bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of ABT-700, an anti-c-Met antibody, in patients (pts) with advanced gastric or esophageal cancer (GEC).
Authors: Kang Yoon-Koo , LoRusso Patricia , Salgia Ravi , Yen Chia-Jui , Lin Chia-Chi , Ramanathan Ramesh K. , Kaminker Patrick , Sokolova Irina , Bhathena Anahita , Wang Lan , Naumovski Louie , Strickler John H.
Published: February 2017

167

Background: MET is a receptor tyrosine kinase associated with treatment resistance. MET amplification (MA) results in c-Met overexpression and activation through autodimerization, and may be an important oncogenic driver in patients (pts) with advanced GEC. MA is relatively rare in primary tumors (<5%), but may increase under the selective pressure of systemic therapy. ABT-700 is an anti-c-Met antibody with significant preclinical single-agent activity against MA human xenograft tumors. Efficacy and safety data for ABT-700 in patients with MA advanced GEC are presented. Methods: MA was assessed in tumor biopsy tissue by fluorescence in situ hybridization (FISH; Abbott Molecular Diagnostics) or DNA sequencing. MA, identified by FISH, was defined as a MET/CEP7 ratio>2 in ≥20% of cells. The dose of ABT-700 is 15 mg/kg IV, once every 3 weeks, established during the dose escalation phase of the study. Responses were assessed using RECIST version 1.1. Results: As of May 31, 2014, 6 pts with chemotherapy refractory GEC have been treated with ABT-700. All pts had disease progression on 3 or more prior lines of chemotherapy. 4/6 pts had MA. 1 pt had MA identified retrospectively, and 3 pts had MA identified through a prospective screening effort. Among the 4 pts with MA GEC, 3 pts had a partial response (PR) and 1 pt had progressive disease (PD) as best response (ORR= 75%). Of the 3 pts who responded, the best response in target lesions was –56%,-52%, and –58%, and the PFS was 27, 18, and 24 weeks, respectively. Each of these three responders had a longer PFS with ABT-700 than with their preceding chemotherapy. In each of the 4 cases of MA identified in this study, MA was only detected in metastatic recurrent tumors and not the primary tumor tissue. The 2 pts without MA had PD as best response. ABT-700 was well tolerated, with no treatment related Grade 3-5 adverse events. Conclusions: In 4 pts with MA GEC, ABT-700 was well tolerated and appeared to have substantial single-agent activity. In this small cohort of gastric patients MA appears to be more common in treatment-refractory tumors than in primary untreated tumors, suggesting that screening efforts should focus on this treatment-refractory patient population. Clinical trial information: NCT01472016.
Quality of life (QOL) in patients with esophageal cancer treated with radiation (RT) in the radical setting.
Authors: Choudhary Anita , Liu Geoffrey , Chacko Pravin Philip , Fadhel Ehab , Cho Charles , Woo Rachel , Cheung Agnes , Vanderwater Catherine , Xin Cindy , Xu Wei , Wong Jason , Lee Alex , Kassam Zahra
Published: February 2017

186

Background: QOL is poorly documented in patients with esophageal carcinoma treated with curative intent, especially trimodality therapy. QOL and survival outcomes were evaluated in a single centre prospective cohort study of esophageal carcinoma patients treated with RT in the radical setting. Methods: Patients completed the EORTC-QLQC30 at baseline, the end of RT, 6 months and 1 year after RT. A 10-point difference in scores was considered clinically significant. Results: Thirty-three of 45 consequently treated patients between February 2012 and June 2014 participated, all male, median age 63 years (range 40-76), with T1-4N1-3M0 disease (AJCC 7thedn), median follow up 0.9 years (range 0.1-2.3). Four patients were treated definitively with chemoradiation 45-50Gy in 25 fractions; 14 neoadjuvantly 45-50Gy in 25 fractions; 15 neoadjuvantly 41.4Gy in 23 fractions, with concurrent chemotherapy. Compliance for questionnaire completion was 80-100%. 2 year overall survival (OS) and disease free survival (DFS) were 77% and 63%. Median scores on role, social, fatigue and appetite showed clinically significant worsening at the end of RT; in addition statistical significance was found for global QOL, physical, nausea/vomiting, and shortness of breath [median difference (MD): global -8.3 p=0.004, physical -6.6 p=0.003, role -16.6 p=0.001, social -16.6 p=0.78, nausea/vomiting 8.3 p=0.02, fatigue 22.2 p=0.001, shortness of breath 0 p=0.037, appetite 33.3 p=0.009]. At 6 months post RT global QOL (MD -16.6 p=0.23), physical (MD -13.3 p=0.007), role (MD -16.7 p=0.11) and fatigue (MD 11.1 p=0.18) were clinically significantly depressed. At one year all scores had returned to baseline, except pain, which was clinically significantly worse (MD 16.7 p=0.41); 64% of the cohort reported worse pain compared to baseline. Although global QOL on average returned to normal, 46% reported this to be clinically worse at one year compared to baseline. No association was found between baseline global QOL and OS (p=0.15) or DFS (p=0.57). Conclusions: QOL was worsened in several domains during and up to 6 months post RT. At one year all scores had returned to baseline except for pain which was significantly worsened in 64% of patients.
Surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal cancer (EC) trials with preoperative therapy (PreTx): Literature-based meta-analysis.
Authors: Kataoka Kozo , Nakamura Kenichi , Mizusawa Junki , Eba Junko , Katayama Hiroshi , Kato Ken , Shibata Taro , Fukuda Haruhiko
Published: February 2017

199

Background: Disease-free survival after adjuvant chemotherapy in colon and gastric cancer has already been validated as a surrogate endpoint for OS. However, there have been no reports evaluating PFS as a surrogate endpoint in resectable EC. Standard treatment for resectable EC is preoperative chemotherapy (preCx) or chemoradiotherapy (preCRT) followed by surgery. This study was conducted to evaluate the trial level correlations between PFS and OS in resectable EC with PreTx and to explore potential merit of PFS as a surrogate endpoint for OS. Methods: A systematic literature search of randomized trials with preCx or preCRT for EC reported from January 1990 to September 2014 was conducted using PubMed and the Cochrane library. Weighted linear regression using sample size of each trial as a weight was used to estimate coefficient of determination (R2) within PFS and OS. 95% confidence interval of R2 was estimated by bootstrap method. The primary analysis included trials in which the HR of PFS and OS were reported. A sensitivity analysis included trials in which either HR or median survival time of PFS and OS was reported. In the sensitivity analysis, HR was estimated from the median survival time of PFS and OS, assuming exponential distribution. Results: Of 615 articles, 9 trials (2,725 patients) were selected for the primary analysis and 12 (3,020) for the sensitivity analysis. Median numbers of enrolled patients were 256 (range 101-802) in primary analysis, and 209 (75-802) in sensitivity analysis. The numbers of trials including only preCx, only preCRT and both, were 5, 4 and 0 in the primary analysis, and 5, 6 and 1 in the sensitivity analysis. The primary analysis did not show the correlation between treatment effects on PFS and OS (R2 0.217, 95%CI [0.003-0.910]). The sensitivity analysis did not show the association of PFS and OS (R2 0.153, 95%CI [0.000-0.682]). Conclusions: Although the number of randomized controlled trials evaluating PreTx for EC is limited at the moment, PFS was not suitable as a surrogate endpoint for OS. OS should be used as the primary endpoint in trials of PreTx for resectable EC.
Impact of sarcopenia (Sp) on outcomes in patients (pts) undergoing trimodality therapy for esophageal cancer.
Authors: Weston Brian , Shaikh Talha , Handorf Elizabeth , Scott Walter Joseph , Cohen Steven J. , Meyer Joshua E.
Published: February 2017

221

Background: Sp, or severe muscle wasting, has been implicated as an important prognostic factor in cancer pts. We assessed the association between body composition changes and outcomes in pts with esophageal cancer undergoing tri-modality therapy. Methods: Following IRB approval, we reviewed all pts who underwent chemoradiation followed by esophagectomy at an NCI-designated cancer center from 2000-2013. Pts who underwent CT assessment pre- and post-neoadjuvant chemoradiation were included in the analysis. Sp was defined as a lumbar skeletal muscle area/height of 55.4 cm2/m2 for males and 38.9 cm2/m2for females. Fat mass (FM), fat-free mass (FFM), subcutaneous fat to muscle ratio (SFMR), and visceral to subcutaneous adipose tissue ratio (VSATR) were also derived using CT-based measures. Changes in the above parameters and Sp were correlated to post-operative (post-op) complications (cx), treatment (tx) response, disease free survival (DFS), and overall survival (OS). Analysis was performed using non-parametric Wilcoxon and Kruskal-Wallis tests, and Kaplan-Meier curves with log-rank tests. Results: A total of 48 pts met the inclusion criteria; the median age was 62 (range 42-80) with a median follow up of 28 months (range 4-103). Most pts had T3 (85%), N1 (70%), or M0/M1a disease (92%). Ten pts (21%) had Sp at the initiation of tx, with 9 of these remaining Sp post-tx, and 1 patient developing Sp. Post-tx Sp was associated with an increased rate of post-op mortality (p=0.03). Three of the 10 patients with Sp died post-op versus 1/36 in the non-Sp group. Post-tx Sp was associated with a decreased rate of post-op strictures (p = 0.04). Thirteen of the 36 pts in the non-Sp group developed strictures versus none in the Sp group. There was a significant change in all other measures pre vs. post-tx; FM (-4.3 kg/m2, p<0.01), FFM (-5.0 kg/m2, p<0.01), SFMR (-0.1, p=0.04), and VSATR (-0.02, p<0.01). None of these were correlated with post-op cx, tx response, DFS, or OS. Conclusions: Post-tx Sp was associated with an increased incidence of post-op mortality but a lower rate of strictures. Our study was limited by sample size, and further studies should examine the relationship between Sp and peri-operative outcomes.
Patterns and severity of chemotherapy-induced nausea (CIN) in patients with gastrointestinal cancers associated with highly to moderately emetogenic chemotherapy (HEC and MEC).
Authors: Aiba Keisuke , Tamura Kazuo , Saeki Toshiaki , Baba Hideo , Kitagawa Yuko , Yoshida Kazuhiro , Furuse Junji , Kakeji Yoshihiro , Wakabayashi Go
Published: February 2017

24

Background: Chemotherapy-induced nausea and vomiting (CINV) is well controlled recently thanks to novel antiemetic therapy, but the incidence of nausea remained high in patients receiving either HEC or MEC. The aim of the study is to investigate patterns and severity of CIN in cancer patients who are to receive chemotherapy for the first time. Methods: A nationwide survey on CINV was conducted by the CINV study group of Japan. A 7-day diary for CINV was provided to the patient prior to chemotherapy to record daily occurrence and severity of CINV. CIN was measured using visual analog scales(VAS) of 10cm length scales. Acute and delayed CINV were defined as nausea and vomiting which developed within or after 24 hours after the start of chemotherapy, respectively. Results: A total of 2,068 patients were registered and 1,910 patients were analyzed. A mean age was 62 (range:19-87) and there were 873 males and 1,037 females. MEC was given to 715 as was HEC to 1,195 patients. Underlying diseases were esophageal (192 patients), gastric (152), colorectal (90), hepato-biliary-pancreatic (100), lung (426) and breast cancer (429), and gynecological (214) and hematological malignancy (197). Comparing patients with various cancers treated with similar emetogenic agents or regimens, we easily could find that there are several patterns of CIN severity. Firstly, temporal profiles of CIN severity of esophageal, gastric and lung cancers were similar, having daily increased delayed nausea up to Day 7. The reason of this phenomenon seems due to a single high dose of CDDP. Colorectal and hepato-biliary-pancreatic cancer had a similar mild CIN pattern over 7days, probably due to mild emetogenic nature of oxaliplatin and moderate dose of CDDP. Conclusions: Temporal profile and severity of CIN patterns seem to be divided into several groups and delayed CIN remained to be high and needs further investigation.
Combined use of methylated reprimo cell-free DNA and pepsinogens for noninvasive detection of early gastric cancer.
Authors: Alarcon Alejandra , Olivares Wilda , Maturana Maria Jose , Rodriguez Andres , Padilla Oslando , Wichmann Ignacio Alberto , Calvo Alfonso , Corvalan Alejandro
Published: February 2017

27

Background: Gastric cancer (GC) has been described as a multistep cascade of precursor lesions such as non-atrophic chronic gastritis (NACG), multiphocal atrophic gastritis (MAG), intestinal metaplasia (IM), low grade dysplasia (LGD) and high grade dysplasia (HGD) leading to early stages of GC (EGC). Currently, no non-invasive biomarkers for this progression are clinically available. We have previously identified a potential biomarker based on methylated Reprimo (RPRM) cell-free DNA (cfDNA) (Clin Cancer Res 2008;14:6264-9). In a cross-sectional study of 1,076 patients, we showed a sensitivity of 70.8% (95% CI: 60.3 to 81.3) and specificity of 74.3% (95% CI: 71.5 to 77) for methylated RPRM cfDNA, to distinguish NACG+MAG+IM+LGD vs HGD+EGC+AGC (Digestive Disease Week 2014 #108). However, the crude detection rate of EGC was only 46.6%. Here, we aim to explore the role of the combined use of methylated RPRM cfDNA and well stablished atrophy biomarkers such as pepsinogens, for non-invasive detection of EGC. Methods: A case-control study was performed including 237 patients (NACG:40; MAG:94; IM:55; LGD:11; HGD:5: EGC:15; AGC:17) scheduled for upper gastrointestinal endoscopy (UGIE). A heparinized venous blood sample was collected and methylated RPRM cfDNA and Immunoassays for Pepsinogen I and II were performed. Positive value was considered if methylated RPRM cfDNA > 0 copies/mL and PG I/II ratio <3.0 were found. Results: Overall sensitivity and specificity for the combined use of methylated RPRM cfDNA and PGI/II to distinguish NACG+MAG+IM+LGD vs HGD+EGC+AGC was 67.5% (95% CI: 50.2% to 81.9%) and 63% (95% CI: 55.9% to 69.7%), respectively. Positive and negative predictive values were 25.2% (95% CI: 17% to 34.9%) and 91.3% (95% CI: 85.3% to 95.4%), respectively. Importantly, crude detection rate for EGC increased from 46.6% to 86.7%. Conclusions: The combined use of methylated RPRM cfDNA and PGI/II reached similar sensitivity and specificity compared to methylated RPRM cfDNA alone to distinguish NACG+MAG+IM+LGD vs HGD+EGC+AGC. However, combined use of methylated RPRM cfDNA and PGI/II significantly improved the detection rate of EGC, a lesion with a curability rate over 95%.
Early initiation of chemotherapy after histological diagnosis to improve the prognosis of metastatic pancreatic ductal adenocarcinoma.
Authors: Suzuki Rei , Takagi Tadayuki , Hikichi Takuto , Sato Ai , Watanabe Ko , Nakamura Jun , Konno Naoki , Waragai Yuichi , Kikuchi Hitomi , Obara Katsutoshi , Ohira Hiromasa
Published: February 2017

273

Background: Since pancreatic ductal adenocarcinoma (PDAC) shows aggressive progression, we speculate that prolonged waiting time after detection of disease until initiation of treatment may relate to prognosis of patients with advanced diseases. Methods: We included patients diagnosed to have metastatic PDAC in Fukushima Medical University between September 2006 and January 2014. All patients underwent more than 2 cycles of gemcitabine treatment (1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) after confirming histological diagnosis. We classified waiting time as Time A (detection-to-diagnosis waiting time) and Time B (diagnosis-to-treatment waiting time). Each period was further divided into 2 groups (shorter [-short] or longer [-long] waiting time than median length of each waiting time group). Kaplan-Meier methods, log-rank test and Cox proportional hazard methods were used to analyze overall survival (OS). Results: Twenty three patients were included. Median age was 64 (49-75) and length of waiting time was 19.5 days (4-78) in Time A and 9.0 days (2-34) in Time B. Regarding Time A, there was no significant difference in median OS between Time A-short and Time A-long (198.5 vs. 197.0 days; hazard ration [HR] 1.096; 95% confidential interval [CI] 0.4822-2.537; P=0.81). On the other hand, median OS was significantly better in Time B-short than Time B-long (median OS 290 vs. 160 days; HR, 0.381; 95% CI, 0.096-0.622; P= 0.0078). Conclusions: We foundthat waiting time between disease detection and diagnosis didn’t impact on prognosis of metastatic PDAC contrary to our speculation. However, patients with short waiting time (less than 9 days) after diagnosis until initiation of first chemotherapy had better prognosis than patients who had long waiting time. These findings suggest that early initiation of chemotherapy after histological diagnosis can improve the prognosis of metastatic PDAC.
Role of microbiota and Toll-like receptors in progression of esophageal adenocarcinoma (EAC) in a rat reflux model.
Authors: Kelly Lori A , Zaidi Ali H , Barlek Mark , Kreft Rachael , Omstead Ashten , Kosovec Juliann , Komatsu Yoshihiro , Jobe Blair A
Published: February 2017

28

Background: The discovery of the link between H. pylori and gastric cancer may be the most direct proof that bacterial signaling and host response can result in carcinogenesis. Accumulating evidence supports that activation of the Toll-like receptor (TLR) signaling pathway by microbes is associated with the development of GI malignancies. Using the modified Levrat model of gastroduodenojejunal reflux which mimics the physiological and molecular sequence of human EAC in the rat, this study profiles the expression of genes central to TLR-mediated signal transduction as well as characterizes the esophageal microbiome across the spectrum of EAC development. Methods: Modified Levrat’s surgery induced chronic acid reflux in Sprague-Dawley’s with harvest of esophagus 40 weeks post-surgery. Macordissection of normal adjacent epithelium, Barrett’s esophagus (BE), dysplasia and EAC tumor was performed followed by RNA/DNA isolation. Five samples per group were selected for gene expression profiling on the Qiagen TLR Signaling Pathway PCR Array as well as microbiome analysis by IBIS technology. Validation of IBIS was performed by fluorescence in situ hybridization (FISH). Results: Gene expression analysis identified TLRs 1-3 and 6, 7, 9 as significantly upregulated in EAC compared to normal esophagus. TLR 1 and 5 were significantly upregulated in dysplasia. TLR 1 was significantly upregulated in BE and normal adjacent epithelium. Thirty seven genes involved in the TLR signaling pathway were dysregulated in EAC, 30 in dysplasia, 21 in BE and 23 in normal adjacent. IBIS analysis revealed a prevalence of E. coli in BE and EAC which was validated by FISH. Conclusions: Toll-like receptor (TLR) signaling pathway responses to E. coli may participate in the development of EAC. E. coli may be a potential risk factor for EAC requiring further clinical validation.
Next-generation sequencing: Profiling gallbladder cancer (GBC).
Authors: Chiu Joanne Wing-Yan , Serra Stefano , Kamel-Reid Suzanne , Zhang Tong , McNamara Mairead Geraldine , Bedard Philippe L. , Hedley David W. , Moore Malcolm J. , Dhani Neesha C. , Shek Tony , Kwong Yok-Lam , Yau Thomas Cheung , Doherty Mark , Knox Jennifer J.
Published: February 2017

286

Background: Molecular profiling data of GBC is scant and it is often included with other biliary cancers for analysis, which may hinder advancing drug discovery. Methods: Archival formalin fixed paraffin embedded (FFPE) tissue of GBC from 2 research hospitals in Toronto (n=21) and Hong Kong (n=21) were analyzed by MassARRAY Sequenom panel (23 genes, 279 mutations), or by next general sequencing (NGS) using Proton or Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons, ≥500x coverage). Results of other biliary cancer and ampullary cancer from an ongoing profiling project were also reported. Results: Twelve biliary cancer samples first analyzed with Sequenom revealed no mutations. Reanalysis with NGS of these yielded mutations in 5. All subsequent samples were analyzed with NGS (n=57). Mutations were identified in 80% [53 mutations in 42 GBC, 8 mutations in 9 intrahepatic cholangiocarcinoma (IHC), 7 mutations in 6 hilar/distal bile duct cancers (DBD)]. The most frequent mutations in GBC were TP53 and SMAD4, and KRAS mutation was found in 7% (Table). PIK3CA mutation was found in 5% of GBC but not the other biliary cancers, and IDH1 mutation was exclusive for IHC, in agreement with published literature. TP53 mutations in GBC patients did not correlate with gender, tumor grade, survival, or treatment response to gemcitabine-based chemotherapy. There was no difference in mutation patterns in GBC between 2 institutions/countries. Conclusions: NGS can be utilized for molecular profiling of biliary cancer, detecting potentially actionable targets in the majority of cases. Our preliminary data suggests GBC may have its own molecular profile, deserving special consideration in trial design for biliary cancer. To our knowledge the current study is the biggest cohort of NGS analysis for GBC. [Table: see text]
Effects of neoadjuvant therapy on pancreatic cancer stem cells.
Authors: Miller Adam R. , Horsley Whitney H. , Sandusky George , Stanley Melissa , O'Neil Bert H. , Shahda Safi
Published: February 2017

292

Background: Several factors are involved in pancreatic cancer’s (PC) resistance to therapy. Cancer Stem cells (CSCs) represent a small and unique population of cancer cells, that are resistant to chemotherapy and radiotherapy and have the capability to differentiate and produce further resistant clones. Our hypothesis was that stem cell frequency would differ in treated vs. untreated pancreatic cancers. Methods: Resected FFPE PC specimens were collected under IRB- approved protocols and were separated into two group categories: cases that received neoadjuvant therapy (NA) and matched control cases with no treatment prior to surgical resection (SU). Immunostaining with CD24 and ALDH1 was performed using the DAKO FLEX SYSTEM. Each slide was scanned using the Aperio Whole Digital Imaging System. The digital scans were analyzed using the standard positive pixel algorithm for immunostains (brown positive, blue negative) that gives a percent of positive pixels in the cross section of the tissue. Care was taken to exclude false-positive staining sections of intact physiologic acinar and islet cells. Positivity data was compared between the two groups using a two-sample t-test using unequal or equal variances where an F-test deemed each appropriate. Results: Twenty cases were examined (10 NA and 10 SU). Patients in the NA arm received the following treatments (4 FOLFIRINOX, 2 nab-Paclitaxel + gemcitabine, 2 treated with concurrent gemcitabine/radiotherapy and 2 patients’ details are not available). Using two-sample t-test analysis, we found a statistically significant difference of median expression (percent positive pixels) of CD24 (20.5% vs. 66.9% expression, P <0.01,) and ALDH1 (41.5% vs. 60.5%, P= 0.04) between NA vs. SU respectively. This small study demonstrates lower expression of CSCs markers in patients receiving NA therapy in comparison to SU treated patients, indicating an effect from neoadjuvant therapy on CSCs. Conclusions: This is the first analysis of CSCs markers in patients with PC receiving NA therapy compared to surgery. In this small group, CSCs markers reflecting CSCs numbers in patients’ tumors were lower in the group receiving NA therapy prior to surgery; suggesting that CSCs may in fact be sensitive to standard chemotherapy.
The association of epithelial expression of hENT1 and survival from adjuvant gemcitabine in pancreatic ductal adenocarcinoma (PDAC).
Authors: Renouf Daniel John , Karasinska Joanna , Kalloger Steve , Peixoto Renata D'Alpino , O'Connor Kate , Schaeffer David
Published: February 2017

296

Background: Human equilibrative nucleoside transporter 1 (hENT1) mediates the cellular uptake of gemcitabine. Low tumour hENT1 expression has been associated with reduced survival from gemcitabine in some studies. We analyzed the prognostic effect of hENT1 expression in a cohort of PDAC patients (pts) who underwent surgical resection. Methods: A tissue microarray (TMA) composed of duplicate 0.6 mm cores from 261 resected PDACs was constructed from all available cases derived from the archives of Vancouver General Hospital between 1988 - 2013. TMA sections (4 µm) were stained with an antibody for hENT1 (SP120- Spring Biosciences) and scored using a four-tiered scoring system (negative, weak, moderate and strong staining). The expression of hENT1 in the epithelial component of PDAC was quantified and patient samples were divided into low (negative and weak staining) and high (moderate and strong staining) hENT1-expressing groups. Treatment and survival data were collected. Survival differences were quantified with Kaplan-Meier method and log-rank statistic. Results: Our cohort included pts who received no adjuvant chemotherapy (CT) (n=182) or gemcitabine (n=59). Cases treated with other regimens (n=20) were excluded. There was no significant difference in the median overall survival (OS) between pts with low (14.0 months, n=167) and high hENT1 expression (15.2 months, n=15) in the absence of adjuvant CT. Gemcitabine treated patients with low hENT1 expression (n=51) had a median OS of 20.9 months. Median OS was not reached in the group of pts with high hENT1 expression (n=8) who received gemcitabine, with only 2 deaths at the 24 month time point and 6 censorings (p = 0.045). Pts who received gemcitabine had an increased median OS (24.8 months) compared to pts who did not receive adjuvant CT (14.0 months) regardless of hENT1 expression (p<0.0001). Conclusions: Consistent with the ESPAC-3 data, in our analysis adjuvant gemcitabine was associated with increased OS in PDAC pts with high epithelial hENT1 expression (determined using the SP120 antibody) compared to pts with low hENT1 expression. Prospective evaluation of the predictive value of hENT1 expression in this setting is needed.
Relationship between PD-L1 expression and clinical outcomes in patients (Pts) with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (Pembro; MK-3475) in KEYNOTE-012.
Authors: Muro Kei , Bang Yung-Jue , Shankaran Veena , Geva Ravit , Catenacci Daniel Virgil Thomas , Gupta Shilpa , Eder Joseph Paul , Berger Raanan , Gonzalez Edward J. , Ray Archana , Dolled-Filhart Marisa , Emancipator Kenneth , Pathiraja Kumudu , Lunceford Jared K. , Cheng Jonathan D. , Koshiji Minori , Chung Hyun Cheol
Published: February 2017

3

Background: Tumors use the PD-1 pathway to evade immune surveillance. Pembrolizumab, an anti-PD-1 monoclonal antibody, has shown antitumor activity in advanced cancers. We assessed the safety and efficacy of pembrolizumab in patients with advanced gastric cancer in KEYNOTE-012 (Clinicaltrials.gov identifier NCT01848834). Methods: Archival tumor samples from patients from Asia-Pacific (AP) and rest of the world (ROW) with recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction were screened for PD-L1 expression using a prototype IHC assay with the 22C3 antibody. Only patients with distinctive stromal or ≥1% tumor nest cell PD-L1 staining were eligible. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until complete response, progression, or unacceptable toxicity. Imaging was performed every 8 weeks. Primary efficacy end point is ORR assessed per RECIST v1.1 by independent central review. Secondary end points include duration of response, PFS, and OS. Results: Of the 162 patientts screened, 65 (40%) were PD-L1+. Of these 65 patients, 39 enrolled (19 from AP, 20 from ROW; median age, 63 years [range 33-78]). The number of prior therapies for advanced disease ranged from 0 to 5; 67% received ≥2 prior therapies. Median follow-up duration was 8.8 months (range 6.2-12.6); 13 patients (33%) remain on therapy. Four patients experienced 5 total grade 3-5 drug-related adverse events: peripheral sensory neuropathy, fatigue, decreased appetite, hypoxia, and pneumonitis (n = 1 each). There was 1 drug-related death (hypoxia). ORR was 22% (95% CI 10-39) by central review and 33% (95% CI 19-50) by investigator review. Median time to response was 8 weeks (range 7-16), with a median response duration of 24 weeks (range 8+ to 33+). PD-L1 expression level was associated with ORR (1-sided P = 0.10). The 6-month PFS rate was 24%. The 6-month OS rate was 69%. Conclusions: Pembrolizumab demonstrated manageable toxicity and promising antitumor activity in advanced gastric cancer. These results support the ongoing development of pembrolizumab for gastric cancer. Clinical trial information: NCT01848834.
Exploratory biomarker results from early investigation of PEGPH20 in combination with gemcitabine (Gem) in patients with pancreatic cancer (PDA).
Authors: Hingorani Sunil R. , Harris William Proctor , Beck Joseph Thaddeus , Berdov Boris A. , Wagner Stephanie Ann , Pshevlotsky Eduard M. , Tjulandin Sergei , Gladkov Oleg , Holcombe Randall F. , Jiang Ping , Maneval Daniel C. , Korn Ronald I , Shepard Harold Michael , Devoe Craig E.
Published: February 2017

300

Background: PEGPH20 (PEG), a PEGylated recombinant human hyaluronidase, has anti-tumor activity as a single agent and in combination with chemotherapy in preclinical models. A Phase 1b study of PEG + Gem (P+G) in patients (pts) with advanced PDA showed good anti-tumor activity, particularly in pts with HAhigh tumors (ECCO 2013). In this study, we investigated pharmacodynamic (PD) markers including plasma(soluble) HA (sHA), dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and 18Fluorodeoxyglucose positron emission tomography (PET/CT) to explore additional correlates for PEG activity. Methods: 28 pts with stage IV PDA were treated with PEG at 1, 1.6, or 3µg/kg IV twice weekly for Wks 1-4 and Wks 5-7, followed by 1 wk rest, plus Gem at 1000 mg/m2 IV once weekly for Wks 1-7, then 1 wk rest. Thereafter, P+G was given once weekly for 3 wks in 4-wk cycles. Serial plasma samples were collected and analyzed in a quantitative assay for PEG and sHA. Exploratory imaging by DCE-MRI was performed on selection pts at baseline, 8hr, 24hr and end of cycle 1, PET/CT was performed at baseline and at the end of each cycle. Results: PEG pharmacokinetics was well-characterized by a 2-compartment PK model, peak plasma concentration increased in a dose-proportional manner after a single or repeat administration of PEG. Dose- and time-dependent increases in sHA were observed within 2-3 days after 1.0, 1.6, or 3.0 µg/kg of PEG administration. The median peak concentrations were 3,736; 48,150; and 74,950ng/mL, respectively, and increased with increasing doses. sHA reached steady state approximately 1 wk after repeated PEG administration, consistent with the expected hyaluronidase activity of PEG. Exploratory analysis with DCE-MRI from 6 pts showed an early increase (24hrs) in tumor perfusion (Ktrans) in target lesions. PET/CT from 5 pts showed an average reduction in the maximum standardized uptake value (SUVmax) of 37% at EOC1, and partial metabolic responses using EORTC criteria were achieved in 4 of 5 pts. These results suggest that P+G has measurable biological activity in metastatic PDA Conclusions: Plasma sHA concentration, DCE-MRI and PET/CT are PD markers for evaluation of P+G activity.
DNA repair inhibition by DT01 as an adjuvant therapy at each stage of hepatocellular cancer (HCC) treatment.
Authors: Devun Flavien , Herath Nirmitha , Denys Alban , Sun Jian-sheng , Dutreix Marie
Published: February 2017

303

Background: Hepatocellular carcinoma (HCC) is the most common liver cancer. Radiofrequency ablation (RFA), transarterial chemoembolization (TACE) or chemotherapy (CT) can be considered at each stage of HCC. The efficacy of these DNA damage inducing treatments could be enhanced by DNA damage repair inhibition. DT01 inhibits the complete DNA double-strand break repair machinery. Here, we assess the combination of DT01 with RFA, TACE or CT in preclinical models. Methods: For association with RFA, mice bearing flank-grafted tumors were sham treated (n=18), treated by DT01 (n=22), RFA (n=21) or a combination of DT01 and RFA (n=19). Mice were either sacrificed for pathological study or followed for survival. For association with TACE, rabbits bearing VX2 hepatocellular carcinoma in liver were untreated (n=9), treated with TACE (n=13) or treated with TACE and DT01 (n=14). Tumor growth, vascularization, necrosis and metastases were assessed with ultrasound scanning, color Doppler, pathology and autopsy respectively. For association with CT, mice bearing orthotopic liver tumors were administered NaCl (n=7), CT (doxorubicin) (n=10), systemic DT01 treatment (n=7) or an association of DT01 and CT (n=10). Tumor growth and pathological studies were assessed. Results: Mice treated by RFA and DT01 have longer survival compared to RFA alone (median survival: 57 vs 40 days) with 54% of complete responses while RFA alone improved survival moderately (median survival: 40 vs 28 days for control). Rabbits treated with TACE and DT01, in comparison to CT alone, show efficient tumor growth control, an increase of tumor necrosis (61% vs 40%), a decrease of metastases (21 vs 54%) and an absence of neoangiogenesis rebound. Mice treated with CT in combination with DT01 show a significant decrease in tumor volume and tumor necrosis, compared to the mice treated with CT alone. In all models, DT01 addition to treatments did not add any toxicity. Conclusions: Our results show that the addition of DT01 to RFA, TACE or CT enhances their antitumor activities and provide an experimental basis for the use of DT01 as an adjuvant therapy at each stage of HCC treatment.
Effect of high expression of fatty acid binding protein 5 on prognosis and epithelial-mesenchymal transition in hepatocellular carcinoma.
Authors: Ohata Takanori , Yokoo Hideki , Kamiyama Toshiya , Aiyama Takeshi , Wakayama Kenji , Orimo Tatsuya , Kakisaka Tatsuhiko , Tsuruga Yousuke , Kamachi Hirofumi , Taketomi Akinobu
Published: February 2017

310

Background: Hepatocellular carcinoma (HCC) is one of the cancer types with poor prognosis. The high expression of Fatty Acid Binding Protein 5 (FABP5) has been reported its malignant potential in several cancers. However, the function of FABP5 in HCC remains unknown. We analyzed the correlation between the expression of FABP5 and malignant behavior of HCC using HCC tissues and human HCC cell lines. Methods: A total of 231 HCC samples were obtained through our institute and subjected to immunohistochemical analysis. In vitro, protein expression of FABP5 in HCC cell lines was assessed by Western blot analysis. To the higher FABP5 expression cell lines, we performed proliferation assay, migration assay and invasion assay with or without genetic down-regulation of FABP5 by short hairpin RNA (shRNA). Results: The intensity of immunostaining in HCC tissues was determined comparing to immunoreactivity of Kupffer cells, and the patients were divided into a strong staining group (n=127) and a weak staining group (n=104) according to the intensity of immunostaining. In the strong staining group, 5-year overall survival rate was 58.3%, compared with 90.5% in the weak staining group (p<0.0001). In addition, 5-year relapse free survival rate in the strong staining group was 23.1%, compared with 46.9% in the weak staining group (p<0.0001). Moreover, the strong staining of FABP5 positively correlated with early recurrence, extrahepatic metastasis, AFP, AFP-L3%, PIVKA II, tumor size, poor differentiation, and micro/macro vascular invasion (P<0.05). In vitro, the knockdown of FABP5 significantly inhibited cell proliferation, migration and invasiveness. Additionally, the knockdown of FABP5 was associated with inhibition of epithelial-mesenchymal transition (EMT), including down-regulation of N-cadherin, and Snail converse to the activation of E-cadherin and ZO-1. Conclusions: FABP5 was closely related with the gain of malignant potential through the activation of EMT, and also behaved as a significant prognostic and recurrence factor. Therefore, FABP5 may serve as a new biomarker of HCC and a potential molecular target for the development of HCC therapies.
BRAF mutations in patients with well-differentiated pancreatic neuroendocrine tumors (WD pNETs).
Authors: Raj Nitya Prabhakar , Meyers Paul A. , Saltz Leonard , Reidy Diane Lauren
Published: February 2017

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Background: Whole exome sequencing in WD pNETs demonstrated an increased number of mutations in genes implicated in chromatin remodeling and in the PI3K/Akt/mTOR pathway. Next-generation sequencing (NGS) allows us to bring this technology to the clinic to better characterize WD pNETs and potentially offer tailored therapies. Methods: A NGS platform developed at Memorial Sloan Kettering Cancer Center (MSKCC) termed MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) was used. This platform screens for 341 cancer genes commonly altered across tumor types. Thus far, 14 patients with WD pNETs have consented to MSK-IMPACT. Results: To date, mostpatients harbor no clinically validated or actionable mutations. Two patients, however, harbor different and potentially actionable BRAF mutations. The first patient is a 39 year-old woman with a BRAF V600E mutation. She presented with somatostatin receptor-negative, aggressive disease involving the liver, lymph nodes, adnexa, and peritoneum. She was initially diagnosed elsewhere as having a signet ring cell adenocarcinoma, and responded to FOLFOX and bevacizumab. Pathology review at MSKCC, however, identified the tumor as metastatic WD pNET. Upon disease progression, a repeat biopsy confirmed metastatic WD pNET. She is currently on capecitabine and temozolomide with clinical improvement. The second patient is a 22 year-old woman with metastatic WD pNET with a BRAF K601E mutation. Her tumor also has an aggressive behavior; she has progressed on all conventional and nonconventional therapies. Given the finding of a BRAF K601E mutation, she received trametinib and dabrafenib, but developed disease progression after 3 months. Conclusions: Two potentially actionable BRAF mutations were identified from NGS of WD pNETs. BRAF mutations have not been previously reported in pNETs. It is unclear whether BRAF mutations are oncogenic drivers, and whether BRAF-targeted treatments would be beneficial. Both patients show an atypical, aggressive presentation and course. Further testing is warranted to determine the role and clinical significance of BRAF in pNETs. Evaluation using pNET tissue microarrays is ongoing and will be reported at the meeting.
Use of low-dose cyclophosphaminde followed by low-dose tumoral radiation, intratumoral poly-ICLC combined with local-regional therapy, followed by systemic immune boosting with intramuscular poly-ICLC in patients with cancers of the liver.
Authors: de la Torre Andrew N , Castaneda Ismael , Contractor Sohail , Salazar Andres M.
Published: February 2017

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Background: Cancers in the liver are susceptible immune evasion due to the liver’s role in self-tolerance. Eliminating liver cancers may require multiple steps to reduce tumor tolerance, increase expression of tumor-associated antigens, and turn on immunity against such tumor antigens. Methods: Phase I-II trial to 1) reduce tumor tolerance with oral cyclophosphamide 50 mg/day x 21 days, 2) increase tumor antigen visibility with low dose radiation (2.5 Gy x 3 days), 3) induce a “danger” response with intra-tumoral injection of the TLR3 agonist poly-ICLC (1mg) and concurrent hepatic artery embolization and 4) enhance immunity with intramuscular poly-ICLC (20 mcg/kg). Results: From 2/17/2007 to 7/27/12, 25 patients were enrolled. Cancers were 17 hepatoma (HCC), 3 metastatic pancreas (mPANC), 2 metastatic neuroendocrine (mNEURO), and 2 cholangiocarcinoma (CC). Patients were not liver transplant eligible at enrollment. Patient 1 with cirrhosis died after embolization of a 13 cm HCC. Patients 2-25 had no adverse events (AE) greater than grade 2. The most common AEs were fatigue (13), anorexia (7), injection site rash (7), fever (6), and diarrhea (3). Of 17 HCC patients, the mean survival was 737 days. Two patients were downstaged and underwent liver transplant. One patient was transplanted after 203 days and is still alive. The second patient was transplanted after 1433 days, but died 10 days following transplant. We had one patient who presented with multiple large HCCs and portal vein invasion surviving 984 days and another patient with multiple large HCCs still alive after 2451 days. Both patients with mNEURO tumors are still alive after 1905 and 736 days. All patients with CC and mPANC cancer died. Conclusions: This approach is well tolerated. Caution should be used with embolization of large tumors. Although the overall survival was just over two years, several patients with advanced HCC and mNEURO tumors lived beyond our expectations. Further investigation is needed to optimize this method and identify patients who will benefit most from this immunotherapeutic approach. Clinical trial information: NCT00553683.
Efficacy markers for cisplatin and S-1 in biliary tract carcinoma.
Authors: Sakamoto Yasunari , Ojima Hidenori , Morizane Chigusa , Yamagishi Seri , Hosoi Hiroko , Kondo Shunsuke , Ueno Hideki , Okusaka Takuji , Kanai Yae
Published: February 2017

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Background: Gemcitabine (GEM) + cisplatin (CDDP) combination chemotherapy is the first choice for advanced biliary tract carcinoma (BTC). In Japan, the GEM + S-1 therapy has shown promise for the treatment of BTC. Our aim was to investigate the cytotoxic effects of GEM, CDDP and S-1 on BTC cell lines and find an immunohistochemical marker for predicting the efficacy of chemotherapy. Methods: We evaluated the efficacy of GEM, CDDP, and S-1 by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of 17 BTC cell lines. Furthermore, we subdivided the cell lines into sensitive and insensitive groups on the basis of the sensitivity of each drug. Moreover, pairwise studies were conducted using the MTT assay, Bliss additivism model, and Combination Index for analysis. Immunohistochemical expression analysis of excision repair cross-complementation group 1 (ERCC1), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), and thymidine phosphorylase (TP) were also performed in each cell line to compare the results of the cytotoxic effects of CDDP and S-1. Results: In the single-agent MTT assays, among the 17 tumor cell lines, 11 were sensitive to GEM, 13 to CDDP, and 11 to S-1. In 5 cell lines, <30% of the cells showed ERCC1 expression; these lines belonged to the CDDP-sensitive group. Conversely, the cell lines with >30% ERCC1-positive cells mostly belonged to the CDDP-insensitive group. CDDP IC50 correlated with the percentage of ERCC1-positive cells (P <.05). In contrast, none of the immunohistochemical markers could be used to select a cutoff level that would point to the sensitivity to S-1. In pairwise MTT assays (combination therapy), we demonstrated the synergy of GEM with CDDP in 9 tumor cell lines (53%) and the synergy of GEM with S-1 in 4 tumor cell lines(24%). Although 3 cell lines with the synergy of GEM with CDDP showed <30% ERCC1-positive cells, there was no correlation between them. Conclusions: ERCC1 expression in <30% of cells may help to identify CDDP-sensitive tumors; however, it is unknown whether expression of ERCC1 can help to predict efficacy of treatment with GEM + CDDP.
Cost description of chemotherapy regimens for the treatment of metastatic pancreas cancer (mPC).
Authors: Goldstein Daniel A. , Krishna Kavya , Flowers Christopher , El-Rayes Bassel F. , Bekaii-Saab Tanios S. , Noonan Anne M.
Published: February 2017

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Background: Multiple chemotherapy regimens are now available for the treatment of mPC. With these regimens median overall survival ranges between 6-11 months. Choice of regimen is often based on the patient’s performance status (PS) and toxicity profile of the regimen. Newer combinations may be associated with high financial costs. The objective of this study was to analyze the costs of first-line regimens to further aid in decision-making and develop a platform upon which to assess value. Methods: We calculated the monthly cost for individual standard regimens. These included gemcitabine (G), FOLFIRINOX (5-FU, irinotecan and oxaliplatin), and gemcitabine/nab-paclitaxel (GN-P). Furthermore, we evaluated other novel regimens. These included our institutional experience with dose-modified GN-P (dmG-NP) which will be presented at the ASCO GI conference. We additionally evaluated the cost of 3-weekly carboplatin/paclitaxel (CP) which formed the control arm of a phase II trial in mPC (NCT01280058). The results of this trial are to be presented as Late Breaking Abstract 19 at the upcoming ESMO conference. In addition to the cost of drugs, we included administration costs, and costs of toxicities (including growth factor support, blood product transfusion and hospitalization for toxicities). Costs for administration and management of adverse events were based on Medicare reimbursement rates for hospital and physician services. Drug costs were based on Medicare average sale prices (all 2014 US $). Results: The monthly cost of GN-P is $12,221. FOLFIRINOX costs $3.865 per month. G alone costs $1,363 per month. DmGN-P costs $6.716 per month. CP was the cheapest combination regimen ($2,154 per month) and in a recent phase II trial has been shown to have a similar efficacy to GN-P. Conclusions: Choice of chemotherapy regimen for mPC is usually based on tolerability and efficacy of the regimen individualized to patient’s PS. Healthcare systems have finite resources, thus, there is increasing emphasis on metrics to define value in healthcare These data provide useful financial information to incorporate into the decision-making process.
Treatment strategy for borderline resectable pancreatic cancer with artery involvement.
Authors: Hirono Seiko , Kawai Manabu , Okada Ken-Ichi , Miyazawa Motoki , Shimizu Atsushi , Kitahata Yuji , Ueno Masaki , Hayami Shinya , Yamaguchi Shunsuke , Takifuji Katsunari , Hotta Tsukasa , Nakamura Masaki , Matsuda Kenji , Yamaue Hiroki
Published: February 2017

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Background: It has been still controversial to perform surgical resection with borderline resectable pancreatic cancer with artery involvement (BR-A), because an aggressive surgery leads to high morbidity and mortality with low R0 rate for the BR-A patients. In this study, we evaluated whether or not neoadjuvant therapy followed by surgical resection improves survival benefits for BR-A patients. Methods: There were 138 patients with BR-A among 330 pancreatic cancer patients underwent surgical resection at Wakayama Medical University Hospital. We compared clinicopathological factors between 38 BR-A patients with neoadjuvant therapy followed by surgical resection and 100 BR-A patients with upfront surgery to evaluate the clinical impacts of neoadjuvant therapy. Results: The overall survival (OS) of BR-A patients was significantly shorter than that of the patients with borderline resectbale pancreatic cancer with portal vein/ superior mesenteric vein (PV/SMV) involvement (n=76) and resectable pancreatic cancer (n=105) who underwent surgical resection (median OS: 13.6 vs. 20.6 months, P<0.001). The OS of BR-A patient with neoadjuvant therapy followed by surgical resection was significantly longer than those with upfront surgery (median OS: 20.2 vs. 12.9 months, P=0.047). Multivariate analysis showed that older age (P=0.027), pathological PV/SMV invasion (P=0.031), moderated or poor differentiated tumor (P=0.008), positive lymph node ratio ³a0.1 (P=0.018), and no postoperative adjuvant chemotherapy (P<0.001) were independent poor prognostic factors for BR-A patients. Conclusions: Neoadjuvant treatment might bring the clinical benefits for BR-A patients, and it is important to develop the appropriate regimen of neoadjuvant therapy and postoperative adjuvant therapy for longer survival in BR-A patients. Clinical trial information: 000003795.