bluuebunny/crossref_metadata_2025_split huggingface dataset:
BRCA1 immunohistochemistry in high-grade serous ovarian cancers (HGS-OC) characterized for BRCA1 germ-line mutations.
Authors: Hyman David Michael , Garg Karuna , Grisham Rachel Nicole , Bhatia Jasmine , Arnold Angela G. , Aghajanian Carol , Kauff Noah D. , Levine Douglas A. , Soslow Robert A , Spriggs David R. 
Published: March 2020

5043 Background: The optimal use of BRCA1 germline testing in patients with HGS-OC is unclear. Moreover, BRCA1 germline testing does not provide information on non-germline mechanisms of BRCA1 loss. We investigated the performance of BRCA1 immunohistochemistry (IHC) testing in HGS-OC with known BRCA1 mutation status. Methods: Eligible patients had HGS-OC, underwent surgery at a single institution between 1997 and 2010, and were tested for germline BRCA1 mutations under IRB-approved protocols. FFPE tumor tissue was used in triplicate to construct a tissue microarray (TMA). Two pathologists, blinded to BRCA1 status, independently scored each sample as BRCA1 IHC present (normal) or absent (abnormal). Whole sections were stained for all samples with absent BRCA1 staining on TMA. A commercially available monoclonal antibody against BRCA1, clone MS110 from Calbiochem (OP92) was used with previously optimized conditions. Results: 123 samples (30 BRCA1 +; 93 BRCA1 wild-type) were analyzed and 47 (38%) had abnormal BRCA1 IHC. Inter-observer agreement on BRCA IHC was high (kappa=0.87). BRCA IHC had a sensitivity of 83.3% (CI: 70.0-96.7%), specificity of 76.3% (CI: 67.7-85.0%), PPV of 53.2% (CI: 38.9-67.5%), and NPV of 93.4% (CI: 87.9-99.0%) for BRCA1 germline mutation. There was a trend towards improved overall survival in the BRCA IHC abnormal vs. normal patients (median survival 82 vs 61 wks, HR 0.70, p=0.12). Conclusions: BRCA1 IHC is a reproducible and inexpensive test with a high NPV for absence of a BRCA1 germline mutation. The 22 (17.7%) cases with abnormal BRCA1 IHC and wild-type BRCA1 germline status may have other mechanisms of protein loss such as promoter hypermethylation or somatic mutation and are currently being tested for these changes. This rate of non-germline BRCA1 loss in HGS-OC is consistent with data generated by the Tumor Cancer Genome Atlas Network. BRCA1 IHC may be useful as a reliable biomarker for risk stratification in HGS-OC. [Table: see text]
Neo-escape: Neoadjuvant extended sequential chemotherapy with adjuvant postoperative treatment for epithelial nonmucinous advanced inoperable peritoneal malignancy.
Authors: Poole Christopher John , Marshall Andrea , Higgins Helen B , Fletcher Julie , Williams Sarah Jane , Lo Nangi , Fernando Indrajit Nalinika , Osborne Richard , Crawford S. Michael , Rafii Saeed , Gill Sandeep , Dunn Janet A 
Published: March 2020

5046 Background: Neo-Escape was designed to exploit fully the modest non-cross resistance of carboplatin (CBDCA) and paclitaxel (ptx) in an extended sequential regimen, with dose-dense ptx, and address feasibility of combining gemcitabine (gem) with either CBDCA or ptx. Methods: A randomised phase II trial in patients (pts) with untreated (FIGO stage 3C/4) inoperable ovarian, fallopian, or primary peritoneal carcinoma to assess feasibility of two regimens of sequential neoadjuvant-then-adjuvant chemotherapy (CT); (a) CBDCA AUC 2.5 and gem 1000mg/m2 repeated days 1 and 8 q 3 wks x 6 cycles, then ptx 175mg/m2 q 2 wks x 6 cycles (CG-P) or (b) CBDCA AUC 6 q 3 wks x 6 cycles, then ptx 175mg/m2 and gem 2000mg/m2 q 2 wks x 6 cycles (C-PG). All pts were considered for delayed 1o debulking surgery after neoadjuvant CT. The 1o feasibility outcome was % pts completing 12 cycles of CT. Using Fleming’s single stage procedure 44 patients on each arm were needed to test null hypothesis of feasibility ≤60% with 5% 1-sided significance level and 90% power. 2o outcomes included safety, PFS and ORR. Pts were stratified by serum albumin, stage and tumor differentiation. Results: 75 pts were recruited Sept 2007 - May 2011 (28 CG-P; 47 C-PG), median age 62 yr (range 21-75). Recruitment to CG-P closed early due to futility. 52% had albumin >35g/L, 68% FIGO stage 3C and 80% poorly differentiated tumors. 64% on CG-P and 55% on C-PG had debulking surgery as planned and a further 4% on CG-P and 13% on C-GP after completion of all CT. For CG-P 35% achieved 0cm, 35% <1cm and 30% ≥ 1cm residuum; for C-GP 34% 0cm, 13% <1cm and 34% ≥1cm, 19% TBC. 14/28 pts on CG-P completed all 12 cycles (feasibility 50%; 95% CI 31-67%); 37/47 pts on C-PG (feasibility 79% (95% CI 64-88). Main reason for early discontinuation was toxicity on CG-P and disease progression on C-PG. Similar proportions of pts on each arm had dose reductions (68%) or delays (86% on CG-P; 89% on C-PG), mainly for toxicity. 82% of pts experienced grade 3/4 toxicity on CG-P; 72% on C-PG. Median PFS for CG-P is 14.3 mths (95% CI 11.6-15.7mths) and 13.0 mths (95% CI 11.5-15.4mths) for C-PG. Conclusions: CG-P was not feasible at these doses using pre-specified criteria, but C-PG is feasible.
An updated safety analysis of OCEANS, a randomized, double-blind, phase III trial of gemcitabine (G) and carboplatin (C) with bevacizumab (BV) or placebo (PL) followed by BV or PL to disease progression (PD) in patients with platinum-sensitive (Plat-S) recurrent ovarian cancer.
Authors: Aghajanian Carol , Blank Stephanie V. , Goff Barbara Ann , Judson Patricia Lynn , Nycum Lawrence R. , Sovak Mika A. , Yi Jing , Husain Amreen 
Published: March 2020

5054 Background: OCEANS met its primary end point with a statistically significant and clinically meaningful hazard ratio for progression-free survival (PFS) of 0.484. Secondary end points included objective response rate, overall survival, and safety. Eleven additional months of safety data were collected after the data cut-off date for the final PFS analysis event and updated safety analyses were performed. Methods: Eligible patients (pts) were randomized to arm A: GC (G [1000 mg/m2 days 1 and 8] and C [AUC 4, day 1], q21d for 6–10 cycles) + concurrent PL (q21d), followed by PL until PD or unacceptable toxicity; or arm B: GC + concurrent BV (15 mg/kg q21d), followed by BV until PD or unacceptable toxicity. All adverse events (AE) were recorded and graded per NCI-CTCAE v3.0. Results: The incidence of any grade AE was 100% in both arms and of SAEs was 25.3% (PL arm) and 35.6% (BV arm). The rates of proteinuria, hypertension (HTN), reversible posterior leukoencephalopathy syndrome (RPLS), thrombocytopenia and epistaxis were higher in the BV arm. More pts in the BV arm (20.6%) than in the PL arm (4.7%) experienced an AE that led to discontinuation of study drug, in the BV arm most commonly due to HTN (4%), proteinuria (2.8%), epistaxis (1.2%), thrombocytopenia (1.6%) and RPLS (0.8%). Median number of BV cycles in pts with G ≥3 proteinuria was 22.5 and the AE resolved in 91.7% of pts. Among the pts with G ≥3 HTN, the median number of BV cycles was 16.5 and the AE resolved in 72.7% of pts. Conclusions: The overall safety profile was similar to that seen at the time of the final PFS analysis. Higher incidences of proteinuria and HTN were possibly related to longer BV treatment duration and resolved in the majority of pts. [Table: see text]
The impact of interval cytoreduction and age in advanced-stage ovarian cancer: A GOG ancillary study.
Authors: Lichtman Stuart M. , Java James , Lovecchio John L. , Chi Dennis , Tew William P. , Bookman Michael A. , Menzin Andrew 
Published: March 2020

5056 Background: To determine if an age group exists for which interval cytoreductive surgery (ICS) in patients with suboptimal residual disease at primary surgery influences progression free survival (PFS) and overall survival (OS) among women with advanced ovarian cancer treated on GOG 182. Methods: GOG 182 was a prospective, randomized trial of first-line chemotherapy in patients with advanced ovarian cancer. Patients with both optimal and suboptimal residual disease were included, and those with suboptimal residual were considered for ICS, with intent registered and stratified prior to randomization. Patients were randomized to one of five chemotherapy arms, employing combinations of either two or three agents delivered intravenously, with a control arm of paclitaxel and carboplatin. A retrospective analysis was approved by the GOG Ancillary Study Committee to investigate the influence of age on treatment and outcomes. In that analysis, Cox regression was used to identify independent prognostic factors and estimate their covariate effects on the adjusted PFS and OS of patients with suboptimal residual disease. Statistical significance was set at p<0.05. Results: Among the entire eligible study population, 28% (n=1,042) were registered with suboptimal residual disease (> 1 cm) and 109 of these patients elected to undergo ICS. Hazard ratios (HR) were determined for patients undergoing ICS with reference to patients with suboptimal disease not undergoing ICS. Based on the most current follow-up data, the HR for progression or death was not statistically different between the groups, but the HR of death alone was significant at 0.72 (95% CI: 0.57–0.92, p=0.008). There was no significant association of age with ICS in either the PFS or the OS model. Conclusions: In this trial, a patient’s age did not influence the effect of ICS on PFS or OS. There is no demonstrable benefit in PFS associated with ICS, but there was a statistically significant improvement in OS. To elucidate this finding, further study is warranted, likely in the form of a meta-analysis incorporating data from other prospective trials.
A novel treatment for ovarian cancer (OC): Anti-Müllerian inhibiting substance type II receptor (MISRII) humanized monoclonal antibody (mAb) 3C23K—Preclinical validation.
Authors: Gaucher Christine , Jacquet Alexandra , Kersual Nathalie , Garambois Veronique , Fontayne Alexandre , Fournier Nathalie , de Romeuf Christophe , Tosi Diego , Sadoun Alain , Brune Frederique , Prost Jean-Francois , Urbain Remi , Pelegrin Andre , Teulon-Navarro Isabelle 
Published: March 2020

5069 Background: Expressed on most OC subtypes while displaying a restricted expression profile in adult normal tissues, MISRII represents a potentialtarget for OC immunotherapy. We present here the preclinical assessment of a humanized anti-MISRII EMABling mAb, 3C23K. Methods: Either quantitative RT-PCR or immunohistochemistry (IHC) studies were performed to confirm MISRII expression profile in Granulosa Cell Tumor (GCT) or Epithelial OC (EOC) patient samples and to evaluate tissue cross-reactivity. For in vitro and in vivo experiments, we have generated 4 patient-derived MISRII expressing EOC cell lines. Xenograft studies were conducted in swiss nude mice on established tumors (100 mm3). Mice received 2 to 3 weekly i.p. injections (10 mg/kg/inj) for 4 to 6 wks and tumor volumes were compared with control groups. Comparison of i.p. vs i.v. injections were assessed as well as combination with carboplatin (once a week for 4 weeks, 60 mg/kg/inj). In addition, 3C23K plasma level was monitored to determine half-life. Results: 1) Target validation: we confirmed by IHC the expression of MISRII in most OC tissue sections (4/4 GCT and 13/14 EOC), meanwhile, MISRII mRNA was only detected in 7/48 normal tissues. 2) In vitro assessment: tested in vitro 3C23K displayed both cytotoxic (ADCC) and anti-proliferative activities. 3) In vivo assessment: in the mouse xenograft models 3C23K exhibited a strong anti-tumoral activity as measured by tumor volume, with T/C ratios reaching values below 0.42 shortly after the initiation of treatment. No differences in efficacy were noticed between i.p. and i.v. injections or between thrice vs twice a week administrations. In addition, similar half lives were observed for 3C23K injected either i.v. (96.9 h) or i.p (113.5 h). Finally, the combination of 3C23K with carboplatin (CP), a standard of care in OC, exhibited an even stronger anti-tumor activity with T/C values at D22 of 0.06 (3C23K+CP), 0.18 (3C23K) and 0.69 (CP) vs vehicle. Conclusions: 3C23K represents a promising candidate for OC targeted therapy and a dose-escalation phase I study is planned in patients with OC.
Tumor PIK3CA mutations, lymphocyte infiltration, and recurrence-free survival (RFS) in early breast cancer (BC): Results from the FinHER trial.
Authors: Loi Sherene , Michiels Stefan , Lambrechts Diether , Salgado Roberto , Sirtaine Nicolas , Fumagalli Debora , Claes Bart , Kellokumpu-Lehtinen Pirkko-Liisa , Bono Petri , Kataja Vesa V , Larsimont Denis , Piccart-Gebhart Martine J. , Joensuu Heikki , Sotiriou Christos 
Published: March 2020

507 Background: Tumor PIK3CA mutations (mts) and lymphocyte infiltration (LI) are prognostic in BC, but their importance is unknown in HER2-positive (HER2+) BC treated with adjuvant trastuzumab (T). Methods: The FinHER trial randomized 1010 patients (pts) with pN+ or high-risk pN- BC to 3 cycles of docetaxel (D) or vinorelbine, followed by 3 cycles of FEC. Pts with HER2+ BC were further randomized to 9 weeks of T or no T (n=232). Pts treated with D and T had superior outcome in prior analyses. BC samples were subjected to somatic hotspot mt profiling (Sequenom) and quantification of percentage tumor LI using full-face H&E sections. RFS and interactions with T were explored with Kaplan-Meier and Cox regression analyses. Results: The median FU time was 62 months. 935 (92.6%) and 687 (68.1%) tumors underwent LI and mt analysis, respectively. Correlation of LI assessment between 2 pathologists was 0.78 (p<0.001). 54 mts detected in 13 genes were evaluated. PIK3CA mts (exons 1,2,9,13,18,20) was present in 25.3% (n=174) and ERBB2 mt in 4.5% (n=31) BCs. Only 1 AKT mt was found and none in KRAS, BRAF, NRAS or PTEN. In ER+/HER2-, HER2+ and ER-/HER2- subtypes the prevalence of PIK3CA mts was 30.2%, 19.5% and 9.2%; ERBB2 mt 6.3%, 1.9% and 2.6%, respectively (both p<0.05). Neither PIK3CA nor ERBB2 mts were associated with RFS overall or within BC subgroups. No interaction was found for the benefit with T and presence of PIK3CA mt in HER2+ BC (interaction p=0.17 T vs no T). Increasing LI was associated with favorable RFS in ER-/HER2- BC (continuous score adjusted p=0.032); 3-y RFS was 90% with extensive LI (>30% infiltrated) vs 66% with non-extensive LI (p=0.007). In HER2+ BC, whilst there was no association with prognosis overall, there was a significant interaction with the benefit from T vs. no T and increasing LI (continuous score interaction p=0.042) with 3-yr RFS 96% vs 78% for extensive and non-extensive LI treated with T respectively (p=0.014). Conclusions: We report 3 clinically relevant findings from this large clinical trial dataset: 1) PIK3CA mts were not prognostic; 2) LI is a strong prognostic factor in ER-/HER2- BC and 3) for the first time that extensive LI predicts benefit from adjuvant T.
BRCA1 methylation status in high-grade serous ovarian cancer (HGSOC) patients (pts).
Authors: Ruscito Ilary , Braicu Elena Ioana , Benedetti Panici Pierluigi , Chekerov Radoslav , Dimitrova Desislava , Ganapathi Ram N. , Vasconcelos Ines , Bellati Filippo , Fotopoulou Christina , Lichtenegger Werner , Olek Sven , Sehouli Jalid 
Published: March 2020

5070 Background: Mutations in BRCA1/2 genes contribute to increase risk for breast and ovarian cancer (OC).Hypermethylation of CpG islands in gene promoter regions is considered a frequent mechanism associated with inactivation of tumor suppressor genes which contributes to oncogenic transformation. Studies identified methylation changes in OC pts. Most of the studies analyzed a small cohort and combined different histological subtypes. HGSOC is a special entity of OC associated with poorer OS. Aim of this study was to analyze the clinical impact of BRCA1 promoter gene methylation status in HGSOC. Methods: The cohort comprised 127 HGSOC treated by cytoreduction followed by platinum-based chemotherapy at Department of Gynecology, Charité Medical University Berlin, Germany. Fresh frozen OC tissues provided by TOC were examined to access the tumoral tissue quality. Samples presenting at least 50% of tumour area were included within this study. DNA was extracted followed by sodium bisulfite conversion, and assessment of BRCA1 gene promoter methylation rate was determined by PCR. Statistical analisys has been carried out using SPSS software. Results: In our study, 14.2% of the pts presented a hypermethylation of the BRCA1 promoter gene. The hypermethylation of BRCA1 promoter gene was significantly more frequently encountered in the younger pts (<59 yrs: 77.8% in the Hypermethylation Group vs 47.7% in the Hypomethylation Group, p=0.022). No differences in methylation status between primary and metastatic tissue from OC pts could be observed. Also no correlation with FIGO stage was observed. Optimal tumor debulking could be reached in most of the pts (57.5%), without significant differences between both groups. Platinum response rates were similar between both groups. No differences in PFS and OS could be observed. Conclusions: The study shows that HGSOC pts presenting the BRCA1 gene promoter in the methylated status, developed the disease significantly earlier with respect to OC patients with unmethylated BRCA1 gene promoter. The clinical outcome was similar in HGSOC independently from BRCA1 methylation status.
BRCA mutations and outcome in epithelial ovarian cancer (EOC): Experience in ethnically diverse groups.
Authors: Safra Tamar , Lai Wei-Chu V , Berman Tara , Borgato Lucia , Reich Elsa , Alvear Maria , Muggia Franco , Pelles-Avraham Sharon 
Published: March 2020

5078 Background: EOC patients with BRCA mutations have been reported to have better prognosis than non-hereditary (NH) matched cases, an advantage shown especially in the Ashkenazi-Jewish (AJ) population. We have analyzed our experience in our ethnically diverse patient cohort from NYC, Israel and Italy. Methods: A retrospective chart review of patients diagnosed with Stage IC-IV EOC between 1995-2008 at the NYU Cancer Institute, Tel Aviv Sourasky MC and Padova Clinical Cancer Centers. Out of >700 patients, 183 were tested for BRCA mutations and evaluated. Results: Median age was 55.5 (range 31–83 years). Out of 183, 86 are carriers of BRCA1/2 mutations and 97 tested negative, 67 and 19 are carriers of BRCA1 and BRCA2 mutation respectively. Carrier frequency in EOC population is 46% (45/97) in AJ's and 48% (41/86) in non-AJ's. AJ patients had the following BRCA1 mutations: 185delAG (29), 5382insC (5), unknown (UK) (2) and BRCA2 mutations: 6174delT (8), UK (1). Non-AJ's were divided by ethnicities into non-AJ, Caucasian, African-American, Hispanic, Middle Eastern or unknown. Non-AJ Jewish patients had BRCA1 mutations in 185delAG (7) and BRCA2 in 6174delT (1), UK (1). Non-Jewish Caucasians exhibited the widest variation of mutation types, with the following BRCA1 sites: 185delAG, K1702X (5223A>T), E1373X, 3829delT, 185delAT, IVS11+1G>A, 5385insC, 5083del19>stop1670, 1720delAF>stop536, 1806C/T>Igu536Ter, del ex1a-2, cod1486ex14:4575delAstop1504, 5563G7A;Trp1815stop, 5181delGTT(Val1688del) and UK and the following BRCA2 sites: 6174delT (2), 5301insA (1), 802delAT (1), cod2960ex22:9106C/t (1), cod68ex3:432delAstop79 (1), 7408A/T;Arg2394stop (1). One African-American patient with BRCA1 at 1294del40, 1 Hispanic BRCA1 at 185delAG. OS was significantly prolonged for BRCA carriers at 93.6 months versus 63.2 months [95% CI: 44.5-91.7] (p=0.0016) for NH. Conclusions: Our data reports a wide variety of BRCA mutations in an ethnically diverse EOC population and confirms that BRCA mutations carriers have a better prognosis with a longer median survival compared to NH population. A larger cohort might manifest prognostic differences between the different types of mutations.
Serum IGFBP4 levels in combination with miliary disease: A candidate predictor of ovarian cancer progression-free survival.
Authors: Cohen Samantha 
Published: March 2020

5079 Background: Insulin-like growth factor binding protein, IGFBP4, was shown to be highly expressed across all stages of epithelial ovarian cancer (EOC) and serum levels are elevated in EOC. Moreover, IGFBP4 levels are ~3x greater in women with malignant pelvic masses. We investigated whether ascites volume and the presence of miliary disease in combination with serum levels of IGFBP4 are independent predictors of survival. Methods: A prospective and retrospective analysis was performed. Patients were enrolled at the time of cytoreductive surgery. Ascites volume was either absent, <500 cc (low), or >= 500 cc (high), and the presence of miliary disease was recorded. The IGFBP4 cutoff was 1064.5 ug/ml based upon previous results. The Kaplan-Meier product limit method was used to estimate PFS probabilities. The Cox proportional hazards model was used to estimate hazard ratios (HR) and corresponding 95% CI. Results: 57 cases were included in the analysis of ascites volume and miliary disease. Cytoreductive outcomes were complete gross resection (44.8%), optimal (<=1cm residual disease; 44.8%), and suboptimal ( >1cm residual disease; 10.3%). Histologic subtypes: papillary serous (n=35; 61.4%), mucinous (n=15; 26.3%), endometrioid (n=4; 7.0%), and clear cell (n=3; 5.3%). Stage distribution was 21.1% I/II, and 78.9% III/IV. PFS was unaffected by ascites volume (p=0.341) or miliary disease. Among this cohort, 29 had IGFBP4 levels available for a separate analysis. Patients with high IGFBP4 and miliary disease were 5.5 times as likely to recur compared with patients with miliary disease and low IGFBP4 (HR=5.55 [0.77, 39.82]), and the statistical significance was borderline (p<0.088). No statistically significant differences were detected between rates of recurrence among patients with high and low IGFBP4 values in combination with ascites volume. Conclusions: These exploratory studies suggest that patients with high IGFBP4 serum levels and miliary disease were > 5 times as likely to recur compared to women with miliary disease and low IGFBP4 levels. Future studies examining these variables using a larger population and examining the biologic basis of this relationship are planned.