bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with advanced cancers of the GI tract and anus.
Authors: Schrock Alexa Betzig , Young Lauren , Klempner Samuel Jacob , Bordoni Rodolfo , Ross Jeffrey S. , Stephens Philip J. , Devoe Craig E. , Braiteh Fadi S. , Ali Siraj Mahamed , Miller Vincent A. 
Published: March 2017

618 Background: The treatment of GI carcinomas (CA) is influenced by the presence or absence of prognostic and predictive genomic alterations (GA). Tissue sampling is the historical platform for genomic biomarker assessment, but non-invasive ctDNA assay provides an alternative when tissue is unavailable or cannot be safely obtained. Methods: Hybrid-capture based genomic profiling using a ctDNA assay (FoundationACT) was performed on blood samples from 82 consecutive pts with lower alimentary canal CA. Results: Median age was 62 (range 28-92) and 61% were male. Anatomic breakdown included CRC (n = 51), esophageal (n = 9), gastric (n = 8), gastroesophageal (n = 3) and small bowel adenoCA (SBA, n = 2), anus squamous cell CA (n = 5), and other GI CA (n = 4). At least one GA was reported in 72% of cases. In 23 cases with no GA reported, the average maximum somatic allele frequency was 0.17% (95% CI: 0-0.6%) vs. 16.7% (95% CI: 0-54.4%) for the 59 cases with GAs (P < 0.0001). For the 3 of 18 patients with both blood and tissue testing performed and samples collected within a 30-day interval, 8/9 (89%) GA detected in tissue were also detected in ctDNA. An average of 1.7 GA/sample were detected in ctDNA. The most commonly altered genes were TP53 (61%), KRAS (24%), BRAF (10%) and PIK3CA (10%). Comparative analysis using the tissue-based Foundation Core database showed a similar trend with overall slightly higher frequencies of GAs in individual genes . RAF and RAS short variants (SV) were exclusive to lower GI and anal CA. KRAS and RAF1 amplification (amp) occurred only in esophageal CA (4/11, 36%). FGFR SV or amp was identified in 3 cases across the cohort. Of CRC, 4 (8%) had ≥ 1 ERBB2 activating SV or amp, 2 (4%) had IDH1/2 hotspot SV, and 2 (4%) had BRCA2 inactivating alterations. ERBB2 activating SV and EGFR amp were found in a SBA and an esophagus CA, respectively. A kinase fusion was identified as the sole driver in 1 CRC ( STRN-ALK) and 1 SBA ( GOPC-ROS1). Outcomes to targeted therapies will be presented for the available subset of patients. Conclusions: Our results provide early clinical support and confirm that hybrid-capture based ctDNA testing can reliably detect all 4 classes of GA and provide a molecular profiling option for patients with GI CA.
Differences in mutation rates between right- and left-sided colorectal adenocarcinoma.
Authors: Jensen Christopher E. , Loaiza-Bonilla Arturo , Villanueva Jonathan Yap , Morrissette Jennifer J. 
Published: March 2017

622 Background: Recent reports have demonstrated inferior outcomes for patients with right-sided colorectal cancer (CRC) compared to patients with left-sided disease (Schrag et al 2016, JCO 34 (suppl; abstr 3505)) as well as differences in treatment response based on disease sidedness (Venook et al 2016, JCO 34 (suppl; abstr 3504)). However, the biological and genetic underpinnings of these clinical differences are incompletely understood. Methods: We compared mutation rates among 38 genes in a retrospective review of next-generation sequencing data of CRC samples obtained in routine clinical practice at a single academic medical center. Primary location was identified via chart review. Right = cecum to transverse colon; Left = descending colon to rectum. Results: Among 293 samples (167 left-sided, 103 right, 23 synchronous or without clear primary), BRAF and CTNNB1 mutations were more prevalent in right-sided CRC. BRAF was mutated in 15.5% of right-sided CRC (95% CI: 8.5-22.5%) compared to 4.8% (CI: 1.6-8.0%) (p=0.003). CTNNB1 was mutated in 3.9% of right-sided CRC (CI: 0.2-7.6%) compared to no instances of CTNNB1 mutations in left-sided disease (p=0.01). Among right-sided CRC, there was a trend toward more KRAS mutations at 57.3% (CI: 47.7-66.8%) versus 44.9% (CI: 37.4-52.5%) and more PIK3CA mutations at 26.2% (CI:17.7-34.7%) versus 17.4% (CI: 11.6-23.1%), though these differences did not rise to the level of statistical significance. The overall rate of BRAF mutations in our sample (8.9%, CI: 5.5-12.3%) was consistent with the rate of BRAF mutations among large intestine adenocarcinomas in the COSMIC database (10.6%, CI: 10.4-10.8%), lending support to the external validity of these data. Conclusions: These differing mutation rates may implicate these genetic pathways in the mechanisms underlying the discrepant outcomes and treatment responses between right and left-sided disease described in prior studies. Further work is needed to more clearly elucidate genetic difference between right and left-sided CRC, as well as the mechanistic relationship between these mutations and prognosis.
FAK expression as a prognostic marker in colorectal cancer: A single institution study of 298 patients.
Authors: Davis Lindy , Lenzo Felicia , Ylagan Lourdes , Omilian Angela , Attwood Kristopher , Cance William G. 
Published: March 2017

623 Background: Focal adhesion kinase (FAK) is an attractive therapeutic target in solid cancers, but there is no method for patient selection based on FAK expression nor biomarker for therapeutic response. Previous FAK expression studies were not standardized and showed varying correlations. This single-institution study aims to define FAK expression patterns in colorectal cancer (CRC) and correlate with patient outcomes and expression in other solid cancers. Methods: We analyzed 635 samples from 298 patients (pt) with CRC using tissue microarrays (TMAs) stained for FAK and scored 0-3 by a single pathologist. The TMAs contained samples of 298 primary tumors with 290 matching normal tissue and 47 matching metastases. As an internal control, we examined FAK and outcomes in 135 breast cancer pt and 145 melanoma pt. FAK expression and pt outcomes were evaluated using Kruskal-Wallis exact and Wilcoxon signed-rank tests. Results: FAK expression correlated with aggressive phenotype in CRC primaries. Matching normal colon had lower FAK than primaries (Mean FAK 0.61 vs 1.87, p < 0.001). Higher primary tumor FAK was associated with higher tumor stage; the 88 T1-2 primaries had a mean FAK 1.54, compared to FAK 2.06 in the 99 T3-4 tumors (p < 0.001). There was no difference in FAK among Stage II-IV pt, nor between mean FAK in the primaries (1.87) versus metastases (1.73). When FAK was dichotomized as high vs low (high = FAK > 2), high primary tumor FAK was associated with shorter overall survival (OS). Median OS was 91 months (95% CI 73-130) in high FAK (n = 122 pt) vs 155 months (95% CI 124-196) in low FAK (n = 176 pt), p = 0.007. The OS rates at 5 and 10 years in high FAK were 65% and 43%, vs 79% and 61% in low FAK. FAK in CRC metastases did not correlate with OS (p = 0.945). In contrast, when CRC was compared to breast cancer and melanoma, FAK did not show the same correlations in outcome. Conclusions: For the first time, by standardizing FAK quantification, we have identified that FAK expression in the primary correlates with outcome in CRC. These data may have implications in selection of patients for adjuvant therapy. Normal colon and earlier stage CRC had lower FAK expression compared to more advanced stages, suggesting a therapeutic window for FAK as a target.
Development of a small molecule drug for EBV-associated gastric cancers.
Authors: Messick Troy E , Soldan Samantha S , Deakyne Julianna , Lieberman Paul M 
Published: March 2017

63 Background: Worldwide, EBV is associated with ~10% of gastric cancer. Currently, no pharmaceutical-based therapies exist that selectively target EBV associated gastric cancers. EBV, in its latent oncogenic form, is dependent on the continuous expression of Epstein-Barr Nuclear Antigen 1 (EBNA1), a multifunctional dimeric protein critical for viral replication, genome maintenance and viral gene expression. Methods: The aim of this program is to advance the development of a New Chemical Entity (NCE) for latent infection of Epstein-Barr Virus (EBV) to treat EBV-associated gastric cancer. We have used structure-based drug design and medicinal chemistry methods to identify and develop a small molecule clinical candidate that selectively inhibits the DNA-binding activity of EBNA1. Results: The clinical candidate inhibits EBNA1 function with nanomolar potency in biochemical assays and low micromolecular activity in several cell-based assays. We demonstrate that our clinical candidate provides protection in 4 different xenograft models of EBV-driven tumor growth, including patient-derived xenografts. Furthermore, RNA analysis experiments confirm in vivo target engagement by the elimination of EBV in treated tumor tissue. The clinical candidate is selective, showing no activity in an EBV-negative xenograft experiments. The clinical candidate has met industry-accepted criteria for drug suitability, safety and toxicology including physicochemical properties, metabolic stability, selectivity in broad-based screens and bioavailability, and lack in vivoliabilities, including genotoxicity and 14-day toxicity studies. Conclusions: IND-enabling studies including safety pharmacology and toxicology and GMP manufacturing have begun with a projected First-In-Human clinical trial in Q4 2017. These data establish proof-of-concept for targeting EBNA1—a protein previously thought to be undruggable.
The impact of sarcopenia on toxicity and pharmacokinetics of 5-fluorouracil (5FU) in colorectal cancer.
Authors: Williams Grant Richard , Deal Allison Mary , Shachar Shlomit S. , Walko Christine Marie , Patel Jai Narendra , O'Neil Bert H. , McLeod Howard L. , Weinberg Marc , Choi Seul Ki , Muss Hyman B. , Sanoff Hanna Kelly 
Published: March 2017

633 Background: Great heterogeneity exists in the ability of adults with cancer to tolerate treatment. Variability in body composition may affect rates of metabolism of cytotoxic agents and contribute to the variable chemotherapy toxicity observed. The goal of this study was to explore the impact of body composition, in particular sarcopenia, on the pharmacokinetics of 5-fluorouracil (5FU) in a cohort of patients receiving FOLFOX +/- bevacizumab for colorectal cancer. Methods: We performed a secondary analysis of a completed multicenter trial that investigated pharmacokinetic-guided 5FU in patients receiving mFOLFOX6 +/- bevacizumab [Patel et al. The Oncologist 2014]. Computed Tomography (CT) images that were performed as part of routine care were used to for body composition analysis. Skeletal muscle area (SMA) and density (SMD) were analyzed from CT scan L3 lumbar segments using radiological software. SMA and height (m2) were used to calculate skeletal muscle index (SMI = SMA/m2). Skeletal Muscle Gauge (SMG) was created by multiplying SMI x SMD. Differences were compared using two group t-tests and fisher’s exact tests. Results: Of the 70 patients from the original study, 25 had available CT imaging. The mean age was 59, 52% female, 80% Caucasian, and 92% with either stage III or IV disease. Eleven patients (44%) had grade 3/4 toxicity, and 12 patients were identified as sarcopenic (48%) [per Martin et al. JCO 2013]. Sarcopenic patients had numerically higher first cycle 5FU AUCs compared to non-sarcopenic patients (19.3 vs. 17.3 AUC, p= 0.43) and higher grade 3/4 toxicities (50 vs 38.5%, p= 0.70). Patients with low SMG ( < 1475 AU) had higher grade 3/4 toxicities (62 vs 25%, p= 0.11) and higher hematologic toxicities (46 v 8%, p= 0.07). Conclusions: CRC patients with sarcopenia had numerically higher first cycle AUCs of 5FU and a higher incidence of severe toxicities; however, this was not statistically significant, possibly due to limited sample size. SMG, an integrated muscle measure, was more highly correlated with toxicity outcomes than either SMI or SMD alone. Further research exploring the role of body composition in pharmacokinetics is needed with a focus on alternative dosing strategies in sarcopenic patients.
Predicting colorectal cancer recurrence by utilizing multiple-view multiple-learner supervised learning.
Authors: Castellanos Jason , Liu Qi , Beauchamp R. Daniel , Zhang Bing 
Published: March 2017

635 Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality in the United States. A key therapeutic dilemma in the treatment of CRC is whether patients with stage II and stage III disease require adjuvant chemotherapy after surgical resection. Attempts to improve identification of patients at increased risk of recurrence have yielded many predictive models based on gene expression data, but none are FDA approved and none are used in standard clinical practice. To improve recurrence prediction, we utilize a machine learning approach to predict recurrence status at 3 years after diagnosis. Methods: A dataset was curated from six publically available microarray datasets, and multiple views were generated to include information from non-tumor tissue gene expression patterns, gene set structure, protein-protein interaction network structure, previously curated molecular signatures, and identified tumor suppressor/driver mutations. These views were used to train a diverse pool of base learners using 10x 10-fold cross-validation. Stacked generalization was used to train an ensemble model, also known as a meta-learner, from the predictions of these base learners. Results: The performance of microarray trained models was significantly better compared to models trained on clinical data (Paired Wilcoxon signed rank test, p = 1.49 x 10-8), demonstrating that molecular data predicts recurrence significantly better than basic clinical data. Review of the model training performances revealed that non-linear classifiers often outperform linear classifiers, and that ensemble methods can also enhance performance. We also demonstrate the feasibility of the multiple-view multiple learner (MVML) supervised learning framework to generate and integrate predictions across a diverse set of learners, with the performance of the meta-learner exceeding or matching that of the best base learners across all performance metrics. Conclusions: This work represents the first effort to use ensemble learning to predict CRC recurrence and highlights the promise of ensemble learning to improve the performance of predictive models in order to realize the goals of precision medicine.
The treatment continuum of panitumumab, cetuximab, and bevacizumab in 1st through 3rd line by KRAS, NRAS, and BRAF mutation status among mCRC patients treated at community cancer centers in the United States.
Authors: Lowe Kimberly , Hool Kristina , Kafatos George , Kelsh Michael Anthony , Garawin Tamer 
Published: March 2017

638 Background: Our objective was to use real world data to evaluate of the treatment continuum of bevacizumab (Bmab), cetuximab (Cmab), panitumumab (Pmab) or no biologics across 1st, 2nd, and 3rd lines among metastatic colorectal cancer (mCRC) patients who were treated at community cancer centers in the United States. This objective was applied separately to patients with confirmed KRAS, NRAS, or BRAF wild-type (WT) or mutation (MUT) status, as well as patient who did not receive biomarker testing (UNK). Methods: This descriptive study utilized data from the Oncology Services Comprehensive Electronic Records (OSCER) database. It included 5,446 (2,064 WT, 1,807 MUT, and 1,575 UNK) patients diagnosed with mCRC between 1/1/2011 and 8/31/2015. Patients were stratified into the following mutually-exclusive categories in 1st, 2nd line, and 3rd line: Pmab only, Cmab only, Bmab only, or no biologic. Patients who survived and continued therapy were followed through the lines of therapy. Results: 23.8% of WT, 36.3% of MUT and 49.5% of UNK patients did not receive a biologic in 1st line. There were 1,003 WT patients who were treated with Bmab in 1st. Of those, n=587 (58.5%) survived and elected to continue treatment in 2nd line as follows: n=221 (37.6%) continued with Bmab, n=216 (36.8%) initiated Cmab, n=65 (11.1%) initiated Pmab, and n=85 (14.5%) received no biologic in 2nd line. Of the 221 WT patients who received Bmab in 1st and 2nd line, n=129 (58.4%) survived and initiated 3rd line treatment, of which n=20 (15.5%) received Bmab in 3rd line. There were 127/2,604 (4.9%) WT patients who were treated with Pmab in 1st line. Of those 127 patients, n=46 (36.2%) survived and elected to continue treatment in 2nd line as follows: n=11 (29.3%) continued treatment with Pmab in 2nd line, while n=14 (30.4%) initiated treatment with Bmab, n=4 (8.7%) initiated treatment with Cmab, and n=16 (36.4%) did not receive a biologic in 2nd line. Conclusions: A small proportion of patients continued treatment with the same biologic throughout subsequent lines of therapy. Many patients were not treated with a biologic in any line, even if they were confirmed WT.
Whole-exome sequencing in radically resected gastric cancer (GC): Analysis of patients (pts) with poor prognostic factors from the Italian Trial of Adjuvant Chemotherapy Adenocarcinoma (ITACA-S) trial.
Authors: Di Bartolomeo Maria , Andrea Devecchi , Canevari Silvana , Pellegrinelli Alessandro , Pietrantonio Filippo , Martinetti Antonia , Paoli Alessandro , Penso Donata , Valle Giorgio , Disciglio Vittoria , Bertoldi Loris , Feltrin Erika , Rosati Gerardo , De Vita Fernando , Dominoni Francesca , De Braud Filippo G. , Berenato Rosa , Niger Monica , Miceli Rosalba , De Cecco Loris 
Published: March 2017

64 Background: At present, the clinical management of resected GC is only based on risk stratification according to the AJCC staging. This project evaluates molecular factors on formalin-fixed, paraffin-embedded (FFEP) specimens of the primary tumor radically resected in an omogeneous group patients considered at poor prognosis according by nodal involvement (pN3a/b AJCC 7th edition) and included in the ITACA-S trial. Methods: Matched pairs of tumor-normal GC FFPE specimens collected from 15 patients were subjected to whole-exome sequencing using TruSeq Exome technology and NextSeq500 (Illumina). Somatic mutations (single-nucleotide variants) were identified, filtered and then searched for recurrently mutated genes and pathways. Patients with recurrence (cases) were compared to an equally-sized sample of patients without recurrence (controls) with the same follow up time (60 months). Results: Clinical characteristics of 15 pts: median age 61 (41-71) yrs. Nodal involvement: pN3a( 5); pN3b (10). Histotype: Intestinal (4); diffuse (8); mixed (3). Primary site: gastroesophageal junction (1); gastric (14). Patients with GC relapse (8) and without relapse (7). Whole exome sequencing revealed the presence of an average of 553 somatic mutations (range: 197 - 1318) following removal of not exonic/silent variants and of variants with an alternative allele depth < 5. Among a list of 48 genes, reported as mutated in some GC studies, we found that CDH1, GNAS and DCC were mutated in 57% of patients, whereas CTNNB1, LRP1B, LRRK2, NOTCH1, and TRRAP were mutated in 42%. Furthermore RHOA, KRAS, FGFR2, PDGFRA and PRKDC showed mutation in 28% of cases. We are currently evaluating the presence of mutual exclusive relationships mechanisms, functions and molecular pathways in “cases” versus “controls”. Conclusions: Our findings confirm a relevant role of disregulation of cell adhesion pathway involving CDH1 and DCC in GC. However, a validation analysis with an independent and bigger cohort of GC patients is ongoing, in order to find outcome-related mutational patterns that could be relevant for the selection of treatment in GC.
Role of the inflammasome of tumor cells in modulating the biology of Tumor Infiltrating T lymphocytes (TILs) in colorectal cancer.
Authors: Bossard Celine , Dansette Delphine , Ouairy Adrien , Jouand Nicolas , Oger Romain , Bou-Hanna Chantal , Laboisse Christian , Mosnier Jean-François , Gervois Nadine , Jarry Anne 
Published: March 2017

640 Background: In colorectal cancer (CRC), little is known about mechanisms by which tumor cells can influence the phenotype and biology of Tumor Infiltrating T lymphocytes (TILs) of the tumor microenvironment. One of these mechanisms could be the inflammasome, a molecular platform present in normal intestinal epithelial cells, whose effector protein, caspase-1, can rapidly mature IL18 and generate a mucosal Th1/Tc1 (IFNg) response. However, the inflammasome status of tumor cells in CRC and its potential role on TILs are unknown yet. Methods: Prospective and retrospective cohort studies aimed to determine in CRC patients: the status of the inflammasome in tumor cells (IL18 immunostaining on tissue microarrays (TMA) and in situ detection of active caspase-1 on frozen sections) and the density of TILs (CD8+, T-bet+) in relation with the microsatellite stable (MSS) or unstable (MSI) status of CRC, and the levels of cytokines (IL18, IFNg) secreted in an ex vivo explant culture model of CRC. Finally, we assessed the effect of recombinant human IL18 (rhIL18) on the IFNg response of isolated TILs. Results: TMA analysis of the retrospective cohort showed that IL18 was significantly expressed (in more than 50% of tumor cells) in 80% of CRC, especially in MSI CRC, and correlated with a high density of T-bet+ and CD8+ intraepithelial TILs (IEL-TILs). Active caspase-1 was detected in tumor cells in 60% of CRC. In the prospective cohort, the presence of active caspase-1 in tumor cells was associated with high levels of mature IL18 secreted in explant cultures, with high density of T-bet+ TILs and with IFNg release in most cases. In addition, isolated TILs expressing IL18 receptors (IL18Ra), cultured with rhIL18, were able to secrete IFNg either unstimulated or stimulated with OKT3. Conclusions: The inflammasome of tumor cells, when maintained and active, can contribute to a Th1/Tc1 antitumor immune response elicited by TILs, that can modulate tumor growth. The inflammasome of tumor cells can thus be considered as a potential new therapeutic target to strengthen the antitumor immune response in CRC, in association with other immunotherapies.