bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of epigenetic silencing of GCNT2 expression by comprehensive real-time PCR screening in colorectal cancer.
Authors: Nakamura Kazunorii , Sawaki Horomichi , Yamashita Keishi , Watanabe Masahiko , Narimatsu Hisashi 
Published: February 2017

506 Background: Glycoprotein expression profile has been proved to be dramatically altered in human cancers, however specific glycogenes which are aberrant in expression in cancer cells has not been fully identified. Recent accumulated evidence supported notion that the reduced expression of tumor suppressor genes is explained by DNA promoter methylation in human cancer. Methods: We used Comprehensive Real time PCR system (CRPS) for glycogenes (189 genes) to identify genes aberrantly expressed in colorectal cancer tissues (CRC) as compared to the corresponding normal mucosa tissues. GCNT2 was of particular interest among the identified genes in CRC. Results: (1) GCNT2 harbors 3 isoforms which have different promoter regions. (2) All of the 3 isoforms of GCNT2 genes were remarkably decreased in CRC as compared to the corresponding normal mucosa, and each isoform expression was strongly associated with other 2 isoforms in primary cancer tissues by TaqMan real time PCR (R = 0.99-995, p < 0.0001). (3) Among the 5 CRC cell lines (DLD1, HCT116, CACO2, LOVO), those which were silenced in expression were reactivated by demethylating agents such as 5-aza-2’ deoxycytidine and trichostatin A. (4) Promoter region of the variant 2 of GCNT2 was consistent with its silenced expression in CRC cell lines by cloned sequence, so we examined DNA methylation status of the promoter of the GCNT2 variant 2 in 50 primary cancer tissues and the corresponding normal tissues. Quantitative MSP revealed that almost half of normal tissues have methylation as high as tumor tissues, while, in the primary CRC with less methylation in the corresponding normal tissues, DNA methylation was higher in primary CRC tissues than in the corresponding normal tissues. Finally, GCNT2 variant 2 stable transfection induced expression of other 2 isoform variants. Conclusions: We identified novel methylation gene GCNT2 among the glycoenes. Glycoenes that were altered in genomic or epigenetic manner have been few, so GCNT2 may play a critical role in cancer progression through glycan change.
SoMore trial: Early metabolic response assessment of a sorafenib (SOR) and capecitabine (CAP) combination in chemorefractory metastatic colorectal cancer (mCRC).
Authors: Deleporte Amélie , Hendlisz Alain , Garcia Camilo , Delaunoit Thierry , Maréchal Raphael , Peeters Marc , Holbrechts Stephane , Van Den Eynde Marc , Houbiers Ghislain , Filleul Bertrand , Van Laethem Jean-Luc , Rolfo Christian Diego , Diaz Marie , Lhommel Renaud , Demolin Gauthier , Moreau Michel , Ameye Lieveke , Paesmans Marianne , Piccart-Gebhart Martine J. , Flamen Patrick 
Published: February 2017

524 Background: The SOR-CAP combination has shown clinical activity in several phase I-II trials involving metastatic breast cancer and mCRC patients (pts). SoMore aims to substantiate the combination’s effects in mCRC refractory to all medications and the predictive value of early metabolic response (MR) on survival. Methods: SoMore (EUDRACT 2010-023695-91) has 2 coprimary objectives: 1) to demonstrate an overall survival (OS) rate at 6 months (mths) > 30%, and 2) to compare OS between pts with and without MR. CAP was given at 1700 mg/m²/day (D), 2 weeks out of 3. SOR was administered at 600mg/D for the first cycle, then at 800mg/D until progression or unacceptable toxicity. FDGPET-CT was performed at baseline and before the 2nd cycle. MR analysis was centralized and blinded for the investigators. Results: From February to October 2011, 92 eligible pts were prospectively recruited in 6 Belgian centers: M/F: 54%/46%; ECOG PS 0/1: 55%/45%; median age: 61. A median of 5 treatment cycles were given (0-28+). Grade 3-4 toxic reactions were reported in 61.2%, mainly fatigue (18%), hand-foot skin reaction (14%) and diarrhea (11%), but no toxic death. 6.9% of the pts stopped therapy due to toxicity. 6 mths OS was 71% (95% CI: 61%-79%), significantly >30% (p<0.001). 47% of the 79 pts evaluable for metabolic assessment showed homogeneous MR (HMR) of all metastatic lesions, 32% mixed MR and 21% homogeneous non-MR. Median overall OS and PFS of the intent-to-treat population and of pts with and without HMR are shown in the table below. Hazard ratio for HMR was 0.34 (95% CI, 0.21 to 0.56) p-value <0.001 for PFS and 0.59 (95% CI, 0.37 to 0.96) p-value 0.03 for OS. Conclusions: These data suggest robust efficacy for the SOR-CAP combination in heavily pretreated mCRC, associated with high but manageable toxicity. Early MR assessment, by detecting unresponsive lesions within the whole body tumoral load, is able to capture the pts’ likelihood of benefit, opening the path to personalized medicine. Clinical trial information: NCT01290926. [Table: see text]
A randomized, open-label phase II study of efatutazone in combination with FOLFIRI as second-line therapy for metastatic colorectal cancer (mCRC).
Authors: Marshall John , Shuster Dale Edward , Goldberg Terri Robin , Copigneaux Catherine , Chen Shuquan , Zahir Hamim , Dutta Dipen , Saleh Mansoor N. , Pishvaian Michael J. , Varela Mirta Susana , Palazzo Felipe , Lazaretti Nicolas , Costa Cassia , Loredo Eugenia , Leon Jorge , Von Roemeling Reinhard W. 
Published: February 2017

535^ Background: Efatutazone, a highly-selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist, has shown efficacy and manageable toxicity in phase I trials in solid tumors, including CRC. This study evaluated efatutazone in combination with chemotherapy for second-line mCRC. Methods: Patients (pts) from the United States and Latin America with mCRC progressing after first-line therapy not containing irinotecan were stratified by Eastern Cooperative Oncology Group (ECOG) status (0/1 vs. 2) and randomized 1:1 to efatutazone + FOLFIRI (E+F) or FOLFIRI alone (F). Treatment was administered in 4-week cycles until disease progression (PD), unacceptable toxicity, or consent withdrawal. Efatutazone (0.5 mg) was administered orally, twice daily; FOLFIRI (irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 1200 mg/m2/d x 2 days) was administered intravenously once every 2 weeks immediately after efatutazone. The primary end point, progression-free survival (PFS) rate at week 16, was assessed locally according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.0. Results: Characteristics of the 100 randomized pts were generally well balanced between the E+F and F treatment arms: median age, 59.7 vs. 58.3 years; male, 56% vs 56%; and ECOG 0/1, 98% vs. 92%. Across the arms, more pts discontinued due to PD than toxicity: 49% vs. 19%, respectively. While PFS rate at week 16 was 60% vs. 67% for the E+F vs F arms (p = 0.30), overall, PFS was somewhat longer with E+F than with F (hazard ratio [HR], 0.87; 90% [confidence interval [CI], 0.57–1.32) with medians of 4.4 vs. 4.2 months, respectively. The objective response rate also favored E+F over F (20% vs. 14%). Overall survival was not significantly different (HR, 0.95; 90% CI, 0.65–1.38). Fluid retention, which was managed with diuretics, was more frequent with E+F than with F: 86% vs. 12% (grade 3/4: 12% vs. 0%). Hematologic adverse events, including neutropenia (66% vs. 20%; grade 3/4: 44% vs. 12%) and febrile neutropenia (14% vs 0%), were more common with E+F than with F. Conclusions: Efatutazone minimally improved efficacy of FOLFIRI for CRC and increased neutropenia and fluid retention. Clinical trial information: NCT00967616.
Right (R) or left (L) primary site of colorectal cancer and outcomes for metastatic colorectal cancer (mCRC): Results from the south Australian registry of mCRC.
Authors: Price Timothy Jay , Beeke Carol , Padbury Robert , Maddern Guy , Roder David , Moore James , Townsend Amanda Rose , Roy Amitesh , Hocking Christopher , Karapetis Christos Stelios 
Published: February 2017

596 Background: Previous reports have described differences in biology and outcome based on whether the primary is R or L sided. Possible differences in response to biological agents have also been reported based on side of primary lesion (SY Brule et al., JCO31, 2013 (supp #3528). Methods: We explored the SA mCRC registry to assess if there were any differences in patient characteristics, treatment received and outcomes based on whether the primary was R (caecum to transverse colon) or L (splenic flexure to rectum) sided (JA Bufill, Ann Int Med. 113, 1990, 779-788). KM was used for survival outcomes and Cox proportional hazards regression modeling was used to assess defined prognostic markers. Results: 2,877 patients were analysed. 33% had R sided primary. Major differences between R and L respectively are as follows; Female 51.3% vs. 37.9% (p = <0.0001), Med age 75.8 yrs vs. 70.5yrs (p = <0.0001), poorly differentiated pathology 34.3% vs. 20.8% (p = <0.0001), KRAS mutation 48% vs. 37% (p = 0.023), and liver surgery 10.5% vs. 16.3% (p = <0.0001). Analysis of chemotherapy (defined as either cytotoxic and/or molecular-targeted) revealed similar rates of first-line therapy, but differences in rates of therapy beyond first-line R vs. L respectively; second-line 46% vs. 60.4%, third-line 17% vs. 30%, fourth-line 7% vs. 13%. There was however no difference in single agent vs. combination first-line therapy. The median overall survival (mOS) for the entire group R vs. L was 9.6 vs. 20.3 months (p <0.0001). For the group who had active therapy defined as chemotherapy (+/- metastasis resection), mOS was R 18.2 months vs. L 29.4 months (p <0.0001). For those (n = 123) who underwent liver resection (+/- chemotherapy) mOS was 6.2 years for both R and L (p = 0.32). Patients who were treated with only chemotherapy, the mOS was 10.7 mths vs. 15.3 mths for R v L (p = 0.0005). Conclusions: Patients with R sided primary have more negative prognostic factors and indeed have inferior outcomes when compared with those with a L sided primary. This did not appear to be the case for patients who were suitable for hepatic surgery.
Toward personalized treatment for gastroesophageal adenocarcinoma (GEC): Strategies to address tumor heterogeneity—PANGEA.
Authors: Catenacci Daniel Virgil Thomas , Polite Blase N. , Henderson Les , Xu Peng , Rambo Brittany , Liao Wei-Li , Hembrough Todd A. , Zhao Lei , Xiao Shu-Yuan , Hart John , Karrison Theodore , Dignam James J. , Kindler Hedy Lee 
Published: February 2017

66 Background: GEC is the second highest cause of cancer mortality worldwide. The promise of ‘personalized’ cancer care with therapies toward specific molecular aberrations has potential to improve outcomes. However, there is recognized molecular heterogeneity within GEC (inter-patient heterogeneity), and within an individual (intra-patient heterogeneity) through space (primary tumor to metastatsis) and time (resistance to treatment) - a hurdle to advancing GEC treatment. Current trial design paradigms are challenged by heterogeneity, as they are unable to test targeted therapeutics against low frequency genomic aberrations with adequate power. Accrual difficulties to GEC trials are exacerbated by low frequencies of molecular ‘oncogenic drivers.’ Oncogenic drivers of GEC including MET and others have even less frequent genomic activation than HER2. To address this challenge, there is need for novel clinical trial designs/strategies implementing novel technologies to account for inter-patient molecular diversity and scarce tissue for analysis. Importantly, there is also need for predefined treatment priority algorithms given multiple aberrations observed within any one individual. Finally, access to multiple therapeutic agents are required to be available for treatment. Intra-patient heterogeneity may be addressed by post-treatment biopsy. Methods: We present a novel trial design 'Personalized Anti-Neoplastics for Gastro-Esophageal Adenocarcinoma' for metastatic GEC, integrating medium throughput proteomic/genomic assays with a practical biomarker assessment/treatment algorithm. Analysis of 50 GEC patients was performed to determine feasibility/timing of testing and treatment assignment into 5 major molecular categories. Results: 50 GEC tumors had biomarker assessment and mock treatment assignment within 60 days, revealing HER2 (26%), MET (30%), FGFR2 (8%), EGFR (20%), KRAS/PI3K (26%). Conclusions: Comprehensive molecular profiling of FFPE tissue was feasible and timely. Tumors were classified into major molecular subgoups. PANGEA is a compromise between the number of potential treatment categories and feasibility of conducting such a trial.
A phase 2 study of a novel transforming growth factor-beta (TGF-β1) receptor I kinase inhibitor, LY2157299 monohydrate (LY), in patients with advanced hepatocellular carcinoma (HCC).
Authors: Faivre Sandrine J. , Santoro Armando , Kelley Robin Kate , Merle Philippe , Gane Ed , Douillard Jean-Yves , Waldschmidt Dirk , Mulcahy Mary Frances , Costentin Charlotte , Minguez Beatriz , Papappicco Pasqua , Gueorguieva Ivelina , Cleverly Ann , Desaiah Durisala , Lahn Michael M. , Ameryckx Sophie , Benhadji Karim A. , Raymond Eric , Giannelli Gianluigi 
Published: February 2017

LBA173 Background: TGF-β signaling is associated with HCC progression in moderate to poorly differentiated tumors overexpressing alpha-fetoprotein (AFP) levels. We report here the safety, antitumor activity, and overall survival (OS) in HCC patients with elevated AFP treated with LY. Methods: Patients with advanced HCC who progressed on sorafenib (SF) or are ineligible to receive SF, advanced Child-Pugh A/B7 HCC, AFP ≥1.5x ULN, ECOG PS ≤1, measurable disease (RECIST 1.1), and ≤1 prior systemic regimen were eligible. LY was administered as intermittent dosing of 14 days on/off (28 days=1 cycle). Patients were randomized to either 160 mg/day (Arm A) or 300 mg/day (Arm B) LY. Primary endpoints were time-to-progression (TTP) and biomarker changes (serum AFP, TGF-β and E-cadherin) for each dose. AFP responders were defined as >20% decline from baseline. Secondary endpoints included toxicity (CTCAE, V 4.0) and pharmacokinetics (PK). Available data from interims are presented. Results: 109 patients were enrolled (Arm A=37; B=72). Baseline characteristics were (Arm A/B): median age 61/63 years; PS=0, 60%/53%; Child-Pugh A 97%/88%; etiology: hepatitis C 30%/38%, hepatitis B 27%/24%, alcohol 24%/25%. Overall, 78%/83% of patients had received prior SF; 57%/53% had AFP >400 ng/mL. Median TTP was 12.0 weeks (90% CI: 6.6, 12.6) in the overall population (Arm A/B, 12.1/10.0 weeks). In SF-naive patients, TTP was 18.3 weeks (90% CI: 6.6-42.4). TTP was higher in the non-alcohol compared to alcohol-only etiology group (median 12.1 vs. 6.1 weeks). Median baseline serum TGF-β1 was 3.4 ng/mL (range: 1.4-3.7) and E-cadherin was 6.1 mg/mL (range: 1.9-17.3). AFP decline of >20% occurred in 24% of patients. Based on the latest interim, median OS was 36 weeks. In AFP responders, median OS was 93.1 weeks vs 29.6 weeks in non AFP responders (Log Rank p=0.0006). Four patients discontinued treatment due to AEs. Most common grade 3/4 related AEs were: neutropenia (n=3), fatigue (n=2), and anemia (n=3). Preliminary PK analysis (n=51) demonstrated moderate interpatient exposure variability (42%). Conclusions: Based on the manageable toxicity profile, the evidence for biomarker responses, analysis of the aggregate PK/PD data, the 300 mg/day dose was chosen for future studies in HCC. Both TTP and overall survival in AFP responding patients is promising.
Effect of KRAS and NRAS mutational status on first-line treatment with FOLFIRI plus cetuximab in patients with metastatic colorectal cancer (mCRC): New results from the CRYSTAL trial.
Authors: Ciardiello Fortunato , Lenz Heinz-Josef , Kohne Claus-Henning , Heinemann Volker , Tejpar Sabine , Esser Regina , Beier Frank , Stroh Christopher , Duecker Klaus , Van Cutsem Eric 
Published: February 2017

LBA443 Background: The phase III CRYSTAL study showed patients with unresectable KRAS exon 2, codon 12 and 13, wild-type (wt) mCRC (n = 666) to benefit from the addition of cetuximab to FOLFIRI first-line. Progression-free survival (PFS), overall survival (OS) times and response rate (RR) were significantly better in patients who received FOLFIRI plus cetuximab, compared with FOLFIRI alone. Recent retrospective analyses of studies involving EGFR-targeted monoclonal antibody therapy have suggested that patients with KRAS and NRAS mutations in other codons were unlikely to benefit from the addition of an EGFR-targeted agent. Thus, the impact of these additional KRAS and NRAS mutations on the efficacy and safety of FOLFIRI plus cetuximab treatment is under investigation in patients from the CRYSTAL study. Methods: KRAS (eight mutations on exons 3 [codons 59 and 61] and 4 [codons 117 and 146]) and NRAS (18 mutations on exons 2 [codons 12 and 13], 3 [codons 59 and 61] and 4 [codons 117 and 146]) mutation detection is ongoing using BEAMing (Beads, Emulsions, Amplification, and Magnetics) with a mutation detection cut-off of 0.1%. Tumor genomic DNA samples from 541 randomized patients with KRAS exon 2 wt disease (81% of KRAS wt patient population) and tumor material available are currently being screened. Treatment arms will be compared using two-sided log-rank tests for PFS and OS, and the Cochran–Mantel–Haenszel (CMH) test for response. Results: RAS mutation status is currently available from 192 patients (28.8% ascertainment) with further RAS assessment ongoing. Currently 63.5% of the samples are RAS wt and 36.5% are new RAS mutations. Conclusions: Updated information on the full RAS mutation dataset of up to 400 samples combined with the clinical data will be presented and implications for patient care discussed.
A phase I study of the multikinase inhibitor cabozantinib (C) plus docetaxel (D) and prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Karzai Fatima H. , Shah Avani Atul , Ojemuyiwa Michelle A. , Madan Ravi Amrit , Apolo Andrea Borghese , Dawson Nancy Ann , Arlen Philip M. , Theoret Marc Robert , Wright John Joseph , Chen Clara , Trepel Jane B. , Couvillon Anna , Chun Guinevere , Harold Nancy , Steinberg Seth M. , Price Douglas K. , Gulley James L. , Figg William Douglas , Dahut William L. 
Published: February 2017

108 Background: Cabozantinib (C) is a multikinase inhibitor of c-Met, vascular endothelial growth factor receptor two and RET. C has shown activity in metastatic castrate resistant prostate cancer (mCRPC), with resolution of bone lesions on bone scan (BS), regression of soft tissue/visceral disease (STD), reductions in circulating tumor cells and bone biomarkers. Combining docetaxel (D) with other agents, without overlapping toxicities, can target different cellular signaling pathways necessary for tumor survival. Methods: Patients (pts), with no prior D for CRPC, receive a fixed dose of D (75 mg/m2 IV day one of each 21 day cycle) and prednisone (P) (5 mg po q12 hours) with C at three escalating dose levels: 20 mg, 40 mg, or 60 mg (all po daily). Using a standard three-plus-three design, three to six pts are treated at each dose level until the maximum tolerated dose (MTD) has been defined. Results: Thirteen pts have been accrued; four on dose level one, six on dose level two, and three on dose level three. Median age 69 (45 to 84). Four pts have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of zero and nine pts have a PS of one. Median Gleason score is nine (7 to 10). Median on-study prostate-specific antigen (PSA) is 129.2 ng/mL (0.01-508.5 ng/mL). Median cycles is six (1 to 17). Grade 1 adverse events (AEs), possibly related to C; dysgeusia (4/12), oral mucositis (4/12), increased ALT (3/12), and epistaxis (3/12). Grade 2 AEs; nausea (2/12), hand/foot syndrome (2/12), fatigue (2/12), dysgeusia (2/12), oral mucositis (2/12), hypophosphatemia (2/12), and anemia (2/12). Grade 3 AE is hypophosphatemia (2/12). Grade 4 AE is neutropenia (1/12). MTD of C is 60 mg. Of nine evaluable pts, six have bone only disease. Of these six, three pts have PSA declines of less than 30% with improvement on BS (two pts) or stable BS (one pt). The other three pts have PSA declines of greater than 30% and bone scan improvement. Three pts have STD and bone disease; one patient had a PSA decline of greater than 30% with improvement on BS and SD by CT scan. One patient had an increase in PSA of less than 30% with improvement on BS and CT. The third pt had PD by CT and an increase in PSA equal to 30%. PFS probability at six months is 90.0% and is 67.5% at eight months and beyond. Conclusions: The addition of C to D and P, has an acceptable toxicity profile. CT scan and BS improvements did not correlate with PSA declines in all pts. An expansion cohort will combine D plus P with C at the MTD (60 mg) to determine clinical benefit. Clinical trial information: NCT01683994.
Methylated glutathione s-transferase 1 (mGSTP1) as a potential plasma epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer (CRPC).
Authors: Mahon Kate Lynette , Qu Wenjia , Devaney James , Paul Cheryl , Castillo Lesley , Wykes Richard , Chatfield Mark D , Boyer Michael J. , Stockler Martin R. , Marx Gavin M. , Gurney Howard , Hiriyanna Gowda Girish Mallesara , Molloy Peter , Horvath Lisa , Clark Susan J. ,   PRIMe Consortium
Published: February 2017

11 Background: GSTP1 is inactivated and displays aberrant CpG island promoter methylation in the majority of prostate cancers (PCs). The aim of this study was to assess whether changes in methylated glutathione s-transferase 1 (mGSTP1) levels are predictive of response to chemotherapy and overall survival (OS). Methods: Plasma samples were collected prospectively from a phase I exploratory cohort of 75 men with castration-resistant prostate cancer (CRPC) (40 treated with chemotherapy) and a phase II independent validation cohort (n=51). Plasma samples were collected at presentation with CRPC and pre- and post-cycle one of chemotherapy (90% Docetaxel). mGSTP1 levels were measured using a methylation-specific head-loop PCR assay from DNA isolated from either (1) immunomagnetic separation of circulating tumor cells (CTCs) or (2) free plasma DNA. The associations between plasma mGSTP1 levels, PSA response (defined by PCWG1 criteria), and OS were tested using non-parametric tests and survival analyses. Results: The ability to detect mGSTP1 was significantly higher for the plasma free DNA assay compared to DNA from CTCs (p<0.0001), so for the remainder of the study the plasma free DNA assay was used. The phase I exploratory cohort identified that detectable mGSTP1 at CRPC presentation predicted for poorer OS (HR 4.2, 95% CI 2.1-8.2; p<0.0001). In the 40 men treated with chemotherapy, a decrease in mGSTP1 levels after cycle one predicted a subsequent more than 50% decrease in PSA prior to cycle 4 (p=0.008). The phase II validation cohort demonstrated that undetectable plasma mGSTP1 after one cycle of chemotherapy predicted for a clinical benefit from treatment (PR+SD vs. PD) (p=0.007). Furthermore, an undetectable plasma mGSTP1after one cycle of chemotherapy was a better predictor of death within 12 months than change in PSA after three months (AUC 0.87, 95% CI 0.77-0.98; p=0.006). Conclusions: We have identified plasma mGSTP1 levels as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for cytotoxic chemotherapy and validated these findings in an independent phase II cohort. Prospective phase III assessment of mGSTP1 as a biomarker of therapeutic response is now warranted.