bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gain of ALK gene copy number to predict lack of response to anti-EGFR treatment in advanced chemorefractory colorectal cancer (CRC) with KRAS/NRAS/BRAF/PI3KCA wild-type status.
Authors: Pietrantonio Filippo , Tessari Anna , Miceli Rosalba , Biondani Pamela , Perrone Federica , Testi Adele , Tamborini Elena , Pelosi Giuseppe , Mariani Luigi , Fanetti Giuseppe , Gevorgyan Arpine , Bossi Ilaria , Di Bartolomeo Maria , De Braud Filippo G. 
Published: March 2020

3641 Background: KRAS, BRAF, NRAS and exon 20 PIK3CA quadruple wild-type CRC is associated with 41.2% response rate to anti-EGFR treatments. Even in molecular characterized patients, there is still a subset of non responders. The identification of additional predictive biomarkers is an unmet clinical need for treatment personalization. Alterations of ALK oncoprotein may interfere with the biological activity of EGFR through cross-talk of downstream signalling pathways. Methods: This retrospective analysis aimed to investigate the correlation between ALK gene copy number (GCN), assessed by fluorescence in situ hybridization (FISH), and clinical outcome in KRAS/NRAS/BRAF/PI3KCA wild-type chemorefractory advanced CRC patients receiving cetuximab or panitumumab. FISH was perfomed with break-apart ALK (2p23) probes and gain of ALK GCN was defined as a mean of 3 to 5 signals in ≥10% of cells and amplification as ≥6 signals. Association of ALK status with RECIST response was performed by Fisher’s exact test. Results: Forty-one patients were identified, of whom 17 (41%) were ALK GCN positive, whereas the remaining 24 cases (59%) were ALK GCN negative. No ALK translocations were detected. Overall response rate was 19/41 (46%). We observed a partial response in 3/17 patients with ALK GCN positive versus 16/24 patients with ALK GCN negative (18% versus 67%, respectively; P=0.0036). Kaplan-meier curves for comparison of median progression-free and overall survival, as well as correlation with ALK expression by immunohistochemistry, will be presented at the Meeting exploring the whole National Cancer Institute data-set. Conclusions: In this study population with KRAS/NRAS/BRAF/PI3KCA wild-type tumors, the response rate greater than 40% is in line with literature data. ALK GCN may be a biomarker for clinical outcome prediction in advanced chemorefractory CRC patients treated with cetuximab or panitumumab.
Bevacizumab before cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis of colorectal origin: Analysis of early postoperative complication rate and long term follow-up.
Authors: Eveno Clarisse , Passot Guillaume , Goéré Diane , Soyer Philippe , Gayat Etienne , Glehen Olivier , Elias Dominique , Pocard Marc 
Published: March 2020

3642 Background: Patients with stage IV colorectal cancer and peritoneal carcinomatosis are increasingly treated with curative intent and perioperative systemic chemotherapy combined with targeted therapy.The aim of the study was to analyze the potential impact of bevacizumab on early morbidity and survival after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal carcinomatosis of colorectal origin. Methods: From 2004 to 2010, in three referral centers, 182 patients with colorectal carcinomatosis were treated with complete cytoreduction followed by HIPEC after either preoperative systemic chemotherapy alone or in combination with bevacizumab. Because there was no control on treatment allocation, propensity score methods were used to control this bias. Results: The median time from discontinuation of bevacizumab to HIPEC was 7 weeks (range, 6-10). Major morbidity was greater in the Beva group (34 vs. 19%, p=0.020). Nine patients died postoperatively: 5 (6.2%) in the Beva group (n=80) and 4 (3.9%) in the group treated with chemotherapy alone (n=102) (p=NS). The rate of digestive fistulas was greater in the Beva group, although not significant (18 vs. 10%, p=NS). After matching, the effect of Bevacizumab on major morbidity (including death) was found to be significant (OR = 2.28, 95% CI; 1.05 - 4.95) (p=0.04). No difference in median of overall and disease free survival was found between the two groups (12 and 36 month in Beva group vs. 14.3 and 49 month in the control group, p=NS). Conclusions: Administration of bevacizumab before surgery with complete cytoreduction followed by HIPEC for colorectal carcinomatosis is associated with 2-fold increased morbidity. The oncologic benefit of bevacizumab before HIPEC remains to be evaluated with prospective randomized study.
Maintenance with the TLR-9 agonist MGN1703 versus placebo in patients with advanced colorectal carcincoma (mCRC): A randomized phase II trial (IMPACT).
Authors: Riera-Knorrenschild Jorge , Schmoll Hans-Joachim , Arnold Dirk , Kroening Hendrik , Mayer Frank , Nitsche Dieter , Ziebermayr Reinhard , Scheithauer Werner , Andel Johannes , Meisel Christian , Schmidt Manuel , Wittig Burghardt 
Published: March 2020

3643 Background: Standard induction chemotherapy for mCRC is often discontinued in patients responding to the treatment. MGN1703, a synthetic DNA-based immunomodulator, acts as TLR-9 agonist. This trial has been conducted to assess clinical efficacy, safety, and immunogenicity of MGN1703 as maintenance therapy vs placebo. Methods: The IMPACT trial is an international, multicenter, randomized (2:1) double-blind placebo-controlled phase 2 trial in mCRC patients with disease control (CR, PR, SD) after 4.5 to 6 months of 1st-line induction chemotherapy with FOLFOX/XELOX or FOLFIRI +/- bevacizumab. Results: 59 patients have been randomized (43 MGN1703, 16 placebo). Median PFS from start of maintenance was not different with 2.8 vs 2.7 months, however the HR was 0.56 (CI 95%: 0.29-1.08; p=0.069) in favor of MGN1703, due to a small favorable subgroup with long-term PFS (20% vs 0% at 9 months; p=0.006). Total PFS from beginning of induction chemotherapy including maintenance was significantly improved: HR 0.49 (CI 95%: 0.25-0.94), p=0.029. After a median follow-up of 13 months 66% of patients are still alive (67% vs 62%), therefore survival data are still preliminary (HR 0.79; CI 95%: 0.3-2.1) and will be mature at the meeting. Activation of cellular immune function as indicated by significant increase of CD14+CD169+monocytes was observed in all but one of the MGN1703 treated patients, while absent in all placebo patients. Treatment was well tolerated: 46.5% vs 31.3% of patients (MGN1703 vs placebo) had any drug-related adverse events (AE) and 20.9% vs 18.8% had AE with grade 3 or 4 (including hypertension, ileus, sepsis, sensory polyneuropathy, nausea/vomiting for MGN1703 and pain, popular exanthema for placebo). Conclusions: MGN1703 maintenance seems to prolong PFS in a subgroup of patients with disease control after induction chemotherapy vs placebo, and is associated with relative mild toxicity. This in an early signal in a selected and very limited patient population which supports further investigation. Predictive biomarkers are under evaluation to identify a potential subgroup which might have benefit from this TLR-9 MGN1703 maintenance. Clinical trial information: NCT01208194.
Olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer: A randomized, double-blind phase II study.
Authors: Bang Yung-Jue , Im Seock-Ah , Lee Keun-Wook , Cho Jae Yong , Song Eun-Kee , Lee Kyung Hee , Kim Yeul Hong , Park Joon Oh , Chun Hoo Geun , Zang Dae Young , Fielding Anitra , Rowbottom Jacqui , Kim Woo Ho 
Published: March 2020

4013 Background: Our multicenter study compared the efficacy of the oral PARP inhibitor olaparib plus paclitaxel (O/P) vs paclitaxel alone (P) as second-line therapy in pts with recurrent/metastatic gastric cancer (GC) (NCT01063517). As initial preclinical data suggested that responsiveness of GC cell lines to olaparib was associated with low ATM protein levels, our study was enriched for pts with low ATM tumors (ATM–) by IHC (50% randomized vs 14% screening prevalence). Methods: Eligible pts were randomized 1:1 (stratified by ATM status) to receiveolaparib 100 mg bid (tablet form) plus paclitaxel (80 mg/m2 iv on days 1, 8, 15 per 28-day cycle) or placebo plus paclitaxel until progression or investigator decision. After combination therapy, pts could take olaparib 200 mg bid monotherapy or placebo until progression. Co-primary endpoints: progression-free survival (PFS; RECIST v1.1) in all pts and ATM– pts. Secondary endpoints: overall survival (OS), objective response rate (ORR), safety. Results: 123/124 randomized pts were treated (O/P=61; P=62). Baseline characteristics were generally well balanced. Use of post-progression therapy was similar in both arms (O/P=48.4%; P=43.5%) as was median paclitaxel duration (O/P=17 wks; P=16 wks); 18 pts received monotherapy (O/P=11; P=7). More pts in the O/P than P arm had delays (79 vs 63%) and reductions (41 vs 27%) in paclitaxel dosing. The most common grade ≥3 AEs in the O/P and P arms were neutropenia (56 vs 39%) and anemia (11 vs 11%). Conclusions: Olaparib plus paclitaxel was well tolerated and led to a statistically significant improvement in OS, but not PFS, vs paclitaxel alone in both all pts and ATM– pts, with a larger benefit in ATM– pts. Clinical trial information: NCT01063517. [Table: see text]
Association of gene expressions of TOP2A, GGH, and PECAM1 with hematogenous, lymph-node, and peritoneal recurrence in patients with stage II/III gastric cancer enrolled in the ACTS-GC study.
Authors: Terashima Masanori , Ichikawa Wataru , Ochiai Atsushi , Kitada Koji , Kurahashi Issei , Sakuramoto Sinichi , Katai Hitoshi , Sano Takeshi , Imamura Hiroshi , Sasako Mitsuru ,   ACTS-GC Group
Published: March 2020

4019 Background: Exploratory biomarker analysis was conducted to identify factors related to relapse sites in the ACTS-GC study, a randomized controlled trial comparing postoperative adjuvant S-1 therapy with surgery alone in 1,059 patients (pts) with stage II/III gastric cancer. Methods: Formalin-fixed, paraffin-embedded surgical specimens were retrospectively examined in 829 pts (78.3%), and 63 genes involved in pyrimidine metabolic pathway, growth factor signaling pathway, apoptosis, DNA repair, etc., were analyzed by quantitative RT-PCR after TaqMan assay-based pre-amplification. Gene expression levels were normalized to the geometric mean expressions of GAPDH, ACTB, and RPLP0, used as reference genes. The expression of each gene was categorized as lower or higher than the median value. The impact of gene expression on relapse site was analyzed using the 5-year relapse-free survival (RFS) data of the ACTS-GC. Results: Among the 829 pts, hematogenous, lymph-node, and peritoneal recurrence developed in 72, 105, and 138 pts, respectively. The hazard ratios (HR) (S-1 vs. surgery alone) were 0.79 (95%CI, 0.54-1.16) for hematogenous, 0.51 (95%CI, 0.31-0.82) for lymph-node, and 0.60 (95%CI, 0.42-0.84) for peritoneal recurrence. Among 63 screened genes, topoisomerase II alpha (TOP2A), gamma-glutamyl hydrolase (GGH), and platelet/endothelial cell adhesion molecule 1 (PECAM1) most strongly correlated with hematogenous, lymph-node, and peritoneal recurrence, respectively. Hematogenous RFS was significantly worse in TOP2A high pts than in low pts (HR, 2.35; 95% CI, 1.55-3.57). Lymph-node RFS was significantly worse in GGH high pts than in low pts (HR, 1.87; 95% CI, 1.13-3.08). Likewise, peritoneal RFS was significantly worse in PECAM1high pts than in low pts (HR, 2.37: 95% CI, 1.65-3.41). These factors were independent and stronger risk factors than tumor histological type on multivariate analysis. Conclusions: Expression levels of the TOP2A, GGH, and PECAM1 genes in primary tumors are respectively linked to high risks of hematogenous, lymph-node, and peritoneal recurrence in pts with stage II/III gastric cancer.
Effectiveness of D2 gastrectomy for lymph node positive and advanced gastric cancer: Survival results of the Italian Gastric Cancer Study Group (IGCSG) randomized surgical trial on D1 versus D2 dissection for gastric carcinoma.
Authors: Degiuli Maurizio ,   Italian Gastric Cancer Srudy Group (IGCSG)
Published: March 2020

4027 Background: It is still unclear whether D2 lymphadenectomy can significantly improve survival of gastric cancer and therefore should be applied routinely or performed in selected cases. We conducted a multicenter randomized trial to compare the efficacy of D2 and D1 lymphadenectomy for gastric cancer. Primary outcome was overall survival; secondary endpoints were disease specific survival, morbidity and in-hospital mortality. Methods: Between June 1998 and December 2006 patients with gastric adenocarcinoma were randomly assigned to either D1 or D2 lymphadenectomy. Intraoperative randomization was implemented centrally by telephone. Results: A total of 267 eligible patients were allocated to either D1 (133) or D2 group (134). Morbidity (12·0% vs 17·9%, p=0·18) and mortality (3·0% vs 2·3%; p=0·72) were similar. There was no difference in the overall 5-year survival (66·5% vs 64·2%, p = 0.70). Subgroups analyses showed a 5-years disease specific survival benefit for pT1 cases treated with D1 dissection (98.0% vs 82.9%, p = 0.01) and of pT>1 LN+ patients treated with D2 resection (38·4% vs 59·5%, p = 0.05 at five years). Conclusions: In intention to treat analysis we observed no overall 5-year survival benefit from D2 resection. The trial showed a survival benefit of D1 procedure in early stages. On the opposite, despite evidence of contamination in the D1 arm, a survival advantage was documented in patients with advanced disease and lymph node metastases submitted to D2 procedure. Clinical trial information: ISRCTN11154654. [Table: see text]
A multicenter, randomized, blinded, phase III study of pasireotide LAR versus octreotide LAR in patients with metastatic neuroendocrine tumors (NET) with disease-related symptoms inadequately controlled by somatostatin analogs.
Authors: Wolin Edward M. , Jarzab Barbara , Eriksson Barbro , Walter Thomas , Toumpanakis Christos , Morse Michael , Tomassetti Paola , Weber Matthias , Fogelman David R. , Ramage John , Poon Donald , Huang Jerry M. , Hudson Michelle , Zhi Xin , Pasieka Janice L. , Mahamat Abakar , Swahn Fredrik , Newell-Price John , Mansoor Wasat , Oberg Kjell E. 
Published: March 2020

4031 Background: The novel somatostatin analog (SSA) pasireotide has a broader binding profile than currently available SSA (octreotide and lanreotide). Results from a phase III study (NCT00690430) of pasireotide LAR (P) vs octreotide LAR (O) in patients (pts) with NET and disease-related symptoms uncontrolled by the maximum approved dose of available SSA are shown. Methods: Pts (N=110) were randomized and stratified by predominant symptom at baseline (diarrhea [D], flushing [F], or D+F) 1:1 to P (60 mg IM) or O (40 mg IM) q28d. Primary objective was symptom response at month (M) 6. Secondary objectives included tumor response and safety. Progression-free survival (PFS) was an exploratory analysis. Results: 53 and 57 pts were enrolled in the P and O arms when the study was halted due to an interim analysis suggesting futility for symptom response. Baseline characteristics were similar between arms. Majority of primary tumor locations were small intestine (72% and 81% in the P and O arms). Symptom response at M6 was 9/43 (21%) and 12/45 (27%) in the P and O arms, odds ratio 0.73 (95% CI, 0.27-1.97; p=0.53). Median numbers of D/day and F/2 weeks and change in symptom from baseline to M6 are in Table. Hyperglycemia (11% vs 0%), diarrhea (9% vs 7%), and abdominal pain (2% vs 9%) were the most common grade 3/4 AEs in the P vs O arms in the core phase, and 7 (13%) and 4 (7%) pts discontinued due to AEs. Median investigator-assessed PFS was 11.8 months and 6.8 months in the P and O arms (HR=0.46; p=0.045). Conclusions: P and O showed a similar safety profile except for the higher frequency of hyperglycemia in P. Pts on P had PFS 5 months longer than pts on O (investigator assessment), despite no differences in symptom response rates. These results warrant a large phase III trial to clarify the role of P as a therapy for NET. Clinical trial information: NCT00690430. [Table: see text]
Hemoglobin-A1c level to predict for clinical outcomes in patients with pancreatic cancer.
Authors: Fan Katherine Y. , Dholakia Avani Satish , Wild Aaron Tyler , Su Zheng , Hacker-Prietz Amy , Kumar Rachit , Hodgin Mary , Hsu Charles C. , Le Dung T. , De Jesus-Acosta Ana , Diaz Luis A. , Laheru Daniel A. , Hruban Ralph H. , Fishman Elliot K. , Brown Todd D. , Pawlik Timothy M. , Wolfgang Christopher Lee , Tran Phuoc T. , Herman Joseph M. 
Published: March 2020

4039 Background: An association between diabetes mellitus (DM) and pancreatic ductal adenocarcinoma (PDA) has long been recognized. While long-standing DM may be a risk factor for developing PDA, new-onset DM may be a manifestation of the cancer. Here we assess the role of an objective and quantifiable measure of glucose intolerance, hemoglobin-A1c (HbA1c), in predicting clinical outcomes in PDA. Methods: HbA1c values were prospectively collected on 656 consecutive patients presenting to the Johns Hopkins Pancreas Multidisciplinary Cancer Clinic from 2009-2012. Patients were diagnosed with benign pancreatic disease (BPD) or biopsy-confirmed resectable (R), borderline/locally advanced (BL), or metastatic (M) PDA. Patients with prior treatment for PDA or a history of DM greater than a 1-year were excluded. Univariate Cox regression analyses and multivariable proportional hazards models were used to identify poor prognostic factors for overall survival. Results: Of 284 patients included, 44 had benign disease, 62 R-PDA, 115 BL-PDA, and 63 M-PDA. Patients with malignant disease (R-, BL-, and M-PDA) collectively had higher HbA1c values on average at presentation than patients with BPD (6.1% vs. 5.6%, p<0.001). There was a trend towards higher HbA1c at presentation in patients with advanced PDA (BL and M) compared to patients with R-PDA (6.2% vs. 5.9%, p=0.100); moreover, the proportion of patients with HbA1c levels in the diabetic range (>6.4%) increased with more advanced stage of disease. Among patients with PDA (n=240), univariate analyses showed HbA1c≥6.5, age≥65, ECOG≥1, CA19-9>90, tumor size >3cm, and advanced stage to be significantly associated with inferior survival (all HR>1, p<0.05). After multivariate analysis with backward elimination, all of the above factors except for tumor size >3cm remained in the model for inferior survival. Conclusions: HbA1c level at presentation appears to correlate with disease stage and, moreover, to predict for survival among all stages of PDA. Patients with PDA have significantly higher HbA1c levels at presentation than patients with BPD. This study highlights the potential utility of HbA1c as a screening tool and prognostic factor.
Circulating cytokines and angiogenic factors (CAF) as markers of clinical response in the study of trametinib (T) plus gemcitabine (G) versus placebo (P) plus gemcitabine for patients (pts) with untreated metastatic adenocarcinoma of the pancreas (MEK113487).
Authors: Heymach John , Tran Hai T. , Nixon Andrew B. , Hurwitz Herbert , Infante Jeffrey R. , Gagnon Robert C. , Steplewski Klaudia , Le Ngocdiep T. , Liu Yuan 
Published: March 2020

4042 Background: T is a reversible and highly selective allosteric inhibitor of MEK1/MEK2. The addition of T to G did not improve overall survival (OS) as first-line treatment for pts with metastatic adenocarcinoma of the pancreas (ASCO GI 2013 #291). CAF profiles have shown potential for identification of prognostic and predictive markers in cancer pts (Tran, Lancet, 2012). Methods: Plasma samples (n = 144 baseline [BL]; n = 112 day 15) from pts who consented to participate in MEK113487 study were analyzed for 30 CAFs (ANG2, IGFBP3, IL2R, IP10, MMP2, MMP9, OPN, PDGFBB, SCF, TIMP1, IL6, MIP1B, SDF1, TRAIL, VEGF, MIP3A, MCP2, FGFB, IL8, VEGFR1, IL10, IL1A, IL12P40, PIGF, EGF, IL1B, TNFA, IL4, MIP1A, MCP3) using SearchLight multiplex assays in a CLIA-certified laboratory. Change from BL was assessed using either paired t tests or Wilcoxon tests. BL and change from BL CAF levels were tested for association with clinical outcome using proportional hazards regression within arm (P < .01 for significance) and between arms (treatment arm by CAF level interaction, P < .05 for significance). Results: Lower levels (< median) of BL ANG2, IL6, TIMP1, and IL8 were associated with an average of 5 mo longer OS in both the T+G and G arms. Lower BL levels (less than first quartile) of IGFBP3 and PDGFBB were associated with 6 mo longer OS in the T+G arm, while higher levels (greater than third quartile) of IGFBP3 and PDGFBB were associated with 4.8 mo longer OS in the G arm. A combined model of low IGFBP3 and/or PDGFBB showed improved survival for T+G vs G (median OS, 10.3 vs 5.6 mo). Decreases of ANG2 and IL2R levels at day 15 from BL were observed in the T+G arm only; additional results will be presented. Conclusions: This study suggests that plasma CAF profiling may aid in the prognostic evaluation of pts, assessing therapeutic response, and identifying pathways modulated by treatment in pancreatic cancer pts. Low IGFBP3 and PDGFBB may identify patients who receive greater benefit from T+G compared with G in this population and merit further investigation as predictive markers. Clinical trial information: NCT01231581.
Assessment of the association of the VeriStrat test with outcomes in patients (pts) with advanced pancreatic cancer (PC) treated with gemcitabine (G) with or without erlotinib (E) in the NCIC CTG PA.3 phase III trial.
Authors: Renouf Daniel John , Parulekar Wendy , Grigorieva Julia , Tu Dongsheng , Moore Malcolm J. 
Published: March 2020

4061 Background: VeriStrat is a mass spectrometry based assay performed on serum or plasma that has been shown to be prognostic in several tumor types, and may predict differential drug benefit in several settings. We investigated the association of VeriStrat with outcomes in the NCIC CTG PA.3 randomized phase III trial of G and E vs. G and placebo (P) in pts with advanced PC. Methods: Pre-treatment plasma samples were available for 499/569 (87.7%) enrolled pts. VeriStrat testing was performed in a CLIA-certified laboratory; pts were classified as either Good, Poor, or indeterminate. The relationship between VeriStrat results and overall survival (OS) and progression free survival (PFS) was assessed by Kaplan-Meier curves and log-rank test in univariate analysis and Cox model adjusting for gender, age [>60 vs. ≤60], race [Caucasian vs. other], ECOG [0-1 vs. 2], and pain intensity at baseline [≤20 vs. >20] in multivariate analysis. The predictive effect was assessed by interaction test. All statistical analyses were performed by the NCIC CTG. Results: Of the 499 samples, 11 were hemolyzed and 4 had acquisition failures. VeriStrat was performed on 484 samples, 9 failed quality control, 22 had indeterminate results. Of the remaining 452, 353 (78%) were classified as Good and 99 (22%) as Poor. In the G and P arm, median OS was 7.16 months (ms) for VeriStrat Good vs. 3.78ms for VeriStrat Poor (p<0.0001); Adjusted Hazard Ratio (AHR) 0.59 (0.43-0.82), p=0.002. In the G and E arm, median OS was 7.33ms for VeriStrat Good vs. 4.50ms for VeriStrat Poor p<0.0001; AHR 0.47 (0.32-0.70), p=0.001. A similar relationship was seen for PFS (G and P arm: median PFS 3.91 vs. 2.07ms (p=0.001); AHR 0.67 [0.49-0.92], p=0.01); G and E arm: median PFS 4.24 vs. 2.86ms (p=0.0004); AHR 0.54 [0.37-0.80], p=0.002). Tests of interaction of VeriStrat status and treatment for OS and PFS were not significant: AHR 0.78 (0.48-1.25), p=0.30 and AHR 0.80 (0.50-1.30), p=0.37 respectively. Conclusions: VeriStrat results were significantly associated with OS and PFS for both regimens in this study. VeriStrat was not predictive of benefit from the addition of E to G.