bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of microsatellite instability (MSI) in cell free DNA (cfDNA) of colorectal cancers (CRC) patients (pts).
Authors: Barzi Afsaneh , Campan Mihaela , Petterson Jonas , Du Lan , Long Tiffany , Dubeau Louis , Lenz Heinz-Josef , Ward Pamela 
Published: January 2019

672 Background: While there is accumulating evidence that tumor specific mutations can be accurately detected in cfDNA, the determination of MSI status in cfDNA has not been investigated, perhaps because the complexity of detecting tumor instability embedded within stutter amplification patterns generated from normal cfDNA was considered too challenging to allow the detection of altered microsatellite profiles. We explored the possibility of detecting MSI in cfDNA. Methods: Circulating cfDNA was isolated from Streck tubes from 13 patients with CRC; 6 pts had serial collections. Isolation and testing of cfDNA for MSI was performed using kits purchased from Promega. Microsatellite alterations were scored by comparing the amplicon stutter profiles of 5 mononucleotide markers generated from cfDNA to those present in genomic DNA extracted from buffy coats from the same pts. MSI was diagnosed based on a shift in the size of a predominant stutter peak together with a commensurate shift in the stutter profile resulting in the appearance of at least one new stutter in tumor-derived DNA compared to matched germline DNA. MSI was scored high when 30% or more of the markers showed MSI or low if present in less than 30% of the biomarkers examined. Results: No MSI was detected in 3 pts with microsatellite stable tumors and 2 Lynch syndrome pts with no evidence of disease. Five of six pts with MSI high tumors (sporadic and Lynch syndrome) had a detectable MSI high biomarker profile in cfDNA at baseline. Four pts with positive MSI in cfDNA started immunotherapy and had a decline in the relative amounts of tumor-derived microsatellite alleles in their subsequent specimens. The pt with MSI high in the primary tumor and no MSI in cfDNA had rapid progression on immunotherapy. Two other pts with MSI high who responded deeply to check point inhibitors had no evidence of MSI in cfDNA at the time of their specimen collection. In each case with MSI in cfDNA, the electrophoretic profile matched that in the respective primary tumor. Conclusions: Detection of MSI in cfDNA is feasible and may be reflective of burden of the disease. A prospective study to establish the validity of cfDNA in the diagnosis and follow up care in pts with metastatic CRC is planned.
Intensive first-line triplet chemotherapy plus cetuximab FIr-C/FOx-C in RAS wild-type MCRC: Preliminary phase II data and prediction of individual limiting toxicity syndromes by pharmacogenomic biomarkers.
Authors: Bruera Gemma , Massacese Silvia , Dal Mas Antonella , Ficorella Corrado , Ciacco Eugenio , Calvisi Giuseppe , Simmaco Maurizio , Ricevuto Enrico 
Published: January 2019

673 Background: Intensive first line bevacizumab added to triplet, and cetuximab (CET) to doublet in RAS wild-type MCRC significantly increased outcomes. We investigated safety/activity of FIr-C/FOx-C adding CET to triplet in RAS wild-type. Methods: Phase II study according to Simon two-step design: delta 15% (p070%, p185%), power80%, α5%, β20%; projected ORR I step 14/19. FIr-C/FOx-C: 5-fluorouracil (5-FU) 12h-TFI 900 mg/m2 days (d) 1-2,8-9,15-16,22-23 associated to weekly alternating irinotecan (CPT-11) 160 mg/m2 d1,15 or oxaliplatin 80 mg/m2 d8,22; CET loading dose, then 250 mg/m2 d1,8,15,22; every 28d. Toxicity, LTS evaluated/compared by chi-square test; activity/efficacy by log-rank. Pharmacogenomic biomarkers of 5-FU/CPT-11, 5-FU degradation rate (5-FUDR), Single Nucleotide Polimorphisms (SNP) ABCB1, CYP3A4, DYPD, UGT1A1, evaluated in individual patients with limiting toxicity syndromes (LTS) and at recommended dose. Results: 29 patients < 75 years, primary/intermediate CIRS. From April 2014, KRAS/NRAS wild-type eligible: median age 59; young-elderly (yE) 7, 24%; liver-limited (L-L) 7, 24%. Recommended CPT-11/5-FU doses 120/750 mg/m2. Activity met primary endpoint: OR 14/18 evaluable as-treated (76%), confirmed in preliminary phase II, 17/23 intent-to-treat (74%). Liver metastasectomies 14%, 57% L-L. At median follow-up 18 months, PFS 12, OS 23 months. At recommended doses, received DI > 80% for each drug; cumulative G3-4 toxicities: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%; LTS, consisting of the LT, associated or not to G2 or other LT, in 19 patients (65.5%), 83% yE. LTS prevalently multiple than single site (59 vs 7% p0.006). Reduced FUDR, CYP3A4 and UGT1A1 SNPs, frequently associated, prevalently in patients with gastrointestinal LTS, while not without LTS. Conclusions: Intensive first-line FIr-C/FOx-C at recommended dose is tolerable, highly effective in RAS wild-type. Reduced FUDR, CYP3A4, UGT1A1 SNPs may predict individual LTS to select fit patients. Prospective studies will confirm efficacy and personalization by companion toxicity biomarkers. Clinical trial information: EudraCT 2009-016793-32.
An assessment of KRAS, NRAS, and BRAF testing prior to 1st line of therapy among mCRC patients treated at community cancer centers in the United States.
Authors: Florea Ana , Garawin Tamer , Sangaré Laura , Kelsh Michael Anthony , Lowe Kimberly 
Published: January 2019

678 Background: We sought to determine the proportion of patients with mCRC in the United States who were tested for KRAS, NRAS, and BRAF mutational status before any 1st line of therapy. Patient demographics that may influence testing, and the turnaround time between key events associated with biomarker testing and utilization of biomarker results were also assessed. Methods: The study utilized the Oncology Services Comprehensive Electronic Records (OSCER) 2.0 dataset, provided by Flatiron Health, which includes mCRC patients from community cancer centers across the United States. Biomarker results are recorded in the Flatiron Electronic Health Record when available. The proportion of patients tested or not tested for KRAS, NRAS, and BRAF mutational status before 1st line of therapy between 2013 and 2017 was calculated, as were the differences in the patient demographics. The median number of days between the date of tissue collection, the date the tissue was received by the laboratory, and the date the oncologist received the test results was calculated. Results: Of the 13,437 patients included in the analysis, the proportion of patients who were tested prior to 1st line of therapy was as follows: KRAS, 30.8%,; NRAS, 9.9%; BRAF, 11.5%. Age, insurance type, race, and presence of liver metastases were all statistically significant factors that influenced testing. Specifically, younger, commercially-insured, Caucasian patients, and those who had liver metastases were more likely to be tested. For KRAS testing, the median time between tissue collection and tissue received by the laboratory was 26 days. Receipt of the results by the oncologist took an additional median number of 27 days. Conclusions: This study found that the testing rate for these key mCRC biomarkers was less than 31% and that the median number of days to assess biomarker results was 26. Further studies conducted in various settings, such as academic cancer clinics, are needed to investigate this low proportion of testing and long time to assess results.
Phase II trial of palbociclib in patients with advanced esophageal or gastric cancer.
Authors: Karasic Thomas Benjamin , O'Hara Mark H. , Teitelbaum Ursina R. , Damjanov Nevena , Giantonio Bruce J. , d'Entremont Tracy S. , Gallagher Maryann , Zhang Paul J. , O'Dwyer Peter J. 
Published: January 2019

68 Background: Dysregulation of the cell cycle is a hallmark of cancer. Progression through the G1/S transition requires phosphorylation of retinoblastoma (RB) by cyclin-dependent kinases 4 and 6 (CDK4/6), which are regulated by cyclins D and E. A positive feedback loop between apoptosis signal-regulating kinase 1 (ASK1), a member of the MAP kinase pathway, and cyclin D1 has been shown to drive cell proliferation in gastric cancer. In addition, amplification of cyclin D loci and/or activating mutations in CDKs are frequent molecular aberrations in gastroesophageal malignancies. We hypothesized that palbociclib, a potent inhibitor of CDK4/6 would disrupt proliferative signaling, and arrest the growth of gastric cancer. We conducted a phase II trial of palbociclib in gastric and esophageal cancers as an initial test of efficacy. Methods: We screened 38 subjects with gastric, GE junction, or esophageal cancer for RB nuclear expression by immunohistochemistry, and 38/38 (100%) were positive. We enrolled 21 subjects, of whom 5 had gastric adenocarcinoma, 3 had GE junction adenocarcinoma, 8 had esophageal adenocarcinoma, and 5 had esophageal squamous cell carcinoma. Four of 19 subjects tested positive for CCND1 overexpression by FISH. Patients received 125mg daily of palbociclib for days 1-21 of 28-day cycles. Results: Subjects remained on treatment for a median of 1.7 months. By the initial 2-month assessment, 5 of 21 subjects had stable disease, and 16 subjects had progressive disease by imaging and/or clinical progression. No objective responses were seen. The maximum duration of therapy was 5.5 months in two subjects. One of these subjects had progressing HER2-amplified gastric adenocarcinoma, and continued concurrent trastuzumab with palbociclib, while the other had squamous cell carcinoma of the esophagus. Grade 3 or 4 cytopenias occurred in 9 of 21 subjects (43%), with neutropenia in 8 (38%), anemia in 4 (19%), and thrombocytopenia in 1 (5%). One subject discontinued therapy due to grade 4 thrombocytopenia with GI bleed. All other subjects discontinued therapy due to disease progression. Conclusions: Palbociclib has modest single-agent activity in gastroesophageal tumors despite universal RB expression. Clinical trial information: NCT01037790.
Cell cycle checkpoint defects in gastrointestinal malignancies.
Authors: Thota Ramya , Lewis Mark Andrew , Nadauld Lincoln , Haslem Derrick S. , Rhodes Terence Duane , Christensen Bryce , Fulde Gail , Abraham Tyler , Romero Robin , Moulton Bryce , Raghunath Sharanya , Barker Tyler 
Published: January 2019

680 Background: Cyclin Dependent Kinases (CDKs) play a significant role in cell cycle regulation. Aberrations involving the cell cycle pathway genes can lead to uncontrolled cell proliferation and genomic instability. These could potentially be targeted with CDK4/6 inhibitors. The frequency and type of these alterations in GI tumors is largely unknown. Methods: We analyzed the frequency of abnormalities in cell cycle genes in patients with diverse GI malignancies (colorectal, liver, pancreas, gastroesophageal, anal, appendix) that underwent next generation sequencing from January 2013 to August 2017. Results: Aberrations in the cell cycle pathway were identified in 33 of 299 (11%) of cancers. The frequency of aberrations was as follows: CDKN2A/B in 10 (30.3%), CCND1 in 7 patients (pts) (21.2%), CCND2 in 2 pts (6%), CEBPA in 2 pts (6%), CDK6 in 2 pts (6%), CDK8 in 2 pts (6%) and CDK2 in 1 (3%). Alteration involving multiple genes of cell cycle noted in 7 patients (21.2%) with combination of CCND1 and CDKN2A being most common combination. The cell cycle checkpoint defects were most frequently seen in 9 pts with colon (27%), 8 pts with hepatobiliary (27%), 8 pts with pancreatic (24%), 7 pts with esophageal (21%), and less commonly in small bowel (6%) and GIST (6%). Conclusions: The alterations in the cell cycle pathway are most common in certain GI tumors mainly colon, pancreatic, hepatobiliary and esophageal tumors. Future clinical trials exploring the potential role of targeted agents such as CDK4/6 inhibitors alone or in combination with other targeted agents such as MEK inhibitors requires further exploration in these tumors.
Molecular profiling to predict outcomes following Y90 radioembolization for metastatic colorectal cancer.
Authors: Prins Petra , Gradzka Alexandra , Kim Alexander Y. , Marshall John , Unger Keith Robert 
Published: January 2019

686 Background: Radioembolizaton with yttrium-90 (Y90) has been shown to decrease progression within the liver in patients with unresectable metastatic colorectal cancer (CRC). Molecular profiling (MP) plays an important role in providing precision based therapy for our patients. The purpose of this study was to evaluate predictive associations between genetic mutations in Y90 treated CRC pts and treatment outcomes. Methods: A retrospective chart review of patients at GUMH was conducted for patients who underwent Y90 radioembolization for metastatic CRC between 2010 and 2017. Inclusion criteria were: Liver metastasis, Y90 treatment and MP. Y90 response of the treated liver lesions was evaluated according to RECIST criteria within 4 months of treatment; non-responders were classified as those with progressive disease (PD) and all others were considered responders. Statistical analysis was performed to reveal any significant associations. Results: Out of 285 CRC records with MP screened, 32 pts adhered to our inclusion criteria. Of these 47% were male and 53% female. The average age at diagnosis was 50.4 yrs. For22 pts (69%) Y90 treatment was combined with chemotherapy. Y90 response data showed response in 50% (n = 16) and PD in 31% (n = 10) of the pts. Six pts did not have Y90 response data. Median OS between groups was not significant but longer for those responders (33 vs 26 m). Next Generation Sequencing revealed pathogenic mutations for APC in 20 pts (63%), KRAS in 12 (38%) and TP53 in 13 pts (41%) none of them showing any significant association with Y90 response data (p > 0.05). OS from date of Y90 was significantly improved in patients with TP53 mutations and KRAS WT. There was no association between differences in MP and OS from date of diagnosis. Conclusions: TP53 and KRAS mutations were predictive of survival but not response following Y90 for metastatic colorectal cancer patients. This hypothesis generating study demonstrates the MP may be helpful in stratifying CRC patients who benefit from radiation therapy. Further study is necessary.
Plasma VEGF-A (pVEGF-A) level in efficacy analysis of metastatic colorectal cancer patients (mCRC) treated with mFOLFOX6/XELOX plus bevacizumab (BV) (WJOG7612GTR).
Authors: Okamoto Wataru , Makiyama Akitaka , Yamamoto Yoshiyuki , Shitara Kohei , Denda Tadamichi , Izawa Naoki , Nakano Yasuyuki , Nishina Tomohiro , Esaki Taito , Hara Hiroki , Ozaki Yukinori , Okuda Hiroyuki , Boku Narikazu , Hyodo Ichinosuke , Yamazaki Kentaro , Hironaka Shuichi , Sakai Kazuko , Yamanaka Takeharu , Muro Kei , Nishio Kazuto 
Published: January 2019

699 Background: Plasma levels of VEGF-A short isoforms (VEGF-A110 and -A121) measured by immunological multiparametric chip technique (IMPACT) were reported to be associated with clinical benefits from bevacizumab (BV) in advanced gastric and pancreatic cancer but not in metastatic colorectal cancer (mCRC). Negative results in mCRC studies might be caused by different sample handling: citrate instead of EDTA and repetition of freeze/thaw. Methods: Blood samples were collected in EDTA before the first-line treatment with BV+mFOLFOX6 or +XELOX for mCRC. Plasma samples were analyzed at Roche Diagnostics Ltd. (Penzberg, Germany) using IMPACT-2 (Roche proprietary multiplex enzyme-linked immunosorbent assay platform). A median value of pVEGF-A was used as a cut-off point to categorize patients (pts) into the low and high pVEGF-A groups. Progression free survival (PFS) and overall survival (OS) between the low and high pVEGF-A groups were compared, using Cox proportional hazards model. We hypothesized that BV-containing treatment extend shorter PFS of pts with high pVEGF-A to that with low pVEGF-A, and estimated a threshold hazard ratio (HR) between them as below 1.15. Results: Among 102 pts enrolled between January 2014 and April 2015, 100 (53 BV+mFOLFOX6 and 47 BV+XELOX) were eligible. Median PFS was 11.4 months [95% CI, 9.5-13.0] and response rate was 64.6 % [range, 53.3-74.9]. pVEGF-A was measured in 97 pts and the median value was 36.8 pg/ml [range, 6.5- 262.2]. The hazard ratios of PFS and OS between the high and low pVEGF-A groups were 1.23 [95%CI, 0.76-1.97, p = 0.40] and 2.47 [95%CI, 1.14-5.36, p = 0.02], respectively. Conclusions: mCRC pts with high pVEGF-A showed shorter PFS than those with low pVEGF-A beyond the predefined threshold (HR 1.15) in BV-containing chemotherapy, suggesting that pVEGF-A could not be a predictive marker for BV efficacy. Clinical trial information: UMIN000012442.
Plasma ctDNA RAS/RAF mutations analysis for monitoring overall survival (OS) and heterogeneity in metastatic colorectal cancer patients (mCRC).
Authors: Mancuso Andrea Petricca , Varchetta Veronica , Montagnese Fabrizio , Campanella Carla , Brandi Rita , Vitale Marco , Soda Giuseppe 
Published: January 2019

701 Background: The study was designed to estimate the clinical usefulness of genetic analysis for circulating tumor DNA (ctDNA) by digital polymerase chain reaction in patients with mCRC. Methods: We compared B-RAF and K/N/H-RAS mutations detected in surgical or endoscopic ultrasound-guided fine-needle aspiration biopsy tissue DNA and in ctDNA from 63 patients with mCRC. p53 mutational status and PD-L1 expression in the serum and in tissues respectively (positivity H score > 55) were also analyzed with a comparison with survival rates. Results: The frequencies of K-RAS mutations in tissue samples at G12V, G12D, and G12R in codon 12 were 18 of 63 samples (28.57%), 5 of 63 samples (7.93%), and 6 of 63 samples (9.52%), respectively. Conversely, the rates of the mutations in ctDNA were 22 of 63 samples (34.92%), 6 of 63 samples (9.52%), and 9 of 63 samples (14.28%), respectively. No H-RAS or N-RAS mutation were detected. 2 tissue samples harbored a BRAF mutation (3.17%) in a complete discordance with same mutation detected in 6 different serum ctDNA (9.52%). Overall, the K-RAS mutation rates in tissue and ctDNA were 45.72% and 58.72%, respectively, and the concordance rate between them was 29 of 37 samples (78,37%). OS did not appear to differ by the presence of K-RAS mutations in tissue or in the serum DNA, but the OS of patients with B-RAF mutations in ctDNA was significantly shorter than that of patients with tissue K-RAS/B-RAF mutations (11 vs 19 months, p < 0.0001). PD-L1 positivity was significantly associated with p53 mutational status (concordance: 82%) and with a worse outcome for OS. Conclusions: Analysis of ctDNA is a new useful procedure for detecting mutations in mCRC patients. This non invasive method may have great potential to understand tumor heterogeneity and appear a new strategy for the planning therapies as well as for predicting survival.
Prognostic relevance of primary tumor location in stage III and II colon cancer: Experience at University Hospital Ramon y Cajal (HURyC) Madrid.
Authors: Barquín García Arantzazu Martínez , Martinez Saez Olga , Serrano Domingo Juan José , Martín Huertas Roberto , Villamayor Delgado Maria , Saavedra Serrano Cristina , Corral de la Fuente Elena , Reguera Puertas Pablo , LONGO FEDERICO , Pachón Olmos Vanesa , Rodríguez Garrote Mercedes , Guillen Carmen , Carrato Alfredo , Ferreiro REYES 
Published: January 2019

703 Background: Primary tumor location of colon cancer (CC) is emerging as an important prognostic factor owing to distinct biological features. However, this factor still does not represent a prognostic parameter when deciding for adyuvant or palliative chemotherapy. In a meta-analysis of 66 studies including patients with all stages of disease, left-sided primary tumor location was associated with a significantly reduced risk of death and this was independent of other prognostic factors. Methods: We retrospectively included patients with stage II and III CC that underwent surgical resection between 2009 and 2014 HURyC. We performed a multivariate Cox model analysis to estimate if tumor location is an independent prognostic factor for overall survival (OS). The model was further adjusted by including the following confounders: ECOG-PS, number of removed nodes ( < 12 or ≥ 12), perforation, grade, use of adyuvant chemotherapy and age. A covariate was considered a confounder factor if the difference between the adjusted and unadjusted coefficient of chemotherapy varied > 10%. Stata 13.1 was used to analyze the data. Results: 564 patients were identified (267 left sided and 297 right sided). The median follow-up of the entire cohort was 49 months. Globally, right sided CC was not significantly associated with better DFS or OS in comparison with left sided CC (HR: 0.74, p: 0.128; HR: 0.94, p: 0.75, respectively). By stages, stage II right sided CC seemed to show better DFS (HR: 0.45, p: 0.02), although no significant differences were found in OS (HR: 1.004, p: 0.98). Stage III right sided CC was not significantly associated with better DFS or OS in comparison with left sided CC (HR: 0.87, p: 0.585; HR: 0.66, p: 0.19, respectively). Conclusions: The multivariate analysis did not show significant differences in terms of prognostic relevance of primary tumor location in the adyuvant setting.
Correlation of BMAL1 expression in colorectal cancer with resistance to anti-VEGFA therapy with bevacizumab.
Authors: Burgermeister Elke , Eladly Fagr , Wu Wen , Schulte Nadine , Betge Johannes , Hartel Nicolai , Gaiser Timo , Marx Alexander , Weiss Christel , Hofheinz Ralf , Miller Ian S. , Byrne Annette T. , Ebert Matthias Philip 
Published: January 2019

705 Background: Mechanisms underlying failure of colorectal cancer (CRC) patients to respond to anti-vascular endothelial growth factor A (VEGFA) therapy with bevacizumab in combination with chemotherapy are largely unknown, and novel predictive markers required. Methods: Tumours from patients/mice and CRC cell lines were analysed by IHC, PCR, EMSA, ChIP, ELISA and Western blot. Statistics of (pre)clinical data was calculated with SAS and Graphpad Prism. Response outcomes including progression-free survival (PFS) and restaging according to RECIST (PR/SD/PD) were analyzed. Results: Circadian rhythm transcription factor and heme receptor REVERBA and its target gene BMAL1 promoted binding to and activation of the -700kB RORE DNA-element in the VEGFA promoter resulting in increased VEGFA mRNA expression and VEGFA protein secretion from human CRC cell lines. Conversely, REVERBA siRNA and its antagonist (Fe3+) hemin inhibited VEGFA synthesis. In C57BL/6J Apcmin/+ mice treated with murinized VEGFA Ab (n=11 mu_chimeric_B20-4.1 vs. n=42 mock; 10 mg/kg*week; i.p.; 4 weeks), Vegfa mRNA was reduced, as was incidence (*p=0.0411 Fisher Exact Test) and multiplicity (*p=0.0157 Cochran Armitage Trend Test) of vascularized CRCs. However, Bmal1 mRNA was up-regulated, and high BMAL1 protein expression in tumor cells positively correlated with Ki67+ proliferation (n=3 B20 vs. n=3 mock; *p<0.05 t-test) in treated Apcmin/+ CRCs. BMAL1 protein was also induced in xenografts from BALB/c nude mice s.c. implanted with the human CRC cell line HCT116 and treated with humanized VEGFA Ab (n=4 bevacizumab vs. n=4 vehicle; 10 mg/kg*week; i.p.; 3 weeks; *p<0.05 t-test). In CRC patients, high BMAL1 protein expression in tumor cells was associated with clinical non-response to bevacizumab (n=15 SD vs. n=29 PD: BMAL1- vs. BMAL1+, *p=0.0061 Cochran Armitage Trend Test,*p=0.0130 Fisher Exact Test) and reduced PFS (BMAL1- [671 days] vs. BMAL1+ [368 days], *p=0.0030 log rank test, HR=0.4792 [95%CI 0.3103-0.7871], n=74). Conclusions: BMAL1 may represent a predictive marker for bevacizumab non-response. Due to its drugability, the REVERBA-BMAL1-VEGFA axis may be a potential target to prevent resistance to anti-angiogenic therapy in CRC.