bluuebunny/crossref_metadata_2025_split huggingface dataset:
NTRK3 as a novel tumor suppressor gene in colorectal cancer.
Authors: Luo Yanxin , Kaz Andrew , Kanngurn Samornmas , Grady William M. 
Published: February 2017

469 Background: Neurotrophin tyrosine kinase receptor 3 (NTRK3) is a receptor tyrosine kinase that has been shown to be an oncogene in breast cancer and possibly in hepatocellular carcinoma. NTRK3 is a trophic dependence receptor, which is a recently described class of receptors that initiate signaling in both the ligand bound and unbound states. Through a genome-wide screen for aberrantly methylated genes, we identified aberrantly methylated NTRK3 as a frequently methylated gene in colon cancer. The aim for the present study is to determine if NTRK3 is an epigenetically silenced tumor suppressor gene in colorectal cancer. Methods: NTRK3 promoter methylation was analyzed in human colon cancer cell lines, normal colon epithelium tissue, colorectal adenomas and colorectal cancers using quantitative methylation-specific PCR and bisulfite sequencing. NTRK3 mRNA and protein expression were studied using quantitative real-time PCR, immunohistochemistry and western blotting respectively. The tumor suppressor function of NTRK3 was examined by assessing the effect of NTRK3 on cell apoptosis, cell migration and in vitro colony formation assays in colon cancer cell lines stably transfected with an NTRK3 expression construct in the presence or absence of NT-3. Results: NTRK3 is methylated in 60% of colon adenomas and in 57% of colorectal cancers. The aberrant methylation of NTRK3 suppresses NTRK3 expression and releases colon cancer cells from NTRK3 mediated apoptosis induced by the expression of NTRK3 in the absence of the ligand NT-3 via the activation of MAPK/ERK pathway. Methylation of NTRK3 also releases colon cancer cells from NTRK3 mediated suppression of motility and anchorage independent growth. The addition of NT3 to colon cancer cells transfected with NTRK3 inhibits the tumor suppressor effects of NTRK3. Conclusions: The aberrant methylation of NTRK3 is likely functionally relevant for colorectal cancer formation as NTRK3 appears to be a conditional tumor suppressor gene in the colon depending on the expression status of its ligand NT-3. NTRK3 is a novel aberrantly methylated conditional tumor suppressor gene that is frequently methylated in colon adenomas and cancers and whose discovery reveals possible novel treatment approaches to colon cancer.
HER2/neu expression in locally advanced rectal cancer cUICC II/III and its correlation with long-term prognosis.
Authors: Conradi Lena-Christin , Styczen Hanna , Sprenger Thilo , Becker Heinz , Ghadimi Michael B. , Beissbarth Tim , Middel Peter , Liersch Torsten 
Published: February 2017

493 Background: With the implementation of multimodal treatment strategies including neoadjuvant radiochemotherapy (RCT), the prognosis of locally advanced rectal cancer has been improved over the last two decades. Most actual clinical trials aim to further develop therapy by intensification of agents administered. We examined Her2/neu in rectal cancer patients to evaluate its expression as a potential drug target as well as its capacity as predictive and prognostic biomarker. Methods: Two-hundred-seventy-seven patients (205 male, 72 female; median age 63.5 years) with locally advanced rectal cancer (cUICC-II/III) were included in this study. Preoperative RCT (50.4 Gy and concomitant either 5-FU or 5-FU and oxaliplatin) was administered in 236 patients followed by surgical resection with total mesorectal excision (TME). Another 41 patients received postoperative RCT. All patients were treated within phase-II/-III-trials of the German Rectal Cancer Study Group or analogous to these standardized protocols. Her2-/neu expression from pre-treatment biopsies and corresponding resection specimens were assessed by immunohistochemical staining and SISH-analysis. Results: A positive Her-2/neu expression was found in 12.3% of all pre-treatment tumor biopsy samples and in 28.7% of the resection specimens. The correlation of the pre-treatment Her-2/neu status did not show a significant correlation with the grade of tumor regression. However, patients with a higher Her-2/neu protein expression as measured in the resection specimen showed a significant survival benefit (p=0.0277) compared with patients having low intratumoral Her-2/neu expression during the follow-up (median 43 months). The 10-year survival rate was 73.2% (Her-2/neu positive) versus 60.1% (Her-2/neu negative). Conclusions: The proportion of patients with a positive Her-2/neu status is relevant in rectal cancer. Her-2/neu might potentially serve as a promising drug target in rectal cancer and should be further assessed within prospective clinical trials. Furthermore the Her-2/neu status seems to be a valuable prognostic marker within the multimodal treatment of advanced rectal cancer.
Genetic differences based on miRNAs of colorectal adenocarcinoma according to age and the presence or absence of MMR defect.
Authors: Guillen-Ponce Carmen , Conde Moreno ELISA , Aguado Elia , Soto Jl , Alenda Cristina , Castillejo Adela , Barbera Victor M , Salas Dolores , Carrato Alfredo , Garcia Bermejo Maria LAURA 
Published: February 2017

495 Background: More than 1.2 million new cases of colon adenocarcinoma (CRC) are diagnosed annually. Specific germline mutations are responsible for hereditary CRC syndromes, while somatic mutations is thought to underlie most sporadic cases. Recently, miRNAs have been described as important regulators of malignant transformation. We aim to study the expression of miRNAs in CRC patients with Lynch syndrome and in patients with CRC without microsatellite instability (MSI-S) who have developed cancer at different ages. Methods: We included 60 cases of CRC patients: 20 with CRC associated with Lynch syndrome in carriers of germline MMR mutation (group 1), 20 with CRC MSI-S diagnosed before 45 years (group 2) and 20 with MSI-S diagnosed after age 50 (group 3). From all these cases we selected 7: 3 from group 1, 2 from group 2, another 2 from group 3, and a control with healthy colonic mucosa. Screening was carried out for expression of miRNAs (850 miRNAs) and hybridization arrays (Exiqon) using paraffin colic tissue. A comparative analysis was made of the expression obtained in the different groups. Results: Hybridization arrays analysis indicates that there are 248 miRNAs differentially expressed between healthy controls and patients with CRC. In addition, there are 165 miRNAs differentially expressed between different groups of patients with CRC according to age at diagnosis (≤ 45 years vs.> 50 years). Moreover, the pattern of miRNAs in patients with germline mutation in Lynch syndrome is very different to that of patients diagnosed with CRC> 50 years. There are 117 miRNAs differentially expressed between these cases. Just a group of 20 miRNAs have different expression among patients with CRC MSI-S ≤ 45 years for CRC patients with Lynch syndrome mutation in MLH1. Conclusions: Differences exist in the profile of CRC mRNAs expression according to the age, as well as between CRC MSI-S patients > 50 years and CRC in Lynch syndrome. Different patterns of miRNAs in CRC indicate different molecular signature in different groups of CRC could became new CRC diagnostic markers and most importantly could point out new targets for therapeutic interventions in CRC.
Feasibility study of irinotecan based on UGT1A1 polymorphisms for metastatic colorectal cancer: Interim report.
Authors: Kashihara Hideya , Shimada Mitsuo , Kurita Nobuhiro , Nishioka Masanori , Iwata Takashi , Sato Hirohiko , Morimoto Shinya , Yoshikawa Kozo , Miyatani Tomohiko , Mikami Chie 
Published: February 2017

505 Background: Although Irinotecan prolongs survival, it causes severe diarrhea and neutropenia. Recent pharmacogenetic studies on irinotecan have revealed significant associations of UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms *28 and *6, the latter being specifically detected in East Asians resulting in severe toxicity. It is necessary that the dose-finding trial that decided the optimal dose according to the gene polymorphism to draw out the maximum therapeutic effect while evading the side effect. Previously, we showed UGT1A1 polymorphisms in Japanese patients (2011 ASCO-GI). Here, we present the interim report of prospective trial of the safety about FOLFIRI therapy according to each gene type of UGT1A1 for Japanese patients with advanced CRC. Methods: From 2008, 250 Japanese patients in TOKUSHIMA University were enrolled in this study. Homo group (*6/*6 and *28/*28 or a both hetero types), hetero group (It was *28 and either *6 was hetero type), and wild group (*28 and *6 were wild types) were defined. On the 30 patients with advanced CRC treated with FOLFIRI after standard chemotherapy, wild and homo groups were administered 150mg/m2 irinotecan, and homo group was 100mg/m2. The incidences of severe toxicities in each gene type of UGT1A1 and the response rate in FOLFIRI therapy were investigated. Results: In Japanese people, UGT1A1*6 polymorphisms were higher than *28 (*6 homo 3%, hetero 27% vs *28 homo 0.5%, hetero 13%). On the 30 patients with advanced CRC treated with FOLFIRI, the genotypes of UGT1A1*28 were homozygous in 1 (3%) and heterozygous in 6 (20%), *6 were homozygous in 0 and heterozygous in 8 (27%). In *6 heterozygous patients, severe toxicities (grade 3 or more) were found (38%). In *28 heterozygous patients, 1 patient (17%) showed severe toxicities. There was no decrease of irinotecan doses in each group. The number of course to PD was 7.6 (1-23). Regarding the response rate, PR, SD, PD was observed in 2 (7%), 6 (20%) and 18 patients (60%), respectively. Conclusions: In our interim report, the dosages of irinotecan based on UGT1A1 polymorphisms are safety in FOLFIRI therapy.
A pilot study of pharmacokinetically guided dose management of capecitabine in CRC patients.
Authors: Makihara Katsuya , Mishima Hideyuki , Azuma Sayaka , Matsuyama Kazuyo , Komori Katsuya , Hasegawa Hiroko , Yasui Masayoshi , Ikenaga Masakazu , Tsujinaka Toshimasa 
Published: February 2017

510 Background: Pharmacokinetically (PK) guided dose adjustment of 5-fluorouracil (5-FU) has been reported better than body surface area based dosing of 5-FU. On the other hand, few articles have been reported about PK guided dose management of oral drug chemotherapy. The aim of this study is to assess the possibility of pharmacokinetically guided dose management of capecitabine with a nanoparticle antibody-based immunoassay for 5-FU (My5-FUR assay). Methods: Colorectal cancer patients receiving chemotherapy with FOLFOX, FOLFIRI, LV5FU2, Capecitabine, CapeOx (capecitabine plus oxaliplatin) were analyzed by My5-FUR assay. Blood samples were collected after 24 hours of 5-FU infusion or 2 hours after administration of capecitabine at day 7. Correlation between liquid chromatography-mass spectrometry (LC-MS) and My5-FUR assay of 5-FU were also examined. Results: A total of 50 patients were analyzed by My5-FUR assay. A linear relationship (r=0.9204) exists between LC-MS and My5-FUR assay. The area under the concentration curve of continuous 5-FU infusion were 15~56mg-h/L, and the concentrations of 5-FU after administration of capecitabine were 41~457 ng/mL. Severe side effects were observed in the patients with plasma concentration of 5-FU greater than 300 ng/mL 2 hours after administration of capecitabine. Conclusions: Plasma concentrations of 5-FU after administration of capecitabine were measurable by My5-FUR assay. The concentrations of 5-FU were lower in capecitabine than continuous 5-FU. The distribution of 5-FU was wider in capecitabine than continuous 5-FU. It is possible to manage dose of capecitabine pharmacokinetically.
Use of wild-type (wt) KRAS, BRAF, and PIK3CA, combined with KRAS mutations (mut) in codon 13 and RNA expression level of amphiregulin (AREG) and epiregulin (EREG), to predict cetuximab (CE) response with high accuracy in colorectal cancer of all four Dukes' stages.
Authors: Pechanska Paulina , Mayr Tobias , Hinzmann Bernd , Klaman Irina , Daniel Abd el Messih Suzette , Becker Michael , Hoffmann Jens , Rosenthal Andre 
Published: February 2017

517 Background: wt KRAS and wt BRAF are established clinical markers to predict response to CE in patients (pts) with mCRC. Some pts with KRAS mut in codon 13 respond to CE, while the majority of them do not. Recently, it was shown that pts with CRC of Duke C and wt KRAS and wt BRAF do not benefit from CE added to FOLFOX (ASCO 2011 abstr 3607). In addition, data indicated that AREG and EREG RNA expression is also correlated with CE response. We established a panel of 133 xenograft models from primary tumor tissue of pts with CRC of all four Dukes stages and conducted a therapy experiment with CE (AACR '11, LB9086). Methods: mut status of KRAS (G12, G13, A146T); BRAF (V600E) and PIK3CA (E542K, E545K, H1047R) was assessed in all xenografts by allele-specific RT-PCR. KRAS codon 61 was sequenced. AREG and EREG expression levels were analyzed by RT-PCR expression assays. Results: We observed response to CE (treated to control ratio < 20%) in 18/67 (27%) of the treated xenografts. The distribution of responder (R) to non-responder (NR) is: Duke A: n=8; 2R / 6NR; B: n= 22; 8R / 14NR; C: n=28; 4R / 24 NR; D: n= 9; 4R / 5NR. Retrospective classification based on KRAS mut status identified R with a sensitivity (S+) of 83%, and NR with a specificity (S-) of 61%. If mut status in BRAF and PIK3CA were added the classifier showed S+ of 83% / S- of 78%. If any mut except in KRAS codon 13 were considered, the classifier reached S+ of 94% / S- of 69%. We improved S- of the classifiers to 86%; 90%, and 86%, respectively by adding AREG and EREG RNA expression data. The most accurate classifier combined wt KRAS, wt BRAF, wt PIK3CA with mut in codon 13 and RNA expression of AREG and EREG and reached S+ of 94% / S- of 86%. Classification in corresponding primary tumors showed similar accuracy. Conclusions: We developed a powerful classifier for all Dukes stages to predict response to CE with S+ of 94% and S- of 86%. In adjuvant setting the mut based classifier reaches S+ of 100% and S- of 68%; S- can be improved to 79% by adding AREG/EREG. This novel classifier has the potential to be used in the adjuvant and metastatic setting to improve pts selection for CE therapy.
Worse prognosis of KRAS C.35 G > A mutant metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx).
Authors: Bruera Gemma , Cannita Katia , Di Giacomo Daniela , Lamy Aude , Troncone Giancarlo , Dal Mas Antonella , Coletti Gino , Frébourg Thierry , Sabourin Jean-Christophe , Tosi Mario , Ficorella Corrado , Ricevuto Enrico 
Published: February 2017

521 Background: Bevacizumab (BEV) addition to doublet chemotherapy significantly increases efficacy without differentially affecting prognosis in KRAS wild-type (wt) and mutant (m) MCRC. Present study evaluates clinical outcome of BEV added to triplet chemotherapy, FIr-B/FOx (Bruera G et al, BMC Cancer 2010, 10:567), according to KRAS genotype. Methods: MCRC patients (pts) were treated with first line FIr-B/FOx regimen including BEV (5 mg/kg, days 1,15) and triplet chemotherapy, weekly alternating irinotecan (160 mg/m2 days 1,15) or oxaliplatin (80 mg/m2, days 8, 22) associated to fluorouracil (900 mg/m2, days 1-2, 8-9, 15-16, 22-23); every 4 weeks. Tumoral samples were simultaneously screened for KRAS codon 12 and 13, and BRAF c.1799 T > A mutations by SNaPshot multiplex assay (Di Fiore F, Br J Cancer 2007;96(8):1166-1169) and/or direct sequencing. Activity and efficacy were evaluated and compared using log-rank test. Results: Forty-five MCRC pts were evaluated: 25 KRAS wt (56%), 20 KRAS m (44%). After 30 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wt 88% (C.I. ± 14), 14 months, 38 months; KRAS m 80% (C.I. ± 19), 12 months, 21 months. PFS and OS were not significantly different. Among KRAS m pts, ORR, PFS and OS at 19 months median follow-up in c.35 G > A (13 pts) were 69% (C.I. ± 26), 9 months, 11 months, respectively. OS of c.35 G > A KRAS m was significantly worse compared to KRAS wt (p = 0.003) and to other than c.35 G > A mutant pts (p = 0.022). Conclusions: First line FIr-B/FOx intensive regimen adding BEV to triplet chemotherapy can further increase activity and efficacy without significantly affecting different clinical outcome in KRAS wt and m MCRC pts. A significant interaction between the most prevalent c.35 G > A KRAS mutation and worse prognosis was observed, compared to KRAS wt pts and to other than c.35 G > A KRAS exon 2 mutations, depending from different biological aggressiveness and sensitivity to BEV addition to triplet chemotherapy.
A phase II, open-label study evaluating the safety and efficacy of ramucirumab combined with mFOLFOX-6 as first-line therapy in patients (pts) with metastatic colorectal cancer (mCRC): CP12-0709/NCT00862784.
Authors: Garcia-Carbonero Rocio , Rivera Fernando , Maurel Juan , Ayoub Jean-Pierre M. , Moore Malcolm J. , Cervantes-Ruiperez Andres , Asmis Timothy R. , Schwartz Jonathan D. , Ballal Shaila , Tabernero Josep 
Published: February 2017

533^ Background: Vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR-2) are overexpressed in CRC and mediate angiogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 MAb that inhibits binding of VEGF ligands to VEGFR-2 and inhibits VEGFR-2 activation and signaling. In preclinical CRC models VEGFR-2 inhibition confers antitumor activity. RAM was administered with mFOLFOX-6 as 1st-line therapy (rx) in mCRC. Methods: Eligible pts had mCRC with no prior chemo Rx (prior adjuvant rx was allowed), at least 1 measurable target lesion by RECIST v1.0, ECOG PS 0-1, and adequate organ function. Pts received RAM (8 mg/kg IV on D1), oxaliplatin (85 mg/m² IV on D1), folinic acid (400 mg/m² IV on D1), fluorouracil (5-FU, 400 mg/m² bolus followed by 2400 mg/m² continuous infusion over 46 hours on D1). Rx cycles were q2w and tumor assessments were q8w. Endpoints included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), safety, and pharmacokinetics/immunogenicity. Sample size was based on an improved median (medn) PFS from 8 to 11 months (m). Results: 48 pts received therapy. All were white; 25 M/23 F; median age 60.5 y. ECOG PS was 0/1 in 30/18 pts. 42 pts (88%) had metastatic disease, with liver (79%) and lung (35%) as most frequent sites. 13 (27%) pts had liver-only mCRC. The most frequently observed RAM-related adverse events (AEs) included hypertension 46% (15% Grade [G] ≥3); diarrhea 31% (2% G≥3); and nausea and infusion-related reactions, each 19% (0% G≥3). 2 pts died on study due to acute MI or cardiopulmonary arrest. Medn PFS was 11.5 m (9-13 m 95% CI) with 1-yr PFS of 48% (32-62% 95% CI). ORR: 67% (52-80% 95% CI); disease control rate (DCR: CR+PR+SD): 94% (83-99% 95% CI; 5 pts had CR, 27 had PR and 13 had SD). Medn duration of response was 11.0 m (7-12 m 95% CI). One-year OS was 85% (72-93% 95% CI). As of 4/15/2011, 2 pts continued to receive rx, 20 had died and 28 (58.3%) remained alive. Conclusions: RAM combined with mFOLFOX-6 was reasonably tolerated in pts with mCRC. Median PFS exceeds 11 m. PFS, ORR, and DCR are encouraging and favor investigation of this regimen and of RAM in mCRC.
Intermittent chemotherapy (CT) plus continuous or intermittent cetuximab (C) in the first-line treatment of advanced colorectal cancer (aCRC): Results of the two-arm phase II randomized MRC COIN-B trial.
Authors: Wasan Harpreet , Adams Richard A. , Wilson Richard H. , Pugh Cheryl , Fisher David , Madi Ayman , Sizer Bruce , Butler Rachel , Meade Angela M. , Maughan Tim 
Published: February 2017

536^ Background: COIN-B is a trial of intermittent chemotherapy (ICT) plus intermittent cetuximab (C) vs ICT plus continuous C in the first-line treatment of aCRC. It complements the COIN trial by investigating how C might safely and effectively be added to an ICT strategy. Methods: Patients (pts) had measurable aCRC; no prior CT for metastases; WHO PS 0-2 and good organ function. Randomisation was: Arm D - continuous OxFU + weekly C for 12 wks then a planned break from all therapy; Arm E - OxFU + weekly C for 12 wks then weekly C. Upon RECIST progression on either arm, OxFU (or FU) plus C was restarted and continued until progression on maximal tolerated therapy. Prospective KRAS testing was introduced in May 2008. Primary outcome measure is Failure-Free Survival (FFS) at 10 months (mo) in KRAS-wt pts who had not progressed, died or failed the treatment strategy within 3 mo of randomisation. The trial was powered to differentiate between a desired 10-mo FFS rate of 50% and a minimum of 35%, in 136 pts (168 allowing for drop-outs). Secondary outcome measures included safety, overall survival (OS) and toxicity. Results: 169 KRAS-wt pts were randomised 07/07 to 06/10, 77 arm D / 92 arm E. Median age 64 years (IQR 55-70); 92% PS 0-1. In Arms D and E respectively, 65 (84%) and 67 (73%) pts were eligible for the primary analysis; 10-mo FFS rates were 48% vs 54% (one-sided 95% confidence limit 37% and 43% respectively). Median FFS was 12.0 vs 13.7 mo respectively (IQR 6.1-20.3 and 8.6-23.2). Median OS was 20.1 vs 18.4 mo. First CFI length was 3.7 mo vs 5.1 mo (IQR 2.5-6.2 and 2.5-8.9). In pre-planned exploratory analysis, median time to progression/death after chemo break was 3.1 mo (IQR 2.1-8.1) in Arm D and 6.0 mo (IQR 2.9-10.9) in Arm E. Toxicity was similar and only 1 arm D pt had G 3 hypersensitivity following C reintroduction. Analyses by BRAF & NRAS (tested retrospectively) will be presented. Conclusions: C was safely incorporated in 2 ICT strategies. Continuous C as maintenance was associated with a longer CFI and longer time to progression/death. This encouraging strategy of incorporating biological maintenance therapy needs validation in phase III trials.