bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comprehensive analysis of BRAF and KRAS mutation status in low-grade serous (LGS) and serous borderline (SB) ovarian cancer (OC).
Authors: Grisham Rachel Nicole , Garg Karuna , Zhou Qin , Iasonos Alexia , Berger Michael F. , Dao Fanny , Hyman David Michael , Levine Douglas A. , Solit David B. , Aghajanian Carol , Iyer Gopa 
Published: March 2020

5030 Background: LGS OC develops in a step-wise pattern from serous cystadenoma to SB tumor to invasive LGSOC. LGSOC accounts for 6-22% of serous OC and is a chemoresistant disease. Prior studies have reported that LGS/SB ovarian tumors harbor BRAF mutations in 28-35% of cases, suggesting that LGS/SB OC may respond to mutant BRAF inhibitors. Methods: We genotyped 75 LGS and SB ovarian tumors for BRAF and KRAS hotspot mutations using a mass spectrometry based Sequenom assay. All samples were collected at MSKCC between 2000-2010. All specimens underwent two independent pathologic reviews for diagnostic confirmation and macrodissection to ensure 80% cellularity. The incidence and identity of BRAF and KRAS mutations were defined and results were correlated with stage, response to treatment, and outcome. Exon capture sequencing is underway to sequence all coding exons of 230 cancer associated genes to identify additional targetable alterations in LGS/SB OC. Results: Of 75 samples examined, 56(75%) were SB and 19(25%) LGS histology. 57% of samples showed KRAS mutation (KRAS+) (n=17, 23%) or BRAF mutation (BRAF+) (n=26, 35%). Mutation status was mutually exclusive. All BRAF + were V600E, KRAS+ were G12D (n=9) or G12V (n=8). BRAF+ was associated with early stage (I-II) at presentation and SB histology. 22 (29%) patients were treated with chemotherapy, 2 (9%) with KRAS + and 0 with BRAF+. 4(15%) BRAF+ patients underwent resection of recurrent disease. All BRAF+ patients are alive without evidence of disease at a median follow-up of 43.3 months (range 1.9- 129.3 months). Conclusions: V600E BRAF mutations are present in 35% of cases of SB/LGS ovarian cancer. Presence of BRAF + in SB/LGS OC is associated with good prognosis and surgical cure of disease. Patients with SB/LGS OC who require systemic therapy are unlikely to have BRAF+. Our group is performing a detailed search for additional targetable alterations in multiple signal transduction pathways through next generation sequencing technology. [Table: see text]
Use of HE4 and CA125 to predict surgical outcome and for prognostic value for progression-free survival (PFS) and overall survival (OS) in primary epithelial ovarian cancer (EOC) patients (pts).
Authors: Braicu Ioana , Chekerov Radoslav , Richter Rolf , Vergote Ignace B. , Mahner Sven , Zeimet Alain G , Ganapathi Ram N. , Woelber Linn Lena , Castillo-Tong Dan Cacsire , Cadron Isabelle , Zeillinger Robert , Fotopoulou Christina , Sehouli Jalid 
Published: March 2020

5034 Background: Optimal surgical cytoreduction and response to platinum (P) based chemotherapy (ChTh) remain the cornerstones of therapeutic management of primary EOC. Aim of this study was to analyze the predictive role of HE4 and CA125 as biomarkers (BM) for clinical outcome in primary EOC pts at diagnosis and during subsequent follow-up. Methods: In the European OVCAD project 275 pts with primary EOC were enrolled. Pts were eligible if radical cytoreductive surgery and P-based ChTh were applied. Plasma collected at first diagnosis and 6 months after 1st line ChTh in P-sensitive pts was analyzed for HE4 and CA125 levels using ELISA and Luminex technique, respectively. Results: Complete cytoreduction with no residual tumor disease (RTD) was obtained in 69.9% pts. HE4 and CA125 expression in plasma at first diagnosis correlated with RTD, p = 0.002 and p=0.002, respectively. The sensitivity (SE) and specificity (SP) of the combinative use of both BM in predicting RTD was 64.8% and 73.5%, respectively. Pts having over-expression of both BM in plasma had a 6.1 greater risk for RTD (p<0.001, OR: 6.107, 95% CI 2.41-15.46). P-resistance occurred more frequently when both BM were over-expressed (p=0.028, OR= 3.1, 95%CI 1.13-8.46). Elevated BM levels during follow-up predicted recurrence (SE 90% and SP 71% for CA125 ≥55U/ml; SE 72.7% and SP 81.4% for HE4 ≥150pM) and when HE4 or CA125 were positive, a SE of 86.4% and SP of 72.9% were achieved. Elevated CA125 and HE4 at 6 months following adjuvant therapy was associated with significantly poorer PFS (p<0.001, HR 9.6, 95%CI 3.93-23.44 with elevated HE4 or CA125, and HR=50.52, 95%CI 14.44-176.78, with elevated HE4 and CA125) and OS (p<0.001, HR=7.42 95%CI 1.43-38.42 with elevated HE4 or CA125 and HR=28.38 95%CI 6.50-123.97 with elevated HE4 and CA125). Conclusions: The combinative use of HE4 and CA125 appears to have a significant value in predicting optimal surgical outcome and development of P resistance disease in EOC pts. Elevated plasma levels 6 months after 1st line ChTh significantly correlate with OS and PFS in P-sensitive pts.
Functional profiling of clear cell ovarian cancer.
Authors: Miller Rowan , Brough Rachel , Bajrami Ilirjana , Kaye Stanley B. , Lord Christopher J. , Ashworth Alan 
Published: March 2020

5035 Background: Clear cell ovarian cancer represents up to 15% of epithelial ovarian cancers. In comparison to other subtypes, clear cell ovarian carcinomas have a poorer prognosis and are relatively resistant to standard platinum based chemotherapy. Recently, loss of function mutations in the tumour suppressor gene ARID1A were identified in up to 50% of ovarian clear cell carcinomas. We have adopted an integral functional and molecular profiling approach as a route to identify new genetic dependencies and therapeutic targets for this disease. Methods: Clear cell ovarian cancer cell lines were functionally profiled using high throughput screening with chemical and siRNA libraries. This has been integrated with molecular profiling data generated from exome and transcriptome sequencing to aid the discovery of novel targets. Results: Using functional screens we have now identified critical gene dependencies and potential therapeutics in a series of clear cell ovarian cancer models. The comparison of functional viability profiles for models characterized by ARID1A loss of function mutations is now enabling an analysis of synthetic lethal effects that could be used to target clear cell ovarian cancers carrying these mutations. Conclusions: The work undertaken so far provides the framework for the discovery of therapeutic targets for clear cell ovarian cancer using an integrated approach. Revalidation of these preliminary results is now underway to characterize new genetic dependencies for this disease.
Phase Ib study of AMG 386 in combination with paclitaxel (P) and carboplatin (C) in high-risk stage I and stages II-IV epithelial ovarian, primary peritoneal, or fallopian tube cancers.
Authors: Casado Antonio , Oaknin Ana , Baurain Jean-Francois , Wong Shirley S. , Yang Xinqun , Wu Benjamin , Zhong Zhandong Don , Puhlmann Markus , Vergote Ignace B. 
Published: March 2020

5038 Background: AMG 386 is a first-in-class investigational peptibody that inhibits angiopoietin-1/-2 binding to Tie2. We report on an ongoing, 2-part, open-label phase 1b study of AMG 386 + PC as first-line treatment of high-risk ovarian cancer. Methods: Part 1 enrolled women, GOG performance status 0/1, with newly diagnosed, FIGO high-risk stage I or stages II, IIIA-B (primary debulking surgery; PDS) or IIIC & IV (PDS or interval debulking surgery; IDS) ovarian cancer. Patients (pts) received AMG 386 at 15 mg/kg QW IV + P at 175 mg/m2 Q3W + C at AUC 6 Q3W for 6 cycles (or until disease progression or unacceptable toxicity); AMG 386 was withheld 4 weeks pre-/post-debulking. Pts completing 6 cycles continued AMG 386 QW as maintenance for up to 18 months. Part 1: incidence of dose-limiting toxicities (DLTs) dictated expansion to 25 pts (part 2). Primary endpoint: DLT incidence; secondary: adverse events (AEs), PK and efficacy measures. Results: At the time of analysis, 16 pts had received ≥1 dose of AMG 386 + PC and completed ≥2 cycles of therapy (PDS, n=8; IDS, n=8). No DLTs occurred in part 1. 15 pts continue on-study; 6 pts have received a median of 6 doses of maintenance AMG 386. One pt discontinued due to progression. AEs are tabulated below. One serious AE (decreased appetite; maintenance phase) required hospitalization. AE incidence and type were similar for PDS or IDS. Combination therapy did not affect the PK of AMG 386 or PC. Non-neutralizing antibodies against AMG 386 were detected in 2 pts. Conclusions: AMG 386 at 15 mg/kg QW + PC is tolerable in pts with high-risk ovarian cancer. AMG 386 maintenance was tolerated and associated with few AEs. Updated toxicity and efficacy data will be presented. [Table: see text]
The combination of intravenous bevacizumab and metronomic oral cyclophosphamide for recurrent platinum-resistant ovarian cancer.
Authors: Barber Emma L. , Neubauer Nikki Lynn , Zsiros Emese , Schink Julian C. 
Published: March 2020

5039 Background: This study was undertaken to determine the progression free survival and overall survival in heavily pre-treated patients with recurrent ovarian carcinoma treated with bevacizumab and metronomic oral cyclophosphamide. Methods: An IRB-approved retrospective review was performed for all patients with recurrent ovarian, fallopian tube or primary peritoneal carcinomas treated with intravenous bevacizumab 10mg/kg every 14 days and oral cyclophosphamide 50mg daily between January 2006 and December 2010. Response to treatment was determined by change in disease status according to RECIST criteria and/or CA-125 levels. Results: Sixty-six eligible patients were identified with a median age of 58 years. Fifty-five patients (83%) originally had optimal cytoreduction and all were platinum resistant. Median time from diagnosis to beginning bevacizumab and cyclophosphamide was 36 months. Median number of prior chemotherapy treatments was 7.5 (range 3-16). Eight patients (12.1%) had side effects which required discontinuing bevacizumab and cyclophosphamide, most common were hypertension, proteinuria, and fatigue. There was one bowel perforation (1.5%). A complete response was noted in 7 patients (10.6%), partial response was seen in 21 patients (31.8%) with an overall response rate of 42.4%. Fifteen patients (22.7%) had stable disease and 23 (34.8%) had disease progression. Median progression free survival (PFS) for responders was 5 months (range 2-14) and 11 months (range 4-14) for those with a complete response. Median overall survival (OS) from start of bevacizumab and cyclophosphamide for responders was 20 months (range 2-56) and 9 months (range 1-51) for nonresponders. Conclusions: Bevacizumab and cyclophosphamide is an effective, well-tolerated chemotherapy regimen in heavily pre-treated patients with recurrent ovarian carcinoma which significantly improves PFS and OS in responders. Response rates were significantly better than the rates we have reported in this same group of patients receiving topotecan (22%) or liposomal doxorubicin (25%) and were superior to reported rates for single agent bevacizumab (18%) in patients with only 2-3 prior regimens.
Changes of serum glycome in patients suffering from ovarian cancer.
Authors: Blanchard Veronique , Biskup Karina , Braicu Elena Ioana , Sehouli Jalid , Tauber Rudolf , Berger Markus 
Published: March 2020

5047 Background: Protein glycosylation plays an important role in many biological processes. Most human serum proteins, with the exception of albumin, are glycosylated. Glycosylation is known to be altered with development of diseases such as cancer. In the case of ovarian cancer, tumor markers among them CA-125 that are clinically used are known to have poor specificity. In addition, they fail to detect the disease at an early stage. Therefore, better biomarkers are needed. The aim of the present research work is to identify new potential glycan biomarkers by analyzing the serum N-glycome of patients suffering from ovarian cancer Methods: Serum was collected from 67 patients as well as from 33 healthy age-matching women. N-glycans were released from 10 ul serum by PNGase F digestion, permethylated and subsequently analyzed by means of MALDI-TOF mass spectrometry. The SPSS software was used for the statistical analysis. Results: The N-glycome of patients was found to have more fucosylated structures, especially in tri- and tetraantennary sialylated glycans. The PCA analysis indicates that there are significant differences between the glycome of ovarian cancer patients in all stages of the disease and the glycome of healthy controls. We identified 14 potential structures that were divided in two categories, one of monofucosylated structures with high antennarity (sensitivity 94%, specificity 97%) and one containing high-mannose structures and an asialylated structures (sensitivity 97%, specificity 97%). Conclusions: Our study is the first trial to identify major differences between ovarian cancer sera and control sera, which could potentially be used in the future as biomarkers.
NGR-hTNF and doxorubicin in relapsed ovarian cancer (OC).
Authors: Lorusso Domenica , Scambia Giovanni , Amadio Giulia , di Legge Alessia , Pietragalla Antonella , De Vincenzo Rosa , Masciullo Valeria , Di Stefano Mirella , Mangili Giorgia , Lambiase Antonio , Bordignon Claudio 
Published: March 2020

5059 Background: NGR-hTNF (asparagine-glycine-arginine human tumor necrosis factor) is able to promote antitumor immune responses and to improve the intratumoral doxorubicin (D) uptake by selectively damaging tumor vessels. Methods: OC patients (pts) with progressive disease (PD) after ≥ 1 platinum/taxane regimen and with a platinum free interval lower than 6 months (PFI <6) or ranging from 6 to 12 months (PFI 6-12) received NGR-hTNF (N) 0.8 µg/m2 and D 60 mg/m2 on day 1 every 3 weeks. Primary endpoint of this phase 2 trial was response rate by RECIST criteria with a target of ≥ 6/37 responding pts. Secondary aims were progression free survival (PFS) and overall survival (OS). Results: 37 pts (median age 57 years; PS 0/1 32/5; PFI < 6/6-12 25/12; prior regimens 1-5) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6/mL (interquartile range 1.2-2.1). In all, 177 cycles were given, with 18 pts (49%) receiving ≥ 6 cycles and 12 pts (32%) 8 cycles. Neither grade 3/4 adverse events (AEs) related to N nor increase of D-related AEs were noted. Common grade 1/2 AEs included chills (65%). Eight pts (23%; 95% CI 12-39) had partial response (PR; 2 with PFI < 6 and 6 with PFI 6-12; median duration: 8.2 months). Fifteen pts had stable disease (SD, 43%; 10 with PFI < 6 and 5 with PFI 6-12; median duration: 4.9 months) for an overall disease control (DC, PR+SD) rate of 66%. Mean changes from baseline in target tumor size after 2, 4, 6, and 8 cycles were 2%, -54%, -69%, and -77%, respectively. Median PFS was 5.0 months (95% CI 3.1-6.9) and median OS was 17.0 months (10.4-23.6). In pts with PFI < 6 or 6-12, median PFS were 3.8 and 7.8 months (p=.03) and median OS were 14.3 and 20.1 months (p=.14), respectively. Pts with DC had longer median OS than those with early PD (24.0 and 4.9 months, respectively, p=.02). Longer PFI (p=.03) and higher PBLC (p=.01) were associated with better PFS, while OS correlated only with PBLC (p=.001). In the subset with PFI < 6, pts with PBLC ≥ or < 1.2/mL (1st quartile) had median PFS of 4.9 and 2.6 months (p=.02) and median OS of 15.8 and 4.3 months (p=.0001), respectivel Conclusions: A randomized phase II trial is currently testing D ± NGR-hTNF in pts with PFI < 6 (refractory/resistant). The role of PBLC as blood-based biomarker deserves further investigation.
Application of an ointment with high radical protection factor as a prevention strategy against PPE.
Authors: Kluschke Franziska , Martschick Anja , Darvin Maxim E. , Zastrow Leonhard , Chekerov Radoslav , Lademann Juergen , Sehouli Jalid 
Published: March 2020

5064 Background: Pegylated liposomal doxorubicin has proved to be highly efficient in the treatment of various tumors. Depending on the application protocol, up to 80% of patients develop palmar-plantar erythrodysesthesia (PPE). So far, a prevention strategy is still unknown. Recently, it was shown that parts of the chemotherapeutics were excreted with the sweat onto the skin surface, spreading there homogeneously and penetrating into the stratum corneum. The formation of free radicals in the tissue results in PPE. The aim of the study was to investigate if a topically applied ointment containing antioxidants with high radical protection factor (RPF) can be a PPE prevention strategy. Methods: 20 patients with ovarian carcinoma, who had been treated with pegylated liposomal doxorubicin (40 mg/m2), were investigated. They applied the ointment at least twice daily, 2 days before and during 3 cycles of chemotherapy. Their skin condition was examined by a trained dermatologist. Results: From 20 patients enrolled in the study, only 12 (60%) met the conditions by applying the cream at least twice daily in the palmar and plantar regions. These patients did not develop PPE. One patient died in the 2nd cycle of therapy. 7 patients (35%) did not follow the ointment application protocol for various reasons; 6 of them developed PPE and resumed ointment application thereafter. As a result, PPE disappeared or was strongly reduced in these patients so that chemotherapy could be continued. Due to the small group of patients, the fact that PPE was not induced in patients who had applied the ointment regularly can be generalized only restrictedly. Far more interesting are the findings in those patients, who had stopped ointment application during chemotherapy and developed PPE, which disappeared after they resumed applying the ointment. The regression or distinct reduction of PPE after re-application of the ointment clearly proves the efficacy of this strategy. Conclusions: The topical application of an ointment containing antioxidants with high radical protection factor (RPF) could be an efficient strategy against the development of PPE during chemotherapy.
Targeting therapy based on preclinical analysis of clinical, molecular, and functional characteristics of individual high-grade serous ovarian cancers.
Authors: Topp Monique , Hartley Lynne , Cook Michele , Etemadmoghadam Dariush , Galleta Laura , Pyman Jan , McNally Orla , Haluska Paul , Swisher Elizabeth M. , Kaufmann Scott H , Wakefield Matthew , Bowtell David , Scott Clare L. 
Published: March 2020

5073 Background: Recent molecular exploration of high-grade epithelial ovarian cancer (OC) has revealed potential targets for novel therapy based on altered DNA repair function, deregulated pathways and recurrent amplifications (Cancer Genome Atlas Research Network. 2011. Nature 474). Improved pre-clinical models allowing analysis of specific molecular subsets of ovarian cancer are urgently required to test novel treatment strategies. Methods: We have generated a novel xenograft model of human high-grade serous OC (HG-SOC). Histologic, functional and molecular analysis of the novel xenograft cohort (at baseline and following xenotransplantation) allows stratification of individual HG-SOC for testing with appropriate targeted therapy. We perform functional analysis of in vitro Homologous Recombination (HR) DNA repair and drug response capabilities on fresh human HG-SOC immediately following surgical resection. Molecular classification (similar to Tothill [Clin Canc Res. 2008;14]); analysis of NHEJ pathway (Proc Natl Acad Sci. 2011;108) and other DNA repair genes (Proc Natl Acad Sci USA 2011;108) is performed. In vivo drug response is studied in murine xenografts. Results: Sixteen chemotherapy-naive potentially HG-SOC samples and associated clinical data have been collected. Functional evidence of DNA repair (HR) capability and response to DNA damaging agents will be presented, including IHC for markers of DNA damage (gH2AX), DNA repair (RAD51AP1) and apoptosis (capsase 3 cleavage). Molecular classification, DNA repair gene and DNA repair pathway analyses are underway. Twelve HG-SOC have been transplanted and 6 of the first 8 have successfully xenografted, with serial transplantation and phenotyping of xenograft derivatives underway. In vivo drug response will be presented. Conclusions: This xenograft model will enable us to address hypotheses generated by recent molecular analyses of human HG-SOC (Cancer Genome Atlas Research Network. 2011. Nature 474; Clin Canc Res. 2008;14). Clinical, functional and molecular annotation will allow pre-clinical drug testing based on the plausible hypothesis approach.
Association of smoking with pulmonary recurrences among women with intermediate- to high-risk early-stage endometrial adenocarcinoma.
Authors: Weinberg Lori Elizabeth , Zanotti Kristine M. , Kunos Charles 
Published: March 2020

5089 Background: While a number of histologic risk factors have been identified in endometrial carcinoma, host factors are less well studied. Our aim was to examine the influence of smoking on the risk of pulmonary recurrences in women with early stage intermediate to high-risk endometrioid uterine cancer (EC). Methods: Women with surgically treated stage I or II EC from 1994 to 2010 were included in this study if they had lymphovascular space invasion (LVSI), FIGO grade 2 or 3 histology (G2/3), or outer half myometrial invasion (OI). All demographic, medical and oncologic data were obtained from chart review. Patients were excluded if their follow-up period was less than six months or if they had a diagnosis of a second primary invasive cancer. We performed univariate and multivariate logistic regression analyses and Fisher’s Exact test for two-way analyses of categorical variables to identify prognostic factors of pulmonary recurrences. Significance was determined by two-sided tests with α=0.05. Results: 349 patients were identified to meet histologic criteria, 3% were excluded. The remaining 337 patients had a median follow-up of 60 months (range 6 to 194). The median age of this cohort was 68 years and median BMI was 30.7 kg/m2. 81 patients (24%) had a past or present history of smoking. There were 14 pulmonary recurrences (4.1%), 36 (10.7%) distant recurrences and 58 (17.2%) total recurrences in the cohort. Smoking (present or past) was significantly associated with pulmonary recurrences, with an odds ratio of 1.09 (95% CI 1.04-1.15; P=0.0002). In a multivariate analysis adjusting for age, BMI, grade, LVSI, OI, cervical invasion, and adjuvant therapy, smoking was still a predictor of pulmonary recurrences. Conclusions: Smoking is a significant and independent predictor of pulmonary recurrences among women with early stage EC. Refining our understanding of host factors that influence risk may further allow us to identify those who may benefit most from adjuvant therapies as well as intensive surveillance.