bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification and validation of gene expression subtypes in a large set of colorectal cancer samples.
Authors: Budinska Eva , Popovici Vlad Calin , Sikora Katarzyna Otylia , Lapique Nicolas , Tejpar Sabine , Hodgson John Graeme , Weinrich Scott , Roth Arnaud , Bosman Fred , Delorenzi Mauro 
Published: March 2020

3511 Background: From a clinical perspective colorectal cancer (CRC) is a heterogeneous disease whose biological background is insufficiently understood. In order to adapt targeted treatment to biologically different categories of CRC patients, in depth understanding of the molecular mechanisms involved in CRC heterogeneity is urgently needed. Methods: Consensus cluster analysis of 1113 stage II-III CRC gene expression profiles from PETACC3 and 4 public datasets defined a set of subtypes which were confirmed in an independent set of 720 samples. The similarity between tumors was based on a set of 54 meta-genes. This approach improves the robustness to measurement noise and gives equal chances to each biological process to be accounted for in the subtype definition. We tested the association of the subtypes with clinical variables, molecular markers and patient survival. Results: We identified and validated 5 major subtypes A-E, with different levels of expression in 6 main molecular processes: epithelial-mesenchymal transition (EMT), immune response, colon crypt differentiation, proliferation, Wnt signaling and chromosome 20q. Significant differences in survival and an enrichment for markers such as MSI, BRAF mutation, site or p53 status were found between the subtypes. In addition, the new subtype classification uncovered heterogeneity within groups defined by these commonly used markers. Survival analysis showed significant prognostic value for meta-genes connected to EMT, proliferation and differentiation. Identical data processing and clustering applied to the validation set on the same meta-genes resulted in subtypes with almost identical expression patterns. Conclusions: We identified and validated robust molecular subtypes in the largest set of stage II-III CRC samples as a combination of multiple molecular processes, that complement current disease stratification based on clinico-pathological variables and molecular markers. The biological relevance of these subtypes was reflected in significant differences in survival. These insights open new perspectives for improving prognostic models and rationalize the prediction of tumor-specific drug sensitivity.
The prognostic importance of miRNA-21 in stage II colon cancer: A population-based study.
Authors: Kjaer-Frifeldt Sanne , Hansen Torben , Nielsen Boye Schnack , Joergensen Stine , Lindebjerg Jan , Sorensen Flemming Brandt , Christensen Rene dePont , Jakobsen Anders Kristian Moeller 
Published: March 2020

3513 Background: Adjuvant chemotherapy for stage II colon cancer patients is still controversial and the debate on which patients should be considered as high risk patients is still ongoing. The decision is based on clinical and pathological markers of risk, which are inadequately informative in most of the patients, and better methods are highly needed. The aim of the present study was to investigate the possible prognostic importance of miRNA-21, quantified by in situ hybridization (ISH), in a unique, large population-based cohort of patients treated for stage II colon cancer patients. Methods: The study included all patients diagnosed with stage II colon cancer in Denmark in the year 2003 (711 patients), representing a full population of five million people. Patients receiving adjuvant chemotherapy were excluded (N=15). One paraffin-embedded tissue block was obtained from each patient. A 6μm-thick section was processed for formazan-based chromogenic miR-21 ISH analysis and counter stained with nuclear red. The blue miR-21 ISH signal was assessed by image analysis to obtain two quantitative expression estimates: the total blue area (TB) and the ratio of TB with the nuclear density (TBR). Results: The miRNA-21 signal was predominantly observed in fibroblast-like cells located in the stromal compartment of the tumors. Patients expressing high levels of miRNA-21 (high mean TBR) had significantly inferior cancer specific survival (CSS): HR = 1.26 (95% CI; 1.15-1.60), p <0.001. In the COX regression analysis (including; gender, T-category, malignancy grade, localization, tumor perforation, tumor fixation, number of lymph nodes and MSI status), mean TBR was found to be an independent predictive marker of poor CSS, HR = 1.41 (95%CI; 1.19-1.67, p< 0.001). The same applied to TB. Conclusions: The present study shows that increasing miRNA-21 expression level is significantly correlated to decreasing CSS. Analyses of miRNA-21 should be considered as a potential adjunct in the selection of high risk stage II patients.
MicroRNA signature to predict sensitivity to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC).
Authors: Cappuzzo Federico , Sacconi Andrea , Landi Lorenza , Biagioni Francesca , Ludovini Vienna , Fontanini Gabriella , Sensi Elisa , Lupi Cristiana , Salvini Jessica , Blandino Giovanni , Crinò Lucio 
Published: March 2020

3521 Background: MicroRNAs (MiRNAs) are post-transcriptional regulators that bind to complementary sequences on target messenger RNA transcripts, usually resulting in gene silencing. Microarray technology is a powerful high-throughput tool capable of monitoring the expression of thousands of small noncoding RNAs at once. In the present study we aimed to investigate whether MiRNA signature was predictive for sensitivity to anti-EGFR monoclonal antibodies in mCRC. Methods: A total of 183 mCRC from two independent cohorts (cohort 1: 74 cases; validation cohort: 109 cases) treated with cetuximab/panitumumab either alone (n=19) or in combination with chemotherapy (n=164) were included onto the study. MiRNA arrays were analysed using Agilent’s miRNA platform. Results: MiRNA array analyses identified the cluster miR-99a/Let7c/miR-125b located on 21p11.1 as associated with different outcome to anti-EGFR therapies. In the first cohort, individuals with high signature (n=25, 33.8%) had a significantly longer progression free survival (PFS, 6.1 versus 2.3 months, p=0.01, HR=0.42) and overall survival (OS, 29.8 versus 7.0 months, p=0.04, HR=0.39) than patients with low signature (n=25, 33.8%). Similar results were observed in the validation cohort. Patients with high signature (n=60, 32.8%) had a significantly longer PFS and longer OS than individuals with low signature (PFS 8.2 versus 4.2 months, p=0.04, HR=0.52; OS 12.8 versus 6.8 months, p=0.09, HR=0.65). To further assess the potential confounding effect of KRAS and BRAF mutations, we analyzed the outcome of patients with high and low signature in the 75 cases with KRAS or BRAF mutation and in 90 cases KRAS and BRAF wild-type. In the wild-type population, high signature patients (n=29, 32.2%) had a significantly longer PFS (8.8 versus 4 months, p=0.002, HR:0.46) and longer OS (17.7 versus 10 months, p=0.015, HR=0.62) than low signature individuals, with no difference in the KRAS or BRAF mutated patients. Conclusions: MiR-99a/Let7c/miR-125b signature is useful for improving selection of KRAS/BRAF wild-type mCRC patients candidate for anti-EGFR strategies.
Effect of oxaliplatin-based adjuvant therapy on post-relapse survival (PRS) in patients with stage III colon cancer: A pooled analysis of individual patient data from four randomized controlled trials.
Authors: Twelves Christopher , Schmoll Hans-Joachim , O'Connell Michael , Cartwright Thomas H. , McKenna Edward , Sun Weijing , Saif Wasif M. , Lee Luen F. , Yothers Greg , Haller Daniel G. 
Published: March 2020

3523 Background: Oxaliplatin-based adjuvant therapy is the standard of care for stage III colon cancer; however, its impact on PRS in these patients is unclear. We therefore compared PRS in trials of patients with stage III colon cancer treated with oxaliplatin plus capecitabine (XELOX) or 5-flourouracil (5-FU; FOLFOX) vs. leucovorin/5-FU (LV/5-FU). Methods: Individual patientdata (N = 4,819) from NSABP C-08, XELOXA, X-ACT, and AVANT were pooled and analyzed by XELOX/FOLFOX vs. LV/5-FU; patients treated with bevacizumab were excluded. Hazard ratios (HR) were estimated by Cox regression analyses and multivariate Cox regression analyses controlled for age, gender, T, and N stage. Post-relapse treatment data were collected when available. Results: Patient demographics and disease characteristics (except lymph nodes examined) were well balanced across analytic groups. Median follow-up was shorter in NSABP C-08 and AVANT (36 and 50 months) than in XELOXA and X-ACT (83 and 74 months). PRS was very similar for XELOX/FOLFOX and LV/5-FU (HR 0.94, 95% CI, 0.82–1.07; P = .33). Multivariate analyses supported these findings, but showed that PRS was associated with younger age and lower N stage at diagnosis after controlling for gender and T stage. PRS was also comparable for capecitabine or XELOX vs. LV/5-FU or FOLFOX (N = 5,819, HR 1.07, 95% CI, 0.95–1.20; P = .26). Post-relapse therapies were comparable across the two cohorts. Conclusions: Adjuvant chemotherapy regimen did not impact on PRS in patients with stage III colon cancer; however, both N stage and age demonstrated independent effects on PRS. Studies have demonstrated significantly improved disease-free and overall survival for oxaliplatin-based therapy, and our data show that survival is not compromised by worsened PRS at subsequent relapse. [Table: see text]
Smoking status and prognosis in patients with stage III colon cancer: A correlative analysis of NCCTG phase III trial N0147.
Authors: Phipps Amanda I. , Shi Qian , Limburg Paul J. , Nelson Garth D. , Sargent Daniel J. , Newcomb Polly A. , Alberts Steven R. 
Published: March 2020

3526 Background: Prior observational studies have suggested that smoking is associated with poorer overall survival after colon cancer (CC) diagnosis. Using data from N0147, a phase III randomized adjuvant trial of patients with stage III CC, we assessed the relationship between smoking status and cancer outcomes (disease-free survival (DFS) and time to recurrence (TTR)), accounting for possible heterogeneity by patient and tumor characteristics. Methods: Patients completed a risk factor questionnaire at baseline prior to randomization to FOLFOX or FOLFOX+cetuximab (N=1968). Information was collected on smoking and other lifestyle factors, including alcohol consumption, body mass index (BMI), and physical activity. Multivariate Cox models assessed the association between smoking history and the primary trial outcome of DFS, as well TTR, adjusting for other lifestyle and clinical factors. The median follow-up was 3.5 years. Results: Overall, 52% of patients were former or current smokers. Compared to never smokers, ever smokers experienced significantly shorter DFS [3-year DFS: 70% vs 74%, hazard ratio (HR)=1.21, 95% confidence interval (CI): 1.02-1.42]. This association persisted after adjusting for age, sex, tumor subsite, number of nodes involved, T-stage, mismatch repair deficiency, BRAF mutation status, performance score, physical activity, BMI, and alcohol consumption (HR=1.23, 95% CI: 1.02-1.49). There was significant interaction in this association by BRAF mutation status (p=0.02): smoking was associated with shorter DFS in BRAF wildtype CC patients (HR=1.25, 95% CI: 1.04-1.51) but not in BRAF mutant CC patients (HR=0.72, 95% CI: 0.47-1.10). Patterns of association with smoking, overall and by BRAF status, were identical in analyses of TTR. Conclusions: Overall, smoking was significantly associated with shorter DFS and TTR in CC patients. These adverse relationships were most evident in patients with BRAF wildtype CC.
BRAF V600 mutant colorectal cancer (CRC) expansion cohort from the phase I/II clinical trial of BRAF inhibitor dabrafenib (GSK2118436) plus MEK inhibitor trametinib (GSK1120212).
Authors: Corcoran Ryan Bruce , Falchook Gerald Steven , Infante Jeffrey R. , Hamid Omid , Messersmith Wells A. , Kwak Eunice Lee , Ryan David P. , Kurzrock Razelle , Brenner Adrienne A , Luan Jennifer , Sun Peng , Allred Alicia J , Little Shonda M , Patel Kiran , Kopetz Scott , Venook Alan Paul 
Published: March 2020

3528 Background: BRAF V600 mutations occur in 10-15% of CRC and may predict lack of response to standard chemotherapy and anti-EGFR treatment. There have been no significant recent changes in the treatment of CRC. Novel therapeutic strategies for BRAF mutant CRC are critically needed. To collect preliminary efficacy data, an expansion cohort of 25 BRAF mutant CRC patients (pts) was included in part 2 of a phase I/II study evaluating the combination of dabrafenib (BRAFi) and trametinib (MEKi). Methods: Eligible pts had BRAF V600 mutant CRC, measurable disease per RECIST 1.1, and previous treatment with anti-cancer therapies. Pts were treated with established dose of dabrafenib (150mg BID) and trametinib (2mg QD). Results: Data for 23 pts are available at data cut-off: median age 54 years, 74% female, ECOG performance status 0 (48%) or 1 (52%). 39% had received prior EGFR inhibitor treatment. 74% had received ≥ 2 prior chemotherapy regimens; 48% had ≥ 1 biologic therapy. 48% had ≥ 3 metastatic sites. Three of the 23 pts were non-evaluable at data cut-off as they had not reached the first restaging assessment. Among the 20 evaluable pts, 1 (5%) achieved partial response and 10 (50%) stable disease. Minor responses (>10% to <30% tumor shrinkage) were observed in 4/10 patients (40%) with stable disease. The most frequent adverse events observed in all Part 2 patients who received the same dosing combination (n=75) included pyrexia (65%), fatigue (47%), nausea (44%), chills (41%), vomiting (31%), constipation (28%), diarrhea (24%) and rash (21%). Conclusions: Dabrafenib at 150 mg BID combines safely with trametinib 2 mg QD in this BRAF mutant CRC cohort. Based on the preliminary anti-tumor activity seen, further investigation is warranted in BRAF mutant CRC pts. Updated safety and efficacy data and an analysis of the relationship between efficacy and potential predictive biomarkers, including microsatellite status, PTEN loss, PIK3CA mutation, and total and phosphorylated EFGR levels, will be presented.
Randomized phase II open-label study of mFOLFOX6 in combination with linifanib or bevacizumab for metastatic colorectal cancer.
Authors: O'Neil Bert H. , Cainap Calin , Van Cutsem Eric , Gorbunova Vera A. , Karapetis Christos Stelios , Berlin Jordan , Goldberg Richard M. , Qin Qin , Qian Jiang , Ricker Justin L. , McKee Mark D. , Carlson Dawn M. , Kim Tae Won 
Published: March 2020

3532 Background: Linifanib is a potent and selective inhibitor of VEGF/PDGF receptors. This trial assessed the efficacy and safety of mFOLFOX6 in combination with linifanib or bevacizumab as second-line treatment for metastatic colorectal cancer (mCRC). Methods: Patients (pts) with measurable mCRC refractory to 1 prior regimen and ECOG PS 0–1, stratified by prior bevacizumab treatment and radiotherapy, were randomized to receive mFOLFOX6 with bevacizumab 10 mg/kg on day (d) 1 of 14-d cycle (Arm A), mFOLFOX6 with daily linifanib 7.5 mg (Arm B), or mFOLFOX6 with daily linifanib 12.5 mg (Arm C). The primary endpoint was progression-free survival (PFS). Severity of adverse events (AEs) was graded using NCI-CTCAE v3.0. Results: 148 pts were randomized at 45 sites in 14 countries. 32 pts (21.6%) had received prior bevacizumab. PFS and response data are shown below (Table). Median survival (OS) was not reached at median follow up 7.6 months. Palmar-plantar erythrodysesthesia (PPE) was the only Grade 3/4 AE significantly higher on linifanib (high dose, 16.3%) vs. bevacizumab (0%). Rate of any Grade 3+ AE was significantly higher on linifanib vs. bevacizumab.Hypertension rates were 41.7% (Arm A), 40.0% (Arm B), and 36.7% (Arm C). AEs dose-related to linifanib were constipation, proctalgia, stomatitis, fatigue, weight decrease, decreased appetite, and PPE. Conclusions: The addition of linifanib to mFOLFOX6, compared to mFOLFOX6 + bevacizumab, did not provide a PFS advantage for mCRC. OS results will be updated for conference presentation. [Table: see text]
Phase Ib study of dulanermin combined with FOLFIRI (with or without bevacizumab [BV]) in previously treated patients (Pts) with metastatic colorectal cancer (mCRC).
Authors: Kasubhai Saifuddin M. , Bendell Johanna C. , Kozloff Mark , Kapp Amy V. , Ashkenazi Avi , Royer-Joo Stephanie , Portera Chia C. 
Published: March 2020

3543 Background: Dulanermin is a recombinant soluble human Apo2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) that activates apoptotic pathways by binding to the pro-apoptotic death receptors DR4 and 5. This is the final update of the study assessing the safety of dulanermin combined with FOLFIRI (± BV) in previously treated mCRC pts. Methods: This was a multicenter, open-label, dose-escalation and cohort expansion study. Dulanermin was administered intravenously in 14-day cycles on Days 1, 2 and 3 at 9 mg/kg or 18 mg/kg, with FOLFIRI (+ BV in pts not previously treated with BV) on Day 1. Dose-limiting toxicity (DLT) was assessed through 2 cycles (28 days). Adverse events (AE) were recorded through all cycles. Response was assessed with RECIST (v1.0). Results: A total of 27 pts received 1-48 cycles (median 10) of dulanermin with FOLFIRI (1 pt received BV). No DLTs were reported and no relationship between dulanermin dose level and AE incidence or severity was detected. The most frequent AEs reported as dulanermin-related were fatigue (37%), anemia (19%), diarrhea, nausea, stomatitis, and weight decreased (15% each). The most frequent Grade ≥3 AEs reported as dulanermin-related were fatigue (15%), anemia, febrile neutropenia and vomiting (7% each). Serious AEs reported as dulanermin-related included: vomiting, dehydration, and febrile neutropenia (1 pt each). Some of these events were reported as related to dulanermin and other study drugs. One pt died on study due to disease progression. Other reasons for discontinuation of study treatment included disease progression (21 pts, 78%), and physician’s decision and pt’s decision (2 pts each, 7%). One pt is still receiving treatment. Among the 27 pts, best responses included 6 (22%) partial responses (5 confirmed, 1 unconfirmed), 17 (63%) stable disease, 3 (11%) progressive disease and 1 (4%) pt with no on-study tumor assessment. Conclusions: The addition of dulanermin to FOLFIRI (± BV) was well tolerated in previously treated mCRC pts. AEs were similar to those previously reported for the chemotherapy alone. Tumor responses were consistent with treatment response to FOLFIRI in this patient population.
A UGT1A1 *28 and *6 genotype-directed phase I study of irinotecan plus infusional leucovorin and 5-fluorouracil (sLV5FU2) in patients with previously untreated metastatic colorectal cancer (mCRC).
Authors: Hong Yong Sang , Kim Kyu-Pyo , Lee Jae-Lyun , Bae Kyun Seop , Kim Ho-Sook , Shin Jae-Gook , Lee Jung Shin , Kim Tae Won 
Published: March 2020

3592 Background: We designed a phase I study to determine maximum tolerated dose (MTD) of irinotecan when combined with sLV5FU2 in mCRC patients (pts). Methods: Pts were genotyped for UGT1A1 *28 and *6, and stratified into 3 groups according to the number of defective allele (DA), designated 0 (*1/*1), 1 (*1/*28, *1/*6), and 2 (*28/*28, *6/*6, *6/*28). Within each group, the dose of irinotecan was escalated (table) in combination with fixed dose of sLV5FU2. Plasma drug levels and dose-limiting toxicity (DLT) were evaluated at cycle 1. Results: A total of 43 pts were accrued: 19 for 0 DA, 20 for 1 DA and 4 for 2 DA group. The MTD was estimated as 300 mg/m2/2-week for the 1 DA group with 2 DLTs in the level 3, and the MTD was not reached for the 0 DA group with 1 DLT in the level 4 (table). The mean relative extents of glucuronidation, AUClast ratio of SN-38G to SN-38, were 9.36, 6.81, and 5.09 for the 0, 1, and 2 DA groups, respectively (P=0.017). Of the 43 pts, five pts showed AUClast, SN38 that exceeded 400 ng·h/mL (1.02 umol·h/L) and DLT was observed in 40% (2/5). The overall response rate was 67.4% (95% CI, 51.5-80.9) with 6 complete responses and 23 partial responses. Median progression-free and overall survival was 8.0 months (95% CI, 7.1-8.9) and 25.6 months (95% CI, 23.4-27.7), respectively. Grade 3 or 4 toxicity during all treatment cycles included neutropenia (79% [0 DA]; 90% [1 DA]; 75% [2 DA]), leucopenia (21%; 30%; 0%), febrile neutropenia (0%; 10%; 0%) and diarrhea (0; 5%; 0) per patient. Conclusions: Dose-normalized exposure of SN38 was significantly higher in the 2 DA UGT1A1 group. Higher doses of irinotecan based on UGT1A1 genotyping are feasible when combined with sLV5FU2 in mCRC pts. The recommended dose of irinotecan was 330, 270, 150 mg/m2/2-week for pts with 0, 1, 2 DA based on pharmacokinetic analysis. [Table: see text]
Reappraisal of the risks and benefits of major liver resection in patients with initially unresectable colorectal liver metastases.
Authors: Cauchy Francois , Aussilhou Beatrice , Dokmak Safi , Fuks David , Farges Olivier , Faivre Sandrine J. , Belghiti Jacques 
Published: March 2020

3609 Background: Improvements in both surgical technique and efficacy of chemotherapy have increased the rate of resection for patients with initially unresectable colorectal liver metastases (IU-CRLM). We aimed to evaluate the short and long-term outcomes of major hepatectomy for such patients. Methods: From 2000 to 2011, 257 patients underwent major hepatectomy for CRLM. Seventy-eight (30%) of these patients were considered IU and required portal vein occlusion and/or ≥12 cycles or change in induction chemotherapy regimen to achieve resectability. Results: IU patients had respectively more lesions (5.6 vs.3.6, p=0.001), more frequently bilobar (70% vs.50% p=0.008) and synchronous (83.3% vs.70%, p=0.027) than initially resectable (IR) patients. Post-operative mortality (12.8% vs.1.7%, p=0.001) and major complications (46.2% vs.22.3%, p=0.0001) were higher in IU patients. An associated metabolic syndrome (HR 5.2, CI 1.2-21.9, p=0.025), high grade sinusoidal lesions (HR 2.4, CI 1.1-5.8, p=0.044) and the need for vascular reconstruction (HR 6.3, CI 1.2-34.4, p=0.032) were significant risk factors for major morbidity in IU patients. Significantly fewer IU patients received adjuvant chemotherapy in case of major postoperative complications compared to IR patients (47% vs. 83%, p=0.001). Overall 5-year survival was significantly lower in IU than in IR patients (26% vs.55%, p=0.032) and all IU patients had tumor recurrence within 3 years. The absence of adjuvant chemotherapy and tumor size ≥5 cm were the only factors associated with poor survival in multivariate analysis for IU patients. Conclusions: IU-CRLM patients requiring major liver resection displayed higher morbidity and mortality rates than IR ones, therefore compromising both short and long-term outcomes. Multimodal strategy should be reassessed in the presence of metabolic syndrome, sinusoidal lesions or major vascular involvement.