclin B1 and trigger mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by activation of caspase-dependent effector pathways. This triple treatment prevented endoreduplication and reduced CIN, two mechanisms that are associated with aggressive tumors and the acquisition of drug resistance. This “two-punch strategy” (strong mitotic arrest followed by blocking mitotic exit) has important implications for developing paclitaxel-based combinatorial treatments in ovarian cancer.

Background: We have previously shown that expression of the IL8/VEGFA-metagene eliminates the good prognostic effect of TILs in TNBC (PMID 21978456, 28750120). We also showed that the VEGFA metagene predicted response to neoadjuvant bevacizumab in the GeparQuinto trial (Karn 2017 SABCS #851166). The main cellular sources of the transcripts that comprise the VEGFA metagene are unknown since mRNA profiling of bulk biopsies contains signals from different cell types. Methods: Individual genes that comprise the VEGFA metagene were measured in bulk tissue- and single cell-RNA-Seq from breast cancer subtypes and normal cells on different platforms (Affymetrix n=4915, Agilent n=597, Illumina n=2433, RNA-Seq n=1215, Exome Capture RNA-Seq n=226, HTG-Seq n=243, sc-RNA-Seq n=24710). For blinded, orthogonal validation we performed immunohistochemistry. Effect of neoadjuvant chemotherapy with or without bevacizumab was studied by RNA-Seq and IHC on samples from GeparQuinto trial. SWOG S0800 (GSE114403), PROMIX (GSE87455), and GeparSixto trials were used for validation. TCGA was mined for mutations and somatic CNA. RNA-Seq from GeparNuevo was used for correlation with checkpoint inhibitor treatment. Results: We identified a stable core of six genes (VEGFA, ANGPTL4, ADM, NDRG1, DDIT4, CSTB) in different cohorts. Strong expression of this signature was mainly restricted to TNBC subtype and associated with poor prognosis within this subgroup. Single cell RNA-Seq of breast epithelial cells from 4 reduction mammoplasties and 4 TNBC revealed that these genes are coexpressed in individual epithelial cells and not associated with endothelial cells. In line with their presumed functions in cellular stress and hypoxia, immunohistochemistry revealed strong para-necrotic expression in TNBC. Moreover, high gene expression in TNBC was associated with mutations in DNA damage control pathways, somatic copy number alterations, and lower TILs. While chemotherapy led to downregulation, bevacizumab increased expression. In multivariate analysis, high pretreatment values predict pCR to both bevacizumab and chemotherapy (OR 2.40, P=0.006), which may be explained by sensitivity of tumors which are already under cellular stress. On the other hand, expression of the VEGFA metagene seems to create an immunosuppressive environment that counteracts the positive prognostic effect of TILs. In pre-treatment biopsies from the GeparNuevo checkpoint inhibitor trial we found a negative correlation of VEGFA metagene expression with the amount of the recently identified tissue-resident memory T cell subset (CD8TRM, PMID 29942092; P=0.002), while the subsequent increase of CD8TRM during treatment was larger in tumors with high VEGFA (P=0.019). Conclusions: Perinecrotic carcinoma cells under stress from hypoxia and or chromosomal instability are the source of the VEGFA metagene signature. Its predictive value in TNBC suggests estimating and reporting the amount of necrosis in the pathology report may be helpful in predicting response to preoperative chemotherapy, and could be used as stratification factor in clinical trials. The signature indicates an immunosuppressive environment and should be further studied in the context of immune therapies in combinations with anti-angiogenic treatment. Citation Format: Karn T, Denkert C, Sinn BV, Weber K, Nekljudova V, Rody A, Meissner T, Hatzis C, El-Balat A, Becker S, Solbach C, Untch M, Schneeweiss A, von Minckwitz G, Loibl S, Pusztai L, Holtrich U. Single-cell profiling identifies hypoxic carcinoma cells as source of an immunosuppressive VEGFA metagene [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-01.

5571 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial, the addition of maintenance olaparib (ola) to bevacizumab (bev) in patients (pts) with newly diagnosed advanced high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for pts with HRD-positive tumors including a BRCA1/ BRCA2 mutation (BRCAm; Ray-Coquard et al. NEJM 2019). Preclinical data suggest that pts with mutations (mut) in the RING domain of BRCA1 are less sensitive to ola. The magnitude of benefit from ola + bev, according to the location of mut in the functional domains (FD) of BRCA , remains to be explored. Methods: Pts with newly diagnosed advanced HGOC in response after platinum-based chemotherapy + bev received maintenance bev (15 mg/kg q3w for 15 months [mo]) + either ola (300 mg bid for 24 mo) or placebo (pbo). In this post hoc exploratory analysis, PFS was analyzed in pts with BRCAm according to mut location in the FDs of BRCA1 (RING, DNA-binding domain [DNA-BD], or BRCA1 C terminus [BRCT]) and BRCA2 (RAD51-BD; DNA-BD). Results: Among the 806 randomized pts, 235 (29.2%) harbored a BRCAm: 160 (19.9%) with a BRCA1 mut and 76 (9.4%) with a BRCA2 mut. BRCA1 mut in FDs of RING, DNA-BD and BRCT were detected in 19 (11.8%), 41 (25.6%) and 34 (21.2%) pts, respectively. BRCA2 mut were detected in FDs of RAD51-BD and DNA-BD in 37 (48.7%) and 14 (18.4%) pts, respectively. With a median follow-up of 25.5 mo, 24-mo PFS rates and hazard ratios (HRs) according to mut locations are reported in the Table. In pts with a BRCA1 DNA-BD mut, 24-mo PFS was 89% and 14% (ola + bev vs pbo + bev; HR 0.08, 95% confidence interval [CI] 0.02–0.26) compared with 64% and 24% for pts with mut in RING + BRCT + other domains (HR 0.33, 95% CI 0.19–0.57). In pts with BRCA2 mut, 24-mo PFS for pts with mut in the DNA-BD was 91% vs 100% (ola + bev vs pbo + bev) compared with 82% and 44% for pts with mut in RAD51-BD + other domains (HR 0.21, 95% CI 0.08–0.54). Conclusions: In this exploratory analysis, pts with newly diagnosed advanced HGOC and a BRCAm had a PFS benefit from maintenance ola + bev regardless of mut locations in BRCA1/BRCA2. Sensitivity to ola + bev maintenance was particularly high for pts with mut in the DNA-BD of BRCA1. Pts with a mut in the DNA-BD of BRCA2 commonly had excellent outcomes. Clinical trial information: NCT02477644. [Table: see text]

Aims The primary aim of the present study was to assess the association between levator ani muscle (LAM) integrity and function on the one hand, and the risk of urinary incontinence (UI) on the other. A secondary objective was to assess the association between fundal pressure in the second stage of labor (Kristeller maneuver) and the risk of postpartum UI. Methods In this prospective cohort study, women underwent a clinical and transperineal ultrasound examination at rest, at pelvic floor muscle contraction (PFMC), and at Valsalva maneuver 3-6 months after their first vaginal delivery. LAM avulsion and levator hiatal area (LHA) were evaluated. In addition, women were interviewed about the presence of UI, whether stress (SUI) or urgency (UUI). Results Overall, data of 244 women were analyzed. SUI was reported in 50 (20.5%), while UUI was reported in 19 (7.8%) women. Women who reported SUI had a higher prevalence of LAM avulsion and less proportional reduction in LHA from rest to a maximum contraction in comparison to women with no SUI. Women who reported UUI had a greater LHA at rest, during contraction, and during maximal Valsalva in comparison to women without UUI. No significant association was found between the Kristeller maneuver and the incidence of any UI. Conclusion Levator ani avulsion and less proportional reduction of LHA with PFMC appear to be associated with a higher risk of postpartum urinary stress incontinence.

Objective: To assess the feasibility and reliability of transperineal ultrasound in the assessment of fetal breech descent in the birth canal, by measuring the breech progression angle (BPA). Methods: Women with a singleton pregnancy with the fetus in breech presentation between 34 and 41 weeks' gestation were recruited. Transperineal ultrasound images were acquired in the midsagittal view for each woman, twice by one operator and once by another. Each operator measured the BPA after anonymization of the transperineal ultrasound images. BPA was defined as the angle between a line running along the long axis of the pubic symphysis and another line extending from the most inferior portion of the pubic symphysis tangentially to the lowest recognizable fetal part in the maternal pelvis. Each operator was blinded to all other measurements performed for each woman. Intra- and interobserver reproducibility of BPA measurement was evaluated using the intraclass correlation coefficient (ICC). To investigate the presence of any bias, intra- and interobserver agreement was also analyzed using Bland–Altman analysis. Student's t-test and Levene's W0 test were used to investigate whether a number of different clinical factors had an effect on systematic differences and homogeneity, respectively, between BPA measurements. Results: Overall, 44 women were included in the analysis. BPA was measured successfully by both operators on all images. Both intra- and interobserver agreement analyses showed excellent reproducibility in BPA measurement, with ICCs of 0.88 (95% CI, 0.80–0.93) and 0.83 (95% CI, 0.71–0.90), respectively. The mean difference between measurements was 0.4° (95% CI, −1.4 to 2.2°) for intraobserver repeatability and −0.4° (95% CI, −2.6 to 1.8°) for interobserver repeatability. The upper limits of agreement were 12.0° (95% CI, 8.9–15.1°) and 13.6° (95% CI, 9.9–17.3°) for intra- and interobserver repeatability, respectively. The lower limits of agreement were −11.2° (95% CI, −14.3 to −8.1°) and −14.4° (95% CI, −18.2 to −10.7°) for intra- and interobserver repeatability, respectively. No systematic difference between BPA measurements was found on either intra- or interobserver agreement analysis. None of the clinical factors examined (maternal body mass index, maternal age, gestational age at the ultrasound scan and parity) showed a statistically significant effect on intra- or interobserver reliability. Conclusions: BPA represents a new feasible and highly reproducible measurement for the evaluation of fetal breech descent in the birth canal. Future studies assessing its usefulness in the prediction of successful external cephalic version and breech vaginal delivery are needed. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

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

hTFM in primary vulvar cancer is an important prognostic factor. Ideally, a diameter of 8 mm should be achieved after primary surgery. The role of VIN III persistence after primary surgery in vulvar cancer is still unclear. The main objective of the current study was to study the role of residual VIN III re-excision and compare differences in disease-free survival among patients with different hTFM and in primary vulvar cancer.Forty-two patients with residual adjacent VIN III after primary surgery for vulvar cancer which were operated between 2000 and 2016 in our clinic were enrolled in this retrospective study. Re-excision rates for residual adjacent VIN III were calculated. According to the histological margin patients were divided into three group: 3, 3-8 and 8 mm. Univariate and multivariate analyses were conducted using the Kaplan-Meier method and Cox proportional hazards models, respectively.The vast majority of patients had pT1b stage (57.1%), grading G2 (71.4%) and lymph node-negative (45.3%) disease at first diagnosis. The re-excision rate was 57.1%. The 5-year disease-free survival (DFS) rates in patients with 3, 3-8 and 8 mm hTFM were 50.0, 50.0 and 81.0%, respectively (p = 0.032). The 5-year DFS rates in patients with re-excision and without re-excision for VIN III were 77.3 and 52.9%, respectively (p = 0.060). In univariate analysis was solely hTFM 8 mm a prognostic factor for DFS (p = 0.017).hTFM may be a potential prognostic indicator for DFS in vulvar cancer patients. Re-excision for residual adjacent VIN III could not be established as a prognostic factor for DFS after primary surgery in squamous cell cancer of vulva.

HIFU steht fur „high intensity focussed ultrasound“ und ist eine relativ neue Technologie, die als MRT(Magnetresonanztomographie)- oder als ultraschallgesteuertes HIFU angeboten wird. Wahrend der letzten Jahre sind vermehrt Arbeiten erschienen, die mogliche Optionen klarer definieren und den medizinischen Nutzen dieser neuen Methode objektiv nachweisen wollen. Inhalt der vorliegenden Publikation ist eine Darstellung der dominanten Techniken und der existierenden Literatur zum Stand der verfugbaren evidenzbasierten Medizin. Es soll herausgearbeitet werden, inwieweit Behauptungen zu Therapieerfolgen berechtigt sind und welche Entwicklungen in der Zukunft realistischerweise zu erwarten sind. Durchsicht der relevanten Datenbanken (PubMed, Medline, Embase) und der verfugbaren Industrieinformationen. HIFU ist eine komplexe Technologie, hinter der beachtliche technische Leistungen stehen. Der konkrete klinische Nutzen wird aktuell etabliert. Wie bei vielen neuen Technologien in der Fruhphase ist die Zukunft von HIFU weder garantiert noch komplett abzusehen. Aufgrund der einzigartigen Wirkweise konnte es sich um eine hochrelevante Zukunftstechnologie handeln. Bei der Kritik an aktuellen Insuffizienzen wird ubersehen, welche Schwierigkeiten ahnlich revolutionare Neuerungen, wie der diagnostische Ultraschall oder die Laparoskopie, uberwinden mussten, bevor sie aus der taglichen Routine nicht mehr wegzudenken waren. Die Frauenheilkunde sollte gegenuber dieser Zukunftstechnologie offen sein; es ware ein Fehler, ihr hohes innovatives Potenzial in Deutschland nicht weiter zu verfolgen.

Myomas, also known as fibroids, are a specific characteristic of the human species. No other primates develop fibroids. At a cellular level, myomas are benign hyperplastic lesions of uterine smooth muscle cells. There are interesting theoretical concepts that link the development of myomas in humans with the highly specific process of childbirth from an upright position and the resulting need for greatly increased “expulsive” forces during labor. Myomas might be the price our species pays for our bipedal and highly intelligent existence. Myomas affect, with some variability, all ethnic groups and approximately 50% of all women during their lifetime. While some remain asymptomatic, myomas can cause significant and sometimes life-threatening uterine bleeding, pain, infertility, and, in extreme cases, ureteral obstruction and death. Traditionally, over 50% of all hysterectomies were performed for fibroids, leading to a significant healthcare burden. In this article, we review the developments of the past 20 years with regard to multiple new treatment strategies that have evolved during this time.

Background/Aim: Totally implanted venous access devices (TIVAD) are increasingly used in the treatment of cancer patients. The aim of this study was to assess the incidence of early and late complications resulting from subcutaneous TIVADs in patients with breast cancer. Materials and Methods: Between 2004 and 2009, we reviewed patients with breast cancer who had a TIVAD placed. Early and late complications, as well as risk factors for TIVAD-associated thrombosis were retrospectively assessed. Results: A total of 281 patients were included. Complications occurred in 26% of patients, the majority of which were late complications (21.4%.) The development of TIVAD associated thrombosis was the most frequent late complication (16.4%). In the univariate analysis followed by a multivariate model, risk factors for TIVAD associated thrombosis were not identified. Only within the subgroup of metastatic breast cancer patients an increased risk of TIVAD-associated thrombosis of left compared to right venous access was detected (p=0.015). Conclusion: TIVAD implantation done in a gynecological outpatient setting is feasible and safe.

Claudin-1 is a tight junction protein that has been demonstrated to be involved in tumorigenesis and tumor progression in various types of solid tumors. In the present study, the protein expression of claudin-1 in squamous cervical cancer tissues obtained from 106 patients was analyzed by immunohistochemistry. In addition, the grade of claudin-1 expression was analyzed for associations with certain clinicopathological parameters. A significant overexpression of claudin-1 was detected in the tumor cells, when compared with that in the peritumoral stroma. There was no significant association between claudin-1 expression and FIGO stage, tumor size, grading or the appearance of distant metastases. Cervical cancer patients scoring positive for claudin-1 protein expression tended to exhibit more lymph node metastasis (28.3%), compared with claudin-1-negative patients (7.1%). Regarding overall survival, the results of the present study suggest a better prognosis for claudin-1-negative patients. In order to elucidate whether claudin-1 overexpression has a significant prognostic impact on squamous cervical cancer, further studies are required.

Dargestellt wird die aktuelle Datenlage bezuglich epidemiologischer Beobachtungen und atiologischer Faktoren fur die unterschiedlichen Vulvamalignome. Das Wissen um die Epidemiologie, die Pathogenese und die atiologischen Faktoren des Vulvakarzinoms ist nicht nur relevant fur Praventionsstrategien, Fruherkennungsmasnahmen, die Implementierung von Screnningprogrammen und fur therapeutische Entscheidungen, sondern auch fur das postoperative Management im Sinne der Risikostratifizierung. Skizziert wird auch das beginnende Verstandnis der molekularbiologischen Pathways. Die weitere Forschung kann kunftig eine dezidiert neue Systematisierung der nosologischen Subentitaten initiieren, ferner moglicherweise auch innovative therapeutische Ansatze und Strategien ermoglichen.

Background: Tumors with infiltrating lymphocytes (TIL) demonstrate a better prognosis particularly in TNBC and HER2 positive breast cancer. Two competing hypothesis predict contrasting relationships of TILs and genomic heterogeneity. On one hand, a strong immune response may lead to “pruning” of intratumor heterogeneity by eliminating immunogenic clones resulting in a near equilibrium, hence better prognosis, while cancers that escape the surveillance may evolve towards greater clonal heterogeneity and genomic complexity. In some cancers, the predicted neoantigens are less frequent than expected by chance also suggesting immune mediated elimination of neoplastic clones (Rooney et al. 2015). Studies also showed an inverse association between immune cell infiltration and intratumor clonal heterogeneity (Morris et al. 2016). On the other hand, cancers with greater genomic instability and mutational burden will have larger clonal heterogeneity and therefore more neoantigens and greater immune infiltration. Indeed, a positive correlation between overall mutation load and immune activity in the tumor microenvironment was observed in pooled data across a broad range of cancer types (Brown et al. 2014, Rooney et al. 2015, Schumacher and Schreiber 2015). Methods: We assessed these two competing hypothesis and examined the relationship between genomic complexity and immune gene expression in different breast cancer subtypes. We used previously described immune metagene expression (DNA microarray n=655) as measures of immune infiltration in the TCGA data set (RNA-Seq n=1215). We compared somatic mutations, mutation count, neoantigen load, clonal heterogeneity metrics and the distribution of mutations in 119 canonical cancer genes and 12 cancer pathways between good and poor prognosis TNBC (n=208) corresponding to high and low immune infiltration. Results:A positive but weak correlation between mutation count and immune metagene expression was observed when all breast cancer subtypes were analyzed together (P=0.08). This was driven by the generally higher mutation count and immune infiltration in TNBC. When TNBC was analyzed separately, good prognosis TNBC with high immune infiltration had lower total mutation count (P=0.021) and predicted neo-antigen count (P=0.035). Clonal heterogeneity was also lower in good prognosis TNBC (P=0.001). There was a strong inverse relationship of dispersion in mutation variant allele frequencies and immune metagene expression. CASP8 was the top enriched mutation in TNBC with high immune infiltration (P=0.007 with no adjustment for multiple testing). Conclusions:High immune infiltration is associated with reduced intratumor heterogeneity in TNBC suggesting immune sculpting of the tumor and a near equilibrium between the cancer and immune surveillance. Surgical resection of the primary tumor may tilt the balance towards the immune system resulting in the better prognosis of high-TIL TNBC. TNBC with low immune infiltration has greater clonal heterogeneity and mutation load and may represent the consequence of escape from immune surveillance. Mutation of CASP8 may be one way to evade tumor cell killing in high-TIL TNBC as previously noted. Citation Format: Karn T, Jiang T, Hatzis C, Sänger N, El-Balat A, Holtrich U, Becker S, Bianchini G, Pusztai L. Immune sculpting of the triple negative breast cancer genome [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-07.

BACKGROUND/AIM Borderline ovarian tumors (BOTs) have a less aggressive behavior than invasive epithelial ovarian tumors. Still some patients relapse or succumb to disease. Molecular markers that reliably predict prognosis are lacking. Insulin-like growth factor II mRNA-binding protein (IMP3) has been suggested as a prognostic marker in colorectal, hepatocellular, and ovarian clear-cell carcinomas. MATERIALS AND METHODS We analyzed the expression of IMP3 by immunohistochemistry in a cohort of 140 BOT and its association with histopathological features. RESULTS We found no association of IMP3 expression with patients' age, FIGO stage, microinvasion, and presence of implants. In contrast, IMP3 expression correlated to mucinous subtype of BOTs (42.2% vs. 9.5% among other subtypes) (p

Introduction/Background In the Phase III SOLO1 first-line trial, maintenance therapy with the PARP inhibitor olaparib provided a substantial progression-free survival (PFS) benefit to advanced ovarian cancer (OC) patients who have a BRCA1/2 mutation (BRCAm) and are in complete or partial response to first-line chemotherapy (Moore K et al. N Engl J Med 2018). VEGF inhibitor may increase PARP sensitivity, particularly in some OC patients with BRCA wild type (Liu JF et al. Lancet Oncol 2014). PAOLA-1/ENGOT-ov25 (NCT02477644) is the first Phase III trial to evaluate the efficacy and safety of a PARP inhibitor with bevacizumab as first-line maintenance therapy, and in patients regardless of BRCAm status. Methodology PAOLA-1 is a randomized, double-blind, international Phase III trial. Eligible patients had newly diagnosed, advanced (FIGO stage IIIA-IV) high-grade serous or endometrioid ovarian, fallopian tube or peritoneal cancer. Patients had no evidence of disease or were in partial response following first-line platinum-based chemotherapy plus bevacizumab. Bevacizumab was to be given for up to 15 months, including the initial combination with chemotherapy. 806 patients were randomized (2:1) in maintenance therapy to olaparib (300 mg bid) or placebo plus bevacizumab (15 mg/kg, d1, q3w), stratified by first-line treatment outcome and tumour BRCAm status. The primary endpoint is investigator-assessed PFS (modified RECIST v1.1). The 458 PFS events required for the primary analysis to show significance at the two-sided 5% level with an estimated >80% power have been reached in March 2019. Database lock was in July and analyses are ongoing. Results The LBA will report: investigator-assessed PFS, PFS by BRCAm/HRD status, health- related quality of life, and safety and tolerability results. Conclusion PAOLA-1 will demonstrate whether addition of olaparib to bevacizumab maintenance therapy following first-line platinum-based chemotherapy plus bevacizumab provides a clinically meaningful benefit to OC patients. Disclosure P Harter declares honoraria from AstraZeneca, Roche, Sotio, Tesaro, Stryker, ASCO, Zai Lab and MSD; and consultancy/advisory board fees from AstraZeneca, Roche, Tesaro, Lilly, Clovis, Immunogen and MSD/Merck. Marie Ange Mouret-Reynier declares no conflicts of interest. S Pignata declares honoraria from Roche, AstraZeneca, MSD, Pfizer, Incyte, Novartis, PharmaMar, Clovis and Tesaro; and travel expenses from Roche, AstraZeneca and MSD. Claire Cropet declares no conflicts of interest. A Gonzalez-Martin declares consulting/advisory board fees from Roche, AstraZeneca, Tesaro, Clovis, Pfizer, ImmunoGen, PharmaMar, MSD, Genmad and Novartis; and speaker bureau/expert testimony fees from Roche, AstraZeneca, MSD Tesaro and PharmaMar. Gerhard Bogner declares consulting/advisory board fees from AstraZeneca Tesaro and Roche; and travel expenses from GSK, Roche, Pharmamar, AstraZeneca and Tesaro. K Fujiwara declares honoraria from AstraZeneca, Chugai Roche, Zeria, Taiho, Nihon Kayaku, Kyowahakko Kirin, Janssen and Daiichi Sankyo; consulting/advisory board fees from Pfizer, MSD and Eisai; research funding from AstraZeneca, MSD, Chugai Roche, Eisai and Kaken; and travel expenses from Pfizer. I Vergote declares consulting/advisory board fees from Advaxis, BIOCAD, Eisai, MSD, Roche, Genmab, Roche, PharmaMar, Millenium Pharmaceuticals, Clovis, AstraZeneca, Tesaro, Oncoinvent, ImmunoGen and Sotio; contracted research with Oncoinvent and Genmab; research funding from Amgen, Roche and Stichting tegen Kanker; and Takeda Oncology, PharmaMar, Genmab, Roche, AstraZeneca, Tesaro, Clovis and Immunogen. N Colombo declares honoraria from Roche, AstraZeneca, PharmaMar, Tesaro, Clovis, Pfizer, MSD, BIOCAD and Takeda; consulting/advisory board fees from Roche, AstraZeneca, PharmaMar, Tesaro, Clovis, Pfizer, MSD, BIOCAD, Takeda; and travel expenses from PharmaMar, Tesaro and Roche. J Maenpaa declares honoraria from Roche, AstraZeneca and Tesaro; consultancy/advisory board fees from AstraZeneca, Tesaro, Clovis and MSD; and travel expenses from Roche. Anne Floquet declares consultancy/advisory board fees from GSK, AstraZeneca and Clovis; and travel expenses from Roche, GSK and AstraZeneca. Ahmed El-Balat declares honoraria from AstraZeneca, Roche, Pharmamar, MSD, Tesaro, Clovis; and consultancy/advisory board fees from AstraZeneca and Roche. D Lorusso declares honoraria from Merck; consultancy/advisory board fees from Merck, AstraZeneca, Tesaro, Clovis, Immunogen, PharmaMar and Roche; research funding from Clovis, PharmaMar, Merck and Roche; and travel expenses from Tesaro, Roche and PharmaMar. EM Guerra Alia declares consultancy/advisory board fees from Roche, Clovis and AstraZeneca; and travel expenses from Roche and Baxter. Michel Fabro declares honoraria from Tesaro and AstraZeneca; and consultancy/advisory board fees from Tesaro and AstraZeneca. Barbara Schmalfeldt declares honoraria from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MSD; consultancy/advisory fees from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS; speaker bureau/expert testimony fees from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS; research grant funding from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS and travel expenses from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS. Anne Claire Hardy Blessard declares honoraria from AstraZeneca, Lilly, Novartis, Pfizer, Roche and Tesaro. Ingo Runnebaum declares honoraria from AstraZeneca. I Ray-Coquard declares honoraria from AstraZeneca, Clovis, Tesaro and PharmaMar; consulting/advisory board fees from AstraZeneca, Roche, Clovis, Tesaro, Genmab, PharmaMar, MSD and Pfizer; research funding from MSD; and travel expenses from AstraZeneca and Roche; consulting/advisory board fees from Roche; and travel expenses from Roche, MSD, Tesaro and AstraZeneca. E Pujade-Lauraine declares honoraria from AstraZeneca and Tesaro; consulting/advisory board fees from AstraZeneca, Roche, Clovis, Tesaro, Genmab, Incyte, MSD and Pfizer; research funding from AstraZeneca, Roche and Tesaro; and travel expenses from AstraZeneca, Roche and Tesaro.

Introduction/Background Olaparib (50 mg hard capsules, HC) was the 1st PARPi approved in the EU in 12/2014 as monotherapy for maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (BRCAm) ovarian cancer (PSR-OC) who are in response to platinum-based chemotherapy. In addition, film-coated tablets (FT, 100/150 mg) were approved in 05/2018 regardless of BRCA status. Here, we report for the first time data on real-world olaparib treatment from patients who switched from HC to FT. Methodology The German prospective non-interventional study C-PATROL (NCT02503436) collects routine clinical and patient-reported outcome data in BRCAm PSR-OC patients treated according to label with olaparib with the recommended total daily dose of 800 mg (HC) or 600 mg (FT). The 3rd interim analysis (cut-off: 01APR2019) for patients treated with olaparib (HC/FT) reflects data on patient characteristics and safety by using descriptive statistics focussing on ‘switcher’ (here patients can be treated with FT since 08/2018). Results 252 olaparib-treated patients were analysed; 177 (70.2%) were treated with HC, 47 (18.7%) switched from HC to FT, and 28 (11.1%) were newly initiated with FT. Median therapy durations for the three subgroups were 9.0 months (HC), 17.4 months (switcher; 13.4 months before [HC] and 4.4 months after [FT] switch) and 9.2 months (FT). 44 switcher (93.6%) had adverse events (AEs); 41 (87.2%) before and 26 (55.3%) after switching. Treatment modifications due to AEs were more frequent prior to switching (i.e. during HC treatment). In total, 30 switcher had therapy modifications; 25 (83.3%) before and 11 (36.7%) after switching. Conclusion The 3rd interim analysis indicates that under routine conditions, olaparib is well tolerated in patients who switched from HC to FT. In fact, fewer AEs occurred after switching. The toxicity profile observed so far is in line with the results of the clinical trial program for olaparib in PSR-OC and 1st-line maintenance. Funding AstraZeneca. Disclosure F. Marme: honoraria received for speaker, consultancy or advisory role, travel, from AstraZeneca, Tesaro, Roche, Novartis, Pfizer, PharmaMar, GenomicHealth, CureVac, Amgen, Eisai, MSD,Celgene, Clovis. F. Hilpert: membership on advisory boards for AstraZeneca, Roche, Tesaro, Clovis, MSD, PharmaMar, receipt of honoraria from Astra Zeneca, Clovis, Roche, Tesaro, MSD, PharmaMar, Pfizer, Novartis. M. Welslau: No conflict of interest, nothing to disclose. J. P. Grabowski: Advisory, consultancy and speakers activities for AstraZeneca, Tesaro, Clovis, Riemser, honoraria from AstraZeneca, Tesaro, Roche, Clovis, Pfizer, Riemser. J. Seitz: no conflict of interest, nothing to disclose. A. El-Balat: membership on advisory councils, speaker’s activities for AstraZeneca, Roche, PharmaMar, Olympus. A. D. Hartkopf has received honoraria (speakers bureau and consulting fees) from AstraZeneca, Eisai, GenomicHealth, Lilly, MSD, Novartis, Pfizer, Roche, Tesaro, Teva. R. Glowik: employee of AstraZeneca. J. Sehouli: Advisory and expert activities for PharmaMar, Clovis, Tesaro, Roche, Roche Diagnostics, Astra Zeneca,Merck, Bayer,Eisei, Johnson and Johnson, MSD, Novocure, Amgen, Lilly; Receipt of professional fees from PharmaMar, Clovis, Tesaro, Roche, Astra Zeneca, receipt of research grant support (institution) from PharmaMar, Clovis, Tesaro, Roche, Astra Zeneca, Medimmune, Bristol Myers, Lilly.

BackgroundFor individuals with ovarian cancer (OC), therapy options mainly depend on BRCA1/2 germline status. What is the prevalence of deleterious somatic variants, that is, does genetic tumour testing identify subgroups of individuals who also might benefit from targeted therapy?MethodsPaired analysis of tumour-derived versus blood-derived DNA to determine the prevalence of deleterious somatic variants in OC predisposition genes (ATM, BRCA1/2, BRIP1, MSH2/6, PALB2, RAD51C/D and TP53) and the PIK3CA and PTEN genes in individuals with OC (AGO-TR1 study, NCT02222883). Results were complemented by BRCA1, PALB2 and RAD51C promoter methylation analyses and stratified by histological subtype; 473 individuals were included.ResultsThe combined analyses revealed that deleterious germline variants in established OC predisposition genes (all: 125/473, 26.4%; BRCA1/2: 97/473, 20.5%), deleterious somatic variants in established OC predisposition genes excluding TP53 (all: 39/473, 8.2%; BRCA1/2: 30/473, 6.3%) and promoter methylation (all: 67/473, 14.2%; BRCA1: 57/473, 12.1%; RAD51C: 10/473, 2.1%; PALB2: 0/473) were mutually exclusive, with a few exceptions. The same holds true for deleterious somatic PIK3CA and/or PTEN variants (33/473, 7.0%) found to be enriched in endometrioid and clear cell OC (16/35, 45.7%); 84.3 % of the deleterious single-nucleotide/indel germline variants in established OC predisposition genes showed significantly higher variant fractions (VFs) in the tumour-derived versus blood-derived DNA, indicating a loss of the wild-type alleles.ConclusionTumour sequencing of the BRCA1, BRCA2, PIK3CA and PTEN genes along with BRCA1 and RAD51C promoter methylation analyses identified large subgroups of germline mutation-negative individuals who may be addressed in interventional studies using PARP or PI3K/AKT/mTOR inhibitors.Trial registration numberNCT02222883

e18061 Background: Risk factors for invasive recurrence of borderline tumours (BOT) of the ovary are needed. The actin-bundling protein Fascin-1 (FSCN1) is involved in alteration of adhesion and cell motility and has been associated with invasion and metastasis in different cancers. Methods: We studied a retrospective cohort of 124 bordeline tumors of the ovary (BOT) with validated diagnosis by an independent pathologist for expression of FSCN1 as potential prognostic biomarker. Results: We found strong expression of the actin-bundling protein FSCN1 in 62 of these tumors. FSCN1 positive patients were slightly younger (46.9±2.2 vs. 53.3±2.3 years, P = 0.049). Expression of FSCN1 was more frequently detected in BOT with serous compared to mucinous histotype (58/78 [74.4%] vs. 3/41 [7.3%], p < 0.001), and in cases with micropapillary pattern (25/28 [89.3%] vs. 38/98 [38.8%], P < 0.001). In addition, a non significant trend was observed for more frequent expression of FSCN1 among cases with implants (8/10 [80.0%] vs. 55/116 [47.4%], P = 0.095). When we compared progression free survival of the patients we found numerical lower but not statistically significant PFS rates of 90.5±6.4% vs. 94.4±5.4% for 10 years, and 81.4±10.3% vs. 94.4±5.4% for 15 years, in BOT with FSCN1 expression compared to those tumors negative for FSCN1, respectively. Conclusions: Our analysis suggests an association of FSCN1 expression in BOT with micropapillary pattern and implants, which have been linked to inferior prognosis. Cases with FSCN1 expression in our cohort displayed numerical lower PFS rates prompting further studies of this marker.

AimsExpression of Claudin-1 has been associated with prognosis in several cancers. Here we investigated the expression pattern of Claudin-1 in borderline tumours of the ovary (BOT).MethodsWe analysed a cohort of 114 cases of borderline tumour (BOT). Claudin-1 expression was studied by immunohistochemistry using a polyclonal antibody and was compared with clinical and histopathological characteristics.ResultsStrong Claudin-1 expression was found in 30 cases (26.3%) independent of histological subtype. Expression was significantly less frequent in International Federation of Gynecology and Obstetrics (FIGO) stage I (p= 0.045), while the presence of microinvasion did not correlate with Claudin-1 expression. In contrast, we detected a highly significant association of Claudin-1 expression with the presence of peritoneal implants (p=0.003) and micropapillary pattern (p=0.047), which are features exclusively seen in serous BOT. Moreover, when we restricted our analysis to the subtype of serous BOT, the association of Claudin-1 expression with peritoneal implants (pConclusionsIn conclusion, Claudin-1 expression is associated with the presence of peritoneal implants and micropapillary pattern, which have been shown to be associated with poor prognosis. We speculate that overexpression of Claudin-1 might be linked to the mitogen-activated protein kinase pathway activation in BOT and suggest further studies to define its prognostic and potential therapeutic value.

Summary Background Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer. Methods We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m2 on days 1–5) plus either oral sorafenib 400 mg or placebo twice daily on days 6–15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression. Investigators and patients were masked to allocation of sorafenib or placebo; topotecan treatment was open label. The primary endpoint was investigator-assessed progression-free survival, analysed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov , number NCT01047891 . Findings Between Jan 18, 2010, and Sept 19, 2013, 185 patients were enrolled, 174 of whom were randomly assigned: 85 to sorafenib and 89 to placebo. Two patients in the sorafenib group had serious adverse events before treatment and were excluded from analyses. 83 patients in the sorafenib group and 89 in the placebo group started treatment. Progression-free survival was significantly improved with sorafenib versus placebo (hazard ratio 0·60, 95% CI 0·43–0·83; p=0·0018). Median progression-free survival was 6·7 months (95% CI 5·8–7·6) with sorafenib versus 4·4 months (3·7–5·0) with placebo. The most common grade 3–4 adverse events were leucopenia (57 [69%] of 83 patients in the sorafenib group vs 47 [53%] of 89 in the placebo group), neutropenia (46 [55%] vs 48 [54%]), and thrombocytopenia (23 [28%] vs 20 [22%]). Serious adverse events occurred in 49 (59%) of 83 sorafenib-treated patients and 45 (51%) of 89 placebo-treated patients. Of these, events were fatal in four patients (5%) in the sorafenib group (dyspnoea and poor general condition, septic shock, ascites and dyspnoea, and sigma perforation) and seven (8%) in the placebo group (pulmonary embolism in two patients, disease progression in two patients, and one case each of sepsis with fever, pleural effusion, and tumour cachexia). Sorafenib was associated with increased incidences of grade 3 hand-foot skin reaction (three [13%] vs 0 patients) and grade 2 alopecia (24 [29%] vs 12 [13%]). Interpretation Sorafenib, when given orally in combination with topotecan and continued as maintenance therapy, showed a statistically and clinically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer. These encouraging results support the crucial role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies. Funding Bayer , Amgen , and GlaxoSmithKline .

The taxanes are effective microtubule-stabilizing chemotherapy drugs that inhibit mitosis, induce apoptosis, and produce regression in a fraction of cancers that arise at many sites including the ovary. Novel therapeutic targets that augment taxane effects are needed to improve clinical chemotherapy response in CCNE1-amplified high grade serous ovarian cancer (HGSOC) cells. In this study, we conducted an siRNA-based kinome screen to identify modulators of mitotic progression in CCNE1-amplified HGSOC cells that may influence clinical paclitaxel response. PLK1 is overexpressed in many types of cancer, which correlates with poor prognosis. Here, we identified a novel synthetic lethal interaction of the clinical PLK1 inhibitor BI6727 and the microtubule-targeting drug paclitaxel in HGSOC cell lines with CCNE1-amplification and elucidated the underlying molecular mechanisms of this synergism. BI6727 synergistically induces apoptosis together with paclitaxel in different cell lines including a patient-derived primary ovarian cancer culture. Moreover, the inhibition of PLK1 reduced the paclitaxel-induced neurotoxicity in a neurite outgrowth assay. Mechanistically, the combinatorial treatment with BI6727/paclitaxel triggers mitotic arrest, which initiates mitochondrial apoptosis by inactivation of anti-apoptotic BCL-2 family proteins, followed by significant loss of the mitochondrial membrane potential and activation of caspase-dependent effector pathways. This conclusion is supported by data showing that BI6727/paclitaxel-co-treatment stabilizes FBW7, a component of SCF-type ubiquitin ligases that bind and regulate key modulators of cell division and growth including MCL-1 and Cyclin E. This identification of a novel synthetic lethality of PLK1 inhibitors and a microtubule-stabilizing drug has important implications for developing PLK1 inhibitor-based combination treatments in CCNE1-amplified HGSOC cells.

To evaluate the actin-bundling protein fascin-1 (FSCN1) as marker for borderline ovarian tumours (BOTs).We analysed a retrospective cohort of 140 BOTs with validated diagnosis by an independent pathologist. Immunohistochemical detection of FSCN1 was quantified as combined immunoreactive score (CIS) blinded to clinical patient data. Analyses were first performed for FSCN1 positive versus negative, and then verified using three categories derived from the observed distribution (negative, weak, strong; CIS 0, 1-2, 3-9).We detected FSCN1 positivity in 51.4%, and strong expression (CIS 3-9) in 14.3% of the samples. FSCN1 positivity was associated with serous subtype (p0.001) and micropapillary pattern (p0.001). Correlation with micropapillary pattern remained significant within the serous BOT (SBOT) subgroup (p=0.022). Strong FSCN1 expression (CIS 3-9) was associated both with the presence of implants (p=0.022), and a higher International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.020).Our analysis links FSCN1 with SBOT with micropapillary pattern. Strong expression is associated with higher FIGO stage and the presence of implants, both related to elevated risk of recurrence. Hence, FSCN1 is an interesting marker worth further analyses of its prognostic value in BOTs.