bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating tumor DNA testing and research in patients with gastrointestinal malignancies.
Authors: Shahjehan Faisal , Kamatham Saivaishnavi , Kasi Pashtoon Murtaza 
Published: January 2019

525 Background: The hallmark of circulating tumor DNA (ctDNA) is its rapid turnaround and non-invasive nature. According to American Society of Clinical Oncology (ASCO) and College of American Pathologists joint ctDNA review published in March 2018, there is no sufficient evidence to support the use of ctDNA in practice for GI cancers. However, there were numerous studies presented at ASCO Annual Meeting supporting its value. We aimed to summarizing on its role in the management of gastrointestinal cancers based on the studies presented recently. Methods: We limited our search to keywords ‘ctDNA’, ‘circulating tumor DNA’, ‘cell-free DNA (cfDNA)’ and/or ‘liquid biopsy’, at the 2018 ASCO Annual Meeting library abstracts and presentations. Results: There were 35 studies that revolved around ctDNA as a diagnostic tool, prognostic marker and a measure of tumor heterogeneity in gastrointestinal cancers. Depending on the assay used, the results of several studies showed that ctDNA was able to identify relevant mutations including RAS, HER2/Neu, BRAF, MET, BRCA2, APC, TP53, ROS1, PTEN and NF1. The prognosis in terms of tumor mutation burden, objective response rate, metastasis and survival was also estimated based on ctDNA. The findings showed that higher baseline ctDNA levels and/or increased number of mutations detected in ctDNA were associated with poor survival and multi-site metastasis. Right-sided colon cancer was associated with higher number of mutations in ctDNA than left-sided colon and rectal cancers. Similarly, tubular adenocarcinoma subtype of gastric cancer was more likely to have higher ctDNA levels than signet-ring cell subtype. The response to therapy and the residual metastatic disease which was otherwise not detected on imaging could be detected by ctDNA as well. Conclusions: The research at ASCO 2018 report an increasingly promising role of ctDNA in many forms in patients with gastrointestinal malignancies. Experts at the meeting argued that this may well indeed be ready for prime time for certain GI malignancies including colorectal cancers. Prospective studies and studies showing its feasibility into practice can potentially help revise the current guidelines.
Racial disparities and treatment outcomes among patients admitted with a diagnosis of colorectal cancer: Analysis of the 2014 national inpatient sample database.
Authors: Enofe Ikponmwosa , Rai Manoj P. , Osaghae Osamuyimen 
Published: January 2019

529 Background: Colorectal cancer is the fourth most common cancer in the United states and the second most common cause of death. Despite universal advocacy for screening colonoscopies and early diagnosis, racial disparities in screening and diagnosis of colorectal cancer exist and affect patients outcomes. In this analysis we determine racial disparities and treatment outcomes for colorectal cancer treatment in the United States. Methods: We performed a retrospective analysis of the National Inpatient Sample 2014 Database (HCUP_NIS) which contains records of all hospital discharges in the United States Patients 18 years and older with a diagnosis of colorectal cancer were identified by their ICD 9 codes along with treatment they had for colorectal cancer. We then used multivariable regression to identify the effect of race on receiving a therapeutic procedure (open surgical, laparoscopic or robotic) during hospitalization and outcomes as it relates to inpatient mortality. We adjusted for patients age, sex, number of comorbidities (elixhauser comorbidity score), insurance type, and hospital level charactertistics (i.e. size, teaching status) and location (urban and rural location). Results: There were 25,749 discharge diagnosis of colorectal cancer in the United States in 2014 of which 19,300 were associated with undergoing a procedure for colorectal cancer treatment. Whites accounted for the majority of colorectal cancer admissions (65%) while blacks 11.4 %, Hispanics 8.0%, Asian/Pacific Islanders 3.2 %, and Native Americans 0.4%. Blacks had the lowest frequency of procedure related admissions and were less likely to undergo a therapeutic procedure relating to colorectal cancer treatment (67.5 vs. 76.6 OR 0.84 CI 0.75 - 0.93) compared to whites. For specific procedures, blacks (OR 0.81, CI 0.72-0.91) and Hispanics (OR 0.85, CI 0.74-0.98) had a significantly lesser odds of undergoing open surgical procedures when compared to whites but were similarly likely (Blacks OR 0.93, CI 0.81-1.05, Hispanics OR 0.84, CI 0.61-1.14) to undergo laparoscopic/robotic surgical procedure. On multivariable analysis, Asian/Pacific Islanders had a significantly higher mortality (OR 1.61 CI 1.01-2.60) for non-procedure related colorectal cancer admissions. However, this increase mortality was not seen in procedure related colorectal cancer admissions. Overall, after adjusting for potential confounders and treatment, there was no significant variation amongst different races for colorectal cancer mortality in patients admitted to the hospital. Conclusions: Among patients with colorectal cancer there was no procedure related mortality differences between various races. However, for some reason Asian/Pacific Islanders had a significantly higher mortality for non-procedure related colorectal cancer admissions. Further studies are warranted to understand the above findings.
Phase Ib study of andecaliximab (GS-5745, ADX) in combination with S-1+platinum chemotherapy in Japanese subjects with advanced gastric or GEJ adenocarcinoma.
Authors: Muro Kei , Satoh Taroh , Yamaguchi Kensei , Takashima Atsuo , Kadowaki Shigenori , Sakai Daisuke , Ichimura Takashi , Mitani Seiichiro , Kudo Toshihiro , Chin Keisho , Kitano Shigehisa , Bhargava Pankaj , Zavodovskaya Marianna , Liu JieJane , Fukui Masato , Boku Narikazu 
Published: January 2019

53 Background: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. In preclinical models, anti-MMP9 inhibited tumor growth, reduced metastases, and increased survival. In this study, safety, tolerability, PK, exploratory biomarkers, and preliminary efficacy of ADX in combination with anti-cancer agents were assessed. Methods: The safety and efficacy of ADX in combination with S-1+cisplatin (SP) or S-1+oxaliplatin (SOX) were evaluated in subjects with systemic chemotherapy naïve advanced gastric or GEJ adenocarcinoma. For SP cohort, six Japanese subjects received ADX 800 mg via IV infusion Q2W. For SOX cohort, 10 subjects received ADX 1200 mg IV Q3W. All subjects continued until PD or unacceptable toxicity. Results: As of August 2018, a total of 16 subjects received S-1+platinum with six subjects enrolled into the SP combination cohort and 10 subjects enrolled into the SOX combination cohort. ≥ Grade 3 AEs were mainly neutropenia (31%), amylase increased, CPK increased, hepatic function abnormal, anorexia, hyperglycaemia, hyponatraemia, anaemia, stomatitis, and peripheral sensory neuropathy (each 6%). The ORR in subjects with measurable target lesions was 73% (8/11) based on investigator evaluation. Median PFS and OS have not been reached. Exploratory biomarker analyses are ongoing. Conclusions: Preliminary safety data demonstrate a manageable safety profile for ADX in combination with S-1+platinum, and the combination appears to show promising response rates. Clinical trial information: NCT02862535.
KRAS mutation status to predict response in first-line capox and bevacizumab therapy for metastatic colorectal cancer.
Authors: Yone You , Abdallah Mohammad , Tahir Saad Sabih , Cellek Selim , Zhang Jufen , Lester Yvonne , Shillito Lauren , Child Jennifer , Dawson Lizzie , Singizi Bryan , Bustin Stephen 
Published: January 2019

536 Background: Capecitabine and Oxaliplatin (CAPOX) combined with the humanised anti-vascular endothelial growth factor Bevacizumab represents a standard first-line treatment for metastatic colorectal cancer (mCRC). However, the response rate is only approximately 50% and currently there is no biomarker to predict treatment response. This study aims to correlate KRAS status with response to CAPOX and Bevacizumab (CAPOX-Bev). Methods: Forty-five patients with mCRC were retrospectively screened between January 2012 and December 2015 at Broomfield Hospital, UK. DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue samples (Qiagen FFPE tissue kit). Twelve types of mutations in Exons 2, 3 and 4 of the KRAS gene were analysed using a real-time quantitative polymerase chain reaction (qPCR) assay (EntroGen). Treatment response was assessed according to RECIST criteria version 1.1 by comparing pre-treatment and post-treatment radiological CT scans. The KRAS status was correlated with CT tumour response (responders: partial response and complete response; non-responders: progressive disease and stable disease). A Chi-square test was used to determine the correlation between KRAS status and tumour response. Results: 19/45 patients were KRAS wild type (WT, 42%) and 26 were KRAS mutant (MT, 58%). 8/19 (42%) KRAS WT patients were responders, compared to 3/26 (12%) KRAS MT patients. Conversely 11/19 (58%) of WT patients were non-responders, compared to 23/26 (88%) MT patients. The correlation of treatment response and KRAS status was statistically significant (p = 0.018), with a 31% difference in response rate between KRAS WT (42%) and KRAS MT (12%) groups. Conclusions: Within this pilot retrospective analysis, KRAS mutations demonstrated clinical value in identifying patients who are more likely to respond to first-line CAPOX-Bev in advanced colorectal cancer. This finding requires prospective evaluation within a large patient cohort powered to further detect potential differences in overall and progression free survival. [Table: see text]
Expanded RAS and BRAF V600 testing as predictive biomarkers for single agent cetuximab in the randomized phase III CO.17 trial.
Authors: Loree Jonathan M. , Dowers Anthony , Tu Dongsheng , O'Callaghan Christopher J. , Edelstein Dan , Quinn Hannah , Jonker Derek J. , Karapetis Chris , Price Timothy Jay , Zalcberg John Raymond , Moore Malcolm J. , Waring Paul Michael , Kennecke Hagen F. , Hamilton Stanley R. , Kopetz Scott 
Published: January 2019

537 Background: KRAS/NRAS ( RAS) testing of exons 2, 3 and 4 is standard prior to anti-EGFR treatment in metastatic colorectal cancer and many consider BRAFV600 ( BRAF) mutations predictive. CO.17 was a randomized phase III trial comparing cetuximab vs best supportive care (BSC) in unselected patients (pts). Re-analysis tested only KRAS exon 2, thus the benefit of cetuximab in RAS/BRAF wild type (WT) pts is unclear. Methods: We retrospectively performed expanded RAS/BRAF testing using a highly sensitive digital PCR method (BEAMing; 1% allele frequency detection limit) on micro-dissected archival tissue from 248 CO.17 pts. Additional pts without available archival tissue, with prior Sanger sequencing or therascreen results were included in analyses if mutations were previously detected (n = 77). Overall survival (OS), progression free survival (PFS), and response rates (RR) were compared by molecular profile. Results: Of 248 sequenced pts, 139 (56%) were RAS mutant, with 112 (45%) exon 2, 11 (4%) exon 3 and 6 (2%) exon 4 KRAS mutant, and 10 (4%) NRAS mutant pts. Seven (3%) BRAF mutant, and 97 (30%) confirmed RAS/BRAF WT pts were identified. Results are summarized below. A test of interaction indicated RAS status was predictive for PFS (p = 0.0001) and OS (p = 0.037) and BRAF status neared significance as a predictive marker for PFS (p = 0.089) but not OS (p = 0.24). Conclusions: These updated results demonstrate an improved PFS (HR 0.25 vs 0.40 previously) and OS (HR 0.51 vs 0.55 previously) for cetuximab in RAS/BRAF WT pts compared to prior analyses that included only KRAS exon 2 mutation status. We provide an estimate of single agent cetuximab efficacy for future anti-EGFR re-challenge studies and demonstrate further support that BRAF mutations may predict lack of benefit from anti-EGFR therapy. Clinical trial information: NCT00079066. [Table: see text]
Excision repair cross-complementing group-1 (ERCC1) gene induction in peripheral blood mononuclear cells as a marker of outcome in patients with colorectal cancer treated with oxaliplatin.
Authors: Rao Devika , Basu Mallick Atrayee , Merla Amartej , Jiffry Jeeshan , Chaudhary Imran , Augustine Titto A , Rajdev Lakshmi , Kaubisch Andreas , Maitra Radhashree , Goel Sanjay 
Published: January 2019

542 Background: Oxaliplatin is a third generation platinum agent that confers tumoricidal effect by forming platinum-DNA adducts and is an integral part of the standard of care regimens for patients with colorectal cancer (CRC). Tissue resistance to oxaliplatin appears to be multifactorial, with the nucleotide excision repair (NER) pathway playing a major role. We have previously demonstrated that Excision Repair Cross-Complementing group-1 (ERCC1), can be induced in colorectal cell lines on exposure to Oxaliplatin and high levels confer resistance to apoptosis. We aim to further this knowledge by analyzing gene expression in vivo, using PBMC as a surrogate, to assess ERCC1 as a biomarker of sensitivity to Oxaliplatin therapy. Methods: Patients with CRC who received oxaliplatin were consented to blood (PBMC) sampling at 0, 2, 48 hours, and 14 days during any cycle of chemotherapy. ERCC1 gene expression was quantified by qPCR (quantitative real time polymerase chain reaction) and WB (western blotting). Clinical benefit from oxaliplatin was determined using the parameters of relapse free survival (RFS) for limited stage and progression free survival (PFS) for mCRC. Results: Fifty-four patients were enrolled on study, 25 (46.3%) had mCRC. Twenty-four patients were included in final analysis based on clinical data. Thirteen (52%) had an increase in ERCC expression from baseline, while 11 (48%) showed no change or decrease. Median PFS was 190 and 237 days respectively (log-rank test HR 2.35, CI 1.005-5.479; p = 0.0182). In the 29 patients with limited stage disease, 19 (65.5%) had an induction of ERCC. However, in these patients change in expression did not correlate with RFS. We did not find any significant correlation of PFS with baseline expression of ERCC1 in either group. Conclusions: We confirm our hypothesis that the ERCC1 gene is induced in vivo in a sub-population of patients on treatment with Oxaliplatin. This induction can serve as a potential marker of resistance to oxaliplatin based chemotherapy in mCRC as evidenced by the significant difference in PFS. Further analyses of the influence of ERCC1 polymorphisms on outcomes is underway.
CEA response at four weeks as an early predictor for outcomes in patients (pts) with metastatic colorectal cancer (mCRC) treated with first-line cetuximab-based chemotherapy: A STEP-analysis in the JACCRO CC-05/06 trials.
Authors: Sunakawa Yu , Fang Xuemin , Kotaka Masahito , Tanioka Hiroaki , Takagane Akinori , Tani Satoshi , Yamaguchi Tatsuro , Watanabe Takanori , Masuishi Toshiki , Tsuda Masahiro , Okuno Tatsuya , Tamura Takao , Furushima Kaoru , Kuramochi Hidekazu , Koike Junichi , Yonemura Yutaka , Yasui Hisateru , Takeuchi Masahiro , Fujii Masashi , Ichikawa Wataru 
Published: January 2019

543 Background: We have reported that carcinoembryonic antigen (CEA) response correlated with clinical outcomes of 1st-line cet-based therapy (Target Oncol 2017). Early tumor shrinkage (ETS) is considered to be an on-treatment biomarker for outcomes of chemotherapy; however, clinical biomarkers to predict outcomes earlier are warranted. Methods: This study included 69 pts who were assessable for CEA at baseline and 4 wks, and with observed survival time from 2 phase II trials of 1st-line therapy for KRAS exon2 wild-type mCRC; JACCRO CC-05 of cet plus FOLFOX (UMIN000004197) and CC-06 of cet plus SOX (UMIN000007022). We investigated the influence of baseline age, gender, PS, primary tumor sidedness (PTS), number of tumor sites, as well as the CEA decrease at 4 wks to the patient’s OS and PFS. Results: PTS and the CEA decrease at 4 wks were found to be important predictors to OS and PFS. Baseline CEA and CEA decrease at 4 wks were median of 31.0 (range, 1.0-20920.0) and median of 35% (range, -259%-97%), respectively. The STEP-analysis indicated that CEA response was most significantly associated with OS when a cut-off value of 50% for CEA-responder (HR 0.49, log-rank test p = 0.03). Median OS in responders (n = 25) and non-responders (n = 44) were 36.2 m and 21.5 m, respectively. When the same cut-off value was used, median PFS in responders and non-responders were 11.6 m and 6.5 m, respectively (HR 0.64, log-rank test p = 0.08). In addition, a multivariate Cox Proportional-Hazards Model with both PTS and CEA response as risk factors showed that PTS correlated with both OS and PFS. In pts with left-sided tumors, non-responders (n = 33) had shorter OS and PFS compared to responders (n = 23). In the above 2-covariate Cox proportional hazard model, adjusted HR for CEA 50% decrease is 0.55, p = 0.1; adjusted HR for PTS is 2.66, p = 0.008. Conclusions: Our analysis suggests 50% CEA decrease at 4 wks as an early on-treatment biomarker for 1st-line cet-based therapy in mCRC. It may potentially predict outcomes earlier compared to ETS. Also, CEA response at 4 wks may differentiate pts who receive more benefit from cet treatment in left-sided tumors. Clinical trial information: UMIN000004197 and UMIN000007022.
The correlation between DPYD*9A (c.85T > C) genotype and dihydropyrimidine dehydrogenase deficiency phenotype in patients with gastrointestinal malignancies treated with fluoropyrimidines: Updated analysis.
Authors: Singh Maharjan Anu , McMillin Gwendolyn A. , Patel Girijesh K. , Awan Saad , Taylor William R. , Pai Sachin , Frankel Arthur E. , Nelson Cindy , Wang Bin , Hosein Peter Joel , Singh Ajay , Khushman Moh'd M. 
Published: January 2019

544 Background: The correlation between DPYD*9A (c.85T > C) genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. In our cohort of 28 patients with gastrointestinal malignancies (GI) treated with fluoropyrimidines, DPYD*9A was the most commonly diagnosed variant (46%) and there was a noticeable genotype-phenotype correlation (Khushman et al). In this updated analysis, a larger cohort of a mixed racial background was genotyped for DPYD*9A variant to confirm the incidence and genotype-phenotype correlation. Methods: Between 2011 and 2018, in addition to genotyping for high risk DPYD variants (DPYD*2A, DPYD*13 and DPYD*9B), genotyping for DPYD*9A variant was performed on 113 patients. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (v 5.0). Results: DPYD variants were identified in 61 patients. DPYD*2A was identified in 3 patients and DPYD*9B was identified in 2 patients (one patient had double heterozygous *9A and *9B). Heterozygous DPYD*9A was identified in 46 patients (41%) and homozygous DPYD*9A was identified in 11 patients (10%). Among patients with DPYD*9A variant, Caucasians represented 51% and African Americans represented 46%. 27 patients (47%) were females. Grade 3-4 toxicities were experienced in 26 patients with mutant DPYD*9A (3 patients had homozygous DPYD*9A) and in 20 patients with no identified DPYD mutation (P = 0.7035). In patients who received full dose fluoropyrimidines (N = 85), grade 3-4 toxicities were experienced in 22 patients with mutant DPYD*9A (2 patients had homozygous DPYD*9A) and in 17 patients with no identified DPYD mutation (P = 0.8275). Conclusions: In our updated analysis, DPYD*9A variant was the most commonly diagnosed variant. The correlation between DPYD*9A variant and DPD clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely due to small sample size and patients’ selection and testing bias.
Germline pharmacogenomics of thymidylate synthase gene in patients with gastrointestinal malignancies treated with fluoropyrimidines-based chemotherapy regimens.
Authors: Awan Saad , Patel Girijesh K. , Singh Maharjan Anu , McMillin Gwendolyn A. , Taylor William R. , Pai Sachin , Frankel Arthur E. , Smith Clayton , Grimm Leander , Rider Paul , Hunter John , Liles Spencer , Nelson Cindy , Wang Bin , Hosein Peter Joel , Singh Ajay , Khushman Moh'd M. 
Published: January 2019

545 Background: Fluoropyrimidines are antimetabolites that target the S phase of the cell cycle. The active metabolite, 5-fluorodeoxyuridine monophosphate inhibits thymidylate synthase (TS) enzyme, thus preventing DNA synthesis and ultimately cell death. While controversy exists in the literature, polymorphism in the promoter region of thymidylate synthase gene (TYMS) that decrease TS expression has been associated with increased fluoropyrimidines-associated toxicities. This study explored the association between polymorphism in the promoter region of TYMS gene and fluoropyrimidines-associated toxicities in patients with gastrointestinal malignancies with mixed racial background. Methods: Between 2011 and 2018, 126 patients were genotyped for TYMS. Patients with known high-risk dihydropyrimidine dehydrogenase gene variants were excluded. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institiute Common Terminology Criteria for Adverse Events (v 5.0). Fisher’s exact test was used for statistical analysis. Results: TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 toxicity (22%) while among patients with genotypes that predict decreased TS expression, 30 patients had grade 3-4 toxicities (42%) (P = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3-4 toxicity (P = 0.0039) and 15 out 40 patients (38%) with 2R/3RC and 3RC/3RC TYMS genotype had grade 3-4 toxicity (P = 0.1108). Among patients with 2R/2R TYMS, Caucasians represented 61% and African Americans represented 39%. Females represented 65% of the patients. Conclusions: Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3-4 fluoropyrimidines-associated toxicities.