bluuebunny/crossref_metadata_2025_split huggingface dataset:
A whole transcriptome sequencing (WTS)-based cMet dysregulation biomarker assay with correlates to cMet DNA mutations and cMet protein expression.
Authors: Zhang Xiaoling , Stafford Phillip , Baker Brian , Kimbrough Jeffery , Benedetti Fabio M. 
Published: May 2020

e15676 Background: Selective cMet kinase inhibitors (cMet-i) have demonstrated promising clinical activity as single-agents in non-small cell lung cancer (NSCLC) with cMet exon-14 skip mutations (MET∆14). APL-101 (PLB-1001) is a selective cMet-i and has demonstrated single-agent anti-tumor activity in secondary glioblastoma (GBM) harboring MET∆14 and/or MET fusion with evidence of blood-brain barrier permeability (Cell. 2018, 175: 1665-1678). A WTS-based cMet biomarker assay is being developed under Caris MI Transcriptome platform to predict clinical response to monotherapy APL-101 in tumors with cMet dysregulation (NCT03175224). Methods: In a pilot study, we used Caris WTS to analyze 202 patient samples of NSCLC (78%) and other tumor types (22%) mostly GBM and gastrointestinal tumors to establish key parameters of Caris WTS in detection of cMet dysregulation. These samples were also analyzed by DNA-seq and IHC to understand the correlations of Caris WTS to DNA-based cMet mutation detection and cMet protein expression. The samples included 63 (31%) MET∆14, 48 (24%) MET fusions based on WTS and covered a broad dynamic range in cMet expression and copy number variations. In order to establish a stable baseline against which to compare MET mRNA expression, 123 unique tissue samples from 93 unique non-tumor tissues covering 27 unique tissue types were analyzed for wild-type MET expression. Results: Concordance between WTS and DNA-seq in detection of MET∆14 was 84% based on 67 cases analyzed by both methods. WTS identified 45% positive MET∆14, compared to 35% by DNA-seq. Out of 11 discordant cases, 9 were positive by WTS and 2 positive by DNA-seq. The number of transcripts carrying MET∆14 variants correlated with cMet wild type mRNA expression (n = 63, r = 0.88, p< 0.0001). cMet mRNA expression correlated with total cMet protein by IHC in MET fusion subset (n = 43, ρ = 0.65, p= < 0.0001), MET∆14 subset (n = 55, ρ = 0.64, p< 0.0001), and in all samples (n = 175, ρ = 0.75, p< 0.0001). In 175 cases with both WTS and IHC results, 9 MET∆14 positive cases had no detectable cMet protein on plasma membrane albeit all showed a detectable level of total cMet protein. Conclusions: A cMet WTS assay has been established to identify patients with cMet dysregulation including MET∆14 and MET fusion. cMet IHC and DNA-seq may offer secondary utility to differentiate WTS-identified METΔ14 patients to further strengthen the prediction of clinical response to a cMet inhibitor.
20q amplification defined by genomic and clinical characteristics as a subgroup with increased prevalence and better survival in metastatic colorectal cancer.
Authors: Maharaj Satish , Xue RuoBing , Cheema Anmol 
Published: May 2020

e16003 Background: Genomic instability from 20q amplification is an oncogenic pathway in colorectal cancer (CRC). Several genes have been implicated, including BCL2L1, AURKA, SRC, ASXL1, GNAS and TOP1. There is a lack of data regarding 20q amplified group and one study implicating these genes suggested these patients have better overall survival. Next Generation Sequencing (NGS) has become widely used in metastatic CRC (mCRC) and easily identifies patients with 20q amplification. Nevertheless, most oncologists do not routinely consider 20q amplification status and this subgroup remains underinvestigated. This study aims to investigate genomic and clinical characteristics of 20q amplified mCRC using a single-center retrospective cohort and a multi-center genomic dataset. Methods: A cohort was identified comprising patients with mCRC who had NGS testing of tumor DNA and were treated between 2014-2019. Cases with and without 20q amplification were identified. Genomic, clinical and survival data were analyzed. Significant genomic findings were compared with all-stage CRC data using the AACR Genomic Evidence Neoplasia Information Exchange (GENIE) and The Cancer Genome Atlas (TCGA) databases. Results: Of the mCRC cohort ( n= 72), 15% ( n= 11) had 20q amplification. Amplified and non-amplified groups had no significant differences in age, sex or follow-up time. Patients with 20q amplification were more likely to have never smoked, and less likely to have treatment with targeted therapy. Survival analysis showed clear separation with longer overall survival for the amplified group. Eight genes at loci 20q11 to 20q13 were amplified - in order of frequency: ASXL1, GNAS, ARFRP1, ZNF217, AURKA, BCL2L1, SRC and TOP1. 20q amplification was significantly associated with wild-type RAS and BRAF, microsatellite stability, mutant TP53 and mutant APC. Using the GENIE and TCGA databases, it was found that metastatic disease had increased prevalence of all 20q amplified genes except TOP1, when compared to all-stage CRC. Conclusions: Clinical use of NGS identifies the 20q amplification subgroup that has increased prevalence in mCRC (compared to all CRC). Compared to non-20q amplified mCRC, this group had better survival, suggesting genomic pattern in mCRC is a novel independent prognostic marker. We believe mCRC patients would benefit from further studies defining a genomic prognostication model and development of therapy targeting the 20q amplification pathway.
Image-guided navigation for locally advanced primary and locally recurrent rectal cancer: Evaluation of its early cost-effectiveness.
Authors: Lindenberg Melanie , Kramer Astrid , Kok Esther , Retel Valesca P. , Ruers Theo , van Harten Wim 
Published: May 2020

e16015 Background: Radical resection is an important prognostic factor in patients with locally advanced primary (LARC) and locally recurrent rectal cancer (LRRC), but achieving this can be challenging. Therefore, an intraoperative surgical navigation system has been developed, showing improved radical resection rates for LARC and LRRC. This study evaluates the early cost-effectiveness of navigated surgery in LARC and LRRC compared to standard surgery. Methods: Two Markov decision models; one for each indication, were used to estimate the expected costs and outcomes for navigated and standard surgery from a Dutch healthcare perspective over a 3-year time horizon. The models started with a decision tree resulting in a radical or non-radical resection. Subsequently, the Markov-models comprised the health states “stable disease”, “progression” and “death”. The input parameters were based on prospective (navigation cohort n = 33) and retrospective (control group n = 142) data collected at the Netherlands Cancer Institute, reference and unit prices and expert opinion. Quality-Adjusted Life Years (QALYs) were measured by the EQ5D-5L. Additionally, a probabilistic sensitivity analysis and a scenario analysis were performed. Results: Navigated surgery showed incremental costs of €3139 and €2857 in LARC and LRRC, respectively. For LARC, for navigation and standard surgery we found: 2.54 vs 2.52 Life Years (LYs), and 2.06 vs 2.04 QALYs. For LRRC we found 2.17 vs 2.11 LYs and 1.73 vs 1.67 QALYs. The base case analysis showed an Incremental Cost-Effectiveness Ratio (ICER) of €144,192 for LARC and €51,802 for LRRC per QALY gained. At a willingness to pay threshold of €80,000, navigated surgery is not cost- effective in LARC but is cost-effective in LRRC. When a hospital lacks a hybrid OR and needs to invest in one to use the navigation system, which will increase the ICERs for both indications. Finally, more utilization of the navigation system (12% to 50% utilization rate) shows ICERs of € 65,257 and €20,648 for LARC and LRRC, respectively. Conclusions: Based on the current data, the navigation system is expected to be cost-effective in LRRC and has the potential to become cost-effective in LARC. To decrease the costs, it is crucial to identify more surgical indications for image-guided navigation. Especially as in the near future, image-guided surgery is expected to be a standard option in surgical practice. As these findings are sensitive to uncertainty in the data, a randomized controlled trial is advised to perform for relevant indications.
The results of a study of the concordance of RAS status in liquid and invasive biopsies in patients with metastatic colorectal cancer in the Republic of Kazakhstan.
Authors: Smagulova Kaldigul , Kaidarova Dilyara , Ukolova Yelena , Orazgalieva Madina , Kurmankulova Anel 
Published: May 2020

e16017 Background: Liquid biopsy is increasingly of interest as an alternative to invasive biopsy of solid tumors for predicting, making decisions about the treatment and monitoring of the disease. Particular preference is given to liquid biopsy in cases where it is not possible to obtain a sufficient amount of material or material of poor quality with a tumor biopsy. However, in order to find out the clinical significance of circulating tumor DNA (ctDNA), it is important to first establish the sensitivity of the method using tumor-plasma consistency studies. Methods: We selected 38 patients with a confirmed diagnosis of colorectal cancer (CRC), in whom was established the progression of the disease. All patients underwent two diagnostic methods, which we divided conditionally into 2 groups: A – invasive biopsy from available metastatic foci; to detect mutations in exons 2, 3, and 4 the KRAS gene used a reagent kit to detect 18 point mutations in codons 12,13,61,117,146 and a reagent kit to identify 10 mutations of the NRAS gene in codons 12,13,61,146 (Entrogen) on a Rotor-Gene 6000 Amplifier; B - liquid biopsy, to determine 21 mutations in the codons 12,13,59,61,117,146 of the KRAS gene, 18 mutations in the codons of 12,13,59,61,117,146 of the NRAS gene, was used Idylla automated molecular diagnostic system. Results: Of the 38 studied samples of group A: 22 (57.9%) had wild type KRAS, 16 (42.1%) were mutated, in group B: wild type had 25 (65.8%) patients, mutated - 13 (34, 2%). Thus, we see a discrepancy in the results in 3 (7.9%) of 38 cases. Conclusions: The results indicate a high degree of sensitivity (92.1%) of liquid biopsy as a diagnostic method, but confirmation of concordance with traditional tissue biopsy requires further in-depth study of this issue in a larger sample of patients.
Survival impact of metastasis surgical resections and sidedness of primary (1º) tumor location in metastatic colorectal cancer (mCRC) without monoclonal antibodies: Retrospective review from 2003 through 2019.
Authors: Portella Marcos André Marques , Gonçalves Mariana Paula Cunha , Murad Junior Munir , dos Santos Borges Robson , Preisser Ana Livia Alves , Azevedo Junia Brunelli Cassétte , Fernandes Amandio S. , Fonseca Roberto Porto 
Published: May 2020

e16022 Background: Recent data demonstrated a median overall survival (OS) about 35 months for patients with mCRC based on the use of monoclonal antibodies (MA), anti-VEGFR and / or anti EGFR, with sidedness of primary tumor as an independent prognostic marker. However the influence of surgical resections of metastases has not yet been quantified especially after 2003 when were attributed to the inclusion of MA (Kopetz et al 2009). We hypothesized the impact of metastatectomy rate (MR) in the OS of a population without MA and their influence on primary tumor location. Methods: Data from 291 consecutive patients diagnosed with mCRC treated in a clinical center in Brazil, from 2003 to 2019, without MA. 1° location was determined by chart review: R-sided = cecum to hepatic flexure; L-sided = splenic flexure to rectum. Pts with transverse tumors were excluded. Survival from diagnosis was calculated via kaplan-Meier and compare between the right and the left side has estimated via Cox Regression. Results: 50.85%(148) of patients had a primary tumor in the left colon. Oxaliplatin was used in 1° line in 85 % and irinotecan in 75% in 2° line, most of the metastasis was metachronous, only to a single-organ (50,9% liver, 18% lung) and 40 % underwent resection at the diagnosis. The overall survival for the entire cohort was 34.1 months (95% CI, 28.9 to 45.4 months) with 39 % MR. Sidedness (R vs L) had interaction with resected and non-resected metastasis p < 0.001). See OS Table results by sidedness below. Conclusions: It was possible to infer that the metastasectomy rate still have a significant and isolated benefit in the OS of this cohort without the use of MA, regardless of the mutational status of the tumors, being influenced by the sidedness of the primary tumor in the analyzed outcomes. [Table: see text]
Cohort study on patients with metastatic colorectal cancer with integrated Chinese and western medicine.
Authors: Zhang Tong , He Wenting , Tang Mo , Yang Yufei 
Published: May 2020

e16030 Background: To investigate the efficacy of integrated Chinese and Western medicine in the treatment of mCRC in a cohort study (Registry No. ChiCTR-IOR-17010497). Methods: The survival outcome of patients receiving integrated Chinese and Western medicine was compared with that of patients receiving Western medicine alone. The study design was adopted with "continuous administration of traditional Chinese medicine for ≥ 3 months" as the exposure factor. Patients who met this exposure factor were assigned to the integrated Chinese and Western medicine cohort. Patients who did not meet this exposure factor were assigned to the Western medicine cohort. The overall survival, 5-year survival rate in the two cohorts were compared. Results: 335 subjects were assigned into two groups (Group A 129 patients, Group B 206 patients). The median overall survival (OS) in Group A and B were 19.2 months (95% CI 16.2–23.2) and 15.2 months (95% CI 13.3–17.2), P= 0.019. Group A demonstrated significantly longer OS and PFS than Group B in the following subgroups: female patients, right-side colon, first-line treatment, RAS mutation. Conclusions: Integrated traditional Chinese and Western medicine can prolong the survival of patients with mCRC. Clinical trial information: ChiCTR-IOR-17010497 .
Combination of anlotinib and irinotecan in the second-line treatment of patients with advanced colorectal cancer: An open-label, multicenter phase I/II study.
Authors: Zhang Bo , Wang Xi , Zhu Lingjun , Li Qun , Liu Yun , Qi Ling , Shu Yongqian , Huang Jing 
Published: May 2020

e16036 Background: Efficacious therapeutic options for advanced colorectal cancer (CRC) are limited, and treatment outcomes remain to be improved in the second-line setting. Anlotinib is a multi-target antiangiogenic small molecule that primarily inhibits VEGFR1/2/3. We conducted this open-label, multi-center phase 1/2 study to evaluate the safety and efficacy of anlotinib plus irinotecan in patients with previously treated advanced CRC. Methods: We enrolled patients with advanced CRC whose disease had progressed after first-line systemic therapy and had not previously received irinotecan. In the 3+3 dose escalation (phase 1) part of the trial, patients received anlotinib (8mg, 10mg and 12mg, po, 2 weeks on/1 week off) in combination with fixed-dose irinotecan (180mg/m2, iv, q2w) to define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). In the dose-expansion (phase 2) part, patients were treated with the RP2D of anlotinib and irinotecan. The primary endpoints were MTD and objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and disease control rate (DCR). Results: A total of 31 patients were enrolled from 2 centers between May 2018 and Jan 2020. The median follow-up duration was 12.48m (95% CI 7.43-15.24). Anlotinib was well tolerated in combination with irinotecan with no MTD identified in the phase 1 part, and the RP2D was therefore 12mg. Twenty-eight patients were evaluable for efficacy analysis. Eight patients achieved partial response (PR), in which 6 had confirmed PR and 2 were unconfirmed. The ORR was 21.4% (95%CI 8.3%-41.0%) and the DCR was 100% (95%CI 87.7%-100%). The median PFS and OS were 6.97m (95%CI 3.71-11.20) and 13.87m (95%CI 11.47-NR), respectively. All patients were included in the safety analysis. The most common grade 3 treatment-related adverse events (AEs) (≥5%) were diarrhea (16.1%), neutropenia (12.9%), fatigue (6.5%) and hypertension (6.5%). Grade 4 AEs included neutropenia (6.5%) and thrombocytopenia (3.2%). There were no treatment-related deaths. Conclusions: The combination of anlotinib and irinotecan had promising anti-tumor activity in the second-line treatment of advanced CRC with a manageable safety profile. Clinical trial information: NCT03545711 . [Table: see text]
Differential genetic variations and prognostic predicting factors in colorectal cancer patients with or without liver metastasis.
Authors: Peng Honghua , Liu Guifeng , Song Lele , Bao Ying , Zhang Xi , Zhou Lehong , Cao Sudan , Dang Shiying , Chen Shifu , Xu Mingyan , Cao Peiguo 
Published: May 2020

e16049 Background: Although liver metastasis is the most common metastasis for colorectal cancer (CRC), the molecular mechanism determining the metastasis has not been clarified. Our study aims to investigate the potential molecular mechanisms of liver metastasis by comparing the genetic variations between patients with or without liver metastasis, and to explore the prognostic factors for the two groups of patients. Methods: 57 stage I-IV CRC patients (49 with stage III/IV) were enrolled. 26 patients had no liver metastasis while 31 patients had liver metastasis when they were recruited. Whole-exome sequencing was performed on the primary cancer tissues of all patients. All patients were followed up for up to 50 months. Results: We found that the tumor mutation burden (TMB) of primary cancer tissue from patients with liver metastasis was significantly higher than those without metastasis (P < 0.05). When the mutation frequency was compared at whole-exome level, the mutation frequency of TCF7L2 and TRIM77 genes of primary cancer tissues was found to be significantly higher in patients with liver metastasis (TCF7L2: 35.48% vs. 3.85% (P = 0.0037) for patients with or without metastasis; TRIM77: 16.13% vs. 0% (P = 0.050) for patients with or without metastasis). Further study revealed that in patients with liver metastasis, patients with TRIM77 mutations showed worse overall survival (OS) than those without TRIM77 mutations (P < 0.0001). Similarly, patients with 7_12p.13.33 amplification, 10_14q32.33 amplification, and 4_10q23.31 deletion showed worse OS than those without the mutations (P < 0.05). In contrast, in patients without liver metastasis, patients with 6_20q13.33 amplification showed worse OS than those without the amplification. Conclusions: The TMB of CRC patients with liver metastasis was significantly higher than those without liver metastasis. TCF7L2 and TRIM77 gene mutations may be predictive for liver metastasis. TRIM77 mutation, 7_12 p.13.33 amplification, 10_14q32.33 amplification, and 4_10q23.31 deletion were related to poor OS in patients with liver metastasis, while 6_20q13.33 amplification was related to poor OS in patients without liver metastasis.
FGFR expression, fusion and mutation as detected by NGS sequencing of DNA and RNA.
Authors: De Dios Ivan , Ma Wanlong , Antzoulatos Spiraggelos , Estella Jeffrey , Albitar Maher 
Published: May 2020

e16061 Background: Fibroblast Growth Factor Receptors (FGFR1-4) abnormalities (fusion, amplification and mutations) are common in urothelial, breast and endometrial cancers. However, FGFR1-4 have been shown to play a major role in cell proliferation, differentiation, and apoptosis in other types of cancers including colorectal (CRC) and lung cancers. We explored the value of using DNA and RNA next generation sequencing (NGS) in determining the presence of abnormalities in FGFR1-4 in various types of cancer. Methods: Using targeted panel and next generation sequencing (NGS), we analyzed DNA sequencing data (434 genes) in 438 Solid tumors and RNA data (1408 genes) in 160 lung cancers and 53 colorectal cancers (CRC). The expression levels of the CRC and lung cancer were also compared with expression levels of 32 cases of endometrial, urothelial and breast cancers as a group of cancers known to have high incidence. Results: The DNA data showed mutations in 85 samples and CNV in 12 samples. The detected mutations were 18% in FGFR1, 25% in FGFR2, 45% in FGFR3, and 12% in FGFR4. Only 20% of the detected mutations by NGS testing can be detected if the PCR-based FDA-approved kit was used. Analysis of the expression levels of FGFR1-4 mRNA in CRC and lung cancer showed highest expression in FGFR2, followed by FGFR1 then FGFR3. Expression of FGFR4 was the lowest (P < 0.0001). There was no difference between CRC and lung cancer in FGFR1 and FGFR2 mRNA, but FGFR3 was slightly higher in lung cancer as compared with CRC (P = 0.01). FGFR4 was significantly higher in CRC as compared with lung cancer (P < 0.0001). No fusion involving FGFR1-4 was detected in any of the tested CRC or lung cancers. Upon comparing overall expression between CRC/lung cancer with the group of cancers that are known to have high incidence of FGFR1-4 abnormalities (urothelial, breast, and endometrial), FGFR1 and FGFR2 mRNA were significantly lower in CRC/lung cancers (P < 0.0001 and P = 0.0002, respectively), but there was no significant difference in FGFR3. However, significant overlap is noted. In contrast, FGFR4 was significantly higher in CRC (P < 0.0001). Conclusions: This data suggests that while FGFR1-3 genes are overall expressed in CRC and lung, some cases may have significantly high expression of FGFR1-3 and perhaps these cases should be singled out for treatment with FGFR inhibitors. Furthermore, NGS testing for mutations significantly more efficient and can detect significant number of mutations that can be missed if PCR-based testing is used. NGS testing of DNA and RNA is the most appropriate testing for abnormalities in FGFR1-4.