bluuebunny/crossref_metadata_2025_split huggingface dataset:
Laboratory cross-comparison of tumor BRCA1/2 analysis in a multicenter epithelial ovarian cancer series: The BORNEO GEICO60-0 study.
Authors: Romero Ignacio , Oaknin Ana , Garcia-Casado Zaida , Marquez Raul , Yubero Esteban Alfonso , Gallego Alejandro , Sanchez Ana Beatriz , Perez Segura Cristina , Alarcon Jesus , Barretina-Ginesta Maria Pilar , Palacio Vázquez Isabel , Farinas-Madrid Lorena , Cueva Juan Fernando , Matito Judit , Poveda Andres , Lopez Guerrero Jose Antonio , Vivancos Ana 
Published: May 2020

6055 Background: Epithelial ovarian cancer (EOC) identification of BRCA1 and BRCA2 mutations is usually carried out in germline, representing around 17% in high grade serous ovarian cancer (HGSOC) and further 5-7% are only identified in the tumor (somatic). The aim of this study was to identify in EOC tumor BRCA mutation frequency and inter-laboratory reproducibility using different Next-generation Sequencing (NGS) approaches. Methods: In an ambispective study design, a population of unselected consecutive non mucinous EOC was clinically annotated and Formalin-Fixed Paraffin-Embedded (FFPE) tumor BRCA1/2 mutation analysis was undertaken in two laboratories (Lab-1 and Lab-2) simultaneously. Both laboratories used their own validated NGS panels; variant allele frequency threshold was 5% for single nucleotide polymorphism and 10% for indels. Each laboratory classified variants into three categories based on ACMG criteria: non-mutated (class 1-2), Variants of Uncertain Significance (VUS: class 3) and likely pathogenic/pathogenic (class 4-5). Germline BRCA analysis was available according to local clinical practice or centralized in Lab-1 if histology was low grade. Results: Ninety FFPE samples were received, 8 had insufficient material to be analyzed in both laboratories and 6 cases were discarded due to tumor cellularity below 20% leaving 76 cases to be sequenced. The population had a median age of 58 (25-84) years, 87% (66/76) of HGSOC histology and 70% of advanced stages (III-IVB: 53) and 14.5% (11) germline BRCA mutations (3 with not available results). Lab-1 identified 17 class 4-5 mutations, 11 correspond to germline, 4 (5.3%) are just somatic and 2 have germline results not available yet. Lab-2 had one not valuable analysis and identified 16 class 4-5 mutations, 10 corresponding to germline and 4 somatic variants. Percentage of concordance between both laboratories was 96% (kappa coefficient 0.883; p value < 0.0001). Three discordant out of 18 class 4-5 mutations included 2 undetected (VAF of 14.9% and 60.3% respectively) and one class 4 in Lab-2 classified as VUS in Lab-1 due to different interpretation criteria. Conclusions: The global BRCA mutation frequency in our series was 22.3% for Lab-1 and 21.0% for Lab-2. Concordance between tumor BRCA mutation analysis was high (96%). Nevertheless, further effort is required on harmonizing the technical and analytical aspects in tumor mutational analysis.
Laparoscopy compared with laparotomy for comprehensive surgical staging of early ovarian cancer: Results of a retrospective multicenter case-control study.
Authors: Radosa Julia Caroline , Radosa Marc P , Mertke Pauline , Hugo Marie-Luise , Radosa Christoph Georg , Brucker Sara , Taran Florin Andrei , Kommoss Stefan , Ulrich Uwe Andreas , Hackethal Andreas , Tuschy Benjamin , Suetterlin Marc , Deeken Martin , Solomayer Erich-Franz 
Published: May 2020

6067 Background: The objective of this study was to compare laparoscopy and laparotomy for comprehensive surgical staging of early ovarian cancer in terms of efficacy and oncologic safety. Methods: Patients who had laparoscopic staging for early stage (I/II) ovarian cancer between 01/2000 and 10/2018 at the participating sites (Gynecologic comprehensive cancer centers with respective expertise in minimal invasive surgery) were included in this retrospective case-control study. The control group consisted of all patients treated via laparotomy during the study period. Clinical data were abstracted from medical record and recent follow up information were obtained. Comparisons were made between patients regarding surgical parameters and oncologic outcome and multivariate models were used to identify factors independently associated with disease recurrence. Results: Among 313 patients, staging was performed via laparoscopy in 208 (66 %) patients and via laparotomy in 105 (34 %) patients. Patients staged laparoscopically were younger (median 52 (15-86) vs. 59 (17-92) vears, p≤0.01) and had a lower BMI (24.4 (16.5-46.8) vs. 26 (15.5-53.8), p≤0.01). Regarding surgical parameters, duration of surgery was longer (291 (159-778) vs. 277 (159-690) minutes, p≤0.01), postoperative hospitalization was shorter (7 (0-27) vs. 9 (0-92) days, p≤0.01) and postoperative complications were lower in the laparoscopy group. On univariate analysis there were no differences in rates of tumor stage according to FIGO, intraoperative rupture of ovarian cysts (14 % vs. 13 %, p=0.87), number of lymph nodes removed (24 (0-89) vs. 22 (0-96), p=0.81) or any recurrence of disease (14 % vs. 16 %, p=0.52). At a median follow-up of 46 months (0-227), there were no differences in DFS and OS by surgical technique (5yr DFS 82 % (SE 0.04) vs. 83 % (SE 0.05), p=0.43; OS 91 % (SE 0.03) vs. 87 % (SE 0.04), p=0.87). On multivariate analysis route of surgery was not associated with an increased risk of recurrence. Conclusions: According to this preliminary analysis, laparoscopic surgical staging in patients with early ovarian cancer seems to be adequate and safe, but a longer follow-up and prospective data are needed to enhance evidence on oncologic outcomes.
Efficacy and safety of olaparib according to age in BRCA-1/2 mutated patients with recurrent platinum-sensitive ovarian cancer: Analysis of the phase III SOLO2 (AGO-OVAR 2.23/ENGOT-Ov21) study.
Authors: Trillsch Fabian , Mahner Sven , Ataseven Beyhan , Asher Rebecca , Dubot Coraline , Clamp Andrew R. , Penson Richard T. , Oza Amit M. , Amit Amnon , Huzarski Tomasz , Casado Antonio , Scambia Giovanni , Friedlander Michael , Colombo Nicoletta , Fujiwara Keiichi , Sonke Gabe S. , denys Hannelore , Lowe Elizabeth S. , Pujade-Lauraine Eric 
Published: May 2020

6068 Background: Adding olaparib as maintenance treatment to BRCA-1/2 mutated patients (pts) with recurrent platinum-sensitive ovarian cancer (PSOC) has significantly improved progression-free survival (PFS) as well as patient-centered endpoints. As BRCA mutated pts tend to be younger, specific information on efficacy and safety of olaparib for elderly pts is of special interest. Methods: 295 pts from the SOLO2 trial that randomly assigned to olaparib or placebo were categorized according to age cutoff at 65 years. The efficacy and tolerability of olaparib relative to placebo within in each age group was assessed based on PFS and toxicity outcomes. Quality of life (QoL) was assessed using EQ-5D-5L descriptive system score and FACT Trial Outcome Index (TOI) and evaluated using generalized estimating equations (GEE) and time without significant symptoms of toxicity (TWiST) analysis. Results: Baseline characteristics were similar in pts ≥65 years (N=62; 21%) compared to pts <65 years (N=233; 79%), except for more BRCA2 mutations in elderly pts (39% vs. 23%). There was no significant difference in the magnitude of PFS benefit from olaparib in elderly as compared with younger pts (interaction P=0.33). The PFS adjusted hazard ratio (HR) of olaparib vs. placebo arms were respectively HR≥65 0.43 (95%-confidence interval [CI] 0.24-0.81) and HR<65 0.31 (95%-CI 0.22-0.43). Elderly and younger pts also had comparable safety profiles with no significant differences in median time on olaparib treatment (≥65: 27 vs. <65: 33 months), percentage of pts experiencing at least one grade >2 adverse event with olaparib (≥65: 73% vs. <65: 79%), or requiring at least one dose interruption or dose reduction (≥65: 77.5 vs. <65: 77.6%). No differences were found with regards to QoL scores. Quality adjusted TWiST analysis showed only non-significant differences in duration of good QoL under olaparib (≥65: 8.02 vs. <65: 9.24 months, P=0.48). Conclusions: In this large cohort of BRCA mutated PSOC pts treated with a PARP inhibitor within a phase III trial, no significant differences were detected in terms of efficacy, safety, and QoL with olaparib treatment for pts ≥65 years compared to younger pts. This information supports the use of PARP inhibitors as maintenance therapy for PSOC pts irrespective of age. Clinical trial information: NCT01874353.
Combined regimen of inhalable STING agonist plus chemoimmunotherapy in platinum-resistant or platinum-refratory ovarian cancer: A randomized, open-label, phase II trial.
Authors: Zhang Yan , Mei Qian , Meng Yuanguang , Chen Meixia , Liu Yang , Yang Qingming , Han Weidong 
Published: May 2020

6071 Background: Approximately 70% patients with advanced ovarian cancer have a relapse and ultimately succumb to their disease. Treatment options are limited in this context with an unacceptable low response (less than 20%). Immunotherapy with checkpoint inhibitors presented to date are not very convincing with 10-15% response because of inadequate immunity. We previously discovered the critical role of manganese in innate immune sensing of tumors by activating STING signaling. This ongoing, randomized, phase II study is to assess STING agonist plus nPP chemotherapy and anti-PD-1 antibody sintilimab in platinum-resistant/refractory ovarian cancer. Methods: Enrolled patients were 2:1 randomizedly assigned to receive nab-paclitaxel (180-220mg/m2), cisplatin (60-80mg/m2) and sintilimab 200mg per 3 weeks with (cohort 1) or without (cohort 2) inhalable MnCl2 (0.4mg/kg) daily. Safety was assessed by CTCAE v5.0, and clinical response by MRI or CT every 2 cycles referred to RECIST version 1.1. The primary endpoints were objective response rate (ORR) and safety. Key secondary end points were disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: 27 patients were enrolled, and 21 were included in efficacy population by the end of Jan. 2020. All enrolled patients were with heavily treated history, median 4 lines of prior therapy, median 19 cycles of multiagent regimens. The addition of MnCl2 to the combined chemo-immunotherapy did not appear to exacerbate treatment-related adverse events (AEs). The most common AEs are hematological toxicity (87%), nausea (56%) and vomiting (47%) in both two cohorts. All 14 evaluable patients (14/19) from cohort 1 had an effective control (11 PR [78.6%], 3 SD [21.4%]) . Ten patients (71.4%) achieved PR at the first tumor scan assessment. For 8 cases from cohort 2, 7 were assessable and all showed SD, 4 of whom exhibited SD with enlarged lesions and disease progression after 4-cycle treatment. Conclusions: MnCl2 administration induced encouraging objective clinical responses (78.6%) and disease control (100%) in relapsed/refractory ovarian cancer. The combined regimen showed accepted and manageable safety profile. Clinical trial information: NCT03989336.
Infiltration of tumor by T cells following treatment with DPX-Survivac and intermittent low dose cyclophosphamide (CPA) leads to clinical responses in advanced recurrent ovarian cancer (OvCa).
Authors: Dorigo Oliver , MacDonald Lisa Diana , Schindler Joanne , Bramhecha Yogesh , Torrey Heather , Kaliaperumal Valarmathy , Hrytsenko Olga , Dirk Brennan , Patterson Kelcey , Stanford Marianne , Fiset Stephan 
Published: May 2020

6075 Background: DPX-Survivac is a novel T-cell activating therapy designed to elicit an effective immune response against survivin expressing tumors. Its unique mechanism of action (MOA) facilitates active and sustained uptake of target peptides by APC at the injection site. APCs subsequently present the antigen in local lymph nodes generating survivin-specific T cells that traffic to distant tumor sites and elicit effective tumor cell death. DPX-Survivac is used in combination with intermittent low dose CPA which acts as an immunomodulator of T-cell responses. Methods: The study enrolled 22 patients with recurrent, advanced platinum-sensitive and -resistant ovarian cancer. Patients received 2 subcutaneous injections of DPX-Survivac 3 weeks apart and every 8 weeks thereafter, and intermittent low dose CPA for up to 1 year. Paired tumor biopsies were performed prior to treatment and on treatment. Primary endpoints were ORR, DCR and safety. Secondary endpoints include cell mediated immunity, immune cell infiltration in paired biopsy samples, DOR, TTP, OS and biomarker analyses. Results: Twenty-two patients were enrolled in the study. Three patients were discontinued prematurely due to early progression leaving 19 patients for response evaluation. The population is heavily pre-treated with a median of 3 lines of prior treatment [range 1 to 8]; 77.3% of patients are platinum-resistant. At the time of data cut-off, 3/19 patients (15.8%) achieved PR and one additional patient met PR on target lesions but had a newly detected lesion; 10/19 patients (52.6%) showed tumor regression on target lesions at > 1 scan. The median time on study (N=19) is 131 days [63 to ˃295]. Six patients are still on trial. The clinical responses and benefits observed with treatment are associated with an increase in systemic survivin-specific T cells and tumor immune-infiltration. Moreover, RNAseq analysis on paired tumor tissue revealed an enrichment in cytolytic T-cell signature. The most common AEs were grade 1-2 injection site reactions; 4 treatment-related SAEs were reported. Conclusions: DPX-Survivac and intermittent low dose CPA shows promising clinical activity in heavily pre-treated patients with recurrent OvCa. The preliminary results, supported by strong translational data, link the observed clinical benefits with the unique MOA of DPX-Survivac. These clinical results suggest that DPX-Survivac/CPA is an active regimen in OvCa and warrant testing in an expanded cohort of patients. Clinical trial information: NCT02785250.
Elucidating resistance mechanism to PARP inhibitors for the development of novel therapeutic approaches in high-grade serous ovarian cancer.
Authors: Kulbe Hagen , Kassuhn Wanja Nikolai , Ringel Frauke , Welsch Gabriele , Treffkorn Peggy , Taube Eliane T , Horst David , Sehouli Jalid , Braicu Ioana ,   TOC (Tumor Bank Ovarian Cancer) Network
Published: May 2020

6078 Background: PARP inhibitors (PARPi) have been established as a targeted therapeutic approach not only in patients with high-grade serous ovarian cancer (HGSOC) that have genetic loss of function of BRCA1/2-associated DNA repair. However, treatment efficacy varies and neither BRCA mutation, nor homolog recombination deficiency (HRD) status seem to be optimal predictors. Moreover, mechanisms of treatment resistance are poorly understood and novel approaches are urgently required. Methods: Here we created gene expression data of HGSOC patients (n = 52) before PARPi treatment to elucidate key signaling pathways of resistance to increase their efficacy in combinatorial therapeutic strategies. We performed a comprehensive bioinformatics analysis of the differentially expressed genes between the 25% extreme responders (n = 26; 13 each group), including gene set enrichment analysis (GSEA) and causal inference analysis with the CARNIVAL pipeline to elucidate the underlying molecular and regulatory mechanisms governing treatment efficacy and resistance. Results: In accordance with recent publications, we found higher levels of MYC activity in non-responders and deregulation of the Wnt/ß-catenin signaling pathway resulting in PARPi treatment resistance. The pathway enrichment analysis also revealed specific pathways especially PDGFR, FGFR, PI3K/mTOR and MAPK signaling pathway associated with resistant phenotype. Furthermore, we have identified key kinases, particularly JAK1/2 and SRC that might mediate resistance to PARP inhibition. In addition, differential gene expression analysis revealed folate receptor 1 (FOLR1) to be significantly higher expressed in non-responders (logFC = 2.66; p < 0.0026) with the potential as a serum-based biomarker not only for ovarian cancer, as it correlates closely with CA125, but also PARPi treatment efficacy. Conclusions: In conclusion, these findings define a network of pathways, that are crucial to mediate mechanism of PARPi resistance and identified key signaling kinases as therapeutic targets in ovarian cancer.
Mutation in homologous recombination to predict a better prognosis in endometrial cancer.
Authors: Zhao Luyang , Yibo Dai , Hu Yuanjin , Wang Zhiqi , Li Chengcheng , Wang Guoqiang , Wang Jianliu 
Published: May 2020

6082 Background: Endometrial cancers have been categorized into four genomic classes by The Cancer Genome Atlas Research Network (TCGA) with comprehensive genomic analysis. However, TCGA molecular subtypes are hard to utilize in clinic as the expensive cost and a simply version of POLE, TP53 genes cannot fully differentiate the four subtypes. Therefore, more convenient and reliable biomarkers need to be identified for clinical practice. Methods: Whole-exome sequencing and RNA sequencing data for 515 patients with endometrial carcinomas were downloaded from TCGA. Mutations in 48 genes of homologous recombination repair (HR) signaling were defined as HR mutation. Associations between HR mutation and survival and RNA expression were analyzed.Gene set enrichment analysis (GSEA) were used to invesgate the gene signaling. Results: HR mutation was associated with a prolonged disease specific survival (DSS) (HR, 0.39; 95% CI, 0.22-0.71; P = 0.002), progression-free survival (PFS) (HR, 0.46; 95% CI, 0.31-0.68; P < 0.001) and overall survival (OS) (HR, 0.45; 95% CI, 0.28-0.72; P = 0.001) in endometrial cancers. HR mutation was related with clinical characteristics including histological types (P < 0.05). In the multivariable cox proportional hazards regression model including FIGO 2008, histology types, tumor grade and TCGA subtypes, TP53 mutation, POLE mutation, the association between HR mutation and PFS was still significant (HR, 0.48; 95% CI, 0.27-0.86; P < 0.05), which indicating the HR mutation is an independent prognostic factor for PFS. HR mutations were associated with a higher tumor mutation burden. GSEA suggested that HR mutation was involved with the increase of genes related to activated T cells, immune cytolytic activity, and IFN-γ release. In MSS endometrial cancers, HR mutation still showed a longer PFS (HR, 0.57; 95% CI, 0.34-0.98; P = 0.04), suggested HR mutation may help predict the effect of immunotherapy in MSS endometrial carcinoma. Conclusions: HR mutation was related with a favorable prognosis through increasing T cells signature. Identification of HR mutation by genomic profiling provides a potentially novel and convenient approach for endometrial cancer patients to predict the prognosis independent of TCGA four subtype classifications and provides an inspiration for screening patients who may benefit from ICBs in endometrial cancer in the future.
Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort.
Authors: Erickson Britt Kristina , Najjar Omar , Klein Molly , Shahi Maryam , Dolan Michelle , Cimino-Mathews Ashley , Grandelis Anthony , Buza Natalia , Delaney Paris , Tymon-Rosario Joan , Santin Alessandro , Ferriss James Stuart , Stone Rebecca Lynn , Nickles Fader Amanda 
Published: May 2020

6084 Background: Uterine serous carcinoma (USC) is a rare and aggressive malignancy, accounting for 40% of all endometrial cancer deaths. Human Epidermal Growth Factor Receptor 2 (HER2) has emerged as an important prognostic and therapeutic target in USC. Given recent randomized trial results, HER2-directed therapy is now recommended in advanced-stage or recurrent, HER2-positive disease. The significance of tumoral HER2 expression in early-stage disease has not yet been established. Methods: In this IRB-approved, retrospective, multi-institutional cohort, women diagnosed with stage I USC from 2000-2018 were identified. Patient demographic, treatment, and survival data were collected. Immunohistochemistry (IHC) was performed for HER2 and scored 0-3+. Equivocal IHC results (2+) were further tested with in-situ hybridization (ISH) per the 2007 ASCO-CAP HER2 breast cancer guidelines. HER2 overexpression (“positive”) was defined as 3+ IHC or ISH positive. Kaplan-Meier analyses and Cox-proportional hazards were used to compare survival between the cohorts. Results: In total, 173 patients with stage I USC were tested for HER2; 25% were HER2-positive, 77.4% had stage IA and 22.6% had stage IB disease. Adequate clinical follow up was available for 168 patients. There were no significant differences in age, race/ethnicity, body mass index, surgical management, sub-stage, tumor size, adjuvant therapy, or follow-up duration between the HER2-positive and negative cohorts. On univarite analysis, presence of lymph-vascular space invasion was correlated with HER2-positive tumors (p=0.003). After a median follow-up of 50 months, there were 41 (24.4%) recurrences. Significantly more recurrences were observed in the HER2-positive cohort (47.6% vs. 16.7%, p<0.001). HER2 overexpression was also associated with poorer progression-free (PFS) and overall survival (OS) (p<0.001 and p=0.012). After adjusting for prognostic factors including sub-stage and adjuvant treatment, those with HER2-positive tumors experienced inferior PFS (aHR 3.67, 95%CI 1.92-6.98; p<0.001) and OS (aHR 2.03, 95%CI 1.03-4.01; p=0.042) compared to HER2-negative tumors. Conclusions: Uterine serous carcinoma is a poor prognostic tumor, even in patients with early-stage disease. Given its significant association with worse survival outcomes, tumoral HER2 overexpression appears to be a prognostic biomarker in women with stage I disease. These data provide rationale for clinical trials with HER2-directed therapy in early-stage uterine serous carcinoma.