bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trastuzumab (TRA) in combination with different first-line chemotherapies for treatment of HER2-positive metastatic gastric or gastroesophageal junction cancer (MGC): Findings from the German noninterventional observational study HerMES.
Authors: Hegewisch-Becker Susanna , Moorahrend Enno , Kröning Hendrik , Petersen Volker , Hannig Carla , Pott Dirk , Tirier Christian , Lerchenmuller Christian A. , Schlag Rudolf , Schneider-Kappus Wolfgang , Kaechele Volker , Al-Batran Salah-Eddin 
Published: March 2020

4065 Background: The international phase III study ToGA has recently shown that TRA is effective in prolonging survival in HER2-positive MGC. However, few data are available for TRA as part of routine clinical practice. Methods: This non-interventional observational study was conducted to evaluate the efficacy, safety and feasibility of TRA in previously untreated pts with HER2-positive MGC. Results: Between Apr 2010 and Jan 2012, data from 110 pts were collected. All pts were evaluable for safety. Baseline pt characteristics were as follows: median age 63 yrs (range 29–88); gender (male 70%; female 29%); ECOG PS (0: 25%; 1: 50%; 2: 15%; 3: 5%); distant mets (91%); liver mets (54%), lymph node mets (35%); peritoneal carcinomatosis (23%). The median duration of TRA treatment was 4.4 months (0–17.1). According to the schedule of chemotherapy TRA was administered every 2–3 wks in a median dose of 4–6 mg/kg BW. Only 28% of pts received TRA according to the label in combination with cisplatin and 5-FU or capecitabine. The remainder received: cisplatin, 5-FU and leucovorin (17%); 5-FU, leucovorin, oxaliplatin and docetaxel (8%); 5-FU, leucovorin and oxaliplatin (7%); capecitabine (6%); other combinations (25%); TRA monotherapy (7%). Although most pts didn’t receive cisplatin-based therapy, preliminary median progression-free survival was 6.8 months, thus comparable to the ToGA data. Most common adverse events (AEs, all grades) were diarrhoea (7%), vomiting (5%) and nausea (5%). Most common grade 3/4 AEs were vomiting (3%), nausea (2%) and fatigue (2%). Health-related quality of life as assessed by EORTC QLQ-C30 and QLQ-STO22 remained stable during observation time. An updated analysis of approx. 200 pts will be presented at the meeting. Conclusions: TRA combined with diverse chemotherapies is safe and effective in the routine treatment of MGC. Cisplatin-free less toxic regimens are feasible and equally effective. The results are in line with those from the ToGA trial and suggest that treatment with TRA should be regarded as standard of care for pts with HER2-positive MGC.
Measuring transcripts of components of the BRCA1 DNA repair pathway, components of the hippo-YAP pathway, β-TrCP, HER2, AEG-1, EZH2 and other genes in advanced gastric cancer.
Authors: Wei Jia , Costa Carlota , Liu Baorui , Sanchez Jose Javier , Gimenez Capitan Ana , Yu Lixia , Zou Zhengyun , Qian Xiaoping , Sun Xia , Shen Jie , Mayo Clara , Molina-Vila Miguel Angel , Benlloch Susana , Taron Miquel , Rosell Rafael 
Published: March 2020

4068 Background: The primary goal of this study was to classify gastric cancer in two different sub-groups. We speculated that HER2-positive gastric cancers could be regulated by β-TrCP, while tumors unaffected by β-TrCP activation could be more dependent on the Hippo-YAP signaling pathway, in which TAZ increases the expression of AXL. Gastric cancer can overexpress AEG-1 and EZH2. The relationship between EZH2 and the Hippo-YAP pathway was explored in this study. We also explored BRCA1 complexes, including upstream components, such as 53BP1 and MMSET. Methods: Paraffin-embedded samples were collected from 132 advanced gastric cancer patients (p) treated with first-line FOLFOX, 58 of whom received second-line docetaxel-based treatment. Gene expression levels of HER2, β-TrCP, TAZ, AXL, EZH2, AEG-1, BRCA1, and genes involved in DNA repair pathways (RAP80, PIAS1, PIAS4, MDC1, 53BP1, MMSET, and UBC9) were quantified by real-time PCR. BIM, IDO, and SPINK1 were also examined. Results: A close correlation was found for the majority of the genes, for example, BRCA1-MMSET (rho=0.28; P=0.002) and AXL-TAZ (rho=0.58; P>0.001). Median overall survival (OS) was 12.5 months (m). Among the 58 p receiving second-line docetaxel, in p with high levels of BRCA1, OS was 24.9 m, while it was 19.1 m in p with intermediate levels and 9.5 m in p with low levels (P=0.009). OS was 28.6 in p with high levels of MMSET, 13.8 in p with intermediate levels and 12.3 in p with low levels (P=0.001). In the multivariate analysis, only BRCA1 was a significant marker for OS (Table). Conclusions: The study showed the predictive value of BRCA1, which could be useful for customizing chemotherapy with or without docetaxel. In addition, MMSET requires further study since it is involved in DNA repair upstream of BRCA1. [Table: see text]
Cetuximab, paclitaxel, cisplatin and concurrent radiation in Chinese patients with locally advanced esophageal squamous cell carcinoma: An open-label, multicenter, phase II study.
Authors: Yu Jinming , Meng Xue , Wang Jian hua , Sun Xindong , Wang Lv hua , Ye Ming , Feng Ping bo , Zhu Guang ying , Lu You , Han Chun , Zhu Shu chai , Liao Zhongxing X. 
Published: March 2020

4073 Background: In China more than 90% of esophageal malignancies are of squamous cell carcinoma (SCC). We conducted this Chinese multicenter trial to determine the efficacy and safety of the addition of cetuximab with paclitaxel, cisplatin, and concurrent radiation for patients with esophageal SCC and to determine whether KRAS status predicts response. Methods: Patients with unresectable locally advanced cervical, upper or mid-esophageal SCC without distant metastasis were eligible for this open-label phase II trial. All patients received cetuximab (400 mg/m2 day 1 before chemoradiotherapy and 250 mg/m2 q1w × 7 weeks), paclitaxel (45 mg/m2 q1w × 7 weeks) and cisplatin (20 mg/m2 q1w × 7 weeks) with 59.4 Gy of radiation. The primary end point was response rate. Second end points included toxicity, overall survival (OS), progression-free survival (PFS), and KRAS mutation status. Results: Fifty-five patients were enrolled and evaluable to safety. Non-hematological adverse events were generally grade 1 or 2, and were most often rash (94.5%), mucositis (58.2%), fatigue (45.5%), nausea (41.8%) and hepatic dyfunction (40%). Hematologic adverse events included grade 3 neutropenia (32.7%) and grade 3 anemia (1.82%). Ten patients did not complete the protocol therapy (6 for chemotherapy dose delays, 1 for paciltaxel hypersensitivity, 1 by the treating physicians for unstated reasons, 1 for concurrent unrelated infection, and 1 for tracheo-esophageal fistula). The response rate was 97.7%. The 1-year OS and median OS was 87.3% and 16.8 months, the 1-year PFS and median PFS was 30.4% and 13.9 months, respectively. No mutations were detected at KRAS codons 12 or 13 in the 52 available specimens. Conclusions: Cetuximab can be safely administered with chemoradiation for Chinese patients with esophageal cancer and may improve the clinical response rate. KRAS mutations were too rare to be analyzed as a predictor of response.
Prognostic impact of FHIT, APC, and HER2 status in resected gastric cancer: A clinical-biological risk stratification model.
Authors: Bria Emilio , Barbi Stefano , De Manzoni Giovanni , Beghelli Stefania , Tomezzoli Anna , Frizziero Melissa , Sperduti Isabella , Bersani Samantha , Tortora Giampaolo , Scarpa Aldo 
Published: March 2020

4076 Background: The dismal prognosis of gastric cancer prompts for the identification of factors predictive of survival/response to treatment. The potential prognostic value of 11 molecular markers was investigated in a retrospective series of 208 resected gastric cancers. Methods: Molecular/clinicopathological data were correlated to cancer-specific/overall survival (CSS/OS) using a Cox model. Molecular data were: microsatellite instability, CDX2, APC, ß-catenin, E-Cadherin, FHIT, P53, p21, HER-2 (IHC/FISH), TOPO2A amplification (FISH) e PIK3CA mutation (exons 9/20). ROC analysis provided optimal cut-offs and model validation. A logistic equation with regression analysis coefficients was constructed to estimate individual patients’ probability (IPP) of death. Internal cross-validation (100 simulations, 80% of the dataset) was accomplished. Multivariate model Ratios served to derive a prognostic continuous score to identify risk classes. Results: 208 patients were studied (median follow-up 16 months, range 1-155). Multivariate analysis selected 8 independent CSS predictors: sex (HR 1.53, p=0.04), stage (HR 5.40, p<0.0001), R (HR 2.69, p<0.0001), localization (HR 1.64, p=0.008), LN (HR 1.55, p=0.02), APC (HR 1.91, p=0.001), FHIT (HR 1.54, p=0.05) and HER-2 (HR 1.92, p=0.08). Independent OS predictors were: sex, age, stage, R, localization, LN, APC and HER-2. Cross-validation analysis confirmed APC, FHIT and HER-2 as the biological variables displaying significant correlation with CSS (replication: 98%, 51%, 31%). The multivariate model predicted a 2-yr IPP of cancer-death/death with a prognostic accuracy of 0.87 (SE 0.02)/0.91 (SE 0.02). A 2-class risk stratification model was developed with the ROC generated cut-off prognostic score (AUC 0.87, SE 0.03; Sensitivity 85.3%, Specificity 78.9%); see table below. This 2-class model has a prognostic performance for CSS/OS of 0.82 (SE 0.03)/0.81 (SE 0.02). Conclusions: FHIT, APC and HER-2 represent powerful prognostic factors for resected GC and may complement clinical parameters to accurately predict individual patient risk. [Table: see text]
Phase II trial of tesetaxel, an oral taxane, as second-line therapy for patients with advanced gastroesophageal cancer.
Authors: Mulcahy Mary Frances , Baker Jackie S. , Sun Weijing , Rha Sun Young , Danesi Hassan , Itri Loretta , Ajani Jaffer A. 
Published: March 2020

4077 Background: Tesetaxel is a novel, orally administered taxane. It is not a substrate for P-glycoprotein, and preclinical data suggest tesetaxel has potent antitumor activity that exceeds standard taxanes in human tumor xenografts while causing substantially less neuropathy. Tesetaxel is not associated with hypersensitivity, thus eliminating the need for premedication and extended observation. A prior study showed an overall major response rate (ORR) of 20% with tesetaxel used as 2nd-line therapy in patients (pts) with advanced gastric cancer. We previously showed that “flat” (i.e., non weight-based) dosing with tesetaxel was associated with excessive variability; therefore, we amended the final trial design to evaluate whether we could extend the prior observations in a confirmatory Phase 2 trial using the MTD. Methods: Eligibility included: adenocarcinoma of stomach/GE junction; 1 prior fluoropyrimidine-platinum regimen; ECOG PS 0-1; and adequate organ function. Tesetaxel was administered orally once every 3 weeks starting at 27 mg/m2 escalated to 35 mg mg/m2 pending tolerance. ORR was the primary endpoint; estimated overall survival (OS) was secondary. Results: To date, 24 pts -- from a final target of 27 – have been enrolled (10 men, 14 women; median age, 58 yrs [range, 26-81]). Preliminary ORR in 15 evaluable cases to date are shown in the table below. At this time, only 4 pts have died and median survival is too early to estimate. Grade 3-4 adverse events have included neutropenia (27%), anemia, fatigue (13% each), and anorexia (7%). One pt (7%) experienced Grade 3 peripheral neuropathy. There have been no episodes of febrile neutropenia. Conclusions: Oral tesetaxel administered once every 3 weeks is active against gastric cancer in the 2nd-line setting. The observed 20% ORR confirms earlier data and appears at least equivalent to docetaxel (ORR= 5%-19%), as reported in 4 prior studies in this population. Tesetaxel was well tolerated and was not been associated with hypersensitivity. We expect to present final ORR and estimated OS from this trial. [Table: see text]
A phase II study of tivantinib monotherapy in patients with previously treated advanced or recurrent gastric cancer.
Authors: Muro Kei , Ryu Min-Hee , Yasui Hirofumi , Nishina Tomohiro , Ryoo Baek-Yeol , Boku Narikazu , Kang Yoon-Koo 
Published: March 2020

4082 Background: Tivantinib is a selective, non-ATP competitive, small-molecule inhibitor of c-MET and is under development in several cancers such as NSCLC and HCC. Elevated expressions of c-MET and its ligand, hepatocyte growth factor, have been frequently found in gastric cancer, and are associated with a more aggressive phenotype. In this single-arm phase II study, we evaluated the efficacy of tivantinib monotherapy in Asian patients (pts) with previously treated metastatic gastric cancer (MGC). This is the first clinical trial evaluating the efficacy of a selective c-MET inhibitor for MGC. Methods: Eligibility criteria included MGC with at least 1 measurable lesion per RECIST; 1 or 2 prior chemotherapy regimens; ECOG PS 0 or 1; and normal CYP2C19 metabolism. Tivantinib was daily administered 360 mg bid orally. The primary endpoint was disease control rate (DCR) defined as CR, PR or SD after 8 weeks administration. Pretreatment tumor tissue collection was required to evaluate the relationship between biomarkers and efficacy. Pharmacokinetic (PK) evaluation was also conducted. Results: Thirty patients received tivantinib and were eligible for analysis: median age 62.5 (41-70) years; ECOG PS 0/1 (8/22); 1/2 prior regimen (16/14); 12 pts (40%) with prior gastrectomy. No objective response was observed, and DCR was 36.7% (11/30 pts). Median progression-free survival was 43 (95% CI: 29.0-92.0) days. Grade 3 or 4 adverse events (AEs) occurred in 13 pts (43.3%), in which neutropenia (n = 4) and anemia (n = 4) were recognized as drug-related. Only 2 pts discontinued due to AEs. There is no treatment-related death and novel safety concern. c-MET gene amplification (≥ 5 copies/cell) was observed in 4 pts (13.3%). No obvious relationship of treatment outcome with biomarkers including c-MET gene amplification, c-MET, p-c-MET and HGF expression in tumor and serum HGF was identified. Gastrectomy and/or ethnicity (Korean or Japanese) did not affect PK parameters. Conclusions: Tivantinib as a monotherapy showed only a modest efficacy in previously treated MGC, and further trial testing in combination would be warranted in MGC. It would be an important finding that gastrectomy do not affect PK profile of tivantinib.
Assessment of HER2 status from an epidemiology study in tumor tissue samples of gastric and gastro-esophageal junction cancer: Spanish results of the HER-EAGLE study.
Authors: Gomez Lourdes , Concha Angel , Garcia-Caballero Tomas , Busteros Jose Ignacio , Burgos Emilio , Company Maria , Landolfi Stefania , Ruiz Irune , Gonzalez-Carrero Joaquin , Ortiz Duran Rosa Maria , Ibanez Martinez Jose , Martinez Carmen , Iglesias Mar , Florez Maria del Pino , Peligros Isabel , Rodriguez Rufo , Musulen Eva , Leon Paola Beatriz , Parra Juan Francisco , Vilardell Felip 
Published: March 2020

4089 Background: Overexpression of HER2 is an important biomarker in gastroesophageal junction (GEJ) and gastric cancer (GC) and a predictive factor for trastuzumab (T, Herceptin). The ToGA phase III trial showed the benefit in overall survival of adding trastuzumab to chemotherapy inHER2-positive advanced GEJ/GC patients, following validated scoring criteria by a central laboratory. This study examines the incidence of HER2 positivity (local laboratories) in GEJ/GC according to EMA Herceptin label. Methods: HER-EAGLE was an epidemiological, non–interventional, international study assessing HER2 status by IHC/ISH in tumor samples from any stage GEJ/GC patients. Neutral buffered 10% formalin embedded tissues (surgical excision specimens or minimum 6-8 biopsies) analyzed via validated Ventana and Dako methods and scoring criteria used in ToGA: HER2-positive if IHC 3+ or IHC 2+ (FISH/SISH confirmed; HER2/CEP17 ratio ≥ 2.0); HER2-negative if IHC 0 or IHC 1+. Overall and subgroup estimates calculated with 95%CI. Data from the Spanish cohort are presented. Results: The Spanish cohort of HER-EAGLE included 1,954 participants (63.7% males) from 33 hospitals (Dec2010 to Aug2011), with 469 biopsies (24.0%) and 1,479 excisions (75.7%). Samples were 13.7% GEJ and 86.3% GC, and the adenocarcinomas were 1,137 intestinal (58.2%), 510 diffused (26.1%), 163 mixed (8.3%; Laureen classification), and 144 not available (7.3%). Median time from sampling to HER2 analysis of 5.1 years (range from days to 12 years). Total of 210 cases tested IHC 3+ (10.7%), 215 IHC 2+ (11.0%), 308 IHC 1+ (15.8%), and 1,221 IHC 0 (62.5%). Overall, HER2 positivity (IHC 3+ or IHC2+/ISH+) was 14.1% (95%CI 12.61 – 15.75). HER2 positivity by histological type was higher in intestinal adenocarcinomas (19.5%) compared to diffused (4.5%) or in mixed (9.2%). Conclusions: HER-EAGLE confirmed the feasibility of community based HER2 testing in GC as the first study with a high number of samples analyzed by local laboratories. The incidence of HER2-positivity (EMA label definition) was similar to the ToGA screening population, and it was again higher in adenocarcinomas of intestinal type (19.5%).
Positive association of gastric cancer surgery outcome with surgeon specialization in a Shanghai high-volume general hospital.
Authors: Shen Zhenbin , Sun Yihong , Wang Cong , Zhao Naiqing , Chen Weidong , Wang Xuefei , Wang Hongshan , Fang Yong , Liu Fenlin , Tang Zhaoqing , Wang Yanna , Li Haojie , Piao Yongzhe , Chu Laura , Wang Lisa , Dong Wei , Qin Xinyu 
Published: March 2020

4092 Background: Numerous studies suggest positive relationship between hospital volume and cancer treatment outcomes, the surgeon’s experience and specialty training may also be important. This was examined in a high volume hospital in Shanghai among patients who underwent gastric cancer (GC) surgery. Methods: Data on consecutive patients (pts) undergoing R0 or R1 GC resection in Zhongshan hospital between January 2003 and June 2010 were collected and analyzed. Follow-up on pts who were non-Shanghai residents were less complete therefore excluded. Post-operative mortality, pathologic results and survival outcome for pts treated by surgical training, i.e., sub-specialized vs., non-specialized, were obtained. Survival was calculated by the Kaplan-Meier method and Log-rank test was used to determine statistical significance. To determine whether sub-specialty surgical training was an independent factor for overall survival (OS), univariate and multivariate analyses were performed using Cox proportional hazards regression. Results: Total 5,046 pts underwent R0 or R1 GC resection were identified.1594 pts had complete covariate data, survival information and were included in the study. Of them, the sub-specialized group included 217 cases treated by 3 surgeons, while the non-specialized group included 1377 cases treated by 52 surgeons. 5-year cumulative OS was higher in the sub-specialized group (62.9% vs. 54.6%, p=0.032). Multivariate analysis showed that tumor stage(p<0.001), location of tumor (p=0.003), vascular invasion (p<0.001) and surgeon (HR=1.54, p=0.001) were all associated with OS. The incidence of positive margin was higher in non-specialized group (2.0% vs. 2.7%, p<0.001) and the probability of retrieved lymph nodes less than 15 was more in non-specialized group (25.9% vs. 7.3%, p<0.001). Postoperative mortality was also higher in non-specialized group than in specialized group(1.5% vs. 0.9%, p<0.001). Conclusions: In high volume general hospital, sub-specialty training is desirable in gastric cancer surgery, the quality of gastric cancer surgery can be further improved by sub-specialty training leading to better treatment outcome.
A phase I/II study of AZD6244 in combination with sorafenib in advanced hepatocellular carcinoma.
Authors: Choo Su Pin , Ng Quan Sing , Chen Wallace Jian Jun , Tham Chee Kian , Yong Wei-Peng , Wang Ling Zhi , Koh Tong San , Goh Boon C. , Thng Choon Hua , Huynh Hung The , Zee Ying Kiat , Low Li shan , Toh Han Chong 
Published: March 2020

4100^ Background: Preclinical studies have shown that pharmacological inhibition of the MEK/ERK pathway by AZD6244 enhanced the anti-tumor effect of sorafenib in both orthotopic and ectopic models of HCC. We conducted this study to determine tolerability, pharmacokinetics, and pharmacodynamics of AZD6244 when combined with sorafenib in advanced HCC. Methods: Patients with biopsy-proven unresectable BCLC B/C hepatocellular carcinoma were recruited. Only those with Childs-Pugh A or B (7) liver cirrhosis and without prior systemic therapy were included. Sorafenib at 400mg bd was given 1 week before initiation of AZD6244 which was escalated in subsequent cohorts from 75mg om based on 3+3 design. PK and PD studies and QOL assessments were performed. DCE-MRI imaging was performed to assess tumor vascularity in response to treatment. Results: Fourteen patients were recruited (including 2 replaced). 11 had evaluable disease. Characteristics: all male, all Chinese, 12 were BCLC C stage. Two DLTs were seen out of 6 patients at dose level 1 (AZD6244 at 50mg bd) which were grade 3 fatigue and grade 3 abdominal pain with elevated transaminases. When an additional dose level 1A was added (ADZ6244 at 100mg om), 2 out of 3 patients had DLTs of grade 3 raised aspartate transaminase and grade 3 diarrhea. Thus, the MTD was determined to be AZD6244 at 75mg om when combined with sorafenib 400mg bd. Common toxicities were diarrhea (83%), rash (58%), fatigue (50%), hypertension (42%), anorexia/vomiting/thrombocytopenia (25%). Two patients had reversible LVEF dysfunction and there were no eye toxicities. PK of AZD6244 showed oral clearance of 11.2 + 6.8 L/h and terminal half-life of 6.0 +2.0 h.Objective responses were 3 PR, 6 SD and 2 PD.DCE-MRI measurements demonstrated significant reductions in permeability surface area product (PS, ml/100ml/min) and fractional intravascular blood volume (v1, ml/100ml) seven days after starting sorafenib. No additional antivascular activity was observed when AZD6244 was added to sorafenib. Conclusions: The recommended phase II dose for AZD6244 is 75mg om when combined with sorafenib 400mg bd for advanced HCC patients. This combination is feasible, shows activity and warrants further investigation.