bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validity of 1% hormonal positivity cutoff by American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines at Georgia Cancer Center.
Authors: Abdul Sater Houssein Talal , Sadek Ramses F. , Zhang Li fang , Gopal Aaron , Blaize Jean-Pierre , Yashar David , Patel Reena , Aribindi Swetha , Patel Hiral S , Tang Shou-Ching 
Published: September 2018

1094 Background: Hormone Receptor Status (HS) in breast cancer (BC) is a universally accepted biomarker. ASCO/CAP 2010 guidelines set the threshold of Estrogen and Progesterone Receptor positivity to 1 %. BC with 1-9% HS expression remains controversial with recent data disputing these guidelines. The objective of this retrospective study was to validate these guidelines at Georgia Cancer Center (GCC) with high percentage of black race. Methods: All female patients with invasive BC diagnosed between 2005-2010 at GCC (11y follow-up) were chart reviewed. We used Cox proportional hazards model to explore survival among three HS groups ( < 1%, 1-9%, ≥10%) adjusting for standard prognostic factors. Hazard ratios (HR) and 95% confidence intervals (CI) were also reported. 1-9 %, and ≥10% groups were further explored using same method to test survival difference with or without hormone therapy (HT). Fischer’s Exact test was used to evaluate response to HT in these groups. Results: 400 patients (all stages) with mean age of 59, were 24.75% HS < 1%, 17.5% HS1-9%, and 57.75% HS≥10%. Race was 43.75% Black, and 54% White. Disease stages were 84.4% early (I-IIIA) and 15.56% late (IIIB-IV). Grades were 51.42% low (1-2) and 48.58% high (3). The 2 groups (1-9%, ≥10%) received chemotherapy (42.86%, 39.83%), and HT (58.57%, 80.52%) respectively while 70.71% of < 1% HS group had chemotherapy. Mortality in HS < 1% was significantly higher than HS ≥10% (HR 1.8, 95% CI 1.07-3.02), while mortality between HS 1-9% and HS ≥10% was not different (HR 1.05, 95% CI 0.48-2.30). Treated (HT) subjects had lower mortality than untreated subjects in the 1-9% group (HR 0.10, 95% CI 0.01-0.85). 100% of HT group had no evidence of tumor at last follow up compared to 87.5% in non-treatment group (p = 0.048). There was no significant difference in mortality between treated (HT) 1-9% and ≥10% groups. Conclusions: Hormone receptor expression as low as 1-9% was found to be equi-prognostic to ≥10% expression. It also predicted response to hormonal therapy. Whether other factors as lympho-vascular invasion, grade, and other parameters change the behavior of the 1-9% HS group remain to be explored.
Immune response, safety, and survival impact from CMB305 in NY-ESO-1+ recurrent soft tissue sarcomas (STS).
Authors: Somaiah Neeta , Chawla Sant P. , Block Matthew Stephen , Morris John Charles , Do Khanh Tu , Kim Joseph W. , Druta Mihaela , Sankhala Kamalesh Kumar , Hwu Patrick , Gnjatic Sacha , Lu Hailing , Kenney Richard T. , Bohac Gerry C. , Pollack Seth 
Published: September 2018

11006 Background: CMB305 is an active immunotherapy regimen designed to generate and expand anti-NY-ESO-1 T cells. It consists of LV305, a dendritic cell targeting lentiviral vector encoding NY-ESO-1, and a boost with G305, an NY-ESO-1 recombinant protein plus GLA-SE, a TLR-4 agonist. An LV305 phase 1 study demonstrated a 1-yr survival of 81% and induction of anti-NY-ESO-1 T cells in sarcoma patients (pts). This first-in-human study of CMB305 examined safety, immunogenicity, and efficacy in pts with NY-ESO-1 positive (+) solid tumors. Methods: Adults with previously treated NY-ESO-1+ sarcomas, NSCLC, ovarian cancer were enrolled in a 3+3 dose-escalation with an expansion phase 1 study. The CMB305 regimen included 4 intradermal injections of LV305 at 109 or 1010 vector genomes, alternating with 3 intramuscular G305 injections at 250 µg for 3 months, then bimonthly G305 injections up to 1 yr. Results: As of 31Dec2016, 25 pts with STS (15 synovial (SS), 8 myxoid/round cell liposarcoma (MRCL), 2 other) were evaluable for safety; 23 SS/MRCL pts were evaluable for immune response (IR) and efficacy. All SS and MRCL pts received prior therapy for locally advanced/metastatic disease, 67% > = 2 prior chemo regimens. No DLTs were observed; treatment related AEs were grade 1 and 2, except 1 pt with grade 3 SAE (prostatic pain). Of 11 SS/MRCL pts tested, 64% pts developed NY-ESO-1 specific T cells and 72% pts anti-NY-ESO-1 antibodies. T cell receptor sequencing indicated increased clonality, and antigen spreading after CMB305. Best response by immune related response criteria was stable disease in 8/15 (53%) SS pts and 6/8 (75%) MRCL pts. The 3 month PFS rate was 74% and 75% for SS and MRCL pts. Median survival has not been reached with 1-yr survival rate of 86% and 100% for SS and MRCL pts. Conclusions: CMB305 is safe, well tolerated, and demonstrates a survival rate that is favorable when compared with approved agents for recurrent STS. CMB305 resulted in a stronger and broader integrated IR than LV305, including antigen spreading. These data warrant further investigation of CMB305 as a monotherapy in a randomized clinical study in STS. A randomized study of CMB305 in combination with atezolizumab in SS/MRCL pts is ongoing. Clinical trial information: NCT02387125.
The clinical impact of performing routine next generation sequencing (NGS) in gastrointestinal stromal tumors (GIST).
Authors: Kelly Ciara Marie , Bowler Timothy Geoffrey , D'Angelo Sandra P. , Dickson Mark Andrew , Gounder Mrinal M. , Keohan Mary Louise , Vonya Taylor , Yoon Sam S. , Singer Samuel , DeMatteo Ronald P. , Antonescu Cristina R. , Zehir Ahmet , Ladanyi Marc , Solit David B. , Chi Ping , Tap William D. 
Published: September 2018

11010 Background: The majority of GISTs harbor activating mutations in KIT or PDGFRα but the clinical relevance of other genomic alterations is unknown. We sought to determine the clinical impact of performing routine NGS and to describe the molecular landscape in GIST. Methods: From April 2014 to August 2016, 177 patients (pts) consented to an IRB-approved protocol. Tumor and matched normal samples were prospectively analyzed in a CLIA-compliant laboratory, with MSK-IMPACT, a NGS assay of up to 468 cancer-associated genes. Results: 191 samples were analyzed. NGS was most often performed in the setting of advanced disease (n = 108 (57%)). The primary tumor was most commonly tested (n = 120 (63%)). NGS guided clinical management in 79% (n = 150) of cases [matched therapy (MT) offered, n = 120/150 (80%); MT not offered, n = 24/150 (16%)]. In 25/41 cases (61%) where NGS did not influence management, treatment was not indicated because the GISTs were low risk. Most samples had ≤ 3 mutations (muts) (range: 0-17). Actionable muts were identified in 155/191 samples (81%). These included muts in KIT, PDGFRα and BRAF [oncoKB stratification: level 1 (84%), 2A (13%), 2B (2%), 3A(1%)]. 33/177 pts did not have a KIT/ PDGFRα mut [SDH deficiency, n = 15 (45%), NF1, n = 10 (30%), BRAF, n = 1(3%), NF1&BRAF, n = 1 (3%)]. 5pts had quadruple wild type GIST. Most GISTs had at least one genetic alteration in a non-driver allele (74%, n = 141/191)[frequently mutated genes in KIT exon 11 driven i) primary tumors include TP53, MAX, MLL2, SETD2, PIK3CA, TSC1; and ii) metastatic tumors include RB1, SETD2, PTEN, ANKRD11, TP53, TSC1]. CDKN2A deletion was the most common copy number alteration identified in KIT driven GIST and occurred most often in metastatic samples (with and without co-occurring, secondary KIT muts) and those with high mitotic rate. Conclusions: NGS of GIST informs clinical management in the majority of pts through the identification of muts in canonical driver genes. NGS also identifies a high prevalence of tumor-specific genetic alterations in non-canonical driver genes. These genes function in multiple pathways including intracellular signaling, chromatin remodeling, proteasomal degradation and cell cycle regulation.
Cost effectiveness of surveillance for distant recurrence in extremity soft tissue sarcoma.
Authors: Royce Trevor Joseph , Punglia Rinaa S. , Patel Sagar Anil , Thornton Katherine Anne , Raut Chandrajit P. , Baldini Elizabeth H. 
Published: September 2018

11021 Background: Optimal surveillance strategies for extremity soft tissue sarcoma (STS) are unknown. We performed a cost-effectiveness analysis of competing imaging modalities performed at National Cancer Comprehensive Network guideline-specified intervals. Methods: We developed a Markov model simulating lifetime outcomes for 54-year-old patients after definitive treatment for Stage II-III extremity STS using four surveillance strategies: watchful waiting (WW), chest x-ray (CXR), chest computed tomography (CCT) and positron emission tomography-computed tomography (PET/CT) performed every 3-6 months for the first 3 years, every 6 months until year 5, and then annually. We used probabilities, utilities and costs extracted from the literature and Medicare claims to determine incremental cost-effectiveness ratios (ICER). Results: While the model showed that CCT is the most effective strategy, CXR is the most cost-effective strategy at a societal willing-to-pay (WTP) of $100,000/quality-adjusted life year (QALY). The ICER is $14,306/QALY for CXR versus $117,683/QALY for CCT while PET/CT is never cost effective (Table). Sensitivity analyses demonstrated CCT becomes the preferred imaging modality as the lifetime risk of DR increases beyond 38% or as the societal WTP increases beyond $130,000/QALY. Conclusions: Optimal DR surveillance imaging for Stage II-III extremity STS should be individualized based on patients’ risks for DR. CXR, or CCT at more protracted intervals, may be preferred for lower risk patients (i.e. DR risk less than 38%), whereas CCT may be preferred for higher risk patients (i.e. DR risk greater than 38%). These findings can help refine guidelines to reduce resource overutilization during surveillance of sarcoma patients. [Table: see text]
Association of genomically unstable Ewing sarcoma tumors with HOTAIR overexpression and clinical outcome.
Authors: Gardiner Jamie D. , Huang Xiaomeng , Lazaris Evangelia , Jones Kevin , Yap Jeffrey T. , Randall R Lor , Abegglen Lisa , Amatruda James , Schiffman Joshua David 
Published: September 2018

11035 Background: Ewing sarcoma (ES) is the second most common bone cancer in children, characterized by the EWS-FLI1 fusion protein. Like most translocation-driven pediatric cancers, ES is a genomically “quiet” cancer with a low mutational burden and strong epigenetic regulation. However, recurring copy number alterations (CNAs) still arise in some ES tumors (e.g., chromosome 1q gain, 8 gain, 12 gain, and 16q loss) while other ES tumors completely lack genomic CNAs. We hypothesized that clinical, molecular, and epigenetic differences exist between these two unstable vs. stable genomic subtypes of ES. Methods: We performed CNA analysis on over 200 ES FFPE tumors. 30% of ES tumors had stable genomes while 60% had one or more CNAs across the genome. We performed gene expression and methylation microarray analyses on 24 ES FFPE tumors (11 stable, 13 unstable). Expression and methylation signatures were compared between stable vs. unstable ES and combined with clinical outcome. Results: Patients with unstable vs. stable ES tumors revealed worse 5-year overall (OS) and event-free survival (EFS) (38% vs. 67% EFS, p = 0.005; 58% vs. 84% OS, p = 0.0016). The subtypes had distinct expression and methylation signatures and clustered by methylation patterns. We identified differentially expressed and methylated genes, including upregulation (p = 0.0005) and unmethylation (p = 0.0009) of the long non-coding RNA HOTAIR in unstable vs. stable ES tumors. HOTAIR expression is higher in metastatic ES tumors compared to primary ES tumors (p = 0.02). Per the Cancer Cell Line Encyclopedia (Broad), ES cell lines have increased HOTAIR expression compared to 36 other cancers. Conclusions: ES genomic profiling through copy number, gene expression, and methylation identified at least two subtypes of ES (stable and unstable) that differ in outcome, gene expression and methylation. This data suggests HOTAIR’s involvement in ES pathogenesis, particularly in unstable tumors that have worse prognosis. Investigation is ongoing for HOTAIR expression as a prognostic and therapeutic target for ES, including a marker for LSD-inhibitor response.
LMTK3 as a novel regulator of oncogenic KIT in KIT-mutant cancers.
Authors: Klug Lillian Rose , Tyner Jeffrey , Heinrich Michael C. 
Published: September 2018

11044 Background: Multiple cancers, such as gastrointestinal stromal tumors (GIST) and melanoma, have been shown to be caused by somatic activating mutations in the receptor tyrosine kinase KIT. The major cause of death in patients with advanced KIT -mutant cancers is due to the development of KIT tyrosine kinase inhibitor-resistant (TKI-resistant) metastatic disease. Drug resistance arises almost exclusively from secondary mutations within KIT, highlighting the importance of KIT in the proliferation and survival of these tumors. Methods: We performed a human kinase siRNA screen in multiple KIT -mutant cancer cell lines using viability as a read out. We defined candidate targets as those whose knockdown decreased viability in all cell lines. Validation and mechanistic studies were done using a library of KIT-mutant GIST and melanoma cells. Results: We identified lemur tyrosine kinase 3 (LMTK3) as candidate target in three KIT -mutant cell lines. LMTK3 silencing reduced the viability of all KIT -mutant GIST and melanoma cells tested to date, including cell lines with KIT TKI-resistance mutations. Importantly, LMTK3 silencing decreased the viability of KIT -mutant cells specifically, but not that of KIT-independent GIST and melanoma cells. Further, we found that decreased cell viability was due to induction of apoptosis, as assessed by measuring caspase 3 and 7 activity within 96 hours of LMTK3 silencing. LMTK3 knockdown also reduced tumor growth in vivo in a GIST xenograft model. Because these cells depend so heavily on KIT and the loss of KIT signaling results in cell death, we hypothesized that LMTK3 silencing may affect this pathway. Indeed, LMTK3 silencing decreased levels of autophosphorylated KIT. We also observed a significant decrease in total KIT protein expression. This phenotype and corresponding viability was rescued with exogenous expression of full length LMTK3. Conclusions: LMTK3 is an important regulator of oncogenic KIT expression and activity in KIT-mutant GIST and melanoma and represents a novel, tractable target.
Elevated preoperative peripheral blood neutrophil-to-lymphocyte ratio to predict clinical outcome in patients with localized soft tissue sarcoma.
Authors: Chan Jason Yongsheng , Zhang Zewen , Chew Winston , Tan Grace Fangmin , Lim Chloe Liwen , Zhou Lingyue , Goh Wei Lin , Selvarajan Sathiyamoorthy , Sittampalam Kesavan , Chin Francis , Teh Jonathan Yi Hui , Tan Mann Hong , Soo Khee Chee , Teo Melissa , Mohamad Farid , Quek Richard Hong Hui 
Published: September 2018

11049 Background: Recent studies suggest that markers of systemic inflammation such as blood neutrophil-to-lymphocyte ratio (NLR) may be prognostic for various cancers, though its clinical utility has not been widely accepted. This study aims to investigate its clinical relevance in patients (pts) with soft tissue sarcoma (STS). Methods: Five hundred and twenty-nine pts with localized STS who had available pre-operative blood counts at the time of diagnosis were retrospectively examined. An optimal cutoff for high NLR ( > 2.5) in predicting overall survival (OS) and relapse-free survival (RFS) in pts who underwent curative surgery (n = 473) was determined using receiver operating curve analyses. Cutoffs for platelet-lymphocyte ratios (PLR, > 180) and lymphocyte-monocyte ratios (LMR, < 3.6) were similarly obtained. Survival analysis was performed using the Kaplan-Meier method and multivariate Cox proportional models. Median follow-up was 40 months. Results: A high NLR was present in 311 (58.8%) pts, which was significantly associated with tumor grade ( p< 0.0001), depth ( p= 0.003) and size > 5 cm ( p= 0.0242), but not with age at diagnosis, sex or ethnicity. High NLR was associated with both worse OS (HR 1.78; 95%CI 1.28-2.47; p= 0.0005) and RFS (HR 1.54; 95%CI 1.17-2.03; p= 0.0019), as were age at diagnosis, tumor grade, size, PLR and LMR. In multivariate models adjusted for clinicopathological predictors of survival, only NLR, in addition to tumor grade and size, were independently associated with worse OS (HR 1.52; 95%CI 1.09-2.11; p= 0.0131) and RFS (HR 1.42; 95%CI 1.08-1.85; p= 0.0114). Analysis of survival according to American Joint Committee on Cancer (AJCC) stages subdivided as NLR-high and NLR-low revealed a significant worse prognosis for NLR-high subgroups ( p< 0.0001), with a 2.2-fold and 1.5-fold higher risk of death within stages II (HR 2.20; 95%CI 1.20-4.01; p= 0.0103) and III (HR 1.55; 95%CI 1.01-2.37; p= 0.0459), respectively. Conclusions: High NLR is an independent marker of poor prognosis among pts with localized STS. Inclusion of NLR as a classifier into the AJCC staging of STS may improve estimation of survival.
Phase 2 multicenter study of the EZH2 inhibitor tazemetostat in adults with synovial sarcoma (NCT02601950).
Authors: Schoffski Patrick , Agulnik Mark , Stacchiotti Silvia , Davis Lara Emily , Villalobos Victor Manuel , Italiano Antoine , George Suzanne , Cote Gregory Michael , Blakemore Stephen , Clawson Alicia , Daigle Scott , Ribich Scott , Roche Maria , Rodstrom Jill , Ho Peter T.C. , Gounder Mrinal M. 
Published: September 2018

11057 Background: Synovial sarcoma (SS) accounts for 5-10% of all soft tissue sarcomas (STS). Metastatic and/or locally advanced disease occurs in up to 70% of patients (pts), with reported median overall survival (OS) as short as 22 months. SS18-SSX translocations, a defining molecular feature of SS, generate a fusion protein that competes with native SS18 during SWI/SNF complex assembly disrupting complex function. SWI/SNF complexes containing the fusion protein lack INI1 and cellular INI1 expression levels are reduced to varying degrees in SS. This mechanism of INI1 reduction is distinct to that observed in malignant rhabdoid tumors, epithelioid sarcoma or other INI1 negative tumors. Tazemetostat, a potent and selective EZH2 inhibitor, has demonstrated activity in preclinical SS models with the proposed mechanism of sensitivity being via INI1 reduction inducing compromised SWI/SNF activity and tumor dependence on EZH2. Methods: This is a phase 2 multicenter open-label non-randomized study with 5 cohorts of different tumor types with INI1 loss/reduction or evidence of SS18 rearrangement. Adult pts in the SS cohort were treated with tazemetostat (800 mg po BID). Up to 30 pts were enrolled using a 2-stage Green-Dahlberg design. The primary endpoint is complete response, partial response or stable disease (SD) at 16 wks. Success at the end of stage 2 requires ≥9 of 30 treated pts meet this criterion. Key secondary endpoints include overall response rate, PFS, OS, safety/tolerability, PK and biomarkers of response. Results: In 33 treated SS pts with a median of 2 prior systemic treatments, best response of SD was observed in 11 pts (33%) with 5 pts (15%) having SD lasting ≥16 wks. No objective responses were observed. The protocol-defined success criterion at the end of study was not met. Tazemetostat was well-tolerated with grade 1/2 cough (36%), dyspnea (33%) and fatigue (33%) as the most frequently reported adverse events regardless of attribution. Conclusions: Tazemetostat was well tolerated with a favorable safety profile. Although there were no objective responses in heavily pretreated pts, the observation of SD in a subset of pts suggests further studies with tazemetostat in combination may be warranted in SS. Clinical trial information: NCT02601950.
Rates of survival throughout the years in soft tissue sarcoma with synchronous metastases: Results of a population-based study.
Authors: Vos Melissa , Ho Vincent K.Y. , Oosten Astrid W. , Verhoef Cornelis , Sleijfer Stefan 
Published: September 2018

11068 Background: Roughly 10% of patients with soft tissue sarcoma (STS) present with synchronous metastases and generally cannot be cured anymore. With the registration of trabectedin, pazopanib and the identification of other agents exerting activity against STS, the treatment of these patients in the Netherlands has changed considerably in the last decade. The aim of this population-based study is to examine whether the overall survival (OS) of patients with STS and synchronous metastases has improved over the years. Methods: All patients diagnosed with adult-type STS and synchronous metastases between 1989 and 2014 were queried from the Netherlands Cancer Registry. Trends in OS were assessed by the Kaplan Meier method and log rank test in different timeframes based on year of registration of trabectedin ( < 2007 vs. ≥2007) and pazopanib ( < 2012 vs. ≥2012). A multivariable Cox regression analysis was performed to identify relevant characteristics prognostic for OS. Results: In total, 1,393 patients with adult-type STS and synchronous metastases were identified. Over the whole time period, median OS did not improve significantly (5.8 months in 1989-1994 to 8.1 months in 2010-2014, p = 0.095), but median OS < 2007 compared to ≥2007 did improve significantly (5.8 months to 7.3 months, p = 0.035). This was particularly apparent in the liposarcoma subgroup, where median OS doubled (5.2 months to 11.5 months, p = 0.020). Median OS < 2012 compared to ≥2012 did not increase significantly (6.1 months to 7.6 months, p = 0.062), though there was a relatively short follow-up of 2 years while the survival curve seems to reach a plateau phase. Aside from not receiving (any type of) treatment, elderly age, STS subtype other than lipo- or leiomyosarcoma, high or unknown grade and nodal involvement were significant negative predictors for OS, whereas primary tumor site in the extremity and surgery in an academic center had a favorable effect on OS. Conclusions: OS of STS patients with synchronous metastases has not improved significantly over the years, except for the subgroup of liposarcomas after 2007. A longer follow-up period is needed to clarify the impact of pazopanib on OS in patients with metastatic STS.