bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of genetic variants in immune response genes to predict clinical outcome in mCRC patients treated with cetuximab-based therapy.
Authors: Schultheis Anne Maria , Volz Nico Benjamin , Zhang Wu , Yang Dongyun , Ning Yan , Stintzing Sebastian , Wakatsuki Takeru , El-Khoueiry Rita Elie , Li Joseph Ethan , Kardosh Adel , Barzi Afsaneh , El-Khoueiry Anthony B. , Lenz Heinz-Josef
Published: March 2020

3567

Background: Cetuximab is a monoclonal antibody targeting the EGF receptor. One of its anti-tumor mechanisms is the stimulation of the immune system via ADCC (Antibody-Dependent-Cell mediated Cytotoxicity). Immune response through T-cell activation may also play a role in antitumor efficacy of chemotherapy. CTLA4, PDL1, IDO1 and CD24 are inhibitory co-receptors or ligands that may downregulate the immune system through suppression of T-cell response. We tested whether Germline polymorphisms in these genes are involved in the cetuximab dependent immune response pathway and thus predict outcome in mCRC patients treated with cetuximab. Methods: DNA was isolated from blood of 108 patients with mCRC treated with either irinotecan+cetuximab (n=73) or single agent cetuximab (n=35). Twelve prospectively functionally relevant SNPs; IDO1(rs9657182, rs3739319, rs1010866), PD1(rs2227981, rs7421861), PDL1(rs2297137, rs2297136, rs10122089, G>C), CTLA4(rs231777, rs231775), and CD24(rs8734) were analyzed by PCR-based direct sequencing and evaluated for association with tumor response, overall survival (OS), and progression free survival (PFS). Results: Results are attached. There were 65 men and 43 women with a median PFS of 3.7 (95%CI: 2.8, 4.6) months and a median OS of 10.5 (95%CI:7.7, 13.3) months. Median follow up was 16.3 (range:1.2, 42.4) months. Conclusions: Our results show that immune response related SNPs may predict efficacy of cetuximab treatment in patients with mCRC. To the best of our knowledge this is the first data linking PDL1(rs2297137) to cetuximab efficacy in mCRC patients. [Table: see text]
Influence of sex and anthropometric factors on tumor biologic characteristics of colorectal cancer: A cohort study.
Authors: Brandstedt Jenny , Wangefjord Sakarias , Borgquist Signe , Nodin Bjorn , Eberhard Jakob , Jirstrom Karin
Published: March 2020

3579

Background: How body size influences risk of molecular subtypes of colorectal cancer (CRC) remains unclear. In this study, we investigated the relationship between height, weight, BMI, WHR and risk of CRC according to expression of beta-catenin, cyclin D1, p53 and microsatellite instability (MSI) status. Methods: Immunohistochemical expression of beta-catenin, cyclin D1, p53 and MSI-screening status was assessed in tissue microarrays with tumours from 584 cases of incident colorectal cancer in the Malmö Diet and Cancer Study. Four anthropometric factors: height, weight, body mass index (BMI), waist- hip ratio (WHR) were categorized by quartiles of baseline anthropometric measurements, and relative risks of CRC according to expression of betacatenin, cyclin D1, p53 and MSI screening status were calculated using multivariate Cox regression models. Results: Expression of cytoplasmatic and nuclear betacatenin, cyclin D1, p53 and MSS all revealed a positive association with increased weight and BMI in the overall analysis. Negative expression of the above mentioned factors was more frequently associated with increased height. MSI was not associated with any of the anthropometric factors in overall analysis and according to gender.Gender specific analysis revealed no association between any anthropometric factors and positive and negative cytoplasmatic beta-catenin expression, beta-catenin nuclear negativity, cyclin D1 negativity and p53 positivity. Nuclear beta-catenin positivity, cyclin D1 positivity, p53 negativity and MSS were all associated with increased weight in women. In men, positive expression of cytoplasmatic and nuclear beta-catenin, cyclin D1 positivity and p53 positivity were all associated with increased WHR. Negative expression of betacatenin was associated with increased weight, while there were no associations between any anthropometric factors and cyclin D1 negativity, MSS or MSI status in men. Conclusions: Findings from this large prospective cohort study demonstrate an association between obesity, measured as weight and BMI, and risk of CRC according to the expression of beta-catenin, cyclin D1, p53 and MSI status.
Final results of the AIO 0307 study: A controlled, randomized, double-blind phase II study of FOLFOX6 or FOLFIRI combined with sorafenib (S) versus placebo (P) in second-line metastatic colorectal carcinoma (mCRC) treatment.
Authors: Hoehler Thomas , Decker Thomas , Schimanski Christoph , Schmitz Stephan H. , Kanzler Stephan , Rauh Jacqueline , Vehling-Kaiser Ursula , Bernhard Helga , Hoffmann Thomas , Niederle Norbert , Von Verschuer Ulla , von Wichert Goetz , Wagner Thomas
Published: March 2020

3586

Background: The oral multikinase inhibitor Sorafenib (S) inhibits angiogenesis and tumor growth in preclinical models of CRC. This study investigated the addition of S to standard 2nd line chemotherapy (CTX). Methods: Patients (pts) with mCRC and progression after first-line therapy with an oxaliplatin- or irinotecan based fluoropyrimidine containing regimen ± Bevacizumab (Bev), were randomized to receive chemotherapy (CTX) (FOLFOX6 or FOLFIRI) + S (400 mg bid) or CTX + placebo (P). 240 pts were planned to be enrolled to ensure a power of 80% if median progression-free survival (PFS) with S is increased by 2 months compared to P. Results: Between 04/09 and 10/11, 101 pts were enrolled. Recruitment was stopped prematurely due to slow accrual. 97 pts were evaluable in the full analysis set. Median age was 65 years, 60 pts were male, 97% with ECOG 0 or 1. Median PFS was 5.2 months (mths) in S and 5.6 mths in P (HR 0.84, 90% CI 0.58, 1.22, p=0.439). Best response rate was 25.6% and 12.2% (p=0.106), respectively. Disease control rates were comparable. Median overall survival (OS) was 9.6 mths with S compared to 12.7 mths with P (HR 1.57, 90% CI 1.03, 2.41, p = 0.076). Difference in OS was even more pronounced in subgroup (n=41) with FOLFOX6 backbone (9.6 vs. 13.8 mths, HR 2.37, 90% CI 1.22, 4.60, p=0.026). In 69 Bev-pretreated pts OS was 8.4 vs. 14.9 mths (HR 2.30; 90% CI 1.36, 3.88, p=0.007) compared to 13.1 vs. 7.4 mths (HR=0.61; 90% CI 0.28, 1.36, p=0.308) in 28 pts without Bev pretreatment. Adverse events (AEs) were consistent with the known safety profiles. Most frequent grade 3/4 AEs affected the gastrointestinal tract (diarrhea, mucositis/stomatitis, nausea); other frequent severe AEs included neutropenia and leukopenia, fatigue, fever, sensory neuropathy, and thrombosis. Conclusions: No unexpected safety concerns occurred during the course of the study. S did not lead to improved PFS. There was a detrimental effect of S on OS in patients with Bev pretreatment. Clinical trial information: 2008-000803-26.
Phase Ib dose-escalation study of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, administered by intravenous (IV) infusions in patients with metastatic colorectal carcinoma (mCRC).
Authors: Lee Jeeyun , Park Young Suk , Burke James , Lim Ho Yeong , Lee Jihye , Kang Won Ki , Park Joon Oh , Pelusio Adina , Breitbach Caroline , Kirn David H.
Published: March 2020

3608^

Background: Pexa-Vec is an EGFR-targeted vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating direct oncolysis, tumor vascular disruption and anti-tumor immunity (Nat Rev Cancer 2009). Dose-dependent IV Pexa-Vec delivery was defined previously (Nature2011). This study was designed to assess the safety, maximal tolerated dose and anti-tumor activity of Pexa-Vec administered IV in patients with mCRC after failure of standard therapies. Methods: Nine patients were treated at 1 of 3 dose levels (106, 107 or 3x107pfu/kg IV every 2 weeks x 4) in a standard 3+3 dose-escalation design; 6 additional patients were enrolled at the MFD. Anti-tumor activity according to RECIST was determined using serial CT scans. Pharmacokinetic studies were also performed. Data summarized prior to database lock. Results: 15 patients with mCRC refractory to irinotecan, oxaliplatin, and 5-FU were treated (median lines of therapy 5; range 2-7); 13 of 15 received prior anti-angiogenic agents, and 11 of 12 KRAS WT tumors failed cetuximab. Adverse events were generally grade 1/2 and included: fever (93%), chills (93%), headache (60%), nausea (60%), and hypotension (40%). No dose-limiting toxicities or grade 3/4 events were reported. Only patients treated at high-dose (Cohort 3 & Expansion) exhibited a pustular rash (n=9; 78%). Pexa-Vec genomes detected in blood acutely were above the dose threshold for systemic delivery. Notably, clearance was not more rapid with repeated IV treatments despite the induction of humoral immunity. Furthermore, patients at the top dose level exhibited increased disease stabilization at Week 4 (89% high-dose (n= 9) versus 33% low-dose (n=6)). A trend (p=0.16) towards increased overall survival at high vs low-dose Pexa-Vec was observed with 78% high-dose patients still alive between 5 and 13 mos. Conclusions: Repeat IV Pexa-Vec was well-tolerated with transient flu-like symptoms. Dose-dependent safety, pharmacokinetics and anti-tumor activity were described in treatment-refractory mCRC patients. Clinical trial information: NCT01380600.
Second-line chemotherapy (CT) with or without bevacizumab (BV) in metastatic colorectal cancer (mCRC) patients (pts) who progressed to a first-line treatment containing BV: Updated results of the phase III “BEBYP” trial by the Gruppo Oncologico Nord Ovest (GONO).
Authors: Masi Gianluca , Loupakis Fotios , Salvatore Lisa , Cremolini Chiara , Fornaro Lorenzo , Schirripa Marta , Granetto Cristina , Miraglio Emanuela , Di Costanzo Francesco , Antonuzzo Lorenzo , Marcucci Lorenzo , Barbara Cecilia , Boni Corrado , Banzi Maria , Chiara Silvana , Garbarino Daniela , Valsuani Chiara , Bonetti Andrea , Boni Luca , Falcone Alfredo
Published: March 2020

3615

Background: Retrospective data suggested that the continuation of BV with second-line CT beyond progression (PD) in pts who received BV in first-line can improve the outcome. Recently, results of the AIO/AMG ML18147 study demonstrated an improved overall survival (OS) by continuing BV beyond PD. Methods: This phase III study randomized pts with measurable mCRC treated in first-line with BV plus fluoropyrimidine, FOLFIRI, FOLFOX or FOLFOXIRI, to receive in second-line mFOLFOX6 or FOLFIRI (depending on first-line CT) with or without BV. The primary end-point was progression free survival (PFS).To detect a HR for PFS of 0.70 with an α and β error of 0.05 and 0.20 respectively, the study required 249 events. Assuming an accrual time of 24 months (mos) and a follow up of 12 mos we planned to randomize 262 pts. Results: Considering the results of the AIO/AMG ML18147 trial, the study accrual was stopped prematurely. A total of 185 pts were randomized and 184 pts were included in the ITT analysis (1 pt randomized in error). Pts characteristics were (arm A/arm B): number 92/92, gender M75%-F25%/M57%-F43%, median age 66 (38-75)/62 (38-75) years, PS=0 82%/82%, multiple site of disease 76%/77%. At a median follow up of 18 mos the study met its primary endpoint by improving PFS in the BV arm. We updated results and at a median follow up of 22 mos the improvement in PFS for the experimental arm was confirmed with a median PFS of 5.2 mos for arm A and 6.7 mos for arm B (HR=0.66; 95% CI 0.49–0.90; unstratified p=0.0072). Subgroup analyses showed a consistent benefit in all subgroups including gender (F: HR=0.63; M: HR=0.72) and first-line PFS (≤10 mos: HR=0.57; >10 mos: HR=0.71). Response rates (RECIST) were 18% and 21% (p=0.71). Toxicity profile was consistent with previously reported data. The OS data are still immature, with 56 events in arm A and 54 in arm B and the median OS is 16.0 mos and 16.5 mos respectively (HR=0.83; 95% CI 0.57-1.22; unstratified p=0.34). Conclusions: This study demonstrates an improvement in PFS by continuing BV in second-line in pts who had received CT+BV in first-line. Clinical trial information: NCT00720512.
Phase I dose escalation of the oral histone deacetylase inhibitor (HDACi) resminostat in combination with FOLFIRI in colorectal cancer (CRC) patients: The SHORE trial.
Authors: Schulze-Bergkamen Henning , Jaeger Dirk , Kopp Hans-Georg , Mayer Frank , Bitzer Michael , Mais Anna , Resemann Karin , Hauns Bernhard , Asche Julia , Henning Stefan W. , Hentsch Bernd
Published: March 2020

3625

Background: Resminostat is a novel oral HDAC inhibitor with broad activity in various cancer models. In CRC models, resminostat revealed synergistic effects with 5-FU and irinotecan/SN-38, indicating its (re-)sensitization potential when applied in combination therapy. Furthermore, resminostat downregulates thymidylate synthase, involved in drug resistance to 5-FU and effectively inhibits HDAC2, one of the target enzymes believed to critically support development of CRC. The phase I/II SHORE trial investigates resminostat in combination with FOLFIRI in patients previously treated with 5-FU. Methods: Patients (pts) with advanced CRC having previously received 5-FU alone or in combination with other agents who were scheduled for FOLFIRI in second or later treatment lines were included. The phase I comprised an open-label, inter-patient, ‘3+3’ dose escalation design with increasing doses of resminostat combined with standard FOLFIRI. Pts received resminostat on 5 consecutive days, followed by a 9-day drug free period (‘5+9’ scheme, i.e. 14-day cycles). On days 3 and 4 of each cycle (C), FOLFIRI was administered. Primary objective of the Phase I part was to determine safety and tolerability, the maximum tolerated dose and pharmacokinetics of the combination. Results: 17 pts (median age 61 yrs; 12 males; 11 ECOG 0; 6 ECOG 1; median therapy line 2 [2-6]) were enrolled in 4 dose levels of resminostat 200, 400, 600 mg QD (3 pts each) and 400 mg BID (6 pts) plus FOLFIRI. Two pts discontinued in C1 and were replaced. No DLT occurred. AEs consisted mainly of GI symptoms of mild and moderate intensity (nausea, vomiting and diarrhea) leading to decreased electrolyte plasma levels in some pts. In the highest dose level tested (400 mg BID) hematological toxicity, mainly neutropenia up to grade 4, was observed leading to dose reductions in 3 pts in C3 and C7. No objective responses were reported, however some pts showed SD for prolonged time (up to 32 w). Results of the completed phase I part will be reported. Conclusions: The combination of resminostat with standard FOLFIRI was safe and well tolerated warranting continuation into the Phase II part of the study. Clinical trial information: NCT01277406.
Time profile of adverse events (AEs) from regorafenib (REG) treatment for metastatic colorectal cancer (mCRC) in the phase III CORRECT study.
Authors: Grothey Axel , Sobrero Alberto F. , Siena Salvatore , Falcone Alfredo , Ychou Marc , Humblet Yves , Bouche Olivier , Mineur Laurent , Barone Carlo , Adenis Antoine , Argiles Guillem , Yoshino Takayuki , Lenz Heinz-Josef , Goldberg Richard M. , Sargent Daniel J. , Cihon Frank , Wagner Andrea , Cupit Lisa , Laurent Dirk , Van Cutsem Eric
Published: March 2020

3637

Background: In the CORRECT phase III trial, the multikinase inhibitor REG demonstrated significant improvement in overall survival and progression-free survival vs placebo (P) in patients with mCRC whose disease had progressed on other standard therapies. The most frequent grade 3 AEs were hand–foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash. We examined when these AEs first occurred and what impact they had on REG dosing. Methods: Adults with mCRC progressing after all standard therapies were randomized to receive REG 160 mg (n=505) or P (n=255) orally once daily for the first 3 weeks of each 4-week cycle. AEs were managed with dose modifications (reduction and interruption) according to the protocol. Results: The safety population comprised 753 pts (REG n=500, P n=253). The mean ± SD treatment duration was 12.1 ± 9.7 weeks for REG and 7.8 ± 5.2 weeks for P. Treatment-emergent AEs occurred in 99.6% of REG pts and 96.8% of P pts. AEs occurring in ≥10% more REG than P pts were fatigue, HFSR, anorexia, diarrhea, weight loss, voice changes, hypertension, rash/desquamation, oral mucositis, fever, hyperbilirubinemia, and low platelet count. The incidence of grade ≥3 HFSR, fatigue, hypertension, and rash/desquamation typically peaked in cycle 1 and tapered to a relatively stable lower incidence over later cycles, while the incidence of diarrhea remained relatively constant throughout the study; median time to first occurrence and worst grade of these AEs is shown in the table. AEs led to dose modifications in 66.6% of REG pts and 22.5% of P pts. Conclusions: The most common AEs in the REG group typically occurred early during treatment. Close early monitoring of AEs and proper management by dose modification is recommended. Clinical trial information: NCT01103323. [Table: see text]
Dual MEK/EGFR inhibition for advanced, chemotherapy-refractory pancreatic cancer: A multicenter phase II trial of selumetinib (AZD6244; ARRY-142886) plus erlotinib.
Authors: Ko Andrew H. , Tempero Margaret A. , Bekaii-Saab Tanios B. , Kuhn Peter , Courtin Ryan , Ziyeh Sharvina , Tahiri Sanaa , Kelley Robin Katie , Dito Elizabeth , Ong Anna , Linetskaya Regina , Mirzoeva Olga K. , Wu Christina Sing-Ying , Venook Alan Paul , Korn Wolfgang Michael
Published: March 2020

4014

Background: Pharmacologic inhibition of MEK leads to enhanced signaling through EGFR with hyperactivation of a parallel oncogenic pathway (PI3K) independent of mutant KRAS, supporting a therapeutic strategy of combined target inhibition in PDAC to overcome this negative feedback loop. Based on preclinical evidence of synergistic activity between EGFR and MEK inhibitors, we conducted a non-randomized phase II trial of erlotinib plus selumetinib, a selective, allosteric inhibitor of MEK1/2, in patients with PDAC who had received one prior line of chemotherapy. Methods: A Simon 2-stage design was used, with planned n = 46. Study treatment consisted of erlotinib 100 mg + selumetinib 100 mg daily in 3-week cycles, with CT evaluation every 2 cycles. 1o objective was overall survival (OS). Correlative studies include detection of circulating tumor cells using a novel nonenrichment high definition immunofluorescence assay, and tissue- and serum proteomic-based predictive biomarkers. Results: 46 patients enrolled at 2 sites between 1/2011 and 1/2013 (median age 67 y.o. [range 40-84]; ECOG PS (0/1): 31/15; prior gemcitabine-based vs. FOLFIRINOX vs. other 1st-line chemo: 34/10/2). Patients received a median of 2 cycles (range, 1-7). Of 41 evaluable patients to date, disease control rate is 51% (0 PR; 21 with stable disease (SD) > 6 weeks, 10 with SD > 12 weeks; 11 minor responses). 9/31 patients (29%) had CA19-9 decline > 50%. Estimated median PFS and OS by Kaplan-Meier are 2.6 and 7.5 months, respectively, with 21 patients still alive. Grade 3/4 AEs likely attributable to study treatment include rash (10 patients), hypertension (6), anemia (5), diarrhea (4), and nausea/vomiting (4); no study-related deaths have occurred. 38% of patients have required dose reduction of one/both agents. Conclusions: Dual targeting of MEK/EGFR signaling shows antitumor activity in PDAC in a subset of patients and warrants further exploration, possibly in combination with, or comparison to, cytotoxic therapy. Companion efforts are ongoing to assess candidate predictive markers of benefit to this combination. Supported by CTEP and NIH R21 CA149939. Clinical trial information: NCT01222689.
Cougar-02: A randomized phase III study of docetaxel versus active symptom control in patients with relapsed esophago-gastric adenocarcinoma.
Authors: Cook Natalie , Marshall Andrea , Blazeby Jane M. , Bridgewater John A. , Wadsley Jonathan , Coxon Fareeda Y. , Mansoor Wasat , Madhusudan Srinivasan , Falk Stephen , Middleton Gary William , Swinson Daniel , Chau Ian , Thompson Joyce , Cunningham David , Kareclas Paula , Dunn Janet A. , Ford Hugo
Published: March 2020

4023

Background: Survival in patients who relapse after first-line chemotherapy (CT) for advanced esophago-gastric adenocarcinoma (EGC) is poor though recently randomised trials (RCT) have suggested a small benefit for second line chemotherapy with taxanes or irinotecan. There is very little data on health related quality of life (HRQL) or overall survival (OS), particularly in patients who progress shortly after first-line therapy. Methods: COUGAR-02 was a multicentre open-label, phase III RCT for patients with locally advanced or metastatic EGC of performance status (PS) 0-2 who had progressed within 6 months of previous platinum/fluoropyrimidine CT. Patients were randomised (1:1) to receive either docetaxel 75mg/m2every 3 weeks for up to 6 cycles or active symptom control (ASC). The primary endpoint was OS. The secondary endpoint of HRQL, assessed using EORTC QLQ-C30 and QLQ-ST022, was analysed using standardised area under a curve and compared using Wilcoxon rank sum test. Sensitivity analysis adjusting for dropouts due to death were performed using quality adjusted survival. Results: 168 patients (84 patients in each arm) were recruited between April 2008 and April 2012. Median age was 65 years (range 28-84); 81% were males. PS at randomisation was 0 for 27%, 1 for 57% and 2 for 15%. 86% had metastatic disease. 43% progressed during previous CT, 28% progressed within 3 months of end of previous CT and 29% progressed between 3 and 6 months. Median number of cycles of docetaxel was 3. 23% completed 6 cycles. Docetaxel was well tolerated and resulted in a significantly improved OS over ASC alone (HR=0.67 (95% CI 0.49-0.92); p=0.01). Objective response rate was 7%. For QLQ-C30, patients on docetaxel arm reported significantly less pain (p=0.0008) and trend for less nausea and vomiting (p=0.02) and constipation (p=0.02) than those on ASC arm. Similar global HRQL seen (p=0.53).For QLQ-ST022, trend seen for less dysphagia (p=0.02) and pain symptoms (p=0.01) for patients on docetaxel arm than ASC Conclusions: Docetaxel provided a significant OS benefit over ASC with improvements in symptom scores and no loss in overall HRQL. Docetaxel can be considered a standard of care in this setting. Clinical trial information: NCT00978549.
Multicenter phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in pancreatic neuroendocrine tumor (PNET).
Authors: Hobday Timothy J. , Qin Rui , Moore Malcolm J. , Reidy Diane Lauren , Strosberg Jonathan R. , Kindler Hedy Lee , Shah Manisha H. , Lenz Heinz-Josef , Kaubisch Andreas , Chen Helen X. , Erlichman Charles
Published: March 2020

4032

Background: PNET has long had few effective therapies other than chemotherapy. Placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/PDGF receptor inhibitor sunitinib noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are still <10%. Preclinical studies suggest enhanced anti-tumor effects with combined mTOR and VEGF targeted therapy. Methods: We conducted a phase II trial of the mTOR inhibitor TEM (25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV q 2 weeks) in patients (pts) with well or moderately differentiated PNET and progressive disease by RECIST within 7 months of study entry. Co primary endpoints were RR and 6-month PFS. Planned enrollment was 50 patients, with interim analysis for futility after the first 25 evaluable pts. Pts had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate hematologic and organ function. Continued octreotide was allowed, but not required. Prior interferon, embolization, and ≤ 2 chemotherapy regimens were allowed. Results: 55 pts were eligible for response assessment. Confirmed PR was documented in 20 of 55 patients (37%). 44 of 55 (80%) patients were progression-free at 6 months. Of 49 pts evaluable for this endpoint, 12 month PFS is 49%. 15 patients remain on therapy. For evaluable patients, the most common grade 3-4 adverse events attributed to therapy were hypertension (18%), hyperglycemia (13%), fatigue (11%). leukopenia (9%), headache (9%), proteinuria (7%), and hypokalemia (7%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 37%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 80% in a population of patients with RECIST criteria progression within 7 months of study entry. Phase III trials of combined VEGF/mTOR inhibition in PNET should be pursued. Clinical trial information: NCT01010126.
Genetic, tissue, and plasma biomarkers of outcomes from a prospective study of neoadjuvant short course proton-based chemoradiation for resectable pancreatic ductal adenocarcinoma (PDAC).
Authors: Hong Theodore S. , Deshpande Vikram , Ancukiewicz Marek , Yeap Beow Y. , Borger Darrell R. , Wo Jennifer Yon-Li , Boucher Yves , Kwak Eunice Lee , Clark Jeffrey W. , Zhu Andrew X. , Blaszkowsky Lawrence Scott , Mamon Harvey J. , Jain Rakesh K. , Ryan David P. , DeLaney Thomas F. , Fernandez-del Castillo Carlos , Duda Dan G.
Published: March 2020

4047

Background: The prognosis of resectable PDAC reflects a complex interaction between genotype, growth factor levels, and tumor microenvironment. We performed genetic, plasma, and tissue-based biomarker analysis for a phase I/II study of neoadjuvant short course proton-based chemoradiation. Methods: Patients with radiographically resectable PDAC were treated on an IRB approved, phase I/II trial of neoadjuvant short course-proton-based chemoradiation. Genotyping included KRAS, BRAF, NRAS, TP53, and PIK3CA. Tissue-based IHC on resection specimens included DPC4, CXCR4, CXCR7, and SDF1a in the central and peripheral regions of PDAC. The trial was amended to evaluate plasma biomarkers, drawn before and after chemoradiation, including HGF, VEGF, sVEGFR2, SDF1α, bFGF, PlGF, TNF-α, CAIX, sFLT1, IL-6, IL-8, and IL-1β. Correlation with OS was evaluated by the Wald test in a univariable Cox regression using log-transformed covariates. Results: Surgical specimens from all 38 patients who underwent resection and serial plasma samples from the last 12 patients enrolled were analyzed. Disease-specific results were previously reported (ASCO 2012, abs 4021). DPC4 intact (37% of evaluated patients) was associated with oligometastatic disease (p<0.05) but not OS. KRAS mutation 31/38 patients (82%), did not affect OS (HR=1.57, p=0.88) , but the specific KRAS G12D mutation (14/38, 37%) had a worse OS (HR=2.44, p<0.05). SDF1α and CXCR7 expression was higher and CXCR4 expression was lower in the tumor center versus periphery. Higher CXCR7 expression in the periphery was associated with poor OS (HR=2.29, p<0.05). High baseline plasma HGF was associated with a worse OS (HR=6.60, p<0.05), with a trend for association between high post-treatment plasma HGF and poor OS (HR=9.28, p=0.08). No other biomarker evaluated was significantly associated with OS. Conclusions: In this exploratory analysis, KRAS G12D status, CXCR7 expression, and plasma HGF level were associated with worse OS. DPC4 status correlated with oligometastatic disease. Additional IHC evaluations, including c-MET expression, are ongoing and will be reported. Clinical trial information: NCT00438256.
Search for biomarkers of stage II/III gastric cancer and development of individualized therapy.
Authors: Oshima Takashi , Sakamoto Naoya , Yoshikawa Takaki , Rino Yasushi , Kunisaki Chikara , Yasui Wataru , Imada Toshio , Masuda Munetaka
Published: March 2020

4068

Background: Standard therapy for stage II/III gastric cancer is curative resection followed by adjuvant chemotherapy. Treatment outcomes are expected to be further improved by the development of individualized therapy based on new biomarkers. We have extracted mRNA from frozen specimens of gastric cancer to construct a cDNA bank and searched for new biomarkers of stage II/III gastric cancer. We report currently available results. Methods: The study group comprised 256 patients with stage II/III gastric cancer in whom at least 5 years had passed since surgery (among whom 149 received S-1 as adjuvant chemotherapy). A total of 130 genes were selected on the basis of the results of comprehensive DNA microarray analyses and extraction from serial analysis of gene expression (SAGE) libraries, and other studies. Relative expression levels of each gene in gastric cancer tissue and adjacent normal mucosa were measured by quantitative PCR, and the relations between clinicopathological factors and treatment outcomes were studied. In addition, using 9 types of gastric cancer cell lines, we knocked down the new cancer biomarkers obtained in this study with small interfering RNA (siRNA) and performed functional analysis. Results: In patients with resected stage II/III gastric cancer, INHBA, IGF-1R, CLDN7, and DPD genes were independent prognostic factors. In the subgroup of patients who received S-1-based adjuvant chemotherapy, IGF-1R, INHBA, SULF1, REG4, MMP11, and KIAA1199 genes were independent prognostic factors. Knockdown of the KIAA1199 gene with siRNA markedly inhibited the proliferative and invasive activities of the gastric cancer cell lines and lowered resistance to 5-fluorouracil. Conclusions: Investigatory studies of new biomarkers of gastric cancer identified prognostic factors for patients with resected stage II/III gastric cancer and those who received adjuvant chemotherapy with S-1. At present, the development of small molecule drugs that target KIAA1199 and the joint development of risk stratification tools with the goal of individualized therapy for stage II/III gastric cancer are ongoing.
A phase ll study of new combination regimen with trastuzumab, S-1, and CDDP in HER2-positive advanced gastric cancer (HERBIS-1).
Authors: Koeda Keisuke , Sugimoto Naotoshi , Tanaka Junji , Tsuda Masahiro , Okamoto Wataru , Okuda Hiroyuki , Imamura Hiroshi , Matsuyama Jin , Shimokawa Toshio , Sakai Daisuke , Fukushima Norimasa , Kurokawa Yukinori , Komatsu Yoshito , Tsujinaka Toshimasa , Furukawa Hiroshi
Published: March 2020

4072

Background: S-1, a novel oral fluoropyrimidine, plus cisplatin (SP) regimen is one of the standard chemotherapy as first-line for advanced gastric cancer. ToGA study demonstrated that trastuzumab (T-mab) combination regimen improved the overall survival of patients with HER2-positive advanced gastric cancer. However, there was no study evaluating the efficacy and the safety of T-mab in combination with S-1 plus cisplatin (SP) regimen. Therefore, we planned this study to examine the efficacy and the safety of the SP plus T-mab. Methods: Patients confirmed to be HER2-positive by IHC and/or FISH (IHC 3+ or IHC 2+ and FISH positive) received S-1 at 80 mg/m2 po, day 1-14, and cisplatin 60 mg/m2 iv, day 1 plus trastuzumab 8 mg/kg iv, day 1 (6 mg/kg iv, d1 from 2nd course), repeated every 3 weeks until disease progression. Primary endpoint was response rate (RR). Secondary endpoints were progression-free survival, overall survival and safety. The threshold response rate was defined as 35%, and the expected rate was set at 50% with a 80% power and a 1-sided alpha value of 0.1 and the calculated sample size was 50 patients. Results: A total of 56 patients (median age 66) were enrolled in this study. The efficacy and the safety analyses were conducted in the full analysis set of 53 patients. (Two patients were excluded for ineligibility and one was for no treatment). The confirmed RR assessed by the independent review committee was 67.9% (95% CI: 53.7 – 80.1), and the disease control rate was 94.3%. The median PFS was 7.1 months (95% CI: 6.0 – 10.1). The median OS was not reached. (The median follow-up time: 9.2 months) The main grade 3/4 adverse events were as follows: neutropenia 34%, leucopenia 8%, anorexia 23%, diarrhea 8%, hypoalbuminemia 4%, vomiting 6%, and increased creatinine 6%. Conclusions: This tri-week regimen with SP plus T-mab showed promising results in patients with HER2-positive advanced gastric cancer. Clinical trial information: UMIN000005739.
Prognostic impact of human epidermal growth factor-2 (HER2) status on overall survival (OS) of advanced gastric cancer (AGC) patients (pts) treated with standard chemotherapy without trastuzumab as a first-line treatment: A Japanese multicenter collaborative retrospective study.
Authors: Nishina Tomohiro , Fuse Nozomu , Kuwata Takeshi , Kadowaki Shigenori , Shinozaki Eiji , Machida Nozomu , Yuki Satoshi , Ooki Akira , Kajiura Shinya , Goji Takahiro , Yamanaka Takeharu , Sasaki Takahide , Shitara Kohei , Kuboki Yasutoshi , Yoshino Takayuki , Ochiai Atsushi , Ohtsu Atsushi
Published: March 2020

4075

Background: The prognostic impact of HER2 status on OS of AGC pts treated with standard chemotherapy without trastuzumab for first-line treatment remains controversial. This study investigated whether HER2 status is an independent prognostic factor for AGC pts. Methods: Formalin-fixed paraffin-embedded tumor samples from 293 eligible pts were examined for HER2 by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). Eligible criteria included: 1) histologically confirmed gastric or gastroesophageal junction adenocarcinoma, 2) unresectable or recurrent cancer, 3) treated with S-1 plus cisplatin as first-line chemotherapy, 4) age: ≥20, 5) ECOG performance status score: 0-2 and 6) with archived tumor sample. HER2+ was defined as IHC 3+ or IHC 2+/FISH+. Results: Of 293 pts, 43 (15%) were HER2+. Baseline pt characteristics between HER2+ and HER2- pts were significantly different by histology (intestinal/diffuse, 65%/35% vs. 39%/61%; p=0.001), measurable disease by RECIST v1.0 (91% vs. 69%; p=0.003), No. of metastatic sites (≥2, 72% vs. 46%; p=0.003) and presence of liver metastasis (56% vs. 31%; p=0.003). After median follow-up time of 48.9 months with 270 (92%) death events, there was no significant difference in OS between HER2+ and HER2- pts (median, 11.7 vs. 13.7 months; hazard ratio [HR] 1.11, 95% CI 0.79–1.55; log rank p=0.550). After adjusting other prognostic factors with Cox hazard model, HER2+ was still not prognostic for OS (HR 0.890, 95% CI 0.627–1.262, p=0.513). Conclusions: HER2 status has no significant prognostic impact on OS of AGC pts treated with S-1 plus cisplatin without trastuzumab as a first-line treatment.
Randomized phase II study comparing dose-escalated weekly paclitaxel versus standard dose weekly paclitaxel for patients with previously treated advanced gastric cancer.
Authors: Shitara Kohei , Yuki Satoshi , Takahari Daisuke , Nakamura Michio , Kondo Chihiro , Tsuda Takashi , Kii Takayuki , Tsuji Yasushi , Utsunomiya Setsuo , Ichikawa Daisuke , Hosokawa Ayumu , Ishiguro Atsushi , Sakai Daisuke , Hironaka Shuichi , Oze Isao , Matsuo Keitaro , Muro Kei
Published: March 2020

4076

Background: Retrospective analyses of neutropenia during chemotherapy of weekly paclitaxel (wPTX) suggested better overall survival (OS) among patients with neutropenia. We conducted a randomized phase II trial comparing dose-escalated wPTX with dose adjustments determined by degree of neutropenia versus standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC). Methods: Ninety-patients with AGC that progressed during one or more previous chemotherapy regimens were randomized to a standard dose of wPTX (80 mg/m2, standard dose arm) or an escalated dose of wPTX (80 mg/m2 on day 1, 100 mg/m2 on day 8, and 120 mg/m2 on day 15 unless severe toxicity nor neutropenia<1.5 x 109/L is observed, escalated dose arm) to assess superiority with a one-sided alpha of 0.3 and a power of 0.8. Results: The primary endpoint of median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs. 9.6 months; hazard ratio [HR], 0.75; 95% CI, 0.45-1.22; one-sided P=0.12). Median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs. 2.5 months, HR, 0.55; 95% CI, 0.34-0.90; P=0.017). Objective response rate was 30.3% with dose-escalation and 17.1% with standard dose (P=0.2). The disease control rate (DCR) was significantly higher with dose-escalation (78.8% vs. 48.6%, P=0.009). Subset-analysis according to stratification factors including ECOG PS, presence of measurable lesions and lines of previous chemotherapy indicated that OS benefit of the dose escalation is more prominent in PS 0-1 patients (N=81, median 13.6 vs. 9.8 months, HR 0.68, 95% CI 0.41-1.11) than PS2 patients with significant interaction (p=0.01) Conclusions: Dose escalated wPTX was associated with sufficiently longer OS in patients with pretreated AGC. In addition, significant longer PFS and higher DCR associated with dose-escalation and subset analysis according PS warrant further investigations in phase III trials, especially in patients with favorable PS patients. Clinical trial information: UMIN000004055.
Comprehensive genetic mutation analysis of human gastric adenocarcinomas.
Authors: Chen Jinfei , Xu Zhi , Huo Xinying , Gu Dongying , Wang Meilin , Tang Cuiju , Ye Hua , Zhang Zhengdong , Chen Si-Yi
Published: March 2020

4106

Background: Gastric cancer is the one of the major cause of cancer-related death, especially in Asia. Gastric adenocarcinoma, the most common type of gastric cancer, is heterogeneous and its incidence and cause varies widely with geographical regions, gender, ethnicity, and diet. Since unique mutations have been observed in individual human cancer sample, identification and characterization of the molecular alterations underlying individual gastric adenocarcinoma is a critical step for developing more effective, personalized therapies. Until recently, identifying genetic mutations in an individual basis by DNA sequencing remains a daunting task. The recent advance of new next-generation DNA sequencing technologies, such as the semiconductor-based Ion Torrent sequencing platform, makes DNA sequencing cheaper, faster and more reliable. Methods: In this study, we aim to identify genetic mutations in the genes, which are targeted by drugs in the clinical use or under development, in individual human adenocarcinoma sample by using Ion Torrent sequencing. We sequenced 739 loci from 46 cancer-related genes in 242 human gastric adenocarcinoma samples using the Ion Torrent Ampliseq Cancer Panel. Results: The sequencing analysis revealed frequent mutations in MLH1 (8.3%), MET (11.2%), KIT (21.5%), and PIK3CA (40.5%) genes in the human gastric adenocarcinomic samples. Many mutations that are not previously reported in gastric adenocarcinomas were also identified. Moreover, distinctive patterns and the combination of mutations in various sets of genes, including HER2, EGFR, MET, FGFR, PI3K/MTOR, MLH1, MET, KIT, PIK3CA, and P53, were also identified in these gastric adenocarcinoma samples. Conclusions: Thus, this study indicates the necessity of sequencing individual human adenocarcinoma in order to match the use of personalized single targeted drugs or two or more targeted drugs in combination against individual adenocarcinoma-specific mutations.
Association of YAP1 activation with poor patient prognosis and effect on chemoresistance in gastric cancer.
Authors: Lee Sung Sook , Oh Sang Cheul , Jeong Woojin , Lee Sang Ho , Kim Sang-Bae , Park Yun-Yong , Sohn Bo Hwa , Cheong Jae-Ho , Cho Jae Yong , Lim Jae Yun , Park Eun Sung , Jang You-Jin , Mok Young-Jae , Jung WonKyung , Kim Baek-Hui , Lee Keun-Wook , Tan Patrick , Noh Sung Hoon , Ajani Jaffer A. , Lee Ju-Seog
Published: March 2020

4113

Background: Clinical heterogeneity in gastric cancer is likely due to biological differences among patients. Molecular subtypes and their associated biomarkers need to be established to improve treatment of this disease. We aimed to uncover subgroups of gastric cancer that have distinct biological characteristics associated with clinical outcome and to identify potential best treatments or therapeutic targets for each subgroup. Methods: We analyzed gene expression profiling data from gastric cancer cell lines and 267 patients with gastric cancer to uncover tumor subtypes and identify a gene expression signature associated with prognosis and response to adjuvant chemotherapy. The association of the signature with prognosis was validated in an independent cohort of 200 patients, and its association with response to adjuvant therapy was validated by cell culture experiments. Results: We identified an expression signature of 88 genes that specifically reflected activation of the oncogene YAP1. Compared with patients without this signature, patients with the YAP1 signature had significantly poorer prognosis. In multivariate analysis, the signature was the strongest indicator of overall survival among all demographic and clinical variables examined together (hazard ratio, 2.1; 95% confidence interval, 1.3-3.3;P = .002). Activation of YAP1 was significantly associated with resistance to adjuvant chemotherapy. We also demonstrated that the Notch pathway is a potential therapeutic target for overcoming chemoresistance mediated by YAP1. Conclusions: Activation of the oncogene YAP1 is significantly associated with poorer survival of patients with gastric cancer and induces chemoresistance to this disease. Therefore, YAP1 may be highly attractive therapeutic target for patients with gastric cancer resistant to standard chemotherapy.
Gemcitabine and oxaliplatin (GEMOX) alone or with cetuximab in first-line treatment of advanced biliary cancers (ABC): Exploratory analyses according to tumor KRAS/BRAF mutations and EGFR expression in a randomized phase II trial (BINGO).
Authors: Malka David , Cervera Pascale , Heurteau-Foulon Stephanie , Wendum Dominique , Trarbach Tanja , De La Fouchardiere Christelle , Boucher Eveline , Fartoux Laetitia , Faivre Sandrine J. , Pignon Jean-Pierre , Rosmorduc Olivier , Greten Tim F.
Published: March 2020

4127

Background: Gemcitabine-platinum regimens are the standard of care for ABC. Whether GEMOX-cetuximab may be beneficial in ABC patients (pts) was tested in BINGO, an international, open-label, randomized phase II study (ASCO 2012). With a 4-month progression-free survival (PFS) rate of 63% [CI: 52-74], the primary endpoint was met (target, ≥60%; GEMOX, 54% [43-65]). However, median PFS (6.1 vs. 5.5 months) and overall survival (OS) (11.0 vs. 12.4 months) were similar in both arms. Available data on KRAS/BRAF mutation rates in ABC pts are sparse. Methods: Planned exploratory endpoints included tumor KRAS/BRAF mutational status (high-resolution melting and DNA sequencing) and EGFR expression score (immunohistochemistry [IHC]), and their impact on patient outcome according to treatment arm. Results: Tumor samples were collected for 91 (61%) consenting pts among the 150 randomized pts, and were suitable for DNA analysis and IHC in 75 (50%) and 77(51%) pts, respectively. Tumor KRAS and BRAF mutations (MT) were found in 14 (19%) and 4 (5%) pts, respectively. High EGFR score (≥ 200) was observed in 18 (23%) pts. 4-month PFS rates did not differ according to tumor KRAS MT (wild-type [WT] vs. MT: 62% vs. 57%, p=0.72), BRAF MT (61% vs. 75%, p=1.00) or EGFR score (≥ vs. <200: 56% vs. 63%, p=0.42) overall, or according to treatment arm (table). PFS and OS (log rank test) also did not significantly differ according to these biomarkers, overall or between treatment arms. Conclusions: Tumor KRAS/BRAF mutations and EGFR overexpression were found in 24% and 23% of pts respectively. With the limit of statistical power in these exploratory analyses, they had no statistically significant prognostic or predictive impact. Clinical trial information: 2007-001200-20. [Table: see text]
Use of the mitotic kinase aurora-A activation to predict outcome for primary duodenal adenocarcinoma.
Authors: Chen Jie , Wen Jing-Yun , Chen Zhan-Hong , Lin Qu , Ma Xiao-Kun , Wei Li , Li Xing , Wang Tian tian , Ruan Dan-Yun , Lin Ze-Xiao , Wan XiangBo , Liu Quentin , Wu Xiang-Yuan
Published: March 2020

4131

Background: We and others had proved that hypoxia-inducible factor-1α (HIF-1α) and transcriptionally upregulated Aurora-A were required for disease progression in several tumors. Methods: We addressed the clinicopathologic value of HIF-1α and Aurora-a in primary duodenal adenocarcinoma (PDA). Aurora-a and HIF-1α expression were semi-quantitative evaluated by immunohistochemistry in 140 PDA. Among which, 76 patients from one institute acted as training set, and 64 cases from another two institutes were used as testing set to validate the prognostic effect of Aurora-a and HIF-1α. Results: We found that Aurora-a was high or sufficient expressed in tumor zone, whereas low-expressed in the normal adjacent epithelia. Moreover, Aurora-a high expression, classified by training set ROC analysis-generated cutoff score, predicted an inferior overall survival both in testing set and training set. Multivariate Cox regression confirmed that Aurora-a was indeed an independent prognostic factor (Table). Contrary to previous studies, we did not detect any correlation between Aurora-a and HIF-1α in PDA. Additionally, survival analysis showed that HIF-1α level was not correlated with patient outcome (p = 0.466). Conclusions: Activation of Aurora-A, an independent negative prognostic biomarker, might be used to identify particular patients for more selective therapy. [Table: see text]
Cost-effectiveness and optimal diagnostic sequence of CT, MRI, and PET-CT in the management of colorectal liver metastases.
Authors: Yip Vincent S. , Colins Brendan , Koay Mei Y. , Tang Joseph , Wieshmann Hulya , Fenwick Stephen W. , Poston Graeme John , Malik Hassan Zakria
Published: March 2020

4132

Background: CT, PET-CT and MRI play a role in the decision making process in managing colorectal liver metastases (CRLM). This study aimed to determine the optimal sequence of these investigations in order to reduce the rate of futile laparotomy and improve cost effectiveness of treatment. Methods: All patients referred to our specialist multidisciplinary team (sMDT) with CRLM were reviewed to investigate specific reason(s) for not offering potentially curative surgery. Clinical parameters were recorded for analysis. Three hypothetical scenarios were derived for cost-effectiveness analyses: 1) “up-front” with all imaging prior to sMDT, 2) “sequential”, with individual imaging following each sMDT, and 3) “hybrid” with PET-CT and MRI after review of the initial CT scan. Results: 644 consecutive patients were reviewed. Following assessment of initial CT, 165 patients (26%) were referred for palliative chemotherapy. After further evaluation by PET +/- MRI, 307 patients proceeded for potentially curative resection. Of those excluded from surgery, 48% were following PET-CT. Median overall survival (OS) for the resection and palliative groups were 46 and 14 months respectively (p<0.001). Futile laparotomy rate was 5.5%.The optimum strategy of lowest average time to decision, and lowest average cost is the hybrid model. Cost-utility analyses demonstrated a saving of approx. £319 (USD$ 515) per patient compared to the other 2 models. Conclusions: Decision making regarding further imaging after initial CT scan for CRLM should be performed at the sMDT to minimise delays and maximise efficiency of resources allocation. Triple assessment with CT, PET and MRI and sMDT decision process may reduce risk of futile laparotomy. A hybrid model using PET and MRI following a sMDT discussion of the initial CT provides the most cost effective algorithm for the management of CRLM.