bluuebunny/crossref_metadata_2025_split huggingface dataset:
DCC and RET pathway analysis to identify factors associated with advanced colorectal cancer.
Authors: Shiovitz Stacey , Hsu Li , Qu Conghui , Harrison Tabitha A. , Berndt Sonja , Brenner Hermann , Casey Graham , Chan Andrew T. , Chang-Claude Jenny , Le Marchand Loic , Newcomb Polly A. , Potter John D. , Schoen Robert E. , Slattery Martha L. , White Emily , Peters Ulrike , Grady William M. ,   GECCO Consortium
Published: February 2017

457 Background: DCC (deleted in colon cancer; 18q21.3) is frequently lost in colorectal cancers (CRC), but few mutations in DCC have been discovered, even in tumors with 18q loss of heterozygosity. DCC has been shown to be a dependence receptor, with differential signaling depending on the presence (proliferative) or absence (pro-apoptotic) of the netrin-1 ligand (NTN1). DCC-mutated CRC tend to present at advanced stage and have a poor prognosis. RET, another dependence receptor, is a possible tumor suppressor gene in CRC and associates with CRC progression. Given the apparent role of DCC and RET in CRC progression, we carried out a genetic association study to determine if specific genetic variants in these pathways associate with advanced vs. early CRC. Methods: Imputed HapMap genome-wide association study (GWAS) from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), a collection of 19 international case-control and cohort studies, was used to identify single nucleotide polymorphisms (SNPs) in DCC, NTN1, RET and interacting genes within 5kb upstream to 500mb downstream of each of the 54 genes. With the resultant 10,102 SNPs, we performed a stage-stratified analysis, comparing advanced (AJCC stage III-IV, n = 3500) to early CRC (I-II, n = 5300). An inverse-variance weighted fixed effect meta-analysis was performed with significance set at p=0.05/10102 SNPs=5x10-6 for multiple test correction. Results: Of the examined SNPs within DCC, the lowest p-value comparing advanced vs. early CRC was 3.6x10-3. SNPs in DOCK1 (dedicator of cytokinesis 1), which complexes with DCC and netrin-1, were associated with advanced CRC at p=1.11x10-3. SNPs in NTN1 and RET reached significance only at p = 1.73x10-2 and 1.53x10-2, respectively. No SNPs reached the pre-determined level of statistical significance. Conclusions: Our current analysis does not provide clear evidence for candidate SNPs associated with advanced CRC. Further approaches include expanding the analysis to include 1,000 Genome Project and ExomeChip data (~30,000 added SNPs), comparison of cases and controls, and evaluating candidate SNP-SNP interactions to better evaluate pathway pathogenesis. We plan to present an updated analysis at the symposium.
Molecular profiling of patients (pts) with advanced colorectal cancer (CRC): Princess Margaret Cancer Centre experience.
Authors: Chiu Joanne W. , Bedard Philippe L. , Roehrl Michael H. , Serra Stefano , Kryzanowska Monika K. , Knox Jennifer J. , Mackay Helen , Hedley David W. , Moore Malcolm J. , Liu Geoffrey , Dhani Neesha C. , Kamel-Reid Suzanne , Torlakovic Emina , Wang Tao , Tsao Ming-Sound , Chadwick Dianne , Zhang Tong , Yu Celeste , Chen Eric Xueyu , Sakashita Shingo 
Published: February 2017

459 Background: The prevalence of somatic mutations other than KRAS, PIK3CA and BRAF in CRC has not been well described. This study reports molecular profiling of pts with advanced CRC in clinical practice. Methods: Pts with advanced CRC are enrolled in an ongoing institution-wide screening program. Molecular profiling is performed on FFPE archival tissues using a customized Sequenom panel (23 genes, 279 mutations) or the Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons, ≥ 500x coverage) in our CLIA-certified laboratory. PTEN negative tumor is defined by IHC with H score <1. Demographic and clinical data are collected. Data was analyzed by chi-square test. Results: From March 2012 to August 2013, 132 pts were enrolled. One or more mutations were found in 50% (58/117) and 93%(14/15) of pts using Sequenom and MiSeq platforms respectively. Mutation rate was 40% for KRAS, 9% for PIK3CA, 2% for BRAF, 4% for NRAS, and 1% for each of CTNNB1, ERBB2, FGFR3, and EGFR. Mutations outside of codons 12/13 were found in 8% (4/53) of tumors with KRAS mutations. MiSeq showed additional mutations including ERBB4 (1/15), SMAD4 (1/15), FRXW7 (1/5), APC (5/15), and TP53 (12/15) in CRC. Co-mutation with KRAS was found in 58% (7/12) of pts with PIK3CA mutation and 80% (4/5) of pts with APC mutation. PTEN negative tumor was present in 20% (11/55) of pts. Presence of any mutation was significantly more common for pts with right-sided CRC (73%) compared to those with left-sided CRC (47%) and rectal CRC (38%) (p < 0.01). There was a trend toward increased proportion of KRAS mutation in right-sided CRC (p=0.06). There was no difference in age, ethnicity, gender, smoking status, stage at presentation, pathology grade, and response to first-line chemotherapy between right and left-sided CRC. Conclusions: Somatic alterations are common in advanced CRC. Targeted next-generation DNA sequencing identifies additional clinically relevant alterations than multiplex genotyping. Differences in the mutation profile of right and left-sided CRC tumors should be further investigated. Updated results will be presented at the meeting.
LDH serum levels as a predictive factor for global outcome in pretreated colorectal cancer patients receiving regorafenib: Implications for clinical management.
Authors: Del Prete Michela , Scartozzi Mario , Prochilo Tiziana , Faloppi Luca , Giampieri Riccardo , Bianconi Maristella , Berardi Rossana , Onofri Azzurra , Bittoni Alessandro , Zaniboni Alberto , Cascinu Stefano 
Published: February 2017

497 Background: Although a demonstrated clinical efficacy, a non negligible proportion of colorectal cancer patients does not seem to benefit from regorafenib and are consequently exposed to unnecessary toxicity. LDH serum levels represent an indirect marker of tumour hypoxia, neo-angiogenesis and worse prognosis in many tumour types. In colorectal cancer LDH showed a correlation with treatment outcome for patients receiving antiangiogenetic treatment, thus suggesting a possible interaction with the activity profile of these drugs. We analyzed the role of LDH serum levels in predicting clinical outcome for pre-treated metastatic colorectal cancer patients receiving regorafenib. The final aim was to individuate a potentially reliable and easy to use marker for patients stratification. Methods: 118 colorectal cancer patients treated with regorafenib were available for our analysis. For all patients, LDH values were collected within one month before the procedure and after treatment end. LDH cutoff value was determined by ROC curve analysis, patients were then divided into two groups (A and B, below and above cut-off level respectively). Patients were also classified according to the variation in LDH serum levels pre- and post-treatment (increased patients vs. decreased patients). Results: Patients in group A and B proved homogeneous for all clinical characteristics analyzed. In group A patients median progression free survival (PFS) was 3.18 months, whereas it was 1.87 months in group B patients (p = 0.0018). Median overall survival (OS) was 6.23 months and 3.28 months in group A and B respectively (p = 0.048). Significant differences were not noted among the 2 groups for response rate. All the other clinical variables analyzed failed to show any correlation with patients outcome. Conclusions: Our observations seem to suggest a role of LDH as a marker of clinical outcome in colorectal cancer patients receiving regorafenib. We can then speculate that high LDH patients may not be optimal candidates for regorafenib. After further confirmation in larger trial, these findings may be relevant for a better patients stratification and selection.
The impact of chemotherapy use on financial strain among stage III colorectal cancer patients: A population-based survey.
Authors: Veenstra Christine Marie , Regenbogen Scott E. , Hawley Sarah T. , Banerjee Mousumi , Kato Ikuko , Ward Kevin C. , Morris Arden M. 
Published: February 2017

505 Background: Many colorectal cancer (CRC) patients suffer personal financial hardship from the disease and its treatment. We hypothesized that chemotherapy use is associated with even greater financial burden and worry. Methods: We analyzed data from a population-based survey of patients with stage III CRC in the Georgia and Detroit SEER catchment areas focusing on the effects of CRC and its treatment on personal finances. The primary outcomes were financial burden, assessed with a seven-component composite measure, and financial worry, assessed with a 5 point Likert scale. The primary independent variable was chemotherapy use. We evaluated relationships between chemotherapy use and individual components of financial burden, as well as composite financial burden and worry, using chi square analyses. Logistic regression was used to examine the effect of chemotherapy use on financial burden and worry, after controlling for patient characteristics. Results: Financial burden scores and financial worry were significantly higher among chemotherapy users (P<0.001). Financial burden and worry were associated with younger age, lack of insurance, and lower education. After controlling for these factors, chemotherapy use remained significantly associated with both financial burden and financial worry. 717/844 respondents (85%) reported chemotherapy use. Chemotherapy users were more likely to use savings (34% vs 20%, P=0.001), borrow money/take out loans (14% vs 4%, P=0.001), fail to make credit card payments (14% vs 5%, P=0.003), reduce spending for food and/or clothing (31% vs 14%, P<0.0001), decrease recreational activities (38% vs 15%, P<0.0001), and reduce general expenses (51% vs 24%, P<0.0001) than those who did not use chemotherapy. Conclusions: Adjuvant chemotherapy confers significant survival benefit in stage III colorectal cancer (CRC), but is associated with significantly increased personal financial burden and worry. Because financial stress has the potential to preclude adherence to recommended care, CRC patients who receive chemotherapy may require additional social services and economic support.
A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab-refractory esophagogastric (EG) cancer.
Authors: Janjigian Yelena Yuriy , Capanu Marinela , Imtiaz Tooba , Kelsen David Paul , Ku Geoffrey Yuyat , Schattner Mark , Brown Karen T. , Ilson David H. , Solit David B. , Berger Michael F. , Vakiani Efsevia 
Published: February 2017

52 Background: Trastuzumab (T) combined with chemotherapy has been the standard of care for pts with HER2+ EG cancer. Resistance to T is now emerging in this population. Afatinib (A), a potent ErbB Family Blocker, induced nearly complete tumor regression in MSKCC HER2+ patient derived xenografts (PDX). We report the initial results of a phase II study of afatinib in patients with T refractory EG cancer. Methods: Pts with HER2+ (IHC 3+ or FISH>2.0) EG adenocarcinoma –progressive on trastuzumab -received A 40 mg. Archival pre-T tissue, tumor biopsy after progression on T and after 1 week on A mandated on protocol. The primary endpoint-overall clinical benefit at 4 months: stable disease (SD) or partial response (PR). Results: 14 pts treated with A; median duration 5.1 mos (1.7 to 12.1 mos). Median age 62, KPS 80, median 2 (1 to 4) prior T containing regimens, 64% of tumors IHC3+; 36% IHC2+/FISH>2.2. Adverse events included: diarrhea (Grade 1/2:69%), fatigue (Grade 1/2:54%), rash (Grade 1/2:54%), mucositis (Grade 1:23%), paronychia (Grade 1/2:15%). To date, 13 pts evaluable for response, 3 of 13 pts (23%) had disease stabilization (PR or SD); 1 pt with confirmed PR - a durable 75% regression of biopsy proven metastases. Median OS 6.6 mos (1.9 to NR). PDXs established from biopsies of T refractory tumors of 5 pts. Next generation sequencing of matched pre-T and post-T progression tumors from 6 pts was performed and results will be reported. Conclusions: Afatinib shows clinical efficacy in patients with T refractory EG cancer. The study has been expanded to accrue additional patients. Efforts to elucidate the mechanisms of T resistance including validation of potential drivers of T resistance using HER2+ PDXs are ongoing. Updated molecular and clinical data will be presented. Clinical trial information: NCT01522768.
Tolerability study of adjuvant modified FOLFOX6 treatment in curatively resected stage II/III colon cancer (JFMC41-1001-C2: JOIN trial).
Authors: Shinozaki Katsunori , Kotaka Masahito , Touyama Tetsuo , Manaka Dai , Matsui Takanori , Ishigure Kiyoshi , Hasegawa Junichi , Munemoto Yoshinori , Takagane Akinori , Ishikawa Hiroshi , Ishida Hideyuki , Ogata Yutaka , Tsuji Yasushi , Oba Koji , Goto Koichi , Sakamoto Junichi , Saji Shigetoyo , Watanabe Toshiaki , Ohtsu Atsushi , Yoshino Takayuki 
Published: February 2017

530 Background: Adjuvant FOLFOX is a widely accepted standard regimen for resected colon cancer. The incidence of grade ≥ 3 peripheral sensory neuropathy (PSN) was 12.4% and 5.7% in Western MOSAIC and Eastern MASCOT (outside Japan) trials, while that of grade ≥ 3 allergic reactions (AR) was 2.9% and 3.1%, respectively. JOIN Trial investigated the tolerability of modified FOLFOX6 (mFOLFOX6) in Japanese patients (UMIN ID: 000004443). Methods: Twelve cycles of mFOLFOX6 were given to patients fitting the following criteria, which were the same as those of MOSAIC: stage II/III resected colon cancer, PS of 0-1, 20 years or older, starting FOLFOX within 7 weeks of surgery, and adequate organ function. The primary endpoint was the incidence of PSN persisting for at least 8 days that interfered with daily activities and that of grade ≥ 3 AR. Target sample size was 800, assuming the expected incidence of grade ≥ 3 PSN and grade ≥ 3 AR would be 12.0% and 3.0%, and the two-sided 95% confidence interval (CI) would not include the corresponding threshold levels (16.5% for PSN and 6.5% for AR) with a 95% probability. Results: From Nov 2010 to Mar 2012, 882 patients were enrolled at 198 institutions. The safety data was analyzed in 828 patients whose data were finalized out of 848 patients received mFOLFOX6, and patient characteristics included: median age of 64 years (21-83); Male/ Female: 444/384; PS 0/1: 776/52; colon/rectosigmoid: 633/195; and stage IIA/IIB/IIC/IIIA/IIIB/IIIC: 96/33/23/61/437/178. The incidence of persistent PSN was 3.3% (95% CI: 2.2%-4.7%), while that of grade ≥ 3 AR was 1.7% (95% CI: 1.0%-2.8%), and the primary endpoint was met. Only grade ≥ 3 neutropenia showed a ≥ 10% incidence (28.7%). The incidence of grade ≥ 3 PSN was 5.8% and interstitial pneumonitis was observed in one case. There was no treatment-related death. The median number of cycles of chemotherapy was 12, and the completion treatment rate was 67.0%. The median total dosage of oxaliplatin (L-OHP) was 811.1 mg/m2. The median relative dose intensity of L-OHP, fluorouracil (FU) bolus and FU infusion were 90.0%, 76.9% and 81.7%, respectively. Conclusions: Adjuvant mFOLFOX6 is tolerable in Japanese patients with colon cancer. Clinical trial information: UMIN000004443.
Predictors of clinically significant bleeding in colorectal cancer: Results from a global prospective cohort study.
Authors: Sohal Davendra , Kuderer Nicole Maria , Shepherd Frances A. , Pabinger Ingrid , Agnelli Giancarlo , Liebman Howard A. , Vicaut Eric , Meyer Guy , Lyman Gary H. , Khorana Alok A. 
Published: February 2017

558 Background: Bleeding is an important complication among patients with colorectal cancer but its prevalence and predictors are incompletely understood. We evaluated data from a global prospective cohort study to define the incidence, predictors and consequences of bleeding in patients undergoing adjuvant or palliative treatment for colorectal cancer. Methods: CANTARISK was a prospective, non-interventional, international cohort study in patients with lung and colorectal cancer on chemotherapy, the patients were not on long term anticoagulation. Clinical data were collected at baseline, and at 2, 4, and 6 months. All data were compiled centrally and analyzed after the study had closed. Statistically significant univariable associations and a priori variables were tested in multivariable models; adjusted odds ratios (OR) with confidence intervals (CIs) are presented. Results: A total of 1,789 patients with colorectal cancer were enrolled from 2011-12. Median age was 62 years; 61% were male; 71% were Caucasian and 18% were Asian; 37% were from Europe, 28% from North America, 23% from Asia, and 12% from South America. Ninety-two (5.14%) patients experienced at least one bleeding episode during antineoplastic treatment, ranging from 1 to 5 episodes each, with a total of 109 episodes. The gastrointestinal tract was the source in 49 (45%) episodes. Approximately one-third of episodes (n=34, 31%) necessitated transfusion, but only 1 (0.9%) was fatal. In multivariate analysis, independent predictors of bleeding included presence of metastases (OR = 2.13, 95% CI=1.25-3.65) and surgery within prior 6 months (OR = 3.66, 95% CI=1.78-7.47) but not intact primary tumor (OR = 1.57, 95% CI=0.99-2.51). Notably, age, baseline blood counts, ECOG performance score, and anticoagulant use during study were not associated with bleeding. Conclusions: Bleeding is prevalent amongst patients with colorectal cancer receiving systemic chemotherapy. Post-surgical patients and those with metastatic disease appear to be at highest risk. Resection of the primary tumor does not appear to significantly alter risk.
An interim analysis of a phase II study using an epigenetic biomarker (CHFR methylation status) to personalize chemotherapy in patients with operable esophageal cancer.
Authors: Kelly Ronan Joseph , Wrangle John , Hales Russell K. , Molena Daniela , Yang Stephen C. , Rodgers Kristen , Lang Margaret , Reynolds Jeffrey , Beckman Tammy , Choflet Amanda , Brock Malcolm , Herman James Gordon 
Published: February 2017

76 Background: Preoperative chemoradiotherapy using a platinum plus either a taxane or 5FU results in a pathological complete response rate (pCR) of approximately 25% to 30% in patients with operable esophageal cancer. A predictive biomarker to personalize chemotherapy in an effort to increase pCR would be a significant advance. Checkpoint with forkhead and ring finger domains (CHFR) is an E3 ligase which plays a role in response to mitotic stress. In our retrospective data, hypermethylation and silencing of CHFR, correlates with improved response and prolonged survival following therapy with taxanes. The primary endpoint of this study is to determine if there is a higher pCR rate when CHFR methylation status (MS) is used to decide if patients receive a taxane or 5FU. Methods: All patients presenting to Johns Hopkins with operable T2-T4/N0-N3 esophageal cancer are eligibile. A methylation-specific PCR which demonstrates CHFR MS has been developed by our lab. Methylated (M) patients receive weekly cisplatin (30mg/m2)/paclitaxel (50mg/m2) and unmethylated (U) patients receive previously described regimens of folfox or cisplatin/5FU. All patients receive concurrent radiation. Results: From July 2011 to September 2013, 35 patients have been assessed, 18 U (51%), 14 M (40%) and 3 unknown (9%). Twenty-four patients (22 males and 2 females) have been treated on study (age 48 – 74 years old, median 63.8) with 14 tumors U (58%) and 10 tumors M (42%) respectively. To date, 2/13 U patients (15%) have had a pCR and 3/8 M patients (38%) have had a pCR (p=0.32). Toxicities of each regimen are consistent with previous reports. Conclusions: Trimodality therapy is standard of care for operable esophageal cancer in the United States. Different chemotherapies have been combined with radiation prior to surgery to improve pCR rates but no biomarkers to personalize chemotherapy exist at present. Epigenetic biomarkers such as CHFR MS potentially may be used to decide which patients are more sensitive to taxane based regimens. Accrual to this study is ongoing. Clinical trial information: NCT01372202.
Effect of KRAS and NRAS mutations on treatment outcomes in patients with metastatic colorectal cancer (mCRC) treated first-line with cetuximab plus FOLFOX4: New results from the OPUS study.
Authors: Tejpar Sabine , Lenz Heinz-Josef , Köhne Claus-Henning , Heinemann Volker , Ciardiello Fortunato , Esser Regina , Beier Frank , Stroh Christopher , Duecker Klaus , Bokemeyer Carsten 
Published: February 2017

LBA444 Background: Patients with KRAS exon 2 codon 12/13 wild-type (wt) mCRC benefit significantly from the addition of cetuximab to first-line FOLFOX4 in relation to response and progression-free survival. Patients with KRAS exon 2 codon 12/13 mutations show no benefit with a trend to worse clinical outcomes. Methods: Tumors from OPUS study patients previously defined as KRAS codon 12/13 wt (n=179) were screened for specific mutations in KRAS exons 3 and 4 (8) and NRAS exons 2, 3, and 4 (18) using BEAMing technology. Treatment outcomes were assessed according to mutation status. Results: RAS tumor mutation status was evaluable for 118/179 (66%) patients. Mutations at the screened loci were detected in 36 (31%) patients. In the RAS wt population, there was benefit associated with the addition of cetuximab to FOLFOX4 (Table). In the overall RAS-mutant population, there was less favorable clinical outcome and no benefit from the addition of cetuximab to FOLFOX4. Conclusions: Patients with mCRC harboring any activating mutation of KRAS or NRAS are unlikely to benefit from the addition of cetuximab to FOLFOX4. Definitive conclusions for patients with new tumor mutations cannot be drawn due to low patient numbers. Restricting cetuximab administration to patients with tumors wt at all such loci might enable the further tailoring of therapy to maximize patient benefit. [Table: see text]