bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patterns of KRAS, NRAS and BRAF testing among patients with metastatic colorectal cancer in the EU5.
Authors: Lowe Kimberly , Niu Xin , Kafatos George , Kelsh Michael Anthony 
Published: March 2017

637 Background: In mid-2013, the requirement for mCRC patients treated with panitumumab changed from wild-type KRAS to wild-type RAS ( KRAS and NRAS). The objective of this study was to describe patterns of KRAS, NRAS, and BRAF testing among mCRC patients in the EU5 (United Kingdom (U.K.), Germany, France, Italy and Spain). Methods: This descriptive study utilized Oncology Analyzer data (IMS Health Oncology, Fairfield, CT, USA), which provides real-world quarterly cross-sectional, epidemiologic and clinical data for mCRC patients. Trends in biomarker testing during the study period were evaluated by calculating the frequencies and proportions of patients who were /were not tested for combinations of KRAS, NRAS, and BRAF within each of the five countries. KRAS and BRAF data were available in all countries from quarter three (Q3) 2012 to quarter two (Q2) 2015. NRAS was available in all countries from quarter 1 (Q1) 2014 to Q2 2015. Frequencies and proportions were also calculated to summarize patient demographic and clinical characteristics between groups with different testing choices. Results: A total of 32,961 patients with mCRC were included in the analyses. Prior to 2013, the majority of patients in each country were tested for only KRAS. The proportion of patients tested for both KRAS and NRAS increased substantially during the period of data availability for NRAS (Q1 2014 to Q2 2015), including <1% to 19.1% in the U.K., 8.8% to 31.9% in France, 13.1% to 43.2% in Germany, 5.9% to 24.6% in Italy, and 8.7% to 31.4% in Spain. The proportion of patients who were tested for all three biomarkers also increased during the period of data availability for all three biomarkers (Q1 2014 to Q2 2015), including 2.3% to 16.4% in the U.K., 4.8% to 26.6% in France, <1% to 2.4% in Germany, 4.2% to 22.3% in Italy, and 1.5% to 9.3% in Spain. There were few differences in patient demographic or clinical characteristics between those with different testing groups. Conclusions: This analysis provides a description of biomarker testing using read-world data and suggests an overall increase in testing among mCRC patients in the EU5. Although there was a trend towards increased testing, many mCRC patients are still not tested for these important biomarkers.
Parallel sequencing of a 50 genes panel in metastatic colorectal cancer (MCRC) patients (pts) treated with intensive first-line FIr-B/FOx triplet chemotherapy plus bevacizumab (BEV): Preliminary data and clinical outcome.
Authors: Bruera Gemma , Malapelle Umberto , Pepe Francesco , Pisapia Pasquale , Dal Mas Antonella , Calvisi Giuseppe , Troncone Giancarlo , Ricevuto Enrico 
Published: March 2017

644 Background: RAS/BRAF genotype guide MCRC treatment. First line triplet chemotherapy/BEV significantly improved PFS and OS. OS was significantly worse in KRAS c.35G > A and BRAF mutant (mt). Most CRC (86%) harbored mt genes, prevalently TP53, RAS, BRAF, PIK3CA. Methods: MCRC samples of 67 pts treated with FIr-B/FOx (77% overall) were analyzed through a 50 genes panel (PGM/Colon Lung Cancer) by ION Torrent: 57 (85%) primary, 10 (15%) metastatic samples; 59 (88%) pre-, 8 (12%) post-treatment. Molecular diagnostic criteria: > 50% coverage; > 1% mutant allelic fraction. Clinical outcomes were evaluated and compared by log-rank. Results: All wild-type (wt) and mt MCRC were 6 (8.9%) and 61 (91.1%), respectively; median mt genes 3 (1-12). Mt genes, 35 (%): KRAS 44 (65.6%), TP53 38 (56.7%), APC 26 (38.8%), KIT 23 (34.3%), PDGFRA 19 (28.3%), PIK3CA 18 (26.8%), EGFR and NRAS 15 (22.3%), SMAD4 10 (14.9%), FBXW7 and MET 7 (10.4%), GNAS and PTEN 6 (8.9%), BRAF and NOTCH1 5 (7.4%), ATM, PTPN11 and SMARCB1 4 (5.9%), HRAS, KDR, JAK3 and VHL 3 (4.4%), ERBB2, FGFR2, FGFR3, IDH1 and STK11 2 (2.9%), ABL1, AKT1, CDKN2A, FGFR1, FLT3, HNF1A, RB1, RET 1 (1.4%). BRAF mutations: c.1756G > A, 1796C > T, 1405G > A, 1406G > C. Median follow-up 21 months (m), overall PFS 13, OS 27m: KRAS exon 2 ( KRAS2) wt/mt, PFS 14/12m, OS 28/21m, respectively, not significantly different; c.35G > A KRAS mt showed trendly worse OS 14m; BRAF mt significantly worse PFS (8 vs 14m, p .026) and OS (11 vs 28m, p .002); RAS2-4/ BRAF15 wt/mt, PFS 18/13m (p .954), OS 28/22m (p .956). TP53 wt/mt, PFS 14/12m, OS 28/23m. All wt, PFS 24, OS 44m, not significantly different vs ≥ 1 mt gene. Conclusions: Multigenic analysis of MCRC patients treated with FIr-B/FOx shows worse clinical outcome conferred by uncommon BRAF mutations.
Prognostic impact of preoperative albumin to globulin ratio in curative colon cancer patients.
Authors: Toiyama Yuji , Fujikawa Hiroyuki , Inoue Yasuhiro , Imaoka Hiroki , Okigami Masato , Yasuda Hiromi , Hiro Junichiro , Yoshiyama Shigeyuki , Saigusa Susumu , Kobayashi Minako , Ohi Masaki , Araki Toshimitsu , Mohri Yasuhiko , Kusunoki Masato 
Published: March 2017

647 Background: Albumin to globulin ratio (AGR) has been reported to predict long term mortality in patients with several cancers. However, prognostic impact of preoperative AGR in colon cancer patients with curative intent has not yet been fully addressed. Therefore, we, for the first time, investigated the association between AGR and clinico-pathological findings including overall survival (OS) and disease free survival (DFS) in stage I-III colon cancer patients. Methods: Clinicopathological findings including preoperative laboratory data (carcinoembryonic antigen [CEA] and AGR) from 251 curative colon cancer patients were assessed as indicators of early recurrence and poor prognosis in this retrospective study. AGR was calculated as [AGR = albumin/ (total protein - albumin)]. The cut-off value of AGR was 1.32 in current study. Results: Several clinicopathological categories related with tumor progression such as lymph node metastasis, T4 tumor, large tumor size, undifferentiated tumor, venous and lymphatic invasion, and high CEA were significantly associated with low AGR level. The patients with low AGR were significantly poorer OS (P = 0.001) and DFS (P = 0.003) than those with high AGR, respectively. In addition, multivariate analyses demonstrated that low AGR was independently associated with early recurrence (HR = 2.87, P = 0.007) and poor prognosis (HR = 2.56, P = 0.008), respectively. On the other hand, sub analysis of survival curves revealed that stage III colon cancer patients with low AGR were significantly poorer OS (P = 0.007) and DFS (P = 0.02) than those with high AGR, respectively. Furthermore, significantly poorer OS and DFS were also shown in stage I-II colon cancer patients with low AGR, respectively (OS: P = 0.02, DFS: P = 0.01). Conclusions: Preoperative AGR was an independent predictor of early recurrence and poor prognosis in curative colon cancer patients. AGR may represent a simple, potentially useful predictive biomarker for selecting stage I-II colon cancer patients who might need adjuvant chemotherapy. Furthermore, AGR may select candidates who are better to introduce more intensive adjuvant chemotherapy after curative operation in stage III colon cancer patients.
Prospective, multi-center study of 5-fluorouracil (5-FU) therapeutic drug management (TDM) in metastatic colorectal cancer (mCRC) patients treated in routine clinical practice.
Authors: Salamone Salvatore J. , Jaehde Ulrich , Mueller Lothar , Link Karin , Holdenrieder Stefan , Bertsch Thomas , Ko Yon-Dschun , Kunzmann Volker , Suttmann Ingo , Braess Jan , Roessler Max , Moritz Berta , Kraff Stefanie , Miller Michael Craig , Wilhelm Martin 
Published: March 2017

650 Background: Studies have demonstrated that body surface area (BSA)-based dosing of chemotherapy drugs leads to significant individual exposure variability with a substantial risk of under- or overdosing. This study was initiated to validate use of TDM to personalize 5-FU dosing in mCRC patients treated in routine clinical practice. Methods: 75 mCRC patients from 8 German medical centers received up to 6 administrations of infusional 5-FU according to either the AIO (n = 16), FOLFOX6 (n = 26) or FUFOX (n = 33) regimen. Initial infusional 5-FU dosing for all patients was based on BSA. Individual 5-FU exposure (AUC) was measured by an immunoassay using a blood sample drawn during each infusion. To achieve target AUC of 20 to 30 mg•h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle 5-FU AUC. Tumor markers CEA and CA19-9 were also measured before, during and after treatment. Primary objective was to confirm TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the 4th versus the 1st administration. Secondary objective was to determine whether 5-FU TDM reduced treatment-related toxicities compared to historical data. Results: Average 5-FU AUC at 1st administration was 18 + 6 mg•h/L, with 64%, 33% and 3% of the patients below, within or above target AUC range, respectively. By the 4th administration average 5-FU AUC was 25 + 7 mg•h/L (p < 0.001), with 54% patients within the target 5-FU AUC range (p = 0.0294). Compared to baseline levels, CEA and CA19-9 remained stable or decreased at the end of treatment in 82% and 84% of the patients, respectively. 5-FU-related grade 3-4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%) and mucositis (0.2%) were reduced compared to historical data inspite of 55% of patients having their doses increased. Conclusions: Personalization of 5-FU dosing via TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested lower 5-FU-related toxicities. Clinical trial information: 2011-003553-26.
KRAS testing practice in Denmark between 2009 and 2013.
Authors: Ording Anne Gulbech , Frøslev Trine , Spindler Karen-Lise Garm , McCusker Margaret Elizabeth , Cheng I-Ning (Elaine) , Sørensen Henrik Toft , Ehrenstein Vera 
Published: March 2017

654 Background: Guidelines for managing patients with metastatic colorectal cancer (mCRC) were updated in Denmark in 2013, and anti-epidermal growth factor receptor (EGFR) inhibitors were promoted from third-line to first-line treatment for KRAS wildtype mCRC patients. As a result, more patients became eligible for EGFR antibody therapy. Weexamined KRAS testing practice among patients with mCRC who received systemic cancer treatment in Denmark during 2009-2013. Methods: We linked data from several population registries with nationwide coverage - the Danish Cancer Registry, the Danish National Patient Registry, and the Danish National Pathology Registry - to identify patients diagnosed with mCRC (primary or recurrent) between 2009 and 2013, their systemic cancer treatment, and their KRAS testing status. We obtained all KRAS test results through 2014 and calculated proportions of KRAS-tested patients by year of mCRC diagnosis. Results: There were 7,245 mCRC patients, among whom 4,272 (59%) had a record of systemic cancer treatment within 6 months of mCRC diagnosis and were included in the analysis. The proportion of men was 57%; median age at mCRC diagnosis was 67 years (range 20-94 years). Overall, 2,099/4,272 (49%) of the treated mCRC patients had a recorded KRAS test result, with similar proportions for patients with primary and recurrent mCRC. Among patients diagnosed with mCRC in 2009, the proportion with a recorded KRAS test result was 374/900 (42%). Corresponding proportions for patients diagnosed in 2010, 2011, 2012, and 2013 were 411/891 (46%), 457/870 (52%), 430/807 (53%), and 427/804 (53%). Conclusions: Among patients in Denmark diagnosed with mCRC who received systemic cancer treatment, the proportion of patients with a KRAS test result recorded in the Danish National Pathology Registry increased from 2009 to 2013. This may have resulted from increased testing or increased recording, or both.
CHARTA: FOLFOX+bevacizumab +/- irinotecan in advanced colorectal cancer (CRC)—Final results of the randomized phase II trial of the AIO (KRK 0209).
Authors: Schmoll Hans-Joachim , Garlipp Benjamin , Junghanss Christian , Leithaeuser Malte , Vogel Arndt , Schaefers Michael , Kaiser Ulrich , Hoeffkes Heinz-Gert , Florschütz Axel , Rüssel Jörn , Kanzler Stephan , Edelmann Thomas , Forstbauer Helmut , Goehler Thomas , Hannig Carla , Hildebrandt Bert , Steighardt Jörg , Meinert Fabian Maximilian , Cygon Franziska , Stein Alexander 
Published: March 2017

658 Background: The 4-drug-regimen FOLFOXIRI+Bevacizumab (Bev) was superior to FOLFIRI+Bev (TRIBE F.Loupakis, NEJM 2014). CHARTA investigates the same 4-drug-regimen vs. FOLFOX+Bev. Methods: 250 patients were randomized from 7/11 to 12/14 to standard FOLFOX+Bev (A) vs. FOLFOXIRI+Bev (B), with dose/schedule as in TRIBE, 25% dose reduction in cycle 1 + 2, if necessary. Incl.criteria: ECOG 0-2, ≥ 1 measurable lesion > 1cm; stratified by ESMO-Group 1, 2, 3 (HJ Schmoll et. al., Ann Oncol 2012). Induction: 6 months, maintenance Capecitabine+Bev until progression or max. of 12 months, with reinduction by individual decision. Primary EP: significant improvement of PFS-rate at 9 months (p<0.1, 2-sided Fisher’s-exact test); secondary EP: RR- rate, PFS, OS, sec. resection. Results: Evaluable 241 pts. (1 not elig., 8 prot. violation); m/f: 65%/35%, age 61 yrs. (21-82), left/right: left A: 51, 5%, B: 48, 5%; right A: 45%, B: 55%; ECOG 0-1/2: 96% / 4%, ESMO-group 1/2/3: 29%/ 55%/ 16%. Primary endpoint was met: significantly improved PFS at 9 months 56% vs. 68% (p= 0,086). Preliminary PFS 9,76 vs. 12,0 months (HR 0.77, p=0.61), identical to TRIBE: 9.7 vs. 12.1. Response (A/B): CR: 5/5%, CR/PR 60/70%, SD 25/21%, PD 14/9%; sec. resection: 21/23%. Subgroup - analyses did not show significant differences, except CR / PR left/right (A/B): left 59/68%, right 63/73%; PFS (months) left 10.4/12 (HR 0.69, p=0.03), right: 8.2 /10.7); non-significant improvement in ESMO-group 3 (HR 0.51), RAS-wt (HR 0.67), Koehne-Score High risk HR 0.58; ECOG 1: HR 0.69. QL-Global- Health-Score: slightly worse in A, vs. improved in B. Dose-intensity <70%/ 70-90%/ >90% (A/B): 39/37%/ 18/26%/ 41%/36%; initial dose-reduction 17% of pts. Toxicity: low to moderate without major differences between A &B, except grade ¾ diarrhea 12/16%, neutrophils 14/20%, GI 12/20%. Conclusions: The 4-drug-regimen has superior activity with the same outcome as TRIBE and is well tolerated, without a negative effect of initial dose-reduction, and an improvement of global QoL-Score. Final PFS, OS data and detailed subgroup/multivariate analysis, including Quality of life data, will be presented. Clinical trial information: NCT01321957.
Metabolomic profling in gastric cancer tissues using time-of-flight mass spectrometry.
Authors: Kaji Sanae , Kusuhara Masatoshi , Makuuchi Rie , Yamakawa Yushi , Tokunaga Masanori , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Kami Kenjiro , Ohashi Yoshiaki , Terashima Masanori 
Published: March 2017

66 Background: To explore carcinogenic and prognostic biomarkers for gastric cancer, genomics, transcriptomics and proteomics approaches have been extensively applied;however, little has been investigated regarding the role of metabolomics profiles on progression and prognosis of gastric cancer. Therefore, in order to elucidate the role of metabolome on prognosis of gastric cancer, we investigated the metabolic profiles of gastric cancer tissue using time-of-flight mass spectrometry (TOFMS) Methods: A total of 162 patients with gastric cancer underwent gastrectomy from February 2010 to March 2013 were enrolled in this study. Cancer tissues (CA) and adjacent non-cancerous tissues (NC) were obtained from surgically resected sample and were snap-frozen in liquid nitrogen. The samples were then homogenized and then applied to capillary electrophoresis TOFMS (CE-TOFMS) The metabolomics dates were analyzed using principal component analysis (PCA) and hierachical clustering analysis(HCA) in order to compare the metabolic profiles of NC and CA. Metabolites date were further assessed according by the non-parametric Mann–Whitney U-test on the presence or absence of recurrence . Results: A total 96 metabolites were detected and quantified. PCA of the date well-distinguished CA from NC. In CA, lactate / pyruvate ratio was significantly higher, while adenylate energy charge was significantly lower than NC, which reaffirms the Warburug effect of cancer. Total glutathione and reducted glutathione/oxidized glutathione ratio in CA were significantly higher than in NC which possibly contributes to the homeostasis of redox status in CA. Intriguingly, in patients with recurrence, tumor concentrations of β-Ala, Asp, GDP and Gly were significantly lower than in those without recurrence. Conclusions: Metabolomic profiling clearly differentiated CA from NC. Considerably high lactate and amino acids levels expectedly highlighted the metabolome of tumors. Certain metabolite will be a candidate for biomarker in gastric cancer.
Nintedanib (N) plus best supportive care (BSC) versus placebo (P) plus BSC for the treatment of patients (pts) with colorectal cancer (CRC) refractory to standard therapies: Subanalysis of the phase III LUME-colon 1 study in pts by prior regorafenib (R) treatment.
Authors: Lenz Heinz-Josef , Yoshino Takayuki , Argiles Guillem , Iveson Timothy , Sastre Javier , Harrison Mark , Lim Howard John , Tebbutt Niall C. , Peeters Marc , Satoh Taroh , Dittrich Christian , Sassi Mouna , Loembe Arsene-Bienvenu , Van Cutsem Eric 
Published: March 2017

660 Background: N is a triple angiokinase inhibitor (including VEGFR, PDGFR and FGFR). LUME-Colon 1 (NCT02149108) evaluated the efficacy and safety of N in pts with metastatic CRC (mCRC) after failure of standard therapies and showed a statistically significant improvement in progression-free survival (PFS) (HR [95% CI]: 0.58 [0.49–0.69]; p < 0.0001) but no difference in overall survival (OS) (HR: 1.01 [0.86–1.19]; p = 0.8659). Here, we report results of a prespecified subanalysis in pts by prior R treatment. Methods: Eligible pts (aged ≥ 18 years; ECOG PS 0–1; mCRC adenocarcinoma refractory to standard treatments, including oxaliplatin, irinotecan, fluoropyrimidines, anti-VEGF and anti-EGFR in RAS wt) were randomised 1:1 to N (200 mg bid) + BSC or P (bid) + BSC. Prior R treatment was a stratification factor. Co-primary endpoints were PFS by central review and OS. Results: 768 mCRC pts were randomised; 285 (37%) had received prior R (N, n = 141; P, n = 144) and 483 (63%) were R naïve (N, n = 245; P, n = 238). Baseline characteristics were similar between the groups (pretreated vs naïve) except: race (Asian: 39% vs 19%), time from first diagnosis ( ≥ 36 months [m]: 67% vs 48%), time from onset of metastatic disease ( ≥ 24 m: 85% vs 64%). Median PFS (N vs P) was 1.5 vs 1.4 m (HR: 0.61 [0.47–0.79]) in prior R pts and 1.5 vs 1.4 m (HR: 0.62 [0.51–0.76]) in R-naïve pts (interaction p-value = 0.9245). Median OS (N vs P) was 6.5 vs 4.6 m (HR: 0.90 [0.69–1.17]) in prior R pts and 6.3 vs 6.6 m (HR: 1.09 [0.89–1.33]) in R-naïve pts (interaction p-value = 0.2529). N was tolerable in both subgroups; AEs leading to discontinuation (N vs P) occurred in 12% vs 8% of prior R pts and 16% vs 12% of R-naïve pts. The most frequent AEs with N were diarrhoea, nausea and vomiting in both subgroups. Conclusions: N demonstrated clinical activity in CRC regardless of prior R treatment; significant improvement in PFS compared to P was observed in both R-pretreated and R-naïve pts, supporting the concept of continuous antiangiogenic therapy. A slight improvement in OS was observed in R-pretreated compared to R-naïve pts. Clinical trial information: NCT02149108.
Efficacy/safety analysis of a phase 2 study of ruxolitinib (Rux) + regorafenib (Re) in patients (pts) with relapsed/refractory (r/r) metastatic colorectal cancer (mCRC).
Authors: Fogelman David R. , Bendell Johanna C. , Cubillo Antonio , Garcia Alfonso Pilar , Limón Mirón María Luisa , Nemunaitis John J. , Flora Daniel Blake , Borg Christophe , Mineur Laurent , Vieitez Jose M , Cohn Allen Lee , Saylors Gene Brian , Assad Albert , Switzky Julie C. , O'Neill Peter , Zhou Li , Kochenderfer Mark D. 
Published: March 2017

663 Background: The JAK-STAT pathway plays a role in the systemic inflammatory response in CRC. Rux, a potent JAK1/2 inhibitor, was evaluated in r/r mCRC pts. Methods: After a safety run-in (Rux 20 mg BID + Re 160 mg QD), pts were randomized to Rux 15 mg BID or placebo (Pb) + Re 160 mg QD. Rux could be titrated to 20 mg BID. The randomized phase included Substudy 1 (S1, pts with C-reactive protein [CRP] > 10 mg/L) and Substudy 2 (S2, pts with CRP ≤ 10 mg/L). Primary endpoint: OS. Results: Rux 20 mg BID was well tolerated in the safety run-in (n = 11). 396 pts were randomized (S1: n = 175; S2: n = 221). Median age in Rux vs (v) Pb groups: 62 v 60 yr (S1), 59 v 61 yr (S2). Most pts had ≥ 3 prior chemotherapy regimens: 85% v 84% (S1); 81% v 78% (S2). Median treatment durations: 57 d with Rux v 56 d with Pb (S1), 106 d with Rux v 56 d with Pb (S2). Discontinuations were mainly due to disease progression (S1: 61% v 63%, S2: 62% v 66%) or AEs (S1: 10% v 19%, S2: 9% v 9%). Rux + Re did not improve OS/PFS over Re + Pb in S1/S2 (see Table). S1 was terminated for futility at interim analysis; S2 was terminated per sponsor decision. The number of events required for final efficacy analysis was reached in S1, not in S2. Most common non-hematologic AEs (Rux v Pb): palmar-plantar erythrodysesthesia syndrome (PPES; S1: 42% v 44%; S2: 58% v 47%), diarrhea (S1: 38% v 31%; S2: 39% v 27%), decreased appetite (S1: 37% v 36%; S2: 26% v 33%), fatigue (S1: 34% v 36%; S2: 41% v 44%), hypertension (S1: 21% v 26%; S2: 42% v 40%). Most common grade (G) 3/4 non-hematologic AEs: PPES (S1: 13% v 15%; S2: 17% v 13%) and hypertension (S1: 9% v 7%; S2: 22% v 16%). Most common G 3/4 hematologic AEs (new/worsening lab abnormalities): lymphopenia (S1: 13% v 8%; S2: 14% v 7%) and anemia (S1: 4% v 5%; S2: 9% v 4%). Conclusions: Rux + Re did not improve OS/PFS in mCRC pts over Re alone. There was a nonsignificant trend towards improved OS/PFS in S2. Rux 15-20 mg BID safety profile was consistent with previous studies in other tumors. Clinical trial information: NCT02119676. [Table: see text]