bluuebunny/crossref_metadata_2025_split huggingface dataset:
MET overexpression as a hallmark of the epithelial-mesenchymal transition (EMT) phenotype in colorectal cancer.
Authors: Raghav Kanwal Pratap Singh , Wang Wenting , Overman Michael J. , Kopetz Scott 
Published: February 2017

334 Background: Dysregulation of the proto-oncogene MET (mesenchymal-epithelial transition factor gene) has been implicated in tumorigenesis and correlates with worse survival and chemo/radio-resistance in colorectal cancer (CRC). EMT has been identified as a dominant molecular characteristic of a subset of CRC tumors and represents a key feature in the developing colorectal taxonomy. The purpose of this study was to compare protein expression of MET with protein/gene expression of EMT markers and other clinicopathological characteristics, and to evaluate its impact on overall survival (OS). Methods: We performed an exploratory analysis of 590 CRC samples using data from The Cancer Genome Atlas. Fisher-exact test and Pearson’s method was used to determine the relationship between MET protein expression, clinicopathological characteristics and EMT marker protein expression by reverse-phase protein array (RPPA) and EMT-associated gene expression by RNA-sequencing. Regression tree method was applied to find the best cutoff point for MET using patients with available survival data. Overall survival (OS) was estimated non-parametrically using Kaplan-Meier curve and log-rank test was used to evaluate hazard ratio. Results: MET expression by RPPA did not correlate with traditional clinicopathologic characteristics. MET was overexpressed in 17% of CRC tumors and was significantly associated with OS (HR 2.92; 95% CI: 1.45 - 5.92). Correlation analysis of MET levels with gene expression of EMT markers AXL, CDH1, FGFR1, SNAIL, TWIST1/2, VIM, SLUG, ZEB1/2, FN1 demonstrated that the highest quartile of MET protein expression was associated with a 1.5 fold increase in ZEB1 (p = 0.002), a 1.4 fold increase in AXL (p = 0.005) and ZEB2 (p = 0.008), and a 1.3 fold increase in VIM (p = 0.02). MET expression also correlated strongly with protein expressions of SNAIL (transcription factor for EMT) (r = 0.96) and ERCC1 (r = 0.83) (a marker for oxaliplatin chemo-resistance). Conclusions: Increased MET protein expression is seen in 17% of CRC tumors and strongly correlates with a molecular EMT phenotype and poor survival in patients with CRC. MET protein expression may be a surrogate biomarker for this unique subset of CRC.
Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX).
Authors: Cunningham David , Lang Istvan , Lorusso Vito , Ocvirk Janja , Shin Dongbok , Jonker Derek J. , Osborne Stuart , Andre Niko Alexander , Waterkamp Daniel , Saunders Mark P. 
Published: February 2017

337 Background: Elderly patients (pts) comprise the majority of pts diagnosed with mCRC, although they are in general underrepresented in clinical trials. AVEX, an open-label phase III trial, evaluated the efficacy and safety of cape ± bev in elderly pts with previously untreated mCRC. Methods: Pts ≥70 years with mCRC, for whom single-agent chemotherapy was deemed appropriate, were randomized 1:1 to receive first-line cape (1000 mg/m2 bid days 1–14) as monotherapy or in combination with bev (7.5 mg/kg) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), and safety. The study was powered to show a difference in PFS, but not OS, between treatment arms. PFS and OS estimates were calculated using Kaplan-Meier methods. Results: 280 pts across 10 countries were randomized to cape + bev (n=140) and cape alone (n=140). Median age at enrollment was 76 years (range, 70–87), and 91.1% of pts had an ECOG performance status of 0–1. Baseline pt and disease characteristics were well balanced between arms. Bev + cape was associated with significantly prolonged PFS compared with cape alone (median of 9.1 vs 5.1 months; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.41–0.69; p<0.001). The ORR was also significantly improved in the bev + cape arm (19.3% vs 10.0%; p=0.042). OS was longer in pts treated with bev + cape vs cape alone, although this difference did not reach statistical significance (median of 20.7 vs 16.8 months; HR, 0.79; 95% CI, 0.57–1.09; p=0.182). Grade ≥3 adverse events occurred in 59.0% vs 44.1% of pts in the bev + cape and cape arm, respectively. Treatment was in general well tolerated and the safety profile consistent with previously reported data for bev + cape. Conclusions: This is the first randomized study prospectively evaluating bev specifically in elderly pts with mCRC. Based on the efficacy and safety results, bev plus cape might be an optimal treatment approach to improve outcomes in elderly pts. Clinical trial information: NCT00484939.
Regulation of HDM2 E3-ubiquitin ligase in esophageal adenocarcinoma cells by AURKA.
Authors: Sehdev Vikas , Belkhiri Abbes , Soutto Mohammed , Katsha Ahmed M. , El-Rifai Wael 
Published: February 2017

35 Background: Esophageal adenocarcinomas (EAC) exhibit intrinsic resistance against chemotherapy. AURKA regulates cell cycle progression and its overexpression is associated with oncogenic transformation. We have recently reported that AURKA is significantly overexpressed in about 70% of human EAC tissue samples and EAC cell lines. We have previously shown that AURKA inhibits p53- and p73-mediated apoptotic pathways in GI adenocarcinomas. HDM2 is an E3-ubiquitin ligase which is closely involved in regulating p53 and p73 protein stability and activity. In this study we demonstrate that AURKA directly interacts with HDM2 and regulates HDM2 protein expression and phosphorylation in both FLO-1 and OE33 EAC cells. Methods and Results: Western blot analyses were done following AURKA overexpression with adenovirus, knockdown with si-RNA or inhibition with MLN 8237 (0.5µM) in FLO-1 and OE33 EAC cell lines. The data indicated that overexpression of AURKA induced both total and phospho-HDM2-(Ser166) protein levels. Knockdown or inhibition of AURKA significantly decreased expression of both total and phospho-HDM2-(Ser166) protein levels in FLO-1 and OE33 EAC cells. Additionally, following adenovirus mediated overexpression of AURKA, co-immunoprecipitaion (Co-IP) was done for AURKA and HDM2 in FLO-1 and OE33 EAC cells. The two-way Co-IP data indicated the presence of HDM2 in a complex associated with AURKA and vice-versa. The data from in vitro protein kinase assay indicated that recombinant AURKA directly phosphorylates recombinant HDM2 at Ser166 site. To confirm direct interaction between recombinant AURKA and HDM2 proteins we performed IP following the in vitro kinase assay. The in vitro kinase IP data indicates that kinase intact recombinant AURKA directly interacts and phosphorylates recombinant HDM2 protein. Conclusions: Our data indicate that AURKA regulates HDM2 expression and phosphorylation in both FLO-1 and OE33 EAC cells. Additionally, we also report for the first time that AURKA directly interacts with HDM2 and phosphorylates it at Ser166 site. Therefore, our study suggests that AURKA-mediated regulation of HDM2 could be the major underlying mechanism for induction of apoptosis in p53-negative EAC.
Incidence rates for anal cancer in the United States: 1980-2009.
Authors: Eberly Lauren A. , Wiggins Charles , Nir Itzhak , Morris Katherine T. , Russell John C. , Rajput Ashwani 
Published: February 2017

357 Background: Anal squamous cell carcinoma (SCC) is rare, but results in significant morbidity and mortality. The aim of this study was to characterize the trends of anal SCC in the U.S. between 1980-2009. Methods: Subjects were identified from records in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. The study included incident malignant squamous cell cancer of the anus, anal canal, and anorectum diagnosed among nine core areas of the SEER program from 1980-2009. Average annual age-adjusted incidence rates were calculated by the direct method with the U.S. 2000 standard population. 95% confidence intervals were calculated using the Tiwari adjustment. Temporal trends were assessed by joinpoint regression. Results: Incidence rates of anal cancer in the U.S. more than doubled during this period. A linear increase in anal cancer incidence rates was observed with an Annual Percent Change (APC) of 4.6 (p<0.01) for all races and both sexes-combined. Incidence rates were consistently greater for women than men, however, the increase in incidence rates was greater for men (APC=5.4, p<0.01) than for women (APC=4.3, p<0.01). Similar trends were seen for whites and blacks. Conclusions: Anal cancer is a relatively rare disease, yet incidence rates increased dramatically in the U.S. over the last three decades. Correlation of this increased incidence with HPV infection remains to be determined. [Table: see text]
Identification of risk factors for stage II colon cancer.
Authors: Sawazaki Sho , Shiozawa Manabu , Numata Koji , Numata Masakatsu , Godai Teni , Yamamoto Naoto , Morinaga Soichiro , Rino Yasushi , Masuda Munetaka , Akaike Makoto 
Published: February 2017

375 Background: The use of adjuvant chemotherapy remains controversial in Stage II colon cancer. However, patients with specific clinicopathological features are thought to have high risk for recurrence. The aim of this study was to identify the subgroup of patients at great risk, by investigating the clinicopathological features associated with poor survived in Stage II. Methods: A total of 282 patients with Stage II colon cancer who underwent curative resection from January 1990 to September 2007 at Kanagawa Cancer Center were enrolled. Then, the clinicopathological data of the patients were retrospectively evaluated. Disease-free survival rates were calculated by the Kaplan-Meier method, and survival curves were compared by the log-rank test. Cox’s regression analysis was used for multivariate analyses. P values <0.05 were considered to be statistically significant. Results: The median follow up was 62.5 months. The 5-year disease-free survival was 92.2% in the study group as a whole. Among the recurrent patients (n=23), the most recurrent site was the liver (n=11, 44%), followed by lung (n=6, 24%), and peritoneum (n=5, 20%). Univariate analysis for 5-year disease-free survival identified two factors; tumor diameter (>5cm vs…5cm, p=0.018), and lymphatic invasion (p=0.009). Multivariate analysis for 5-year disease-free survival identified two independent factors; tumor diameter (hazard ratio [HR], 4.82; 95% CI, 1.55-15.0; p=0.006), and lymphatic invasion (HR, 4.15; 95% CI, 1.68-10.2; p=0.002). The 5-year disease-free survival differed significantly among patients with neither of these prognostic factors (98.6%), those with only 1 factor (93.3%), and those with 2 factors (76.6%, p=0.000). Conclusions: Patients with stage II colon cancer who have both 5cm in diameter and lymphatic invasion are at high risk for recurrence. The use of adjuvant chemotherapy should be considered in this subgroup of patients.
Predictive value of baseline CD66e/CEA serum levels on efficacy of bevacizumab-based treatment in advanced colorectal cancer.
Authors: Prager Gerald W. , Bramswig Kira H. , Zielinski Christoph 
Published: February 2017

388 Background: CD66e (Carcinoembryonic antigen, CEA) affects tumorigenesis by enhancing tumor cell survival and by inducing tumor-angiogenesis. This study aimed to evaluate baseline CD66e serum levels as response predictor to bevacizumab-based therapies in patients with metastatic colorectal cancer (mCRC). Methods: 298 patients with mCRC and first-line treatment were analyzed. 169 mCRC received bevacizumab plus chemotherapy and 129 patients with mCRC treated with cetuximab (KRAS w.t.) and identical chemotherapy (FOLFOX6 or FOLFIRI). Disease control (DC), progression-free survival (PFS) as well as overall survival (OS) were assessed and related to baseline CD66e-serum levels. Patients with basal CD66e-serum levels below the statistical median of 26.8 ng/ml (group I) were compared with patients with higher CD66e levels (group II). Results: Baseline CD66e serum levels inversely correlated with therapeutic response in patients receiving bevacizumab-based treatment (chi square i<0.005: OR=0.579, 95% C.I. 0.422, 0.795; p<0.001), inversely correlated with median PFS leading to a median PFS benefit of 2.1 month for patients in group I when compared with group II (p<0.05), as well as inversely correlated with median OS (37.5 month vs. 21.4 month, p<0.05). In an independent cohort of 129 patients treated with cetuximab-based therapy, no association of therapeutic response or PFS with CD66e serum levels was found (p>0.05). Conclusions: These data give first evidence of CD66e as a predictive biomarker for the efficacy of first-line bevacizumab-based therapy in patients with mCRC.
Molecular characteristics of complete PTEN loss in metastatic colorectal cancer.
Authors: Jiang Zhi-Qin , Deaton Laurel , Neishaboori Nastaran , Vauthey Jean-Nicolas , Overman Michael J. , Maru Dipen M , Kopetz Scott 
Published: February 2017

389 Background: Loss of expression of phosphatase and tensin homolog (PTEN) is associated with activation of the PI3K/AKT pathway, and has been identified as a potential modulator of response to targeted therapies in metastatic colorectal cancer (mCRC). The association of PTEN loss with other molecular characteristics and outcomes has not been described for mCRC. Methods: Tumor from 229 mCRC patients (pts) were included for analysis of PTEN staining by IHC from whole-mounts, across two cohorts of unresectable mCRC or resectable liver-limited disease. PTEN loss was defined as complete loss of staining with preservation of expression of stromal components. Mutation status was defined using mass-spectroscopy or next-generation sequencing platforms. CpG island methylation (CIMP) status was determined using a previously defined 6-marker panel, with methylation of ≥3 markers denoting CIMP-High. Methylation findings where confirmed in 193 pts from the Cancer Genome Atlas (TCGA) database, using previously defined classifications. Results: The overall frequency of complete PTEN loss was 12% in the primary tumor and 15% when assayed from metastatic sites (P=NS). There was no difference in clinical characteristics in patients with PTEN-loss tumors. Complete PTEN loss and PIK3CA mutations were not mutually exclusive, with PIK3CA mutation rate of 24% and 14% in PTEN loss and intact, respectively (p=0.3). There was no association of PTEN loss with KRAS mutations (p=0.3), although there were non-significant trends toward higher rates of CIMP-High, BRAF mutations, and R-sided tumors (OR 3.2, 2.7, and 1.6, respectively; p<0.2), consistent with an association with the serrated adenoma pathway and epigenetic inactivation. In the TCGA, PTEN protein loss (defined by the lowest 12% of expression) was associated with increased AKT signaling (77% increase in pAKT/AKT, p<0.01) and a similar trend with CIMP-H tumors (OR 3.1, p=0.13). Conclusions: In patient samples, PTEN loss is independent of KRAS and PIK3CA mutations, associated with robust AKT pathway activation, and may be more prominent in tumors with hypermethylation and BRAF mutations.
Gene expression profiles of rectal cancers with mutant or wild-type Kras.
Authors: Garcia-Aguilar Julio , Chen Zhenbin , Warden Charles , Avila Karin , Zhou Ning , Yuan Yate-Ching , Chen Ching-Tung , Weiser Martin R. 
Published: February 2017

414 Background: The Kras oncogene is one of the most common mutations in colorectal cancer. Kras mutations are associated with increased tumor aggressiveness, poor response to selected targeted therapies, and reduced patient survival. We have previously shown that rectal cancers carrying a Kras mutation were less likely to achieve a pathologic complete response to radiation compared to tumors with wild type Kras. Our objective was to compare the gene expression profiles of rectal cancers with mutant and wild type Kras to identify genes that could be related to the Kras–dependent aggressive phenotype. Methods: Pretreatment biopsy tissue was collected from 120 patients with stages I, II and III rectal cancer treated in two prospective trials (NCT00335816 and NCT00114231). DNA and total RNA were extracted from microdissected cancer cells. Mutations in codons 12, 13, and 61 of the Kras gene were detected by pCR. 50ng of total RNAs were amplified to generate cDNA libraries using Ovation FFPE WTA System (NuGEN Technologies, Inc., San Carlos, CA). The amplified cDNA was labeled using the Encore Biotin Module, and hybridized to GeneChip Human Genome U133A plus 2.0 arrays (Affymetrix, Inc., Cleveland, OH). Differences in gene expression between mutant and wild type Kras tumors were determined using T-test and Q-bound to correct for multiple testing by performing false discovery rate (FDR) analysis. Results: A total of 44 of 117 (37.6%) were mutant Kras. A total of 379 probes were upregulated and 262 were downregulated in tumors with Kras mutant compared to Kras wild type. Heatmap based on differentially expressed genes showed separation according to Kras mutant status. REG4 expression was increased 3 fold and CXCL5 was reduced 2.4 fold in tumors with mutant Kras compared to wild type Kras. The changes in expression on these genes are concordant with their known involvement in prognosis and response to therapy of colorectal cancer. Conclusions: The search for changes in gene expression in response to Kras activation led to identifying a number of genes associated with the tumor aggressive phenotype.
A cost-effectiveness analysis of bevacizumab (BV) plus chemotherapy (CT) versus aflibercept (AFLI) plus CT in patients with metastatic colorectal cancer (mCRC) previously treated with BV.
Authors: Morlock Robert , Yu Elaine , Ray Joshua 
Published: February 2017

417 Background: Trial results from ML18147 and VELOUR have recently reported outcomes for BV+CT and AFLI+CT in mCRC patients previously treated with BEV. This study evaluates cost and outcomes of BV+CT vs AFLI+CT as 2L treatment for patients with mCRC who progressed after receiving a standard BEV containing regimen in the 1L setting. Methods: In the absence of head-to-head trials comparing BV+CT & AFLI+CT, an adjusted indirect comparison was conducted using the Bucher-method. Hazard ratios (HRs) from ML18147 comparing BV+CT vs CT and patients previously treated with BV in VELOUR comparing AFLI+CT vs CT were utilized. An illness-death Markov model was enhanced looking at three states (progression free, progression and death). Distributions were fit to the risks for progression (Lognormal) and mortality (Gamma) and assessed using the adjusted indirect HRs. Only direct costs were considered for patients. Costs of drugs were based on wholesale acquisition costs and costs of treating adverse events were based on Medicare reimbursement. Utilities were derived from the literature; costs and outcomes were discounted at 5%. A probabilistic sensitivity analysis (PSA) was conducted to evaluate robustness of results. Results: Results of the analysis suggest BV+CT combination is less costly compared to AFLI+CT ($39,104 less per treated patient) and similar effectiveness between BV+CT and AFLI+CT [OS 13.3 vs. 12.5 months; HR 0.94 (95% CI 0.70-1.26); 0.498 vs. 0.479 QALYs] in 2L treatment of mCRC in patients previously treated with BV. AE rates and costs were higher for the AFLI+CT arm compared to the BV+CT arm. PSA shows that BV+CT is dominant over AFLI+CT in 98% of model iterations. Increasing the efficacy of AFLI+CT by approximately 100% resulted in an incremental cost-effectiveness ratio of more than $200,000 and AFLI+CT remained dominated by BV+CT. Conclusions: Based on current available data, analysis suggest BV+CT presents lower costs and similar effectiveness outcomes than AFLI+CT in 2L treatment of mCRC in patients previously treated with BV. The higher price of AFLI and the increased rates of AEs are the primary drivers of model results.
Impact of KRAS mutational status on clinical outcomes in patients receiving capecitabine based chemotherapy.
Authors: Yarom Nirit , Gresham Gillian , Boame Nana , Jonker Derek J. 
Published: February 2017

436 Background: Mutations affecting the KRAS gene are established predictive markers of outcome with anti–epithelial growth factor receptor antibodies in metastatic colorectal cancer (mCRC). The relevance of these markers for chemotherapy has not been established. This analysis was performed to assess the predictive impact of KRAS mutation status in patients receiving chemotherapy. Methods: KRAS mutational status was available for 223 patients treated for mCRC. Predictive analysis of mutational status by type of fluoropyrmidine the 1st-line regimen contained (either capecitabine [C] based chemotherapy or infusional 5Fluorouracil [I-5Fu]) for clinical outcomes: progression-free survival (PFS), time to chemotherapy resistance (TTCR) and overall survival (OS). Results: KRAS mutations were observed in 43.5% of the patients. 165 patients received I-5Fu, 44 patients received C. KRAS mutation status (wild type [WT] v mutated [MT]) had no prognostic impact for OS (hazard ratio [HR], 0.81; CI, 0.69 to 1.1 p=0.17) for PFS (hazard ratio [HR], 0.87; CI, 0.66 to 1.14 p=0.3) and TTCR (hazard ratio [HR], 0.85; CI, 0.65to 1.12 p=0.26). C based 1st-line chemotherapy vs. I- 5FU based was predictive of PFS (hazard ratio [HR], 0.52; CI, 0.37 to 0.74 p=0.0003) and TTCR (hazard ratio [HR], 0.54; CI, 0.38 to 0.75p=0.0005) and not of OS (hazard ratio [HR], 0.74; CI, 0.52 to 1.1 p=0.1). KRAS mutational status had predictive impact in patients receiving C based 1st-line chemotherapy on OS (hazard ratio [HR], 0.47; CI, 0.23 to 0.948 p<0.0001) TTCR (hazard ratio [HR], 0.49; CI, 0.25 to 0.97 p=0.0398) and was not predictive of PFS (hazard ratio [HR], 0.78; CI, 0.4 to 1.53 p=0.47) Conclusions: KRAS gene mutation status was predicitve for OS and for TTCR in patients who received C based 1st-line chemotherapy.
Class III β-tubulin as a predictive marker for taxane-based first-line palliative chemotherapy in recurrent or metastatic gastric cancer.
Authors: Hwang Jun-Eul , Kim Dae-Eun , Shim Hyun-Jeong , Bae Woo Kyun , Cho Sang-Hee , Chung Ik-Joo 
Published: February 2017

44 Background: Class III β tubulin (TUBB3) is a prognostic marker in various tumors and role of TUBB3 in advanced gastric cancer is not clearly defined yet. We analyzed the significance of TUBB3 expression along with ERCC1 in recurrent or metastatic gastric cancer patients receiving taxane based first-line palliative chemotherapy. Methods: We reviewed 146 patients with advanced gastric adenocarcinoma who received taxane based first-line palliative chemotherapy between 2004 and 2010 at Chonnam National University Hwasun hospital. Immunohistochemical stain of TUBB3 and ERCC1 was done in paraffin-embedded tumor tissue. We evaluated response to chemotherapy, progression-free survival (PFS), and overall survival (OS). Results: A total of 146 patients with advanced gastric cancer received docetaxel and cisplatin (n=15), or paclitaxel and cisplatin (n=131) with or without 5-fluorouracil (5-FU). The median PFS was significantly shorter for patients with TUBB3 high expression than patients with TUBB3 low expression (3.63 versus 6.67 months, p=0.001). OS was not associated with TUBB3 expression status (12.9 versus 13.1 months, p=0.769). In multivariate analysis, only TUBB3 was related to shorter PFS (HR 2.74, 95% CI 1.91-3.91, p=0.001). Patients with ERCC1 high expression showed lower response rate than patients with ERCC1 low expression (24% versus 63.2%, p=0.001), however ERCC1 showed no clinical influence on PFS and OS. Conclusions: TUBB3 is a strong predictive marker in recurrent or metastatic gastric cancer patients receiving taxane based first-line palliative chemotherapy. Clinical impact of ERCC1 is not evident in this setting.