bluuebunny/crossref_metadata_2025_split huggingface dataset:
RAS mutational status and CEA production at initial presentation in metastatic colorectal cancer.
Authors: Cho May Thet , Goldstein Leanne , Akiba Chie , Lau S. Cecilia , Telatar Milhan , Afkhami Michelle , Sentovich Stephen , Melstrom Kurt , Lim Dean , Chao Joseph , Chung Vincent M. , Fakih Marwan 
Published: February 2017

542 Background: Serial CEA testing is recommended in the surveillance of patients with resected stage II-IV colorectal cancer. However, the sensitivity of CEA in identifying metastatic disease has not been evaluated in the settings of RAS mutant (MT) and RAS/BRAF wild-type tumors (WT). In order to evaluate the impact of RAS mutational status on CEA production, we retrospectively evaluated a single-institute metastatic colorectal cancer (mCRC) population. Methods: We retrospectively reviewed, in a single center, all cases with mCRC with known RAS mutational status based on next generation sequencing (ONCO44 and ONCO48). These assays identify clinically relevant mutations in BRAF, KRAS, and NRAS. Additional eligibility criteria included the availability of CEA levels and imaging studies at first diagnosis of mCRC. Patient demographics, primary tumor location and sites of metastatic disease at 1st diagnosis were captured. CEA levels were stratified as normal or elevated based on a cut point of 5ng/ml. Results: 139 mCRC patients satisfied the eligibility criteria (75 RAS-MT, 59 RAS/BRAF-WT, and 5 BRAF-MT). BRAF-MT patients were excluded from the analysis due to their small sample size. Patients with RAS/BRAF-WT tumors were more likely to present with metastatic disease to the liver, but this did not reach statistical significance (p = 0.056). There was no difference in the incidence of normal CEA at presentation in RAS-MT (30%) and RAS/BRAF-WT (28%) cohorts. CEA production was dependent on the pattern of metastatic disease. Elevated CEA was associated with the presence of liver metastases versus no metastases among RAS-MT (92% vs 47% p <.0001) and RAS/BRAF-WT patients (82% vs 50% p = 0.0101). RAS status did not impact the likelihood of CEA production within the hepatic metastases and non-hepatic metastases groups. Conclusions: RAS status does not appear to influence CEA production in patients with mCRC. CEA elevations are highly associated with liver metastases and are less prevalent in patients without hepatic involvement. These findings confirm the limited predictive value of CEA for non-hepatic recurrence, irrespective of RAS status.
Early-onset small bowel and colorectal cancer patients with BRCA mutations: Actionable variants in atypical presentations.
Authors: Vikstrom Karen 
Published: February 2017

545 Background: The paradigm of genetic panel testing for hereditary colorectal cancer (CRC) continues to emerge. An association between Hereditary Breast and Ovarian Cancer (HBOC) syndrome and early onset CRC and has been reported, though only significantly associated with BRCA1 mutations. Guidelines do not include CRC in the HBOC spectrum. We describe nine early-onset ( < 55 years) gastrointestinal (GI) cancer patients with germline mutations in BRCA1 or BRCA2 to highlight actionable findings that would have been missed by traditional CRC genetic testing. Methods: The nine affected patients underwent genetic testing using NGS-based multi-gene cancer panels. Genomic DNA variants were identified and classified according to ACMG criteria. Patient medical histories were obtained by referring clinician and documented on test requisition forms, and were de-identified for analysis. Results: Nine patients had a pathogenic (P) variant in BRCA1 (three cases) or BRCA2 (six cases). Four patients were under the age of 32 at the time of their CRC diagnosis. Of the nine cases, only one met NCCN testing criteria for HBOC syndrome. All patients were negative for P variants in the canonical CRC genes (APC, MUTYH, MLH1, MSH2, MSH6, PMS2, EPCAM). Conclusions: In this series, nine unrelated patients with early-onset CRC were found to carry a BRCA1 or BRCA2 mutation. The presence of BRCA mutations in these CRC patients is alone not strong evidence of causation; however, it suggests that clinicians should consider expanded panel testing in the presence of complex family histories, as these patients would have been found negative by traditional genetic tests. As the phenotypic spectrum of classical cancer syndromes is expanded by broad panel-based testing, it is important to identify patients that fall outside traditional diagnostic criteria, as some patients will have actionable findings in unexpected genes.
The prevalence of colorectal polyps in patients with gastric cancer.
Authors: Kwon Kyoung-Joo , Shim Ki-Nam , Jung Sung-Ae , Jung Hye-Kyung , Kim Seong-Eun , Kong Kyoung Ae 
Published: February 2017

549 Background: Gastric polyps are found frequently in various colonic polyposis syndromes. Genetic alterations of several genes occur in gastric adenomas and colorectal adenomas. However, it is unknown whether patients with gastric cancers are at higher risk for colorectal adenomas. Methods: We retrospectively reviewed the medical records in 112 patients with gastric cancers from January 2005 to December 2009. Patients who were diagnosed with gastric cancers and had colonoscopy within 6 months were compared to 220 sex and age-matched controls from 3,725 persons who underwent esophagogastroduodenoscopy and colonoscopy for screening at the Center for Health Promotion in Ewha Womans University Medical Center. High risk polyp was defined by any of the following: (1) the presence of three or more polyps; (2) polyp size at least 10mm; (3) high-grade dysplasia or adenocarcinoma confirmed by histopathologic examination. Otherwise the polyps were defined as low risk. Results: Mean age was 59 years-old and 70% was male in patients with gastric cancer. Overweight (BMI ≥ 23) was more common in control group (gastric cancer versus control: 56% and 69%, respectively, P = 0.025). Colorectal polyps were identified in 67 of 112 patients (59.8%) with gastric cancer and in 153 of 220 controls (69.5%). The prevalence of high risk polyps were numerically higher in the gastric cancer group than the control group, although not statistically significant (9% vs. 4%, P = 0.267). In contrast, the prevalence of low risk polyps were significantly frequent in the control group (91% vs. 96%, P = 0.024). The mean size and number of colorectal polyps were not different between the two groups. Adenocarcinoma was diagnosed from polyps in five patients (7%) with gastric cancer and four patients (2%) with control group (P = 0.190). Conclusions: The overall colorectal polyps, especially low risk polyps, were more prevalent in the control group. In contrast, high risk polyps and adenocarcinoma is more frequently found in patients with gastric cancer although not significant. Therefore, we suggest that colorectal polyps should be cautiously examined in patients with gastric cancer.
Validation of the prognostic impact of lymphocyte infiltration (LI) in patients (pts) with stage III colon cancer (CC) treated with adjuvant FOLFOX+/- cetuximab: A PETACC8 translational study.
Authors: Emile Jean-François , Le Malicot Karine , Tabernero Josep , Mini Enrico , Folprecht Gunnar , Van Laethem Jean-Luc , Julie Catherine , Allard Marc Antoine , Bennouna Jaafar , Lepage Come , Laurent-Puig Pierre , Taïeb Julien 
Published: February 2017

553 Background: The prognostic value of LI of CC has been demonstrated by several groups. However no validated test is available for clinical practice. We previously described an automated and reproducible method for testing LI (Allard MA et al 2012) and aimed to validate it for clinical use. Methods: According to NIH criteria, we designed a prospective analysis of this biomarker in pts included in the PETACC8 phase III study. Primary objective was to compare % of pts without recurrence at 2 years in pts with high versus low LI (#NCT02364024). Secondary objectives were comparison of disease free (DFS) and overall (OS) survivals, and prognostic value of LI on these endpoints. Automated testing of LI was performed on virtual slides without access to clinical data. Results: Among the 1,220 CC pts enrolled, LI was high, low and not evaluable in 241 (20%), 790 (65%) and 189 (15%), respectively. High and low LI groups did not differ except for treatment arm (p=0.04) and microsatellite status (MSI/MSS) status (p=0.04). Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in pts with high and low LI respectively (p=0.02). Pts with high LI also had better DFS and OS (table). Stage, grade, KRAS status and LI were the only prognostic markers in multivariate analysis. Sub-group analyses revealed that high LI had better DFS and OS in MSS pts, and in pts without KRAS codon 12-13 mutation, but not in MSI neither in KRAS mutated pts. Conclusions: This is the first prospective validation of a LI testing in pts with stage III CC treated with FOLFOX adjuvant. Automated testing of LI also had a prognostic value for DFS and OS. Funding: Merck-Serono, Sanofi, Région Ile de France. Clinical trial information: NCT02364024. [Table: see text]
Genomic features of primary and recurrent anal squamous cell carcinoma.
Authors: Pike Jonathan W , Mouw Kent William , Braunstein Lior Zvi , Martin Neil E. , Mamon Harvey J. , Hornick Jason L. , Van Allen Eliezer Mendel , D'Andrea Alan D. 
Published: February 2017

556 Background: Approximately 7000 cases of anal squamous cell carcinoma (ASCC) are diagnosed annually in the US, and the incidence is increasing. Combination chemoradiotherapy (CRT) is the standard of care for locally-advanced ASCC, and the 5-year survival rate is approximately 70%. Unlike many other tumor types, no large-scale genomic studies have been reported for anal cancer. In order to characterize the mutational landscape of ASCC and identify potential therapeutic targets, we perform comprehensive genomic analysis of a pilot cohort of ASCC cases. Methods: We performed whole exome sequencing of tumor and matched germline DNA from a pilot cohort of twelve patients with locally advanced (Stage II-IVA) ASCC cases treated at Dana-Farber Cancer Institute. All patients received concurrent chemoradiotherapy (CRT): seven ‘responders’ had complete response and no evidence of recurrence with a minimum of one year follow-up, while five ‘non-responders’ had residual or recurrent disease following CRT. For non-responders, both primary and residual/recurrent tumors were analyzed. Results: The overall mutation rate was 3.7 mutations per megabase (Mb). Recurrent mutations in several known cancer genes were observed. Five of twelve cases had a hotspot mutation in FBXW7, including 3 of the 5 non-responders. Known oncogenic mutations were also observed in PIK3CA (3 tumors) and NFE2L2/KEAP1 (3 tumors). Analysis of paired primary and recurrent samples revealed surprising examples of distinct driver mutations in clonally-related tumors. Copy number analysis revealed focal amplifications of chromosome 3q. Conclusions: This study represents one of the first genome-scale analyses in ASCC. The overall mutation rate was similar to other HPV-associated squamous cell carcinomas, and recurrent mutations in several known cancer genes were observed. Analysis of paired primary and residual/recurrent tumors revealed surprising heterogeneity. To extend our findings, we are currently performing a similar analysis in a larger extension cohort of ASCC tumors.
Novel driver genes and genomic predictors of immune infiltrates in colorectal cancer.
Authors: Giannakis Marios , Mu Jasmine Xinmeng , Shukla Sachet , Qian Zhi Rong , Cohen Ofir , Nishihara Reiko , Cao Yin , Yamauchi Mai , Sukawa Yasutaka , Nosho Katsuhiko , Ng Kimmie , Meyerhardt Jeffrey A. , Lawrence Michael , Gabriel Stacey B. , Lander Eric , Getz Gad , Wu Catherine , Fuchs Charles S. , Ogino Shuji , Garraway Levi A. 
Published: February 2017

557 Background: Despite progress that has been made in the molecular characterization of colorectal cancer (CRC), prior studies have had limited power to detect, as significantly mutated, less-frequently altered CRC genes. In addition, most large-scale sequencing studies have generally lacked clinicopathologic annotations to link genomic features with important CRC characteristics such as immune infiltration. Methods: We performed Whole-Exome Sequencing on 619 archival primary CRCs from two large prospective cohorts, the Nurses’ Health Study and the Health Professionals Follow-Up Study. We identified CRC driver genes using significance-calling algorithms and employed a novel computational pipeline to calculate tumor neoantigens (peptides resulting from somatic mutations and recognized by the immune system as foreign). The neoantigen load and altered genes/pathways were correlated to immunohistochemically determined immune infiltrates and survival data linked to these specimens. Results: We identified 90 significantly mutated genes in non-hypermutated CRC. These include previously underappreciated genes that participate in pathways such as WNT-signaling and RNA processing. Among all samples, the neoantigen load was associated with increased overall lymphocytic infiltration (P = 2.6e-11), tumor-infiltrating lymphocytes (TILs) (P = 2.0e-19), memory T-cells (P = 0.091) and CRC-specific survival (P = 0.025). Neoantigen load was also associated with higher TILs in microsatellite-stable tumors (P = 0.015). We found that HLA and Antigen Processing Machinery (APM) mutations have undergone positive selection in tumors with TILs. Conclusions: In the largest exome-sequencing study of CRC to date, we leveraged the increased number of samples and their associated clinicopathologic annotations to identify new driver genes and genomic predictors of immune infiltrates in this disease. Neoantigen load is prognostic in CRC and predictive of immune infiltration, even among microsatellite-stable tumors. We also find evidence of positive selection for HLA and APM mutations in immune-cell infiltrated tumors. These results have implications for patient selection in CRC immunotherapy trials.
Effect of age and ethnicity on the tumor location, nuclear accumulation of p53 and clinical outcome in colorectal adenocarcinoma.
Authors: Paluri Ravi Kumar , Behring Michael , Posey James , Manne Upender 
Published: February 2017

559 Background: The race/ethnicity based research in colorectal cancer (CRC) care continues to remain a high priority in developing personalized medicine, and to improve overall clinical outcomes. The role of p53 abnormalities in prognostication of CRC has been evaluated earlier. The incidence of nuclear accumulation of p53 (p53nac) and its prognostic relevance in African American (AA) and non-Hispanic white patients (pts) have been investigated, and it was suggested that the clinical consequences of p53nac in CRC varies with anatomic location of the tumor and the race of the patient. However, the clinical value of p53nac in relation to age, the tumor location, and race together is not assessed. Thus, we evaluated prognostic significance of p53nac by considering the tumor location, age, race/ethnicity and p53nacin CRCs in AA and white pts. Methods: Formalin fixed paraffin embedded CRC tissues from 242 AAs and 346 whites who underwent surgery were assessed for p53nac by routine immunohistochemistry (IHC). The routine (not antigen retrieval) IHC will identify the majority of genetic alterations ( > 95% missense point mutations) and have significant association with patient survival in CRC. The association between phenotypes, p53nac status, clinicopathologic features, and overall survival were evaluated using the x2 test and Cox regression analyses. Results: Approximately equivalent proportions of distal (52%) and proximal adenocarcinomas (48%) were positive for p53nac in AA pts. In contrast, distal CRC from whites more frequently were positive for p53nac than from the proximal colon (67% vs. 34%, x2 P = 0.006). p53nac was found to be a strong predictor of poor overall survival in young ( < 65 yr) white pts with proximal tumors [hazard ratio (HR) = 2.8, 95% Confidence Intervals (CI):1.2-6.4] but not in AAs (HR = 0.7, 95% CI: 0.41-1.21). Conclusions: The findings of this study suggest that p53nac is a strong prognostic marker for young white pts with proximal colon adenocarcinomas. Our findings are clinically relevant because several small-molecule inhibitors of mutant p53 are under investigation. These studies were supported by a pilot project grant by the UAB Comprehensive Cancer center.
Effect of combined consideration of distinct signatures of VEGF and soluble VEGFR2 on prognostic implication in gastric cancer.
Authors: Ock Chan-Young , Nam Ah-Rong , Bang Ju-Hee , Kim Tae-Yong , Lee Kyung-Hun , Han Sae-Won , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue , Oh Do-Youn 
Published: February 2017

56 Background: Anti-angiogenic strategy in gastric cancer (GC) has been highlighted again due to the recent success of ramucirumab and apatinib. Therefore, the comprehensive network of VEGF, soluble VEGF receptor-2 (sVEGFR2) and cytokines and other angiogenic factors (CAF) in GC and their prognostic impact would be of importance, although they have been poorly understood. We aimed to find out the CAF signature associated with VEGF and sVEGFR2, and to explore their prognostic implication in GC. Methods: We measured pretreatment serum levels of 52 CAFs, including VEGF and sVEGFR2, using multiplex bead immunoassays and ELISA, in 70 patients who were diagnosed with GC in Seoul National University Hospital, and treated with palliative chemotherapy. Linear regression analysis for correlating CAFs with VEGF and sVEGFR2, and survival analysis by log rank test and Cox regression analysis were performed. Results: The VEGF signature was shown to be associated with seven CAFs (interluekin [IL]-7, IL-12p70, IL-2Ra, IL-10, stem cell factor, Fibroblast growth factor-basic, IL-3). The sVEGFR2 signature was associated with IL-4 and platelet-derived growth factor beta, but VEGF and sVEGFR2 showed no association with each other. Patients with high VEGF had a tendency to have worse overall survival (OS) than those with low VEGF (11.2 months versus 16.7 months; P = 0.061). However, among patients with high-sVEGFR2, OS was not different according to VEGF (12.1 months, high-VEGF versus 15.1 months, low-VEGF; P = 0.546). Interestingly, the poor prognostic impact of high-VEGF was far significant in patients with low-sVEGFR2 (10.9 months versus 16.8 months; P = 0.036). With this perspective, VEGF/sVEGFR2 ratio was significantly correlated with worse OS in univariate as well as multivariate analysis (HR 1.78 [95% CI 1.08-2.94], P= 0.024). Conclusions: Based on the comprehensive network analysis of CAF, VEGF and sVEGFR2 had distinct CAF signatures in GC. Consideration of both VEGF and sVEGFR2 confers more accurate prognostic implication compared with VEGF alone in GC. Regarding the angiogenic aspect, VEGF/sVEGFR2 ratio is significantly correlated with survival outcome in GC.
Clusterin expression (CLU) as a prognostic marker in colorectal carcinoma (CCR).
Authors: Alcaide Julia , Rueda Antonio , Rodrigo Isabel , Tellez Teresa , Funez Rafael , Padilla Maria del Carmen , Zarcos Irene , Pérez-Ruiz Elisabeth , Villatoro Rosa , Perez Diego , Redondo Maximino 
Published: February 2017

563 Background: Increased CLU is involved in malignant progression and anticlusterin treatment with antisense oligonucleotides enhances apoptosis induced by several citotoxics. However, clinical significance of CLU expression in human CRCs has been scarcely studied. We investigated whether changes in CLU could be related to carcinogenesis and survival (sv) of CRC patients (pts). Methods: Formalin-fixed and paraffin-embedded specimens were examined from 31 adenomas and 103 CRCs resected at Costa del Sol Hospital. The study was approved by Research Ethics Committee. Immunohistochemistry using monoclonal anti-α chain clusterin antibody (Upstate-Millipore, Watford, England) was performed, following standard staining procedure. CLU was scored as negative (CLU–) (no staining) or positive (CLU +) (>10% of tumor cells with strong staining). Cytoplasmic CLU in tumors was evaluated for cancer cells only, and in normal mucosa for epithelial cells only. Sv curves were calculated and plotted according to Kaplan-Meier method. Predictors that were significant at p<0.10 in univariate analysis, were entered into a Cox proportional hazards model for multivariate analysis, remaining significant at p<0.05. Results: Median follow-up was 54 months. Median age was 70 years (45-91). TNM stage distribution was: I (13%), II (48%), III (25%) and IV (14%). Epithelial normal cells were always CLU-, but 16% (5/31) of adenomas was CLU+ and this percentage increased in CRCs (30%, 31/103). Positive staining always presented an apical cytoplasmic pattern. Recurrence was more frequent in CLU+ (61%,19/ 31) than in CLU- tumors (37%, 27/72) and CLU was significantly associated with lower disease-free survival (DFS) (p<0.05). In multivariate analysis, CLU and stage remained significant independent prognostic factors for DFS (Table). Conclusions: CLU has a role in colon carcinogenesis and prognostic value. CLU is associated with decreased DFS among pts with CRCs. These findings have important implications for identifying CRC pts with more aggressive tumors who may benefit from targeted therapy against clusterin. [Table: see text]
Comprehensive genomic profiling in colorectal cancer (CRC) to identify differing frequencies of clinically relevant genomic alterations (CRGA) in tumors of patients (pts) less than age 50 as compared to those of pts over age 65.
Authors: Bailey Mark , Mitchell Edith P. , Morosini Deborah , Lipson Doron , Ross Jeffrey S. , Miller Vincent A. , He Jie , Stephens Phil 
Published: February 2017

570 Background: CRC is increasing in young pts and are believed to have worse pathological features than older pts. Mutational profiles may differ in pts. The objective of this study was to compare and describe the genomic complexity of CRC in pts < 50 to > 65 in the FoundationOne database. Methods: DNA was extracted from 2,267 FFPE clinical specimens with colorectal cancer (CRC) (< 50 yo, n=1280; > 65 yo, n = 987). CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 603X for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. All classes of genomic alterations (GA) were identified. Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: Among the 50 genes analyzed, the > differences were noted in BRAF and FAM123B in pts > 65. KRAS mutations occurred in 50.5% vs 51.3%; NRAS, 2.6% vs 4.8%, BRAF, 5.5% vs 11.9% in younger pts vs older pts, respectively. Few differences in genomic complexity were observed, although a trend toward increase frequency of BRAF mutations were observed in pts > 65. Conclusions: While some differences in tumor genomic profiles and complexity were observed in CRC pts < 50 vs > 65, changes in BRAF and FAM123B were more frequent in the > 65. Ongoing studies will assess differences in molecular and genomic features between younger and older CRC pts. [Table: see text]