bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and validation of a targeted sequencing panel for application to treatment-refractory solid tumor.
Authors: Kwon Woo Sun , Che Jingmin , Rha Sun Young , Chung Hyun Cheol , Han Hyo Jun , Kim Jaeyoung , Jadamba Erkhembayar , Lee Yunbeom , Kim Ernie 
Published: January 2021

245 Background: Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted sequencing panel for application to treatment-refractory solid tumor types with particular focus on tumours of the stomach cancer, plus test for utility in FFPE, fluid sample and cancer cell lines. Methods: “CancerMaster” is custom RNA probes for target enrichment sequencing. It consists of all unions (7,811 regions, 2.5Mb) of reported exons of 524 tumor and immune related genes. The panel contains special RNA probes, which enables detection of microsatellite instability, Epstein-Barr virus and Human papillomavirus. Also, the CancerMaster panel analyzes 524 genes as well as genomic signatures including microsatellite instability (MSI), tumor mutational burden (TMB) and HLA allele. FFPE samples and 49 gastric cancer (GC) cell lines were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 117), and specificity by Sanger sequencing, pyrosequencing, FoundationOne CDx. Results: We achieved a mean coverage of 1,032x, with sensitivity and specificity of >99% and precision of >97%. In this study, we evaluated 26 Yonsei Cancer Center (YCC) GC cell lines and 23 GC cell lines from other sources (ATCC, KCLB, and JCRB). Application to 49 gastric cancers cell lines resulted in detection of copy number variant (CNV), single number variant (SNV) and small InDel aligned to whole exome sequencing data. In addition to previous novel EBV infected cell line (YCCEL1/YCC-10, J Gen Virol. 2013), we observed amplification and overexpression of receptor tyrosine kinase (RTK) including HER2 (YCC-19, 32, 33, 38), EGFR (YCC-11, 21), Met (YCC-31, 34), and FGFR2 (YCC-28, 30) in YCC GC cell lines; confirming that protein was overexpression by Western blot or Flow cytometry in 19/49 (38.8%). Interestingly, amplification of RTKs was detected mutually exclusive pattern with other RTK amplification. Conclusions: We have developed and validated an analytically-validated panel for application to cancers of treatment-refractory types.
The impact of prior therapies on outcomes with trifluridine/tipiracil (FTD/TPI) in the phase III TAGS trial.
Authors: Shitara Kohei , George Ben , Taieb Julien , Sundar Raghav , Fakih Marwan , Makris Lukas , Benhadji Karim A. , Ghidini Michele 
Published: January 2021

247 Background: It is unclear whether prior treatment with ramucirumab (RAM) or RAM plus paclitaxel (PAC), standard second-line treatments for metastatic gastric or gastroesophageal junction cancer (mGC/GEJC), can influence outcomes with third-line chemotherapy in this patient (pt) population (pop). In the phase 3 TAGS trial, FTD/TPI showed a survival benefit vs placebo (PBO) in pts with mGC/GEJC who had received ≥2 prior chemotherapy regimens. Post hoc analyses were performed to assess the impact of prior RAM, PAC or RAM+PAC treatment on the efficacy and safety of FTD/TPI in TAGS. Methods: Pts in the TAGS trial were categorized into 5 subgroups based on prior treatment received as follows: A) RAM (alone or combined with other agents), B) no RAM, C) PAC (but no RAM), D) RAM+PAC (sequentially or in combination) and E) neither PAC nor RAM. While subgroups A and B were prespecified, all other subgroups were identified post hoc. Efficacy (overall survival [OS] and progression-free survival [PFS]) and safety were assessed in these subgroups. Results: In the overall pop (N=507), 33% had received prior RAM (alone/combined); 30% prior RAM+PAC; 27% prior PAC but no RAM; and 40% had received neither PAC nor RAM. As only 3% of all pts received prior RAM but no PAC, that subgroup was not considered in this analysis. FTD/TPI treatment was consistently associated with benefits in OS and PFS vs placebo across all pt subgroups (Table). Among pts randomized to FTD/TPI, OS benefit was similar between pts who received RAM+PAC vs those who received neither (HR, 1.15; 95% CI, 0.84–1.58) and between pts who received PAC (but no RAM) vs those who received neither (HR, 0.91; 95% CI, 0.66–1.25). The FTD/TPI safety profile was consistent across all subgroups, with similar overall incidences of grade ≥3 adverse events (AEs). Minor variations in hematologic toxicities were noted (Table). Conclusions: In the phase 3 TAGS trial, FTD/TPI treatment in the third or later line provided efficacy benefits vs PBO and demonstrated a consistent safety profile in pts with mGC/GEJC regardless of prior treatments. Clinical trial information: NCT02500043. [Table: see text]
Comparison of immune activity profiles of microsatellite instable colon tumors to microsatellite stable tumors having high ColoType CMS1-score.
Authors: Buechler Steven Allen 
Published: January 2021

26 Background: Microsatellite instable (MSI) metastatic colorectal cancer (CRC) tumors have been found to be responsive to immune checkpoint inhibitors. Most MSI tumors are in consensus molecular subtype CMS1. Here, in a search for microsatellite stable (MSS) samples that may respond to checkpoint inhibitors, we used the ColoType CMS1-score to identify microsatellite stable (MSS) CRC tumors that have immune activity profiles similar to MSI tumors. Methods: This study was performed in Affymetrix cohort (n = 1,888) of primary CRC tumor samples assayed with hgu133plus2 Affymetrix microarrays. Degrees of infiltration of populations of immune cells were assessed with MCPcounter. Gene Set Enrichment Analysis (GSEA) using the Hallmark gene sets was used to compare biological features between subsets of samples. An 18-gene genomic score (PembroSig) of Ayers, et al, was used to predict response to Pembrolizumab. ColoType 40-gene signature identifies the CMS of a CRC tumor using values of continuous scores, one score for each of CMS1-4. CMS1+ denotes the samples with CMS1-score sufficiently high to predict it is in CMS1. A genomic score was used to predict MSI status for all samples in Affymetrix cohort; MSI predictions using said score had 97% agreement with clinically determined MSI status for 749 Affymetrix cohort samples. Results: The MSI score predicted 240 MSI samples in Affymetrix cohort, and 211 MSS samples in CMS1+ (CMS1+/MSS). The union of MSI and CMS1+/MSS compared to other samples exhibited elevated infiltration of cytotoxic lymphocytes (p < 0.0001) and CD8 T-cells (p < 0.0001), activity of interferon-gamma (p = 0.006) and interferon-alpha signaling (p = 0.012), inflammatory response (p = 0.012), and elevated PembroSig score (p < 0.0001). CMS1+/MSS compared to MSI showed no significance difference in any of these measures. None of the immune regulatory genes PD-1, PD-L1, PD-L2, CTLA4, LAG3, and IDO1 were differentially expressed between CMS1+/MSS and MSI. Of note, the only Hallmark gene sets enriched in MSI compared to CMS1+/MSS were DNA repair (p = 0.002) and MYC targets V1 (p = 0.009) and V2 (p = 0.013). We further analyzed the biological differences between MSI samples in CMS1+ (CMS1+/MSI, n = 190) and MSI samples not in CMS1+ (CMS1-/MSI, n = 50). We found that CMS1+/MSI compared to CMS1-/MSI exhibited elevated cytotoxic lymphocyte infiltration (p < 0.0001), interferon-gamma activity (p = 0.027), and PembroSig score (p < 0.0001), highlighting the relationship between immune activity and CMS1-score. Conclusions: ColoType CMS1-score identified MSS samples in Affymetrix cohort (11%) with similar immune activity as MSI samples (13%) and equivalently high values of a genomic score predictive of Pembrolizumab response.
Second-line tyrosine kinase inhibitors (TKIs) versus immunotherapy (IO) for advanced hepatocellular carcinoma (HCC): Real-world efficacy and safety analysis in patients with varying liver dysfunction.
Authors: Xia Jeffrey , Gelfond Jonathan , Arora Sukeshi Patel 
Published: January 2021

271 Background: Within the last 4 years, the FDA approved five drugs as second-line therapies for advanced HCC. At our cancer center, the majority of our patients are Hispanic with varying liver dysfunction, and this real world population is not represented in registration trials of TKIs and IOs. Therefore, we analyzed survival and toxicities among second-line therapies for HCC at our Hispanic-majority NCI-designated cancer center. Methods: Retrospective analysis of patients with advanced HCC diagnosed at Mays Cancer Center from 1/2015-3/2019 who received second-line therapies, including IO (i.e. nivolumab), TKIs (i.e. cabozantinib, regorafenib), or hospice/best supportive care (BSC). Progression-free survival (PFS) was determined using Kaplan-Meier method, and hazard ratios estimated with Cox proportional hazards model. AEs according to Common Terminology Criteria for AEs v5.0 were analyzed with Fisher’s exact test. Results: Of the patients receiving first-line therapy, the median age was 60 years (n=65), and patients were 75% (n=49) Hispanics. 58 (89%) patients went onto receive second-line therapy. Child-Pugh (CP) score: A 17%, B 55%, C 28%. Median PFS was 3.1 months with TKI (n=6), 3.3 months with IO (n=27), and 1.3 months with BSC (n=25) (Table). There was improved survival with IO when compared to BSC (HR=3.26; 95% CI: 1.58-6.72; p=0.00136). There was no significant difference when comparing IO to TKI (HR=0.94; 95% CI: 0.31-2.86; p=0.92), but a trend to improved PFS with TKI when compared to BSC (HR=3.08; 95% CI: 0.96-9.84; p=0.06). TKI group had significantly more rash (p=0.01) and hand-foot syndrome (HFS) (p<0.001) compared to IO and BSC. All other AEs demonstrated no significant difference between groups (Table). Conclusions: In our Hispanic-majority cohort, patients with varying liver dysfunction, including CP B & C cirrhosis, were more likely to receive IO or BSC. Both second-line treatment groups (IO or TKI) had increased mPFS compared to BSC. Both IO and TKI groups were tolerable compared to BSC, with expected toxicity per class of drug. More prospective studies comparing second-line agents should be done in patients with varying liver dysfunction to understand survival, tolerability, and quality of life. [Table: see text]
Real-world effectiveness of lenvatinib monotherapy among unresectable hepatocellular carcinoma patients treated in United States clinical practices.
Authors: Singal Amit G. , Nagar Saurabh P , Hitchens Abigail , Iyer Shrividya 
Published: January 2021

273 Background: In the United States (U.S.), lenvatinib monotherapy was approved in August 2018 for first-line treatment of patients with unresectable hepatocellular carcinoma (uHCC) based on the pivotal trial, REFLECT. Real-world data are essential to assess if this efficacy translates into effectiveness in clinical practice. The main objective of our real-world data (RWD) study was to assess clinical characteristics and effectiveness of lenvatinib among patients treated in U.S. clinical practices. Methods: A retrospective patient chart review study was conducted among adult patients (≥18 years) in the U.S. initiating lenvatinib monotherapy as first-line (1L) systemic therapy for uHCC between Aug 2018 and Sept 2019 and with ECOG status of 0 or 1. Data were extracted from individual patients’ electronic health records and captured in electronic case report forms. Clinical outcomes assessed include provider-reported best response, progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated using Kaplan-Meier methods. For PFS, patients were censored at end of treatment or end of follow-up in case of ongoing treatment, while censoring occurred at end of follow-up for OS. Results: Among 233 patients treated with 1L lenvatinib monotherapy, majority were male (68%) and most were Caucasian (52%) or African American (25%). Median age was 63 years and median body weight was 76 kg. The most common etiologies of liver disease were hepatitis C (36%), alcohol-related liver disease (28%), hepatitis B (16%) and non-alcoholic steatohepatitis (14%). Most patients had compensated cirrhosis, with 49% Child Pugh A and 43% Child Pugh B. All patients had uHCC, with most having Barcelona Clinic Liver Cancer stage B (29%) or C (44%) disease. Portal vein invasion was reported in 19%, of whom7% had main portal vein involvement. The median starting dose of lenvatinib was 12 mg daily. Over a median follow-up period of 9 months from HCC diagnosis, median PFS and OS were not reached. At 6 and 12 months landmark PFS was 85% and 65%, respectively and landmark OS was 92% and 73%, respectively. In the overall cohort, provider-reported best response was complete response (CR): 21%, partial response (PR):44% and stable disease (SD): 26%. Based on RECIST 1.1 (n = 125) CR:16%, PR:54%, SD:26% and mRECIST (n = 11) CR:73%, PR:0% and SD:18% were reported. Average duration of lenvatinib treatment was 7.4 months (median: 6.7 months) with 61% of patients remaining on lenvatinib at end of follow-up. Second-line (2L) treatment was initiated in 32 patients, with immunotherapy (50%), sorafenib (31%) and regorafenib (9%) being most common. Median time to 2L treatment from initiation of lenvatinib was about 8 months. Conclusions: Results from this retrospective real-world study in an U.S. population affirm the clinical effectiveness of 1L lenvatinib monotherapy among patients with uHCC.
Prospective, multicenter study of apatinib combine with TACE in treating intermediate to advanced stage HCC patients: A real-world study from China.
Authors: Li Hailiang , Hu Hongtao , Cao Guangshao , Wu Gang , Ding Pengxu , Li Zhen , Wei Qiuliang , Niu Huanzhang , Chang Zukuan , Yin Jun 
Published: January 2021

282 Background: Combination of transcatheter arterial chemoembolization (TACE) with apatinib are emerging as an effective treatment for patients with intermediate to advanced stage HCC. However, the data of HCC treated by apatinib in the real-world setting are not reported. In this real-world study, we aimed to explore the efficacy and safety of HCC pts which underwent TACE combine with apatinib. Methods: This was a prospective, multicenter observational study in a real-world setting and this study was approved by our Ethics Committee. Pts aged ≥18 years with well diagnosed intermediate or advanced stage HCC were included. The pts received apatinib plus TACE treatment as the first-line therapy. TACE treatment was performed on demand, the dose of apatinib was selected by the investigator. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival rate (OS), objective response rate (ORR), disease control rate (DCR) and safety profile. All of the objective response was assessed by independent central review per mRECIST criteria. Results: From Jun 2019 to Feb 2020, a total of 98 well diagnosed HCC pts with age from 31 to 86 were enrolled in this study. As of August 2020, the median follow-up was 9.5 months. The mPFS of 98 pts was 7 months. The ORR, DCR and 6 months OS rate was 35.7%, 76.5% and 82.6%, respectively.The PFS was 7.5 months in intermediate stage and 6.4 months in advanced stage. The ORR was 46.3% in intermediate stage (41 cases) and 28% in advanced stage (57 cases) HCC. And the 6 months OS rate was 90.2% in intermediate stage and 77.1% in advanced stage HCC. Overall, 17 (17.3%) pts had grade≥3 treatment-related AEs. All of the safety adverse effects can be tolerated or reduced after symptomatic treatment and no unexpected adverse events were observed. Conclusions: In this real-world study, apatinib showed a favorable efficacy and safety profile in pts with intermediate and advanced stage cancer. Apatinib combination TACE therapy might lead to better survival benefit in first-line treatment for HCC pts. Clinical trial information: ChiCTR1900024030.
The lines of loco-regional therapies received and the healthcare economic burden of patients newly diagnosed with hepatocellular carcinoma in the United States.
Authors: Seal Brian , Abdulhalim Abdulla M. , Lingohr-Smith Melissa , Lin Jay 
Published: January 2021

286 Background: Hepatocelluar carcinoma (HCC) is one of the fastest growing causes of cancer-related deaths in the US. The objectives of this study were to examine the lines of loco-regional therapies received and the healthcare economic burden of patients newly diagnosed with HCC in the US. Methods: Patients (≥18 years of age) diagnosed with HCC who received ≥1 loco-regional therapy (index date) after diagnosis were identified from the MarketScan Commercial and Medicare Supplemental databases (July 1, 2013-May 31, 2018). Patients were required to have ≥6 months of continuous insurance enrollment before the index date and ≥1 month after (follow-up period). The follow-up period was censored when patients received any systemic therapy. During the follow-up periods, the number of patients who received radiation therapy, ablative therapy, and embolization procedures (transarterial embolization/chemoembolization [TAE] and radioembolization [TARE]) were examined. All-cause and HCC-related healthcare costs (total and patient out-of-pocket [OOP] payments per patient per month [PPPM]) were also measured. Results: Among the 2,101 patients newly diagnosed with HCC who received ≥1 loco-regional therapy, median age was 64 years and 75.0% were male; the mean follow-up duration was 11.5 months. During the follow-up periods, 28.1% (n = 590) received radiation therapy, 27.3% (n = 574) ablative therapy, and 77.3% (n = 1,623) embolization therapy (TAE: 68.7% [n = 1,443]; TARE: 20.7% [n = 434]); 30.9% of patients received multiple loco-regional therapies. During the follow-up periods, total all-cause healthcare costs were a mean of $20,316 (OOP: $378) PPPM, of which 70.7% ($14,359; OOP: $227 PPPM) were HCC-related. The breakdown of healthcare costs is shown in the table. Conclusions: According to the findings of this large-scale real-world analysis of patients newly diagnosed with HCC in the US, a vast majority received at least one embolization procedure. The monthly healthcare economic burden of patients with HCC treated with local-regional therapies is relatively high. [Table: see text]
Treatment patterns and survival in patients with late-stage hepatocellular carcinoma in France: A retrospective database analysis.
Authors: Blanc Jean-frederic , Laurendeau Caroline , Kelkouli Nadia , Mathurin Philippe 
Published: January 2021

288 Background: The prognosis for patients with late-stage hepatocellular carcinoma (HCC) is poor, with only one systemic treatment option available for patients until 2017. Aim: To describe treatment patterns and survival of French patients following diagnosis of late-stage HCC (Barcelona Clinic Liver Cancer classification B, C or D), using a comprehensive nationwide claims database, SNDS. Methods: The SNDS database was searched from 1 January 2015 to 31 December 2017 for patients with a diagnosis of HCC (ICD-10: C220) and late-stage disease, defined by the identification of transcatheter arterial chemoembolization (TACE) or radioembolization (TARE), HCC systemic therapy and/or best supportive care (BSC). Patients were followed up for a maximum of 2 years. Results: 17,298 patients (mean age: 68.7 years (SD: 11.3), 82.6% male) were identified, with 72.4% diagnosed at late stage. During follow-up, 29.6% of patients were treated with TACE or TARE, and 27.1% received systematic therapy (sorafenib in 99.5% of cases). The median duration of systemic treatment was 7.9 (95% CI: 7.4-8.5) months. In 62.5% of cases, this treatment was discontinued at 12 months; this proportion fell to 40.3% when using mortality as a competitive risk. Survival since diagnosis of late stage HCC differed according to the type of first treatment received. Median overall survival was 23.7, 11.9, 7.4 and 1 month in patients initially receiving TACE, TARE, systemic therapy or no treatment, respectively. Conclusions: These results confirm the high clinical burden of late-stage HCC over this period and the need for second-line systemic treatments to improve patient outcomes.
Comparison of systemic therapy efficacy in advanced hepatocellular carcinoma: Systematic review and frequentist network meta-analysis of randomized controlled trials.
Authors: Park Robin , Lopes da Silva Laércio , Nissaisorakarn Voravech , Riano Ivy , Saeed Anwaar 
Published: January 2021

293 Background: Several systemic agents are approved for use in the first line and second line treatment settings for advanced hepatocellular carcinoma (aHCC). However, choosing among available options in both first and second line settings remain difficult due to the paucity of head-to-head comparative trials. Therefore, we have conducted a systematic review and network meta-analysis for the indirect comparison of the systemic agents in the first line and second line settings. Methods: Published clinical trials that have evaluated systemic agents in the first line and second line settings in advanced HCC from inception to April 2020 were identified by searching PubMed, EMBASE, and Cochrane Databases and abstracts presented in the main annual ASCO and ESMO conferences from 2017 to 2020. Studies published in English providing clinical outcomes data including overall survival (OS), progression free survival (PFS) and objective response rate (ORR) were included in the analysis. The primary outcomes of interest were pooled hazard ratios (HR) of OS and OR of ORR in first line studies and HR of PFS and OR of ORR for second line studies. OS for second line agents were synthesized in a qualitative analysis. Results: Overall, 8,335 patients (13 studies) and 4,612 patients (11 studies) were analyzed in phase II/III trials for first line and second line settings respectively. In the first line setting, atezolizumab plus bevacizumab and lenvatinib were ranked highest as the regimens associated with the greatest OS (A+B, HR 0.58, 95% CI, 0.42-0.80; P-score 0.993) and ORR (lenva, OR 3.34, 95% CI, 2.17-5.14; P-score 0.080) respectively. In the second line setting, cabozantinib showed the highest probability of greatest PFS benefit (HR 0.44, 95% CI, 0.29-0.66; P-score 0.854) as well as the highest probability of greatest ORR benefit (cabo, OR 9.40, 95% CI, 1.25-70.83, P-score, 0.266). Conclusions: In the first line setting, atezolizumab plus bevacizumab may be the superior regimen whereas lenvatinib may be considered as the initial option when robust tumor responses are preferred. In the second line setting, cabozantinib may be the preferred option including in cases when robust tumor responses are favored.