bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular stratification of endometrioid ovarian carcinomas.
Authors: Stanley Barbara , Thomson John P , Hollis Robert L , Meynert Alison , Rye Tzyvia , Iida Yasushi , Nussey Fiona , Mackean Melanie J , Churchman Michael , Semple Colin , Okamoto Aikou , Gourley Charlie , Herrington C Simon 
Published: May 2019

5553 Background: Endometrioid ovarian carcinomas (EC) have been historically under-investigated. We sought to determine the molecular landscape of contemporarily defined EC using whole exome sequencing (WES). Methods: Tumours diagnosed as EC between May 1980 and December 2013 were identified through the Edinburgh Ovarian Cancer Database. Pathology review was performed according to WHO 2014. Other pathologies including WT1 positive HGSOC were excluded. A selected cohort underwent WES and were analysed for single nucleotide and copy number variants across a panel of genes previously reported as mutated in endometrial, ovarian or pan cancer studies. Tissue microarrays were stained for ER, PR and AR. Multivariable analysis for disease specific survival (DSS) was performed. Results: 125 tumours were included. 61 tumours of all grades underwent WES. 5 molecular groups were identified based on the presence of TP53 mutations (45.9%); or an EClike profile (one or more mutations in ARID1A (41.0%); CTNNB1 (31.1%), PTEN (24.6%) or PIK3CA (23.0%)). Tumours with no mutations in EClike genes were termed ECnull. Each group demonstrated differential DSS (table). Some ECnull: TP53mut tumours also displayed mutations in KRAS, APC and mismatch repair genes. Unsupervised clustering analysis based on the top 100 differentially mutated genes across the dataset validated these groups. Somatic copy number alterations were significantly higher in the TP53mu t groups than the TP53wt groups (P<0.0001), and were identified across EClike genes in the ECnull groups. A PR histoscore of >150, but not ER or AR, was more frequent in the TP53wt group compared to the TP53mut groups (P=0.003). TP53mut status (P=0.0182) and PR histoscore ≤150 (P=0.0115) were independently associated with DSS. Conclusions: EC is a heterogeneous disease comprising 5 molecular subgroups each demonstrating differential clinical outcome. TP53 mutations and PR histoscore ≤150 are independently associated with poor prognosis. [Table: see text]
Olaparib maintenance therapy in patients (pts) with a BRCA1 and/or BRCA2 mutation (BRCAm) and newly diagnosed advanced ovarian cancer (OC): SOLO1 China cohort.
Authors: Wu Lingying , Zhu Jianqing , Yin Rutie , Wu Xiaohua , Lou Ge , Wang Jing , Gao Yunong , Kong Beihua , Lu Xin , Zhou Qi , Wang Yueling , Chen Youguo , Lu Weiguo , Li Wei , Cheng Ying , Liu Jihong , Ma Xin , Zhang Jing 
Published: May 2019

5554 Background: SOLO1 (NCT01844986) is a randomized, double-blind, Phase III trial evaluating the efficacy and safety of the PARP inhibitor, olaparib, as maintenance monotherapy in newly diagnosed advanced OC pts with a BRCAm. A separate pt cohort evaluated the efficacy and safety of olaparib in Chinese pts in this setting. Methods: The China cohort of SOLO1 planned to enroll ~53 newly diagnosed OC pts who had completed first-line platinum-based chemotherapy and were in clinical complete or partial response. This sample size provided around a 90% chance to observe an HR < 1, assuming a true HR = 0.62. Pts were randomized 2:1 to olaparib (300 mg bid; tablet) vs placebo. The primary endpoint was investigator-assessed progression-free survival (PFS; modified RECIST v1.1). Sensitivity analysis of PFS was performed by blinded independent central review (BICR). Results: All 64 randomized pts received study treatment (olaparib, n = 44; placebo n = 20). Median follow-up was ~30 months in both arms. Median PFS was not reached in the olaparib arm and was 9.3 months in the placebo arm (Table). The most common AEs in the olaparib group were nausea (n = 28, 63.6%), anemia (n = 25, 56.8%) and vomiting (n = 18, 40.9%). Grade ≥3 AEs occurred in 56.8% of olaparib pts vs 30.0% of placebo pts; the most common grade ≥3 AE was anemia (n = 16, 36.4%). Olaparib dose interruptions, reductions and discontinuations occurred in 56.8%, 27.3% and 6.8% of pts, respectively (vs in 30.0%, 10% and 0% of pts in the placebo arm). Conclusions: In the China cohort of SOLO1, a clinically relevant improvement in investigator-assessed PFS was observed in newly diagnosed OC pts receiving olaparib maintenance therapy. Olaparib treatment led to a 54% reduction in risk of progression or death vs placebo. The safety results were consistent with the known profile of olaparib in Chinese pts. Clinical trial information: NCT01844986. [Table: see text]
Menopausal symptoms in epithelial ovarian cancer survivors: The GINECO VIVROVAIRE2 study.
Authors: Joly Florence , Pautier Patricia , Kalbacher Elsa , Gernier François , Fauvet Raffaele , Floquet Anne , Berton-Rigaud Dominique , Tredan Olivier , Follana Philippe , Alexandre Jerome , Zannetti Alain , Dohollou Nadine , Trager Stephanie , Licaj Idlir , Grellard Jean-Michel , Clarisse Bénédicte , Ahmed-Lecheheb Djihane , Rousset-Jablonski Christine , Gompel Anne 
Published: May 2019

5555 Background: We have previously shown that Epithelial Ovarian Cancer and its treatments have significant negative effects on Quality of Life (QoL) and long term fatigue. The aim of the present multicentric VIVROVAIRE2 study was to report the main menopausal, VasoMotor Symptoms (VMS) of Epithelial Ovarian Cancer survivors (EOCS). Methods: 166 patients of the 322 EOCS without relapse ≥3 years after first line of treatment accepted to participate to a gynecological consultation carried out by a gynecologist, including a questionnaire related to menopausal symptoms, a clinical examination, and an osteodensitometry. VMS (hot flashes and/or night sweats) were described according to natural menopause (NM) or surgically induced menopause (SIM). QoL and Fatigue were measured with the validated questionnaires FACT-G and FACT Fatigue. Results: Median age was 62 years [20-83], FIGO stage III/IV (48%) and < 10% BRCA1&2 mutated. Histological subtypes were: high grade serous 31%, low grade serous 23%, endometrioid G2-3 (14%) endometriod G1( 4%), clear-cell 21%, mucinous 5%. All EOCS had surgery, 97% of patients received platinum and taxane chemotherapy, median delay from treatment was 5 years [3-24] and 59 (36%) had SIM. 14% of EOCS had osteoporosis; this rate was similar to the general population. 52% of patients (85) reported either hot flashes (47%) or night sweats (32%). 72% with SIM had VMS compared to 41% with NM (p < 0.001). VMS were not associated with poor global QoL or fatigue. At the time of the survey, only 8 (5 SIM & 3 NM) EOCS received hormone replacement therapy (HRT). Among the 85 EOCS with VMS, 80 (94%) (38 SIM (93%) 42 NM (95%)) did not benefit from HRT after cancer treatment. Among 80 EOCS with VMS and no HRT, 25 (66%) with SIM and 34 (81%) of NM had high grade serous, endometriod G2-3, clear cell and mucinous histology. Conclusions: Vasomotor symptoms are frequently reported by EOCS, particularly among surgically induced menopause patients. A majority of EOCS with these symptoms might have beneficiated from hormone replacement therapy.
Cost-effectiveness analysis of laparoscopic disease assessment in ovarian cancer.
Authors: Harrison Ross , Cantor Scott B. , Villanueva Mariana , Suidan Rudy Sam , Sun Charlotte C. , Rauh-Hain Jose Alejandro , Westin Shannon Neville , Fleming Nicole D. , Sood Anil K , Lu Karen H. , Meyer Larissa 
Published: May 2019

5556 Background: Laparoscopic assessment of disease resectability can be useful for treatment planning for patients [pts] with advanced ovarian cancer [OC] but may be associated with added cost. Methods: We performed a cost-effectiveness analysis from a payer perspective to compare (1) a conventional strategy, where standard new pt evaluation was used to assign pts to either primary cytoreduction [PCS] or neoadjuvant chemotherapy with interval cytoreduction [NACT], and (2) an alternative approach, where pts considered candidates for PCS would undergo laparoscopy to evaluate disease resectability using a validated scoring system, who were then triaged to either PCS or NACT based on this evaluation. Diagnostic work-up, surgical and adjuvant treatment, perioperative complications, and progression-free survival [PFS] were included in the model. We derived model parameters from the literature and our institution’s experience with laparoscopic triage. Utility estimates for health states related to primary treatment were assessed prospectively and taken from the literature. Costs were estimated using Medicare reimbursement. Effectiveness was defined in quality-adjusted progression-free life years [QPFLYs]. We performed multiple sensitivity analyses. Results: Under baseline model parameters, the expected cost of treating one pt under the conventional and alternative strategies was $26,539 and $26,653, respectively. The expected quality-adjusted progression-free survival for pts in the conventional and alternative strategies was 0.70 and 0.94 QPFLYs, respectively. The calculated incremental cost-effectiveness was $473.97 per QPFLY saved. The alternative strategy became cost saving if pts found to have resectable disease by laparoscopy underwent cytoreduction during the same procedure. The conventional strategy may be preferred if PCS increased PFS over NACT by ≥5 months. Conclusions: For newly-diagnosed advanced stage OC pts, laparoscopic assessment of disease resectability prior to PCS was a cost-effective strategy. A conventional strategy may be preferred if PCS produced substantially longer PFS. Sensitivity analysis suggests the benefit of utilizing laparoscopic triage is influenced by mitigation of serious perioperative morbidity and associated costs.
Immunologic responses in triple-negative breast cancer patients in a randomized phase IIb trial of nelipepimut-S plus trastuzumab versus trastuzumab alone to prevent recurrence.
Authors: Campf Jessica , Clifton Guy T. , Hale Diane F. , Vreeland Timothy J. , Hickerson Annelies , Holmes Jarrod P. , Litton Jennifer Keating , Murthy Rashmi Krishna , Lukas Jason Jerome , Mittendorf Elizabeth A. , Peoples George Earl 
Published: May 2019

556 Background: Breast cancer (BC) patients (pts) expressing low levels of HER2 by (immunohistochemistry (IHC) 1-2+) are not eligible for trastuzumab (Tz). However, in a randomized phase 2b trial, triple negative BC (TNBC) pts demonstrated a significantly better DFS with nelipepimut-S (NPS) + Tz vs Tz alone. Here, we assess the ex vivo and in vivo immune responses (IR) in both arms. Methods: Disease-free pts (n = 275) with HER2 IHC 1-2+, non-amplified BC who were node positive and/or had TNBC were randomized 1:1 to granulocyte-macrophage-colony stimulating factor (GM-CSF) or NPS+GM-CSF. ±NPS was given every 3 weeks x 6 followed by 4 boosters every 6 months (mo). All pts received Tz concurrently for 1 year per label regimen and were followed for recurrence. IR were evaluated ex vivo by clonal expansion of NPS-specific cytotoxic T lymphocytes (CTL) by dextramer-staining/flow cytometry at time points over 3 years. In vivo IR were assessed by delayed type hypersensitivity (DTH) reactions periodically. Results: The trial enrolled 97 TNBC pts; 60 had 4 timepoints available for analysis (37 NPS + Tz pts; 23 Tz pts). The NPS+Tz group exhibited increases in CTL frequencies vs baseline: 208%, 303%, 379% at 18, 24 and 30 mo, respectively. NPS+Tz pts’ mean CTL frequencies increased from 0.029 ±0.001% at baseline to 0.112±0.026% at 30 mo (p = 0.01) compared to Tz pts who were 0.027 ±0.001% at baseline and 0.057 ±0.016% at 30 mo (p = 0.71). Only 4 NPS+Tz pts recurred as compared to 13 in the Tz arm. While limited by low numbers, recurrent NPS + Tz pt did not mount an IR by ex vivo assessment (range: 0.0 - 0.026%) or by DTH (all measurements: 0 mm), while non-recurrent pts mounted both clonal CTL expansion (range: 0.000- 0.33%) and enhanced DTH (range: 0.0- 80.5mm). Conclusions: NPS+Tz combination is more efficacious in generating time-dependent antigen (NPS)-specific CTL by both ex vivo and in vivo measures vs Tz. Based on these preliminary data, it appears that both ex vivo and in vivo IR to NPS were attenuated in pts with TNBC recurrence. Further analysis of read-outs from these assays to validate the relationship of IRs to clinical effect seen with NPS+Tz in TNBC pts is underway. Clinical trial information: NCT02297698.
Impact of BRCA mutation status and time to platinum resistance on patients with advanced ovarian cancer.
Authors: Tyulyandina Alexandra , Filipenko Maxim , Rumyantsev Alexey , Pokataev Ilya , Nechushkina Valentina , Morkhov Konstantin , Bulanov Anatoly , Stenina Marina , Tjulandin Sergei 
Published: May 2019

5561 Background: The influence of germline BRCA1/2 mutations (gBRCAmt) on ovarian cancer patients (pts) long-term survival remains controversial. Methods: 228 pts with serous and endometrial ovarian cancer stage Ic-IV were enrolled in the retrospective study. Next-generation sequencing testing of BRCA1/2 in blood was employed. Progression-free survival (PFS), overall survival (OS) and time to platinum resistance (TPR) were analyzed. TPR was defined as time from first line chemotherapy to registration of platinum resistance relapse. Results: The rate of pathogenic gBRCAmt was defined in 29.4% (67/228) pts. There was no any significant difference between BRCA1/2 mutation carries and non-carries in both PFS (18.3 and 16.7 months, p = 0.27, HR 0.79, 95%CI 0.52-1.20) and OS (71.9 and 79.1 months, p = 0.69, HR 0.88, 95%CI 0.46-1.68). However, TPR was significantly longer in pts with gBRCAmt than in germline BRCA wild type (gBRCAwt) pts (51.4 and 34.4 months, p = 0.05, HR 0.60, 95% CI 0.36-0.98). Pts with gBRCAmt had poor prognosis after registration of platinum resistance. gBRCAwt pts had longer survival than gBRCAmt after platinum-resistance relapse: 33.7 and 16.9 months respectively (p = 0.05; HR 1.85, 95%CI 1.02-4.08). Conclusions: Our finding provided possible explanation of equal survival of pts with or without BRCA1/2 mutations. Long-term sensitivity to platinum-based chemotherapy allowed pts with gBRCA1/2mt to control the disease for a long period of time. However the non-platinum regimens had less efficacy in pts with gBRCAmt than gBRCAwt after platinum resistance.
Cardiac safety of the trastuzumab biosimilar ABP 980 in women with HER2-positive early breast cancer in the LILAC study.
Authors: Kolberg Hans-Christian , Colleoni Marco , Demetriou Georgia , Santi Patricia Xavier , Tesch Hans , Fujiwara Yasuhiro , Tomasevic Zorica , Hanes Vladimir 
Published: May 2019

557 Background: Although trastuzumab is generally well-tolerated, cardiotoxicity is the main limitation in its use, leading to a severe heart failure in 2-4% of patients in adjuvant trials. In the phase 3 LILAC trial, trastuzumab biosimilar ABP 980 demonstrated similar efficacy, safety, and immunogenicity to trastuzumab reference product (RP) in women with HER2-positive early breast cancer. Here we report analyses comparing cardiac safety of ABP 980 and RP. Methods: In the neoadjuvant phase, all 725 patients received 4 cycles of chemotherapy with epirubicin + cyclophosphamide Q3W and were then randomized 1:1 to ABP 980 (n = 364) or RP (n = 361) with a loading dose of 8 mg/kg, then 6 mg/kg IV Q3W for 3 cycles plus paclitaxel Q3W (4 cycles) or QW (12 cycles). After surgery, patients received investigational product (IP) Q3W for up to 1 year; ABP 980-treated patients continued ABP 980, and RP-treated patients either continued RP (n = 190) or switched to ABP 980 (RP/ABP 980; n = 171). AEs were assessed every 3 weeks and cardiac safety every 3 months. Cardiac safety was monitored by computerized 12-lead ECG; LVEF was assessed by 2D ECHO. LVEF decline was defined as LVEF value decrease from study baseline by ≥10 percentage points and to < 50%. Results: Treatment groups were well balanced with regard to IP disposition. Over the entire study, 22 (3.1%) patients had LVEF decline by ≥10 percentage points compared to baseline and to < 50%; no meaningful between-group differences were observed (ABP 980:10/359 [2.8%], RP: 6/184 [3.3%], RP/ABP 980: 6/171 [3.5%]). The incidence of cardiac AEs was low and comparable in treatment groups. One grade 3 cardiac failure event was reported in the RP/ABP 980 arm; another in the RP arm was coincident with LVEF decline. No patient discontinued IP during adjuvant phase because of cardiac failure. Conclusions: These pre-specified analyses confirm the tolerability of ABP 980 and demonstrate clinical similarity of ABP 980 and RP with respect to cardiac safety. The incidence of LVEF decline was consistent with the known cardiac safety profile of the RP. No new cardiac safety signals were observed whether patients were on ABP 980 or switched from RP to ABP 980. Clinical trial information: NCT01901146.
T cell trafficking within the peritoneal tumor environment and ovarian cancer progression.
Authors: Desai Sharina Palencia , Bahmani Maryam , Adams Sarah Foster 
Published: May 2019

5573 Background: Ovarian cancer is associated with high mortality due to detection at late stages with widespread peritoneal metastases at diagnosis in a majority of patients. Ovarian cancer recurrences are primarily found in the peritoneal cavity, and peritoneal disease is the primary cause of morbidity and mortality in this disease. This pattern of tumor engraftment and recurrence indicates that the peritoneal tumor environment is distinct from other niches. Our data indicate that selective peritoneal dissemination is immunologically mediated, based on functional differences in peritoneal and systemic T cells during ovarian cancer progression. This is consistent with data in other solid tumors demonstrating that tumor immunity is driven by regional lymphocyte populations. However, less is known about the mechanisms that establish a permissive immune environment in the peritoneal cavity. We hypothesize that pathways regulating T cell recruitment and retention in the peritoneal cavity (PC) are co-opted by ovarian cancer cells to enable intraperitoneal cancer dissemination and recurrence. Methods: We have developed a novel model that uses direct in vivo labeling of peritoneal cells in an established immune-competent high grade serous murine cancer model. This functional approach enables us to identify T cell subsets retained in the PC with tumor engraftment and progression. Results: We identified high expression of CD49d (a4 integrin) as the most prevalent cell surface marker on T cells retained in the peritoneal cavity, consistent with prior published data in healthy mice and people. We demonstrated a functional role for CD49dhi in T cell retention by showing preferential binding to VCAM. A role for tumor cells mediating this interaction was observed based on enhanced binding affinity in vitro with tumor monolayers. The importance of this mechanism is supported by high VCAM expression in multiple murine and human ovarian cancer cell lines, and T cell localization to VCAM rich areas within ovarian cancer tumors in vivo. Conclusions: CD49d not only defines a lymphocyte subset with a significant role in tumor immunity but presents itself as an important potential therapeutic target to modulate T cell trafficking.
The Circulating Cell-free Genome Atlas (CCGA) Study: Follow-up (F/U) on non-cancer participants with cancer-like cell-free DNA signals.
Authors: Cohn Allen Lee , Seiden Michael , Kurtzman Kathryn N. , Hubbell Earl , Gross Samuel , Venn Oliver , Fung Eric T. , Liu Minetta C. , Klein Eric A. , Oxnard Geoffrey R. , Hartman Anne-Renee , Waterhouse David Michael 
Published: May 2019

5574 Background: A noninvasive cell-free DNA (cfDNA)-based cancer detection assay offers the hope of a blood test that might reduce morbidity and mortality of cancers, particularly those without recommended screening tests (eg, some gynecologic cancers). CCGA (NCT02889978) is a prospective, multi-center, longitudinal, case-control study evaluating models for discriminating cancer versus non-cancer. Here, we report F/U of control participants (pts) who demonstrated a cancer-signal in CCGA. Methods: Clinically evaluable samples (N = 2508) from pts enrolled without a cancer diagnosis (dx; NC) and treatment-naive pts with newly diagnosed cancer (C) were divided into training (n = 1564; 580 NC, 984 C) and test (n = 944; 368 NC, 576 C) sets. Classification performance (cancer/non-cancer) was assessed via 3 prototype assays: whole-genome bisulfite (WGBS), whole-genome (WGS), and targeted (507 gene) sequencing. Notable outlier NC pts were identified with cancer-like scores in either ≥2 assay classification results or by the presence of known cancer drivers with ≥1 assay classification result suggesting cancer. All pts are currently in F/U in accordance with study protocol (to date: 80% with > 10 mo and 15% with > 22 mo F/U). Results: Among training and test sets, 8 ( < 1%) NC pts were identified with a cancer-like signal. To-date, 2 have been diagnosed with a gynecologic malignancy: 1 stage IIIc clear cell endometrial carcinoma and 1 stage IIIc ovarian cancer, 3 and 2 months (mo) post-enrollment [PE], respectively. Among C pts in the study, sensitivity (at 98% specificity; WGBS) in these cancer types was: uterine/endometrial: 11% (n = 27 train) and 22% (n = 9 test); ovarian: 82% (n = 17) and 71% (n = 7). In addition, a third NC pt was diagnosed with a stage IV lung cancer 15 mo PE. Conclusions: This cfDNA-based assay detected a cancer-like signal that anticipated a clinical presentation of cancer in undiagnosed pts as early as 15 months prior to the actual dx. High specificity ( > 99%) requires accounting for undiagnosed cancers in study design and analysis. Together, these data suggest that this prototype assay may have high performance detecting a variety of gynecological and other cancers. Clinical trial information: NCT02889978.