bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II feasibility trial of neoadjuvant chemoradiotherapy combined with atezolizumab for resectable esophageal adenocarcinoma: The PERFECT trial.
Authors: van den Ende Tom , de Clercq Nicolien C. , van Berge Henegouwen Mark I. , Gisbertz Suzanne S. , Meijer Sybren L. , Schokker Sandor , Bergman Jacques J.G.H.M. , Haj Mohammad Nadia , Ruurda Jelle P. , van Hillegersberg Richard , Mook Stella , Nieuwdorp Max , Soeratram Tanya T.D. , Ylstra Bauke , van Grieken Nicole C.T. , de Gruijl Tanja D. , Bijlsma Maarten F. , Hulshof Maarten C.C.M. , Van Laarhoven Hanneke W.M. 
Published: May 2019

4045 Background: The CROSS study demonstrated the superiority of neoadjuvant chemoradiotherapy (nCRT) over surgery alone (van Hagen et al. NEJM. 2012). However, for resectable esophageal adenocarcinoma (rEAC) 5y survival is only 43%. PD1/PDL1 checkpoint inhibitors have shown promising efficacy for several cancer types, including esophageal cancer. To further improve outcomes in rEAC, we performed a phase II trial of nCRT combined with atezolizumab, a PD-L1 inhibitor. Methods: Pts with rEAC received standard dose CROSS regimen (5 cycles of IV: carboplatin AUC2, paclitaxel 50 mg/m2 and concurrent 23 fractions of 1.8 Gy on weekdays) with atezolizumab (5 cycles: 1200 mg IV, 3 weekly). Primary endpoint was the percentage of pts completing treatment with atezolizumab. Secondary endpoints included: toxicity, post-operative complications (Clavien-Dindo), Mandard score, R0 resection rate, PFS and OS. In total 40 pts will be enrolled. Results: Since July 2017, 39 pts have been enrolled (87% males, median age 63). Neoadjuvant treatment was completed by 31 pts and is ongoing in 8 pts. All cycles/fractions of nCRT were administered in 29/31 pts; 26 pts completed all cycles of atezolizumab, 24 pts finished complete neoadjuvant treatment. Reasons for missing any cycle of chemotherapy/atezolizumab included: toxicity (6 pts, in 3/6 pts immune-related adverse events (irAE)) and progression (1 pt). Grade 3-4 toxicity was observed in 15/31 pts (6/31 irAEs of any grade) which did not delay surgery. Thus far 23/31 pts were resected, 3 pts are planned for surgery, 3 pts had interval metastases preoperatively, 1 pt died during treatment (pulmonary embolism), and 1 pt declined surgery. Clavien-Dindo grade 3-4 complications were seen in 11/23 pts with no surgery related mortality. A pathological complete response (pCR), Mandard 1 was seen in 9/23 (39%) pts. All patients underwent an R0 resection. Updated results will be presented at the meeting. Conclusions: Based on data thus far, atezolizumab added to nCRT is feasible. A pCR was observed in 39% of patients, which is promising compared to 23% in the CROSS study. Treatment is associated with irAE which are manageable. Biomarker research will be performed on blood (circulating tumor DNA), tissue (immune microenvironment) and feces (microbiome). Clinical trial information: NCT03087864.
Clinical and molecular factors predicting resistance to first-line (1L) FOLFOX in patients (pts) with advanced esophagogastric cancer (EGA) and patterns of subsequent therapy.
Authors: Greally Megan , Walch Henry S , Chou Joanne F , Capanu Marinela , Kelsen David Paul , Ilson David H. , Janjigian Yelena Yuriy , Schultz Nikolaus , Ku Geoffrey Yuyat 
Published: May 2019

4047 Background: In the US, FOLFOX is the most widely used 1L treatment for advanced EGA. We evaluated if FOLFOX resistance (FR) impacted subsequent therapy and characterized the clinical and molecular factors that predict resistance to 1L FOLFOX. Methods: We reviewed pts with advanced Her2-negative EGA treated with 1L FOLFOX from Jan 2013 to Aug 2017. Response or stable disease (SD) at time of first restaging scan defined pts as FOLFOX sensitive (FS); progression defined FR. Pt characteristics were compared using Fisher’s exact and Wilcoxon Rank-Sum tests. Outcomes were correlated with clinical variables and MSK-IMPACT data. Microsatellite instable (MSI) pts were excluded from gene and pathway analysis. Overall survival (OS) was calculated from start of FOLFOX using Kaplan-Meier methods. Landmark analysis (2 months [mo] after starting FOLFOX) was used to compare OS between groups. Results: We identified 311 pts, median age 62, 73% male, 82% ECOG 0/1. 246 pts (79%) were FS and 65 (21%) were FR. FR pts had a higher number of metastatic sites, p = 0.001. Median OS was 13.4 mo in FS pts vs 4.3 mo in FR pts (p < 0.001). At time of analysis, 213 pts (172 FS pts and 41 FR pts) and 110 pts (90 FS pts and 20 FR pts) had received 2nd-line (2L) and 3rd-line (3L) chemo respectively. In pts who received 2L chemo (ctx), there was no difference in ctx duration between FS and FR pts (2.1 vs 1.4 mo, p = 0.67). However, in pts who received 3L ctx, the duration was longer in FS vs FR pts (1.6 vs 0.5 months, p = 0.002). In IMPACT tested pts (n = 130), univariate analysis identified EGFR (33.3% vs 10.7%, p = 0.032) and WNT pathway (26.7% vs 4.9%, p = 0.015) alterations more frequently in FR pts vs FS pts. 12 pts were MSI, all were FS (3 SD, 8 PR, 1 CR). Of 63 pts who had IMPACT germline testing, 7 (11%) had germline mutations identified, including CDH1 (n = 2) and ATM (n = 1), all were FS. No pts were enrolled on genotype-matched trials as a result of IMPACT testing. Conclusions: From time of first restaging scan, FR pts have inferior OS to FS pts. The duration of 3L ctx was longer in FS vs FR pts. Higher number of metastatic sites and EGFR and WNT pathway alterations were associated with FR; MSI was not. IMPACT did not facilitate enrolment on genotype-matched studies.
Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab.
Authors: Masuda Ken , Shoji Hirokazu , Nagashima Kengo , Yamamoto Shun , Ishikawa Masashi , Imazeki Hiroshi , Aoki Masahiko , Miyamoto Takahiro , Hirano Hidekazu , Honma Yoshitaka , Iwasa Satoru , Okita Natsuko , Takashima Atsuo , Kato Ken , Boku Narikazu 
Published: May 2019

4049 Background: Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with clinical benefit in patients with melanoma or lung cancer. In advanced gastric cancer (AGC) patients, there have been few reports about the correlation between irAEs and efficacy of immune checkpoint inhibitors. Therefore, in this study, we retrospectively investigated the correlation between irAEs and efficacy in AGC patients treated with nivolumab. Methods: The subjects of this study were AGC patients that had received nivolumab monotherapy between January 2015 and August 2018. IrAEs were defined as those AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy and/or endocrine therapy. We divided the patients who received nivolumab into two groups based on occurrence of irAEs; those with irAEs (irAE group) or those without (non-irAE group). We assessed the efficacy in both groups. Results: Of the 65 AGC patients that received nivolumab monotherapy, 14 developed irAEs. The median time to onset of irAEs was 30.5 days (range 3–407 days). Median follow-up period for survivors was 32 months (95% CI, 10.8 to 34.5). The median progression-free survival was 7.5 months (95% CI, 3.6 to 11.5) in the irAE group and 1.4 months (95% CI, 1.2 to 1.6) in the non-irAE group (HR = 0.11, p < 0.001). The median overall survival was 16.8 months (95% CI, 4.4 to not reached) in the irAE group and 3.2 months (95% CI, 2.2 to 4.1) in the non-irAE group (HR = 0.17, p < 0.001). Multivariate analysis demonstrated that high ALP level (HR = 2.88; 95% CI, 1.51 to 5.51) and absence of irAEs (HR = 3.06, 95% CI, 3.06 to 23.46 for yes vs. no) were associated with a poor prognosis. The most frequent irAEs was diarrhea/colitis (n = 5). Grade 3 adverse events were observed in 6 patients; hyperglycemia (n = 2), diarrhea/colitis (n = 1), adrenal insufficiency (n = 1), increased aspartate aminotransferase increased (n = 1), peripheral motor neuropathy (n = 1). One of the 14 patients experienced the irAE after discontinuation of nivolumab due to progression of disease. There were no grade 4 or 5 adverse events related to nivolumab. Conclusions: Development of irAEs was associated with clinical benefit for AGC patients receiving nivolumab monotherapy.
Molecular comparison between peritoneal metastases (PM) and primary gastric (GC) and gastroesophageal junction (GEJ) cancer.
Authors: Stein Matthew K , Xiu Joanne , Martin Michael Gary , Grothey Axel , Prouet Philippe , Owsley Jeffrey , Williard Forrest W , Glazer Evan Scott , Dickson Paxton Vandiver , Shibata David , Yakoub Danny , Goldberg Richard M. , Korn W. Michael , Shields Anthony Frank , Hwang Jimmy J. , Lenz Heinz-Josef , Deneve Jeremiah Lee 
Published: May 2019

4053 Background: PM from GC or GEJ portend a poor prognosis and molecular differences are ill defined. Methods: We compared genomic profiles of primary (P) GC and GEJ with PM patients (pts) and other metastases (OM) sent to Caris Life Sciences. Testing comprised immunohistochemistry (IHC) including programmed death ligand 1 (PD-L1) combined positive score (CPS), copy number alterations (CNA), 592-gene next-generation sequencing (NGS), microsatellite instability (MSI) and tumor mutational burden (TMB). Results: 1366 cases were identified: 1041 GC (707 P, 98 PM, 236 OM) and 325 GEJ (248 P, 5 PM, 72 OM). PM were increased in GC versus GEJ (9% v. 2%, p < 0.0001). 91% GC and 93% GEJ were adenocarcinoma (AD); GC were more likely signet ring (SR) histology versus GEJ (11% v. 3%, p < 0.0001) and GC PM were more likely SR versus other OM or P (13% v. 12% v. 7%, p = 0.067). The mean age of PM pts (57 years) was younger than primary GC (63, p = 0.002) and OM (61; p = 0.044). More PM GC pts were female than P or OM (48% v. 35% v. 34%, p = 0.03). No molecular profiling differences were seen between GEJ and GC pts and they were combined for analysis; findings from 1246 AD pts are shown below (see Table). OM (9%, p = 0.041) had more CNA in CCNE1 than PM (2%, p = 0.041) or P (5%, p = 0.002). Conclusions: Compared to P and OM GC, PM pts were younger, more likely female and had a higher incidence of SR histology. PD-L1, HER2 IHC and ERBB2 CNA were reduced in PM versus P, suggesting novel therapeutic targets are needed. [Table: see text]
Prospective validation of a serum miRNA panel for early detection of gastric cancer.
Authors: Zhou Lihan , So Jimmy , Kapoor Ritika , Zhu Feng , Zou Ruiyang , Koh Calvin J , Rha Sun Young , Chung Hyun Cheol , Yoong Joanne , Yap Celestial T , Rao Jaideepraj , Chia Chung-King , Tsao Stephen , Shabbir Asim , Lam Kong-Peng , Hartman Mikael , Yong Wei Peng , Too Heng-Phon , Yeoh Khay Guan 
Published: May 2019

4065 Background: High mortality from gastric cancer is related to the late manifestation of its symptoms. A blood-based non-invasive biomarker with the ability to detect all stages of gastric cancer could significantly improve patient outcomes. We aimed to develop a novel serum miRNA assay for diagnosis of gastric cancer. Methods: We conducted a multi-center study involving 892 gastric cancer and control subjects from Singapore and Korea to develop a multi-target miRNA assay. Using RT-qPCR, we quantified the expressions of 578 serum miRNAs and constructed a 12-miR biomarker panel through multi-variant data analysis. The results were generated with the use of a logistic-regression algorithm, with the value of 40 or more considered to be positive. We subsequently validated this multi-miR assay in a large prospective cohort involving 4566 subjects and compared its performance with traditional markers such as H.Pylori and Pepsinogen. All participants underwent gastroscopy independent of the assay results. Results: Of the 4566 subjects that underwent gastroscopy and histopathological examination in the prospective cohort, 125 were diagnosed with gastric cancer. The 12-miR assay achieved an Area-Under-Curve (AUC) of 0.84, significantly outperforming (p-value < 0.01) that of H.Pylori (AUC of 0.64) and Pepsinogen (AUC of 0.62). The sensitivity of the miRNA assay in detecting early (stage 0-2) and late (stage 3-4) stage gastric cancer was 82.6% (95% CI, 68.6% to 92.2%) and 88.4% (95% CI, 78.4% to 94.9%) respectively at a specificity of 70.0% (95% CI, 67.8% to 71.9%). In comparison, H.Pylori showed a sensitivity of 80.4% at a specificity of 44.3% whereas the Pepsinogen showed sensitivity of 9.52% at a specificity of 95.3%. Using the miRNA assay as a pre-screening tool could potentially reduce number of endoscopy needed by 62% in detecting one case of gastric cancer. Conclusions: Our serum miRNA panel is a useful, non-invasive screening test for gastric cancer. It is cost-effective as it can reduce unnecessary diagnostic endoscopy.
Neoadjuvant epirubicyn, oxaliplatin, capecitabine and radiation therapy (NEOX-RT) followed by surgery for locally advanced gastric cancer (LAGC): A phase II multicentric study.
Authors: De Paoli Antonino , Navarria Federico , Torrisi Elena , Polesel Jerry , Fort Eleonora , Foltran Luisa , Palazzari Elisa , Innocente Roberto , Cannizzaro Renato , Canzonieri Vincenzo , Tonin Dino , Ubiali Paolo , Lonardi Sara , Bergamo Francesca , Galuppo Sara , Bellucco Claudio , Merigliano Stefano , Pucciarelli Salvatore , Bertola Giulio , Buonadonna Angela 
Published: May 2019

4066 Background: This study evaluates the feasibility, safety and efficacy of a trimodality treatment, with surgery postponed after neoadjuvant chemotherapy (CT) and chemoradiotherapy (CRT), in LAGC. Methods: Patients (pts) with cT3-4 and/or N+ LAGC were eligible. Staging included endoscopic ultrasound, PET-CT and laparoscopy. Three cycles of EOX (Epirubicyn 50mg/m2,q21 days, Oxaliplatin 130mg/m2,q21 days, and Capecitabine 625mg/m2 bid, by continuous oral administration (c.a.), followed by IMRT with 45Gy/25 frs, concurrent Capecitabine 625mg/m2 bid c.a. and weekly Oxaliplatin 30mg/m2 for 5 wks, was planned. Early PET-CT was performed after the 2nd EOX cycle to assess response or disease progression. Restaging was repeated after CT and CRT. Surgery was planned 4-6 wks after CRT, 22 wks from the start of NEOX-RT. Pathologic complete response (pCR) was the primary endpoint. Results: From November 2008 to March 2016, 51 pts (5 G-E Junction, 17 Cardia, 15 Corpus, 14 Antrum) entered the study. The NEOX-RT program was completed in 46 pts (90%) who proceeded to surgery and are assessable. Grade 3-4 toxicity (NCI-CTC criteria v.3) occurred in 13/51 pts (25%) during EOX, including 1 toxic death, and 9.5% CT cycles required dose modification, resulting in a CT compliance of 90%. No pts had progression during CT. Persistent G2-G3 toxicity occurred in 32/46 pts (69%) during CRT. However, 41/46 pts (89%) received the planned 45Gy with Capecitabine at dose ≥75% and 4-5 cycles of weekly Oxaliplatin in 52% pts. Curative resection (R0) rate was 89%; 4 pts (8.7%) had peritoneal carcinomatosis at surgery done after a median of 23 wks. pCR was reported in 9/46 pts (19.6%). Major postop complications occurred in 5 pts (11%). At median f-up of 62 mos (23-109), 5-yr OS and DFS in all and pCR pts were 58%, 100% and 51%, 75%, respectively. Conclusions: This trimodality program was feasible and safe. Most pts completed the planned treatment. The pCR rate of 19.6% was remarkable and met the hypothesis of pCR = 20%. A high R0 rate was also reported and delayed surgery didn’t increase complications. The notable survival rates are available to be compared with ongoing phase III trials. Clinical trial information: 2008-002715-40.
A landscape of circulating tumor DNA in esophageal adenocarcinoma and squamous cell carcinoma.
Authors: Mody Kabir , Manochakian Rami , Ahn Daniel H. , Roberts Ali , Nagy Rebecca , Lanman Richard B. , Kasi Pashtoon Murtaza 
Published: May 2019

4070 Background: Esophageal cancer (EC) is a lethal malignancy with limited treatment options. Genomic analyses have led to the elucidation of numerous dysregulated genes in esophageal adenocarcinoma (AC) and squamous cell carcinoma (SCC), and the potential for advancement of targeted therapies in this disease. Data regarding circulating tumor DNA (ctDNA) plasma analysis in EC in real-world clinical practice is limited. Methods: We performed ctDNA next-generation sequencing (NGS) analysis in patients (pts) with EC (January 2015- February 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA) which detects single nucleotide variants and insertion/deletion mutations, and specific amplifications and fusions, in up to 73 different genes. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance was defined as alterations within OncoKB levels 1-3B and R1. Results: Among 450 pts, 487 total samples were analyzed (77% AC, 31% SCC). ctDNA NGS revealed at least one genomic alteration (excluding variants of uncertain significance and synonymous mutations) in 81% of pts (90% AC, 88% SCC). Median number of alterations per AC patient was 4 [range, 1-59] and a median MAF of 0.84% (range, 0.02% - 83.7%); SCC was 5 [range, 1-26], with a median MAF of 0.99% (range, 0.01% - 85.2%). The total number of unique alterations was 1,162. The most commonly altered genes in AC: TP53 (70%), KRAS (20%), ERBB2 (18%), EGFR (16%), PIK3CA (16%); in SCC: TP53 (88%), PIK3CA (24%), CCND1 (23%), KRAS (21%), EGFR 15%). Therapeutically relevant alterations will be described. Conclusions: ctDNA plasma profiling of pts with EC is a feasible alternative and non-invasive method to gather comprehensive genomic data. Further large comparison studies to assess landscape of genomic alterations observed through ctDNA versus tissue-based assays, in addition to studies of targeted therapy outcomes based on ctDNA-detected alterations, are needed.
Efficacy and safety of pembrolizumab in patients with PD-L1 positive advanced biliary tract cancer (BTC): A prospective cohort study.
Authors: Kang Junho , Yoo Changhoon , Jeong Jae Ho , Kang Boyeong , Hong YunJin , Kim Kyu-Pyo , Ryoo Baek-Yeol 
Published: May 2019

4082 Background: For patients with advanced BTC, standard chemotherapy has limited benefit and no molecular targeted agents have been approved. Pembrolizumab is an anti PD-1 immune checkpoint inhibitor which has shown modest activity for advanced BTC patients in prior single-arm phase I/II studies. Considering the heterogeneity of BTC, more data are needed to evaluate the clinical outcomes of pembrolizumab in unresectable or metastatic BTC. Methods: In this prospective cohort study, 39 patients with PD-L1 positive BTC who received pembrolizumab in Asan Medical Center, Seoul, Korea were included (ClinicalTrials.gov identifier, NCT03695952). PD-L1 expression was assessed using immunohistochemistry and PD-L1 positive tumors were defined as the expression of PD-L1 in ≥ 1% of tumor cells. Pembrolizumab was given at a fixed dose of 200 mg intravenously, every 3 weeks. Results: The median age was 61 years old (range, 41-76) and 22 (56.4%) patients were male. Intrahepatic cholangiocarcinoma (CCA) was the most common type (n = 18, 46.2%), followed by gallbladder cancer (n = 12, 30.8%) and extrahepatic CCA (n = 9, 23.1%). Most of the patients had distant metastasis (n = 37, 94.9%). Pembrolizumab was administered as 2nd-, 3rd- and 4th or greater line chemotherapy in 18 (46.2%), 16 (41.0%) and 5 (12.8%) patients, respectively, and median 2 cycles (range 1-10) of pembrolizumab were given. In 36 patients whose response was assessable, partial response (PR) and stable disease were achieved in 4 (11.1%) and 13 (36.1%), respectively. In 19 (52.8%) patients, progressive disease was the best response. In patients with PR, the median time to response was 2.1 months (95% confidence interval (CI), 0.4 – 3.9). With a median follow-up duration of 4.4 months (95% CI, 2.4 – 6.4), median progression-free survival and overall survival was 1.5 months (95% CI, 0.4 – 2.6) and 4.3 months (95% CI, 2.6 – 6.1), respectively. No grade 3/4 adverse events (AEs) were reported and grade 1/2 fatigue (n = 4, 10.3%) was the most common AE. Conclusions: In PD-L1 positive BTC, pembrolizumab showed modest efficacy with 11.1% of response rates although our patients were heavily pretreated. Considering the limited therapeutic options and poor survival for these patients, further evaluation of immunotherapy including biomarker analysis is needed.
Efficacy and safety of FOLFIRINOX in advanced biliary tract cancer after failure of gemcitabine plus cisplatin: A phase II trial.
Authors: Belkouz Ali , Vos-Geelen Judith de , Eskens Ferry , Mathot Ron A.A. , van Gulik Thomas , van Oijen Martijn G.H. , Punt Cornelis J. A. , Wilmink Johanna , Kluempen Heinz-Josef 
Published: May 2019

4086 Background: Currently there is no established standard treatment after failure of gemcitabine plus cisplatin (GemCis) for advanced biliary tract cancer (BTC). Based on the efficacy of FOLFIRINOX in advanced pancreatic cancer, which has histological and prognostic similarities with BTC, a Phase 2 study was conducted to determine whether FOLFIRINOX is effective and safe in BTC. Methods: Patients with BTC and an ECOG PS of 0/1 who had disease progression or unacceptable adverse events (AEs) after at least 3 cycles of GemCis were included. Patients received oxaliplatin 85 ml/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus at 400 mg/m2, followed by fluorouracil continuous infusion of 2400 mg/m2 over 46-hour every 2 weeks. This phase 2 study was conducted according to the two-stage Simon’s Design. Stage 2 was activated if at least 1 objective response rate (ORR) or 2 stable diseases were observed among 10 patients in stage 1 and a maximum of 3 patients had severe AEs within the first 6 weeks of treatment. If more than 4 patients required a dose reduction in stage 1, stage 2 was initiated with a standard dose reduction (fluorouracil bolus was omitted and irinotecan reduced to 140 mg/m2). Primary outcome was ORR per RECIST 1.1 and secondary outcomes were overall (OS), progression free survival (PFS), and safety profile. Results: Forty patients were screened and 30 patients were included between May 2016 and July 2018. Median age was 60 years and 63% of patients were males. In stage 1, 5 patients required a dose reduction within the first 6 weeks due to AEs, leading to initiation of stage 2 with modified FOLFIRINOX after inclusion of 10 patients. The partial response rate was 10% (3/30), disease control rate 67% and median OS and, PFS were 10.7 and 6.2 months, respectively. Most common grade 3/4 adverse events include neutropenia (50%), anemia (17%), diarrhea (13%), thrombocytopenia (10%), and deviated liver function tests (10%). Conclusions: This is the first Phase 2 study with modified FOLFIRINOX in BTC showing promising disease control rate, OS, and PFS, with an acceptable safety profile. Modified FOLFIRINOX is currently tested as a first-line treatment for patients with BTC in the ongoing randomized prospective Phase 2/3 AMEBICA trial (NCT02591030). Clinical trial information: NCT02456714.