bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Practice patterns of molecular profiling in colorectal cancer.
Authors: Nweze Nkem , Nadler Ashlie , Reddy Sanjay S. , Luo Biao , Sigurdson Elin R. , El-Deiry Wafik S. , Denlinger Crystal Shereen , Hall Michael J. , Farma Jeffrey M.
Published: March 2017

641

Background: Colorectal cancer (CRC) is a genetically heterogeneous disease. Molecular profiling (MP) using next-generation sequencing is increasingly used to personalize therapy. No guidelines currently exist regarding patient selection and optimal timing. Our goal was to describe our experience at a tertiary cancer center using MP in CRC patients. Methods: This is an IRB-approved, retrospective study in patients with CRC who underwent MP between March 2007 and August 2016. Tissue samples were sent for analysis in the following MP platforms: Foundation One, Caris, and FCCC Targeted Cancer Panel (FTCP), which tests for the 50 most common mutations. Data regarding patient demographics, mutations, and clinical outcomes were analyzed. Kaplan Meier methods were used for survival analysis using SPSS. Results: We evaluated 248 patients with CRC. 60.1% were male and 80.1% were white. The median age was 59.5 years. 66.5% had colon and 33.5% had rectal CA. Initial stages: stage 1 (2.8%), stage 2 (14.1%), stage 3 (22.9%), stage 4 (59.2%). 82.2% were tested via FTCP, 8.9% via Foundation One, and 9.3% via Caris. 60.9% had the primary tumor tested. 5.2% had no mutations, 19% had 1 mutation, 28.6% had 2 mutations, 27% had 3 mutations and 20.2% had >4 mutations. The most common mutation guiding targeted therapy was KRAS (43.5%). 50% of patients had R0 resection and 19.3% went on to targeted therapy. 76.2% of resectable patients had a metastatic recurrence. 51.9% had targeted therapy for recurrence and/or stage 4 disease. The median time from diagnosis to MP was 9.9 months overall and 2.7 months for stage 4 patients. The median time from date of recurrence to MP was 7.7 months. Median length of follow up was 1.7 years. 14.9% had no evidence of disease at last follow up, 73% were alive with disease and 10.9% had died of the disease. Median overall survival was 55.8 months (CI 41.9 - 69.7). Conclusions: MP is utilized commonly in patients with stage 4 and recurrent CRC and occurs within 2.7 months and 7.7 months respectively. Further research is underway to evaluate if the information provided by MP improves outcomes in CRC, provides novel targets and will lead to increased clinical trial accrual.
Prevalence and survival benefit of adjuvant chemotherapy in stage III colon cancer patients: Comparison of overall and age-stratified results by multivariable modeling and propensity score methodology in a population-based cohort.
Authors: Hines Robert Brooks , Bimali Milan , Johnson Asal , Bayakly Rana , Collins Tracie
Published: March 2017

649

Background: Few population-based studies have assessed the effectiveness of adjuvant chemotherapy (ACT) in stage III colon cancer patients according to age. We sought to quantify the prevalence of ACT use and the absolute and relative survival benefit of ACT overall and by age in a population-based cohort. Methods: Stage III patients with adenocarcinoma of the colon identified by the Georgia Comprehensive Cancer Registry for the years 2000–07 were eligible (final N = 3057). We utilized Poisson regression to obtain adjusted mortality rates (MR) and Cox proportional hazards models to obtain adjusted hazard ratios (HRs) for 5-year overall survival. We evaluated control of confounding by comparing HRs obtained via multivariable modeling (MM), propensity score weighting (PSW), and propensity score matching (PSM). Results: Just over one-third of colon cancer patients did not receive ACT, and the proportion increased with age. Overall, receipt of ACT conferred an absolute (MR difference [No ACT rate - ACT rate] 25.4 deaths/ 1000 person-years [py], 95% confidence interval [CI]: 19.1–32.7 deaths/1000 py) and relative (MM HR = 0.67, 95% CI: 0.59–0.76) survival benefit. The survival benefit was demonstrated across age groups. mm and propensity score methods yielded highly similar HRs. Conclusions: Unless contraindicated, efforts to ensure receipt of ACT for stage III colon cancer patients up to 84 years of age are needed to improve the prognosis of patients with node-positive disease.
Interaction between regorafenib and warfarin therapy.
Authors: Beg Muhammad S. , Khosama Leticia , Conley Stefanie , Arriaga Yull Edwin , Syed Samira K. , Karri Sirisha , Verma Udit N.
Published: March 2017

651

Background: Regorafenib is an oral multi kinase inhibitor with clinical activity in colorectal cancer, gastrointestinal stromal tumors and hepatocellular cancer. Drug- drug interactions are commonly encountered in clinical practice and warfarin continues to be the most commonly prescribed anticoagulant among cancer patients in the clinic. The interaction of regorafenib with warfarin has not been studied. Methods: Patients at a single institution being prescribed regorafenib were identified and charts reviewed for concurrent warfarin therapy. Baseline characteristics, indications for regorafenib and warfarin therapy was determined. Patients were followed up to the first 8 weeks of combination therapy. Results: We identified 6 patients on concurrent regorafenib and warfarin. All patients had refractory colon cancer. Median age was 74, 4 were male and 5 white. Indication for warfarin was venous thromboembolism in 5 and atrial fibrillation in 1. Baseline INR ranged from 1.1 to 2.4. An increase in INR was seen in all six patients (peak INR range 4.5 to > 12) which improved with dose modification. Time to peak INR was less than 6 weeks (INR trends in all patients shown in figure 1). There were no bleeding complications noted in any patient. Conclusions: We report a clinically significant interaction between warfarin and regorafenib with patients demonstrating an increase in INR. Patients who are anticoagulated with warfarin and start regorafenib should be closely monitored and upfront warfarin dose reduction should be considered. Further drug-drug interaction studies are needed to determine the exact mechanism of drug-drug interaction between these medications.
Alterations in small leucine-rich proteoglycans in right-sided colorectal cancer.
Authors: Solis Hernandez Maria Del Pilar , García-Suárez Olivia Pilar , Fernández-Vega Ivan , Quirós Luis M , García Beatriz
Published: March 2017

652

Background: Colorectal cancer (CRC) is a heterogeneous disease, and there are anatomic, functional and molecular differences between the tumors of the proximal and distal colorectum. Various molecular phenotypes have been associated with aggressive subtypes in these pathologies, and several of these markers show a relationship with proteoglycans, which in turn show significant alterations in colon tumors, which affect both their core proteins and their glycosaminoglycan chains. Small leucine-rich proteoglycans (SLRPs) constitute a family of molecules encoded by 18 distinct genes. They are grouped into five classes and may appear coupled to different glycosaminoglycan chains ––including chondroitin/dermatan sulfate or keratan sulphate–– or not, depending on the specific species. They are ubiquitously expressed in extracellular matrices, and have been found involved in the regulation of organ size and shape during embryonic development. In this study we investigate the expression patterns of SLRPs in right-sided CRCs. Methods: A transcriptomic approach was used, employing qPCR to analyze SLRP core protein transcriptions. Immunohistochemical techniques were also used to analyze tissue expression of particular genes showing significant expression differences of potential interest. Results: Only two proteins displayed significant alterations: biglycan appeared overexpressed approximately 4 fold (p = 0.015), and osteoglycin decreased about 4 fold (p = 0.05). Transcripts for epiphycan, opticin, nyctalopin and podocan-like 1 were not detected in most patients, while chondroadherin was detected in 50% of healthy tissues but not in CRCs. Expression of lumican, decorin, keratocan, asporin, ECM2, fibromodulin, PRELP, tsukushi, podocan and osteoadherin was detected, but with no significant differences compared to healthy tissue. Conclusions: Normal mucosa of the large bowel expresses most SLRPs, and two, biglycan and osteoglycin, appeared altered in right-sided CRCs. These alterations could be related to binding of different ligands and modulation of homeostasis.
Modified Glasgow prognostic score as a selection marker for colorectal cancer patients with multiple metastases who can underwent primary site resection followed by multidisciplinary therapy.
Authors: Shimura Tadanobu , Toiyama Yuji , Saigusa Susumu , Imaoka Hiroki , Okigami Masato , Fujikawa Hiroyuki , Hiro Junichiro , Kobayashi Minako , Ohi Masaki , Araki Toshimitsu , Inoue Yasuhiro , Uchida Keiichi , Mohri Yasuhiko , Kusunoki Masato
Published: March 2017

655

Background: We often encounter the colorectal cancer (CRC) patients with multiple distant metastases who rapidly progress after resection of primary tumor site due to preventing bowel obstruction, tumor bleeding and perforation. However, there has been few knowledge for identification of these patients at the present time. In this study, we evaluated the association between clinicopathological findings, including with preoperative laboratory data and survival outcome, and possibility of multimodality therapy in CRC patients with multiple metastases after resection of primary tumor lesion. Methods: Clinicopathological findings and preoperative laboratory data, including carcinoembryonic antigen (CEA) and systemic inflammatory response markers, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and modified Glasgow Prognosis Score (mGPS) for 92 CRC patients with multiple metastases from 2005 to 2014 were collected. We performed multivariate analysis for overall survival (OS) in cox proportional hazard model. In addition, we performed multivariate logistic regression analysis to evaluate the factors influencing possibility of postoperative multimodality therapy. Results: Postoperative multimodality therapy improved overall survival significantly. Among serum markers, elevated CEA, NLR, and mGPS were significant indicators of poorer OS. Multivariate analysis for OS revealed that elevated CEA (P = 0.026), mGPS (P = 0.038), and undifferentiated histology type (P = 0.02) were independent poorer prognostic factors. In addition, multivariate logistic regression analysis showed that elevated mGPS (P = 0.029) and higher age (P = 0.013) were independent risk factors for difficulty of introducing postoperative multidisciplinary therapy. Conclusions: Preoperative mGPS is useful objective marker for selection of colorectal cancer patients with multiple metastases who can undergo primary resection followed by multidisciplinary therapy.
Effect of sex on treatment outcomes in rectal cancer patients after neoadjuvant radiotherapy or chemoradiation: A combined analysis of Polish-1 and Polish-2 studies.
Authors: Wyrwicz Lucjan , Spalek Mateusz , Michalski Wojciech , Krynski Jacek , Polkowski Wojciech , Rutkowski Andrzej
Published: March 2017

656

Background: Two independent studies have previously reported the equivalence of short-course radiotherapy (SCRT) and chemoradiation (CRT) in stage II/III rectal cancer patients (Bujko 2006 – Polish-1, Ngan 2012). Recently, in tumors with resection margin at risk (cT4 and fixed cT3), SCRT and chemotherapy when compared with CRT was associated with similar R0 resection rates, but improved overall survival (OS; Polish-2 study; Bujko 2016). The differences in pelvis anatomy and access to surgical field provide the rational for analysis of patients’ sex on treatment outcomes in locally advanced rectal cancers. Methods: We performed individual patients data analysis of Polish-1 (n = 312) and Polish-2 (n = 515) cohorts. The male-to-female ratio was similar in both studies (Polish-1: 65.1%; Polish-2: 65.8%). No major differences in treatment allocation, toxicities, complience to study procedures between males and females were observed. Results: In the combined cohort the prognostic effect of sex on survival was observed (74.5% female and 66.9% of male patients alive at the cut-off time; HR 0.72; p = 0.018). No differences in post-operative mortality were observed with 3-4% of patients dying in 6 months from randomization in each analyzed stratum. When analyzing the treatment outcomes by sex, male patients benefited more from SCRT than CRT. This effect was observed in more advanced tumors from Polish-2 (HR 0.65; 95% CI 0.45-0.95; p = 0.026), while it did not reached the significance in Polish-1 (HR 0.67; 95% CI 0.34-1.33). Conclusions: This individual patients data analysis indicates that female patients with locally advanced rectal has better prognosis than males. This observation is valid either for SCRT or CRT. In the future, rectal cancer studies should be stratified for sex in order to minimize the risk of bias. Although it should be confirmed by other studies, it is very likely that efficancy of SCRT is higher in male patients. Clinical trial information: NCT00833131.
Associations of physical activity with survival and progression in metastatic colorectal cancer: Results from CALGB 80405 (Alliance).
Authors: Guercio Brendan John , Venook Alan P. , Niedzwiecki Donna , Zhang Sui , Sato Kaori , Fuchs Charles S. , Lenz Heinz-Josef , Innocenti Federico , Fruth Briant , Van Blarigan Erin , O'Neil Bert H. , Shaw James Edward , Polite Blase N. , Hochster Howard S. , Atkins James Norman , Goldberg Richard M. , Mayer Robert J. , Bertagnolli Monica M. , Blanke Charles David , Meyerhardt Jeffrey A.
Published: March 2017

659

Background: Regular physical activity (PA) is associated with reduced risk of recurrence and mortality in non-metastatic colorectal cancer. Its influence on patients with metastatic colorectal cancer (mCRC) is largely unexplored. Methods: 1231 patients participating in CALGB 80405 (first-line phase III chemotherapy trial for mCRC) completed questionnaires that included self-report on PA at time of chemotherapy initiation and total metabolic equivalent task (MET)-hours/week were determined based on responses. The primary endpoint of the clinical trial and this companion study was overall survival (OS), with progression-free survival (PFS) as a secondary endpoint. To minimize confounding by poor and rapidly declining health, we excluded patients who experienced progression or died within 60 days of activity assessment and adjusted for known prognostic factors, comorbid illness, and weight loss over the previous six months. Results: Compared with patients engaged in less than three MET-hours/week of PA, patients engaged in 18 or more MET-hours/week experienced an adjusted hazard ratio for OS of 0.81 (95% CI 0.67 to 0.98, P for trend 0.03) and for PFS of 0.84 (95% CI 0.71 to 1.00, P for trend 0.03). Greater nonvigorous PA and walking duration were both associated with improved OS ( P for trend 0.01 and 0.04, respectively). Conclusions: In mCRC patients from CALGB 80405, greater total PA was associated with improved PFS and OS, while greater walking duration and non-vigorous PA were associated with reduced risk of all-cause mortality. Support: U10CA180821, U10CA180882. ClinicalTrials.gov ID: NCT00265850 [Table: see text]
The behavior of colorectal liver metastases in the time frame between the end of preoperative chemotherapy and liver resection: A new selection criterion for technically resectable patients.
Authors: Vigano Luca , Darwish Shadya Sara , Rimassa Lorenza , Cimino Matteo , Carnaghi Carlo , Donadon Matteo , Procopio Fabio , Personeni Nicola , Del Fabbro Daniele , Santoro Armando , Torzilli Guido
Published: March 2017

665

Background: Not all the patients with resectable colorectal liver metastases (CLM) benefit from liver resection (LR). To date, patients with disease progression during chemotherapy are excluded from surgery. The present study aims to elucidate if the CLM behavior in the interval between the end of chemotherapy and LR (stable disease vs. progression) impacts prognosis. Methods: All the consecutive patients undergoing LR for CLM between 2004 and 2014 after a tumor response or stabilization during chemotherapy were considered. The patients having received two separate imaging modalities after chemotherapy (one at the end of chemotherapy and one before LR) with an interval between the two > 3 weeks were included. Any variation of CLM size was registered. Tumor progression was defined according to the RECIST criteria. Results: Overall, 130 patients were analyzed. One fourth of the patients with partial response or stable disease during chemotherapy had a disease progression after the end of chemotherapy before LR, 16% if the interval chemotherapy-surgery was < 8 weeks. The risk of progression was not associated with the response to chemotherapy. Patients with progression after the end of chemotherapy had lower survival than patients with stable disease (5-year overall survival (OS) 19.0% vs. 27.6%; three-year recurrence-free survival (RFS) 6.7% vs. 21.3%, p < 0.001 for both). Survival was extremely poor in case of early progression ( < 8 weeks) (0% two-year RFS and OS). Progression was an independent prognostic factor of OS and RFS (HR = 3.243 and HR = 2.874, p < 0.0001). Eleven patients had a complete radiologic response to chemotherapy and underwent LR at disease reappearance without further chemotherapy after a median delay of 8.7 months. They had excellent survival (five-year OS 39.0%, three-year RFS 36.4%). Conclusions: Early disease progression between the end of chemotherapy and LR occurs in ~15% of patients. It is associated with extremely poor survival and should be considered a contraindication to surgery. Patients with a complete radiologic response can be resected upfront at recurrence without further chemotherapy.
Molecular and clinical characterization of a claudin (CLDN)-low subtype of gastric cancer (GC).
Authors: Nishijima Tomohiro F. , Kardos Jordan , Chai Shengjie , Smith Christof C , Bortone Dante S. , Mose Lisle E. , Selitsky Sara R. , Sanoff Hanna Kelly , Parker Joel S. , Lee Michael Sangmin , Vincent Benjamin Garrett
Published: March 2017

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Background: A CLDN-low subtype has been identified in breast and bladder cancers and is characterized by low expression of tight junction proteins CLDN, enrichment for epithelial-to-mesenchymal transition (EMT) and tumor initiating cell (TIC) features. Given the genomically stable (GS) subtype of GC defined by TCGA has features suggestive of CLDN-low tumors, we evaluated whether the CLDN-low subtype also exists in GC. Methods: 415 tumors from TCGA GC mRNA dataset were clustered on the CLDN, EMT and TIC gene sets with significance testing using SigClust2 to identify CLDN-low GC. A minimal set of genes that could accurately classify CLDN-low GC was defined by prediction analysis of microarrays (PAM). Tumors identified by SigClust2 or the PAM were called CLDN-low GC regardless of the original subtype call. The 300 GCs in the Asian Cancer Research Group (ACRG) dataset [GSE62254] were used to validate the predictor. We characterized clinical and molecular (gene expression, mutation and copy number alteration) features of CLDN-low GC. Results: We identified 46 tumors that had consensus enrichment for CLDN-low features in TCGA. CLDN-low tumors were most commonly diffuse (35/42=83%, 4 tumors=mixed) and GS (36/46=78%). CLDN-low GC showed high expression of immune gene signatures including T and NK cell signatures, but not an immunosuppression signature. Compared to GS subtype, CLDN-low GC had increased frequency of CD44, GATA4, and GATA6 amplification. In ACRG, 28/300 GCs were CLDN-low using the PAM predictor. The CLDN-low GC in ACRG was phenotypically similar to the CLDN-low GC in TCGA based on the CLDN, EMT and TIC gene signatures. Clinically, CLDN-low GC was associated with the shortest overall survival of the 5 subtypes (CLDN-low plus TCGA defined 4 subtypes). Notably, a hazard ratio comparing CLDN-low GC vs GS was 2.10 (95%CI; 1.07-4.11) in TCGA and 2.32 (95%CI; 1.18-4.55) in ACRG cohort, adjusting for age and pathological stage. Conclusions: We identified a CLDN-low GC which has a poor prognosis likely related to the resistance to conventional chemotherapy due to its EMT and TIC-like properties. Further development of targeted therapies against these molecular features is warranted to improve the outcome of CLDN-low GC.
Longitudinal trajectory of cancer survivorship in patients with recurrent rectal cancer: Anatomy of recurrence in relation to quality of life and pain.
Authors: Sammour Tarik , Malakorn Songphol , Chang George J. , Rodriguez-Bigas Miguel A. , Bednarski Brian , Eng Cathy , Das Prajnan , Skibber John Michael , You Y. Nancy
Published: March 2017

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Background: Multiple treatment modalities are utilized for patients with recurrent rectal cancer (RRC). While recurrent pelvic tumor can be highly symptomatic, treatments often carry significant morbidity risks. Patient reported outcomes such as quality of life (QoL) and pain can supplement traditional clinical endpoints in assessing the effectiveness of salvage treatments, and thus aid in treatment decision making. We aimed to examine the longitudinal trajectory of cancer survivorship in RRC. Methods: A prospective protocol enrolled patients diagnosed with RRC between 2008 and 2015. Participants prospectively self-reported QoL (measured by the validated EORTC QLQ-C30 and EORTC QLQ-CR29) and pain (measured by the Brief Pain Inventory, BPI), at presentation, and then every 6 months for 5 years. After accounting for repeated measures, trajectory of mean scores over time was assessed for patients amenable to surgical salvage vs those who were not, using linear mixed-effects modeling. Results: A total of 104 patients were enrolled of which 73 (70.2%) were amenable to salvage surgery with curative intent. Surgical salvage was associated with 30 day morbidity of 68.5% (13.7% and 5.5%, Grade 3 and 4 respectively). Three year overall survival was 56.7% (68.5% in surgical and 29.0% in non-surgical patients). Mean baseline QoL scores did not differ between surgical vs nonsurgical patients but were significantly impacted by the anatomical site of recurrent disease (lowest scores in posterior pelvic recurrence; P=0.012). On longitudinal analysis with a median followup of 33 months, surgically salvaged patients showed gradual sustained improvement in QoL but not pain scores. Anatomy of initial recurrence had an ongoing impact on QoL long term with posterior recurrences having the worst scores. Both QoL and pain scores worsened in patients not amendable to surgical salvage. Conclusions: Disease anatomy determines QoL at baseline and long term in patients with RRC. Surgery improves QoL but not pain in selected resectable cases.
Association of DOCK6 with cancer stem cell development and as an independent prognostic factor of gastric cancer.
Authors: Wang Chia-Siu , Tsai Chung-Ying , Lee Kam-Fai , Kuo Liang-Mou , Lin Kwang-Huei
Published: March 2017

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Background: The prognosis of advanced gastric cancer (GC) remains poor, and the key players in molecular pathogenesis are predominantly unknown at present. Methods: In order to identify novel prognostic factor of GC, we compared the data of iTRAQ proteomics from 6 GC samples with that of Oncomine database from 86 GC samples to intersect 122 high-expression proteins in gastric cancer tissue. The candidate biomarkers were further characterized in fresh GC tumor tissues compared with adjacent non-tumor tissue by using Q-RT-PCR, immunohistochemical staining and western blot. GC cells with depletion of DOCK6 were examined to identify downstream molecules and establish their effects on cell motility, invasion and gastric cancer stem cell (CSC) markers. The possible signaling pathway of DOCK6 were also investigated. Results: DOCK6 is identified as one of the potential GC biomarkers in iTRAQ proteomics. Our data confirm the overexpression of DOCK6 in GC tumor tissue compared with adjacent non-tumor tissue. In addition, the clinical data shows higher DOCK6 expression was positive correlated to depth of invasion, lymph node metastasis, vascular invasion and pathological stage. Furthermore, higher DOCK6 expression represented significantly shorter cumulative survival both in univariate and multivariate analysis for survival outcome. Depletion of DOCK6 repressed the cell migration, proliferation, sphere formation, anchorage-independent growth and tumorigenicity as well as gastric cancer stem cell (CSC) markers. In order to explore the downstream effector of DOCK6, we correlated thousands of gene with DOCK6 in three GC dataset published in the literature. The DOCK6 positive-correlated genes were subsequently analyzed by Metacore. They were significantly involved in WNT/β-catenin signaling pathway. Our result demonstrates nuclear b-catenin, as well as CD44, was decreased accompanied by depleting DOCK6. Moreover, the interaction between DOCK6 and β-catenin was observed in GC cells. Conclusions: Our studies unveil the role of DOCK6 in the self-renewal of CSC and propose DOCK6 as an independent marker of tumor progression.
Factors predictive of receiving neoadjuvant versus adjuvant chemoradiotherapy in locally advanced rectal cancer and the impact on overall survival.
Authors: Coffman Alex Richard , Boothe Dustin , Frandsen Jonathan Evans , Gross Molly , Pickron Thomas Bartley , Scaife Courtney L. , Lloyd Shane
Published: March 2017

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Background: Neoadjuvant chemoradiotherapy (NCRT) is generally accepted as the optimal treatment strategy compared to adjuvant chemoradiotherapy (ACRT) for locally advanced rectal cancer due to improvement in local control and reduced toxicity. However, NCRT has not been shown to improve overall survival (OS). We investigated the effect of NCRT versus ACRT on OS as well as the impact of demographic factors and clinical stage for the selection of each treatment approach utilizing the National Cancer Data Base. Methods: Adult patients with stage II and stage III adenocarcinoma of the rectum diagnosed from 2004-2013 were included. Chi-square analysis was used to compare demographic variables and clinical stage between the NCRT and ACRT treatment groups. Univariate and multivariate logistic regression modeling was used to identify factors predictive of each treatment strategy. Kaplan Meier and log-rank analysis along with propensity score matching was performed to determine the effect on OS. Results: A total of 20,262 patients were identified: 17,737 (87.5%) received NCRT and 2,525 (12.5%) received ACRT. Utilization of NCRT increased over the study period (p < 0.01). Factors associated with receipt of NCRT on multivariate analysis include: treatment at an academic institution (OR 0.76, 95% CI 0.68-0.85), income greater than $46,000 (OR 0.79, 95% CI 0.67-0.92), and living greater than 50 miles from a treatment facility. Factors associated with receipt of ACRT on multivariate analysis include: female sex (OR 1.12, 95% CI 1.01-1.24), Charlson comorbidity index of 1 (OR 1.18, 95% CI 1.04-1.34), and radiotherapy dose greater than 5040 centigray (OR 1.76, 95% CI 1.56-1.98). Compared to ACRT, NCRT was associated with a decreased risk of death on multivariate analysis (HR 0.91, 95% CI 0.84-1.00), which persisted after propensity score analysis. Conclusions: The use of NCRT for locally advanced rectal cancer is increasing and is associated with an OS benefit compared to ACRT.
Application of the ASCO framework for assessing value in metastatic colorectal cancer clinical trials.
Authors: Ezeife Doreen Anuli , Parimi Sunil , Cusano Ellen R. , Smith Matthew K , Truong Tony H. , Raissouni Soundouss , Lin Yongtao , Monzon Jose Gerard , Li Haocheng , Tam Vincent C. , Tang Patricia A.
Published: March 2017

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Background: Phase III trials (P3T) in metastatic colorectal cancer (mCRC) have collectively led to incredible advancements in patient outcomes over the past thirty years. It is unknown how many of these trials have led to clinically relevant improvements based on clinical benefit, toxicity and cost. Our objective was to characterize the evolution of mCRC P3T with the ASCO Value Framework. Methods: P3T of systemic therapy for mCRC published between 1980 and 2015 were identified. Data regarding the trial sample size, journal year of publication, statistical significance, journal impact factor, and citation by the 2015 mCRC National Comprehensive Cancer Network (NCCN) guidelines were extracted. For each trial, the Net Health Benefit (NHB) score was calculated using the June 2015 (original) and May 2016 (revised) ASCO Value Advanced Disease Frameworks. Data were analyzed to identify associations using the Chi-square, Kruskal-Wallis, and t-tests. Results: There were 108 mCRC P3T eligible for calculation of the original and revised NHB score. Median NHB score was 4.1, range -30 to 43.5, using the revised framework. Only 13% of trials received at least 10 bonus points for palliation, quality of life, or tail of the curve. The revised framework demonstrated moderate correlation with the original framework (Pearson correlation coefficient = 0.63, p<0.0001). NHB scores were normally distributed with the revised framework, unlike the original framework. Trials with significant results had significantly higher revised NHB scores (median NHB score 23.1 vs 2.5, p < 0.0001). Clinical trials cited in NCCN had higher revised NHB scores than those not cited (median NHB score 7.6 vs 0, p = 0.03). In multivariate linear regression analysis, the only significant predictor of a high revised NHB score was a statistically significant improvement in the primary outcome. Conclusions: Median revised NHB score for mCRC P3T was 4.1. Higher NHB scores were associated with significant studies and citation by NCCN guidelines, a surrogate for practice-changing trials. The revised ASCO Value Framework can be a useful tool to assess the value of new mCRC treatments.