bluuebunny/crossref_metadata_2025 huggingface dataset:
Pancreatic circulating tumor cells as a diagnostic adjunct in pancreatic cancer.
Authors: Ankeny Jacob S , Hou Shuang , Lin Millicent , OuYang Hank , Song Min , Rochefort Matthew M , Girgis Mark D , Isacoff William H. , Wainberg Zev A. , Tseng Hsian-Rong , Tomlinson James S
Published: February 2017

175

Background: Current diagnosis of pancreatic ductal adenocarcinoma (PDAC) relies upon image guided tissue sampling, which is expensive, inconvenient, and not without patient risk. Circulating tumor cells (CTCs) may improve our ability to diagnose PDAC, obtain pure molecular information uncontaminated by stromal cells, and potentially improve our ability to accurately stage patients at the time of diagnosis. Therefore, we evaluated CTCs as an adjunctive diagnostic biomarker of PDAC at the time of presentation. Methods: We performed a prospective analysis on 50 consecutive pre-treatment patients with either suspicion for, or recent diagnosis of PDAC who were referred to our UCLA Center for Pancreatic Diseases. 2 mL venous blood was evaluated for the presence and number of CTCs. Capture and enumeration was carried out with a novel microfluidic NanoVelcro technology enhanced by anti-EpCAM enrichment. CTCs were defined by size > 10 um and IHC staining pattern (DAPI+, CK+, and CD45-). Of note, KRAS mutational status was assessed in CTCs from 3 patients to confirm PDAC origin of CTCs. Diagnostic performance was then assessed via analysis of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristic (ROC) curves. Results: Of the 50 patients, 32 patients had PDAC and 18 had non-malignant pathology on tissue biopsy. CTCs were detected in 62.5% of PDAC patients, and in 5.5% of patients with non-malignant pathology. Specificity of CTCs for the diagnosis of PDAC was 94.4%, PPV 95.2%, and NPV 58.6%. ROC curve analysis determined optimal ability for CTCs to distinguish between benign and malignant disease with detection of ≥ 1 CTC. Additionally, in patients with a diagnosis of PDAC, CTC number correlated with stage and the presence of ≥ 2 CTCs distinguished local from systemic disease. Conclusions: In this study, CTCs were a useful adjunct for diagnosis of PDAC. Additionally, CTCs were capable of identifying patients with metastases. Addition of outcomes data may allow CTCs to be established as a biomarker for improved staging at the time of diagnosis, with subsequent improvement in delivery of stage-specific treatments.
Updated survival from a randomized phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients (pts) with metastatic adenocarcinoma of the pancreas.
Authors: Goldstein David , El Maraghi Robert Hassan , Hammel Pascal , Heinemann Volker , Kunzmann Volker , Sastre Javier , Scheithauer Werner , Siena Salvatore , Tabernero Josep , Teixeira Luis , Tortora Giampaolo , Van Laethem Jean-Luc , Young Rosemary , Wei Xinyu , Lu Brian , Romano Alfredo , Von Hoff Daniel D.
Published: February 2017

178^

Background: In the phase III MPACT trial, nab-paclitaxel (nab-P) + gemcitabine (G) was tolerable and demonstrated superiority to G alone for all efficacy endpoints in pts with metastatic pancreatic cancer (MPC). nab-P + G vs G alone met the study’s primary endpoint by demonstrating a significant improvement in overall survival (OS; median 8.5 vs 6.7 months; HR 0.72; 95% CI, 0.617 - 0.835; P < 0.001) and the secondary endpoints of progression-free survival (PFS; median 5.5 vs 3.7 months; HR 0.69; 95% CI, 0.581 - 0.821; P < 0.001) and overall response rate (ORR; 23% vs 7%; P < 0.001). The 1-year survival rates for nab-P + G vs G alone were 35% vs 22%. The OS data reported above were based on a database cutoff of September 17, 2012, at which time 80% of pts had died. Here, we report an updated OS analysis (post hoc) from MPACT. Methods: 861 pts with MPC and a Karnofsky performance status (KPS) ≥ 70 were randomized at 151 community and academic centers 1:1 to receive nab-P 125 mg/m2 + G 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle or G alone 1000 mg/m2weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 of a 28-day cycle (cycle ≥ 2). The data for this survival analysis were collected through April 1, 2013. Results: As of the updated data cutoff, 380/431 (88%) pts in the nab-P + G arm and 394/430 (92%) pts in the G alone arm had died. OS was superior for nab-P + G vs G alone in the intent-to-treat population, and the longer follow-up allowed an estimate of the 3-year survival rates (Table). The treatment effect was consistent across all pt subgroups examined. Conclusions: This updated survival analysis revealed a sustained difference in OS over time between the 2 arms. MPACT is the first phase III study in MPC to report 3-year survival rates. These data confirm and extend the previous report of the primary endpoint and support the superior efficacy of nab-P + G over G alone. These results may encourage efforts to build upon this well tolerated backbone to further extend survival. Clinical trial information: NCT00844649. [Table: see text]
Biomarker assessment from EUS-guided biopsy to predict outcomes and treatment in pancreatic cancer.
Authors: Nguyen Nam Q. , Ruszkiewicz Andrew , Chang David , Bambrick Jenna , Biankin Andrew Victor
Published: February 2017

182

Background: Current methods of pre-operative predicting outcome of pancreatic cancer and related pancreatectomy are limited. While several prognostic biomarkers, including S100A2 and S100A4, are associated with poor outcomes, these currently can only be assessed in operatively resected specimens. The amount of tissue from EUS guided fine needle aspirations is often insufficient for biomarker assessment. Procore needles aim to acquire larger volumes of tissue that may be suitable. We aim to (i) evaluate the feasibility of S100A2 and S100A4 assessment in EUS guided biopsy specimens using the Procore needle, and (ii) evaluate the relationship of these biomarkers with outcome. Methods: Clinico-pathological data from 79 patients (70 ± 2yrs; 44M:35F) with pancreatic ductal adenocarcinoma (PDAC) were prospectively acquired. All subjects had EUS guided biopsy with a 22G Procore needle and cell-block preparation was performed. Sections of cell-block material were assessed for S100A2 and S100A4 protein expression using immunohistochemistry. Results: Pre-operative biomarker assessments from EUS acquired specimens were possible in 90% (72/79) of patients, 14 of which then had pancreatectomy. Thirty-five (49%) of patients expressed S100A2 and S100A4, which were co-expressed in 97% of cases. Patients with S100A2/A4 tumours on EUS had a significantly shorter median survival (10.0 vs. 17.5 months, p=0.03). Among patients with S100A2/A4 expressing tumors, pancreatectomy (n=8) didn't lead to a survival benefit compared with those managed non-surgically (n=27) (12.5 vs. 10.0 months, p=0.70). Of patients who had pancreatectomy, those with S100A2/A4 expressing tumors (n=8) had shorter survival than those with S100A2/A4-negative tumors (n=6) (12.5 vs. 20.5 months; p = 0.04). Conclusions: Biomarker assessment from EUS guided biopsy specimens is feasible and successful in 90% of cases. The presence of S100A2 and S100A4 expression predicts both survival and response to pancreatectomy in patients with pancreatic cancer. These findings demonstrate a “proof-of-concept”, that pre-operative EUS guided biopsy could inform clinical decision-making, particularly with regard to selection for operative resection of PDAC.
Next-generation sequencing in pancreatic cancer: Revealing genomic mutations beyond KRAS.
Authors: Teague Andrea S. , Tan Benjamin R. , Lockhart Albert C. , Picus Joel , Strasberg Steven M. , Hawkins William G. , Fields Ryan C. , Linehan David , Wang-Gillam Andrea
Published: February 2017

208

Background: Pancreatic adenocarcinoma (PA) continues to have one of the worst prognoses of all malignancies, prompting the search for known oncogenic mutations that might be targets for therapy. Methods: We conducted a retrospective analysis of patients with PA who had next generation sequencing (NGS) performed by the Genomics and Pathology Services laboratory at Washington University School of Medicine. Some of main genes included APC, ATM, BRAF, FLT3, NOTCH1, MET, FGFR4, MAPK1, MAP2K2, IDH1, IDH2, RET, JAK2, KRAS, NRAS, PTEN, EGFR, PIK3CA, PDGFRA, RUNX1, KIT, ALK, and TP53. Fluorescence in-site hybridization (FISH) for EGFR gene amplification, and MLL and ALK gene rearrangement was also performed. Results: Among 46 patients with adequate tissue for sequencing, 36 (78.3%) had KRAS mutations (G12D: 44.4%, G12V: 33.3%, G12R:11.1%, Q61H:5.6%, G12A:2.8% and G12R:2.8%). Out of 10 patients with wild type KRAS, 7 patients had either novel mutations or potential targetable mutations (table). TP53 mutations were seen in 73.9% of patients. Among 33 novel mutations not previously described in the COSMIC database, more than 10% are predicted to have deleterious effect by PROVEAN and SIFT. For example, a G1137R variant identified in ALK is predicted to be deleterious and damaging. Of 29 patients whose tumors underwent FISH, 3 patients had EGFR gene amplification, 1 patient had both EGFR gene amplification and ALK gene rearrangement, and 1 patient was positive for the MLL gene rearrangement. Conclusions: NGS of pancreatic cancer not only confirmed common mutations such as KRAS and TP53, but also revealed genomic alterations that may potentially be responsive to available targeted agents. The discovery of novel mutations in wild type KRAS tumors warrants further investigation. [Table: see text]
Genomic profiling of intrahepatic cholangiocarcinoma: Refining prognostic determinants and identifying therapeutic targets.
Authors: Pawlik Timothy M. , Borger Darrell R. , Kim Yuhree , Cosgrove David , Alexandrescu Sorin , Groeschl Ryan Thomas , Deshpande Vikram , Lindberg James M. , Ferrone Cristina , Sempoux Christine , Popescu Irinel , Bauer Todd W. , Gamblin T. Clark , Gigot Jean Francois , Anders Robert , Zhu Andrew X.
Published: February 2017

210

Background: The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to define the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection. Methods: 138 patients who underwent resection at 6 centers in the United States and Europe were included in the cohort. Mutational profiling was performed using nucleic acids that were extracted from resected ICC tumor specimens; mutations were identified using a multiplexed mutational profiling platform. The frequency of mutations was ascertained and the impact on outcome determined. Results: Most patients had a solitary tumor (82%) and median tumor size was 6.0cm. Most patients had R0 resection (89%); 19% patients had N1 disease, while 15% had microscopic vascular invasion. A minority received adjuvant therapy (30%). The majority (55%) of patients had no genetic mutation identified. Among the 62 (45%) patients with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5%: IDH1 (17.4%), KRAS (8.7%), BRAF (5.8%), PIK3CA (5.1%). In contrast, other genetic mutations were identified in very low frequency: IDH2 (3.6%), NRAS (3.6%), TP53 (2.2%), MAP2K1 (1.5%), CTNNB1 (0.7%), and PTEN (0.7%). Approximately 7% of IDH1-mutant tumors were associated with a concurrent PIK3CA gene mutation, and to a much lower extent, a mutation in MAP2K1 (2%). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (OR 3.46), while KRAS-mutant tumors were more likely to be associated with perineural invasion (OR 5.72)(both P<0.05). While clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis. Conclusions: Most patients with resected ICC had no somatic mutation identified on multiplexed mutational profiling. IDH1 and KRAS were the most common mutations noted. While certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly impact long-term prognosis.
Phase I/II trial of autophagy inhibition in combination with neoadjuvant gemcitabine in patients with high-risk pancreatic adenocarcinoma: Safety, clinical response, and correlative studies.
Authors: Lotze Michael T. , Boone Brian A. , Zureikat Amer H. , Bahary Nathan , Lehman David , Liotta Lance A. , Zeh Herbert J.
Published: February 2017

218

Background: Autophagy is a cell survival mechanism, upregulated in pancreatic ductal adenocarcinoma, correlating adversely with response to therapy and prognosis. The autophagy inhibitor hydroxychloroquine (HCQ) is a novel treatment. Methods: A Phase I/II trial examined pre-operative gemcitabine with HCQ in the treatment of pancreatic cancer patients. Eligibility was restricted to those predicted to have limited survival following surgical resection. Two doses of gemcitabine (1500mg/m2) were administered with oral HCQ (200-1200mg/day) for 31 days until operation in a Storer phase 1 design. Primary endpoint was the safety and tolerability of HCQ. Secondary endpoints were clinical response as assessed by CA 19-9 and R0 resection rates. LC3 and cleaved caspase 3 staining were assessed as biologic correlates to clinical response. Additional exploratory endpoints included serum levels of HMGB1, IL-6, and DNA DAMPs. Results: Thirty-five patients were enrolled in the safety phase of the trial. Two patients withdrew consent prior to treatment and two others were removed due to a stroke and allergic rash, resulting in 31 patients completing treatment. There were no dose limiting toxicities and no treatment delays. 14 patients (45%) had a decrease in CA19-9 of >50% following treatment. 29 patients (94%) underwent surgical resection with an R0 resection rate of 81%. There was one peri-operative mortality (3.2%) with significant morbidity (Grade 3/4) affecting 29% of patients. Increases in pancreatic LC3 staining were consistent with autophagy inhibition. There was a statistically non significant trend towards increased apoptosis with increasing doses of HCQ. Both mitochondrial and nuclear DNA (p = .09) decreased. During treatment, HMGB1 and IL-6 levels rose and then returned to normal levels. Conclusions: Pre-operative autophagy inhibition with HCQ in combination with gemcitabine is safe and tolerable and associated with biomarkers of response. This regimen has promise as a biologically active strategy and future trials will examine HCQ in combination with Nab-paclitaxol/Gemcitabine combinations. Clinical trial information: NCT01128296.
Phase Ib of anticancer stem cell antibody OMP-59R5 (anti-Notch2/3) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).
Authors: O'Reilly Eileen Mary , Smith Lon S. , Bendell Johanna C. , Rangwala Fatima A. , Schmidt William , Stephenson Joe , Kapoun Ann , Xu Lu , Hill Dawn , Zhou Lei , Dupont Jakob , Cohn Allen Lee
Published: February 2017

220

Background: OMP-59R5, a fully human IgG2 antibody, inhibits signaling of Notch2 and 3 receptors. Tumor regression was seen in Notch3 expressing patient-derived pancreatic cancer xenografts when OMP-59R5 was combined with Nab-P+Gem. The maximum tolerated dose (MTD) of single agent OMP-59R5 was 7.5 mg/kg every other week (Smith, EORTC 2012); the main dose limiting toxicity (DLT) was grade 3 diarrhea. This study is to determine the MTD, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of OMP-59R5 in combination with Nab-P+Gem in mPC. Methods: Cohorts of 3 to 6 pts were treated at each dose level of OMP-59R5. OMP-59R5 is given intravenously every other week (days 1 and 15) with GEM 1,000 mg/m2 alone (first two cohorts) or nab-P 125 mg/m2 and GEM 1,000 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Results: By August 30, 2013, 24 pts were treated. No DLTs have occurred. Frequently reported (≥10%) OMP-59R5 treatment-related adverse events (AEs) were: diarrhea (44%), fatigue (44%), and nausea (16%); most were grade 1 or 2 and managed with supportive care. Frequent chemo-related AEs (≥10%) were cytopenia, fatigue, diarrhea, and nausea. GEM or Nab-P+Gem did not alter PK of OMP-59R5. See table for additional data. Conclusions: OMP-59R5 with Nab-P+ Gem is well tolerated. The MTD has not been reached. Encouraging anti-tumor activity is observed. Updated Safety, PK/PD, and efficacy data will be presented. Clinical trial information: NCT01647828. [Table: see text]
Analysis of the genomic profile of biphenotypic tumors compared to cholangiocarcinoma and hepatocellular carcinoma.
Authors: Keller Jesse W. , Doyle Maria Majella , Wang-Gillam Andrea , Brunt Elizabeth , Vachhajarani Neeta , Chapman William , Tan Benjamin R.
Published: February 2017

226

Background: Biphenotypic (combined HCC/Cholangiocarcinoma) tumors represent a minority of primary liver cancers. While databases such as the Catalog of Somatic Mutations in Cancer (COSMIC) have genetic information on a large number of cases of HCC and Cholangiocarcinoma, there is little known about rarer Biphenotypic tumors. In this analysis we examine the results of targeted next-generation sequencing to assess genomic differences between these tumors. We utilize the COSMIC database for comparison. Methods: The database of theIRB-approved Washington University Hepatobiliary Registry identified patients with HCC, cholangiocarcinoma and biphenotypic tumors with specimens evaluated utilizing next generation sequencing via a Comprehensive Cancer Gene Set. Further data on corresponding genes was collected from the COSMIC database (v66) for comparison. Results: In this descriptive analysis 15 patients with biphenotypic tumors, 7 patients with HCC and 6 patients with cholangiocarcinoma are presented. The percent of samples with corresponding genetic mutations are outlined (table). These are compared to existing COSMIC data. Conclusions: Biphenotypic tumors had high levels of mutations in EGFR, P53 and Flt3. Mutations in MET, BRAF, CSF1, and MAPK1 were largely isolated to biphenotypic tumors. Mutations in CTNBB1 were isolated to cases of HCC. Notably, mutations in EGFR, Flt3 and FGFR4 were found in all three tumors in higher numbers than seen via review of COSMIC data. Overall, Biphenotypic tumors are genetically complex tumors that share many features of HCC and cholangiocarcinoma. [Table: see text]
Variability in immune infiltrates and HLA expression in cholangiocarcinoma.
Authors: Sabbatino Francesco , Milham Lucia , Deshpande Vikram , Konstantinidis Ioannis T. , Zhu Andrew X. , Santos Daniela Dias , Bardeesy Nabeel , Hong Theodore S. , Tanabe Kenneth , Ferrone Soldano , Lillemoe Keith , Ferrone Cristina
Published: February 2017

230

Background: Cholangiocarcinoma continues to have a dismal prognosis. The lack of effective therapy prompted us to determine whether patients develop an immune response against their own tumors. The aim of this study is to evaluate the CD8 infiltrate and expression of HLA class I antigen processing machinery (APM) components in cholangiocarcinoma. The HLA class I antigen processing machinery (APM) components play a crucial role in expression of HLA class I tumor antigen derived peptide complexes. These complexes mediate the recognition of tumor cells by cognate T cells. Defects in the expression of HLA class I APM components by tumor cells suggests that the infiltrating lymphocytes impose selective pressure on tumor cells. This selective pressure would facilitate the outgrowth of tumors by escaping T cell recognition. Methods: Retrospective review of clinicopathologic factors was performed for 18 peripheral cholangiocarcinomas. Formalin fixed, paraffin embedded tumors were evaluated for the content of lymphocyte infiltrates and for the expression of HLA class I APM components. Results: Eighteen patients underwent a partial hepatectomy for peripheral cholangiocarcinoma of whom 10 were female. Median age was 63yo. The majority of patients had node negative tumors (10/12). All tumors had lymphocytic infiltration. Median number of lymphocytes in the fibrous septae between tumor lobules was 42 CD8 T cells per 10 high power field, but only 4 CD8 T cells within tumor lobules. HLA class I APM components was defective and not detected in three tumors, all of which were poorly differentiated. HLA expression was down regulated in 9 tumors. HLA expression was in normal range in the remaining 6 tumors. Median overall survival has not been reached. Conclusions: Lymphocytic infiltrates were seen in all resected cholangiocarcinoma specimens. The loss of HLA class I APM component expression in cholangiocarcinoma suggests that infiltrating lymphocytes reflect a patient’s immune response to his/her tumor. This information provides a sound rationale to consider immunotherapy in the treatment of cholangiocarcinoma, specifically with antibodies to check point molecules which enhance patients’ immune response against his own tumors.
Novel PAK4 inhibitors for pancreatic cancer therapy.
Authors: Azmi Asfar S. , Senapedis William , Baloglu Erkan , Landesman Yosef , Kalid Ori , Aboukameel Amro , Bao Bin , Shacham Sharon , Sarkar Fazlul H. , Kauffman Michael , Mohammad Ramzi M
Published: February 2017

233

Background: Pancreatic cancer (PC) is a deadly disease in urgent need of novel molecularly targeted drugs. Gene copy number amplification studies in PC patient cohorts has shown amplification of the p21-activated kinase (PAK) family member PAK4. PAK4 acts as a key effector of the Rho family GTPases downstream of Ras signaling. Moreover, PAK4 protein is over-expressed in PC cell lines but not in normal human pancreatic ductal epithelial (HPDE) cells. Most importantly, RNA interference of PAK4 has been shown to suppress PC cell proliferation. These studies clearly make PAK4 an attractive therapeutic target especially because direct targeting of Kras has been a failure. Methods: We have identified a new class of PAK4 allosteric modulators that show anti-proliferative activity against several PC cell lines (IC50s <250nM) while sparing normal HPDE (IC50s5 fold higher). Results: Cell growth inhibition is concurrent with apoptosis induction and suppression of colony formation in the PC cell lines (and not in HPDE cells). Our small molecule PAK4 allosteric modulator, KPT-7189, suppresses PAK4 protein expression and caused reversal of anti-apoptotic signaling. PAK4 RNA interference enhances KPT-7189 activity, and co-immunoprecipitation experiments showed disruption of PAK4 binding partners. KPT-7189 also inhibited spheroid forming ability of highly resistant PC cells carrying markers of cancer stem cells (CSCs;triple positive for CD33+CD44+EpCAM+) consistent with epithelial-to-mesenchymal (EMT) phenotype. Molecular analyses of KPT-7189 treated CD33+CD44+EpCAM+ spheroids showed suppression of EMT and CSC markers with re-expression of epithelial phenotype markers. Another potent PAK allosteric modulator in the same series, KPT-7651 showing good oral bioavailability (%F = 95%) was well tolerated by mice with a maximum tolerated dose of 60 mg/kg following oral administration. Pre-clinical animal efficacy trial in sub-cutaneous, orthotopic and LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre transgenic mice model is currently under investigation. Conclusions: This is the first proof of concept study demonstrating the development of a PAK4-targeted drug for the treatment of PC, and thus further pre-clinical and clinical investigations are warranted.
In vitro activity of ABT-888 (A), 5-FU (F), and dacarbazine (D) in neuroendocrine tumors (NET).
Authors: Lubner Sam Joseph , Somnay Yash , Deming Dustin A. , Holen Kyle D. , Chen Herbert
Published: February 2017

236

Background: Low-grade neuroendocrine tumors (NET) have few cytotoxic chemotherapy options. Data suggests that a combination of temozolomide and a fluoropyrimidine has clinical efficacy. ABT-888 is a novel poly-ADP ribose polymerase (PARP) inhibitor that has been tested in a phase 1 setting with temozolomide, with synergy demonstrated in preclinical models of other tumors. We proposed an in-vitro study of ABT-888 with varying concentrations of dacarbazine (D), and 5-FU (F) on human neuroendocrine cells (BON). Methods: BON cells were incubated with varying concentrations and combinations of ABT-888 (2.5, 5 and 10uM), F (25-100uM), and D (25-100uM) for 96 hours. After incubation, cell growth was measured by MTT rapid colorimetric assay with absorbance reported as mean % control. Western blot analysis was performed for chromogranin A, PARP, γH2AXand XIAP to assess for cell death and on-target effects for the population treated with 5-FU. Combination indices (CI) were calculated using the Chou-Talalay method using CompuSyn. CI’s below 1 signified synergy. Results: ABT-888 alone did not demonstrate any antitumor effect (103%). D alone had antitumor effect (74% at 50uM, 67% at 100uM) which was improved by adding ABT-888 (70% at 50uM D; CI 0.73; p=0.06, 60% at 100 uM D; CI 0.88; p=0.0003). F alone had antitumor effect (82% at 50uM and 71% at 100uM) which was improved by adding 2.5uM ABT-888 (71% at 50uM of F; CI=0.59, and 58% at 100uM of F; CI=0.74), and further enhanced with 5uM of concomitant ABT-888 (56% at 50uM of F; CI=0.68, and 49% at 100uM of F; CI=0.76). Western analysis of lysates showed markers of increased apoptosis, decreased PARP, and decreased expression of CgA. The combination of F+D did not demonstrate increased cytotoxicity with the addition of ABT-888 (58% with/without ABT-888 p=0.61). Conclusions: ABT-888 demonstrated in vitro synergy against BON cells with F or D. The combination of all three compounds (A+F+D) did not demonstrate synergy above F+D. Synergy was statistically significant with increasing doses of cytotoxic compounds which are achievable in vivo with current doses of A, F, and D. The combination of ABT-888 with temozolomide or a fluoropyrimidine merits further study in human clinical trials.
Mismatch repair protein loss and microsatellite instability in cholangiocarcinoma.
Authors: Goyal Lipika , Deshpande Vikram , Chung Daniel C , Groeschl Ryan Thomas , Gamblin T. Clark , Zhu Andrew X.
Published: February 2017

237

Background: Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch Syndrome, is an autosomal dominant syndrome characterized by mutations in genes involved in DNA mismatch repair (MMR) and consequent microsatellite instability (MSI). These genetic aberrations lead to an increased incidence of multiple malignancies including colorectal and endometrial cancer, among others. While an association between biliary tumors and HNPCC has been proposed, no published studies have documented MMR protein loss and MSI in a series of biliary tumor samples. After diagnosing cholangiocarcinoma (CCA) in two clinic patients known to have HNPCC and incidentally noting MMR protein loss and MSI in their tumor, we conducted an exploratory study to evaluate the frequency of MMR protein loss and MSI in patients with CCA. Methods: Discarded tissue samples from patients with CCA treated at the Massachusetts General Hospital (n=44) were evaluated for the loss of MLH1, PMS2, MSH2, and MSH6 with immunohistochemical staining. The results were correlated with clinicopathologic features, and the MSI status was collected from the medical record. Results: Four (9.1%) of 44 patients were found to have loss of at least two MMR proteins: 2 pts had MSH2/MSH6 loss, 1 had MLH1/PMS2 loss, and 1 had loss of all 4 proteins. Two patients had previously been tested for microsatellite instability and both were MSI-high. The clinicopathologic features of the 4 patients included: median age 54.5 yo; M:F 1:3; diagnosed with ≥ 1 HNPCC-related malignancy 1/4; family history of ≥ 2 HNPCC-related tumors 2/4, intrahepatic:extrahepatic CCA 3:1; moderately-poorly:poorly differentiated 2:2; T1:T2 3:1; ≥1 positive lymph node 1/4; lymphovascular invasion 2/3; perineural invasion 2/4. Conclusions: MMR protein loss was discovered in 9.1% of patients with CCA in this initial cohort. A second validation cohort from a different institution is currently being tested, and the results will be presented at the meeting. CCA may be an underappreciated co-morbid neoplasm in the spectrum of tumors for HNPCC. MMR protein loss should be further explored as a mechanism of oncogenesis in CCA, and clinicians should be aware of this malignancy in surveillance of patients with HNPCC.
Analysis of metabolic response (MR) by positron emission tomography (PET) compared with tumor response by computed tomography (CT) from MPACT, a phase III trial comparing nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone for patients (pts) with metastatic adenocarcinoma of the pancreas.
Authors: Ramanathan Ramesh K. , Von Hoff Daniel D. , Moore Malcolm J. , Teixeira Luis , Siena Salvatore , Tabernero Josep , Goldstein David , Wei Xinyu , Lu Brian
Published: February 2017

254^

Background: In the MPACT trial, nab-P + G demonstrated superior efficacy vs G alone for the treatment of metastatic pancreatic cancer (PC). Pts with an MR (according to EORTC criteria) had a 5-month improvement in median overall survival (OS) vs those without an MR (13 vs 8 months for nab-P + G and 12 vs 7 months for G alone). This analysis examines the relationship between MR by PET and tumor response by CT. Methods: Previously untreated pts (N = 861) with metastatic PC were randomized 1:1 to receive nab-P 125 mg/m2 + G 1000 mg/m2 on days 1, 8, and 15 every 4 wk or G alone 1000 mg/m2 weekly for 7 wk followed by 1 wk of rest (cycle 1) and then days 1, 8, and 15 every 4 wk (cycle ≥ 2). Tumor responses were evaluated every 8 wk by CT using RECIST v1.0. CT-documented disease progression led to treatment discontinuation. PET scans were evaluated at baseline, wk 8, and wk 16. Results: In 257 pts with a PET scan at baseline, 252 (98%) had ≥ 2 PET-avid lesions. The rate of MR (complete [CMR] or partial [PMR]) was higher for nab-P + G vs G alone (63% vs 38%; P < 0.0001). The ORRs by CT (complete response + partial response [CR/PR]) in the same pts were 31% for nab-P + G vs 11% for G. In a pooled-treatment-arm analysis (n = 255), 130 pts (51%) had an MR by PET, and 54 (21%) had a CR or PR by CT. Among pts with an MR by PET, 32% had a CR or PR, 43% had stable disease, and 16% had progressive disease (PD) by CT. Pts who had an MR by PET in the absence of a CR or PR by CT (n = 88) had a median OS of 10 months (table). Conclusions: Rates of MR by PET in this trial were > 2-fold the response rates by CT, suggesting that PET may be a more sensitive marker of tumor response. Of the pts without a CR or PR by CT, those with an MR by PET had a longer median OS vs those without one. A set of pts who had PD by CT exhibited an MR by PET. Thus, PET may identify a set of pts who may benefit from continued treatment despite PD by CT. Further research is needed to explore the radiological and clinical characteristics of these pts. Clinical trial information: NCT00844649. [Table: see text]
Interim analysis of a phase II study of dose-modified FOLFIRINOX (mFOLFIRINOX) in locally advanced (LAPC) and metastatic pancreatic cancer (MPC).
Authors: James Edward Samuel , Yao Xiaopan , Cong Xiangyu , Stein Stacey , Kaley Kristin , Hahn Carol , Cha Charles , Salem Ronald R , Hochster Howard S. , Lacy Jill
Published: February 2017

256

Background: Although FOLFIRINOX is superior to gemcitabine in MPC, the regimen is associated with significant toxicities (Conroy et al. N Engl J Med 2011;364:1817). In our prior retrospective analysis, efficacy was not compromised by dose attenuations of FOLFIRINOX (Gunturu et al. Med Oncol 2013;30:361). Based on this analysis, we are conducting a prospective phase II open label study to evaluate the efficacy & tolerability of mFOLFIRINOX in pts with advanced pancreatic cancer (PC). Methods: Previously untreated pts with MPC or LAPC received mFOLFIRINOX with 25% dose reductions of irinotecan & bolus 5-FU given every two wks until progression, unacceptable toxicity, or surgical resection. All pts received prophylactic pegfilgrastim. FDG-PET scans were obtained at baseline & after 2 cycles. CAT scans were obtained after every 4 cycles. Toxicities & response rate (RR) were compared to historical data reported by Conroy. Results: 53 pts with ECOG PS ≤1 have been enrolled to date between 11/11 and 08/13, Pt characteristics: LAPC 22; MPC 31; median age 62 yrs (range 46-86); male 30. Median # of cycles was 8 (range 1-21). Grade 3/4 toxicities were: anemia, febrile neutropenia (FN) & peripheral sensory neuropathy (PSN) – 3.8% each; ALT increased & thromboembolism – 5.7% each; diarrhea 7.5%; fatigue 11.3%; neutropenia 17%; thrombopenia 11.3% & vomiting 1.9%. Anemia ( p< 0.04), FN (p<0.04), PSN (p<0.04) and vomiting (p<0.02) were significantly decreased compared to historical data (Conroy). Response by RECIST (CR+PR) in 26 evaluable pts with MPC was 29% (0 CR, 9 PR, 14 SD, 3 PD) & similar to historical data (31.6%; p 0.85). 6/13 evaluable pts with LAPC underwent resection (46%).13/36 pts evaluable for PET response had a >50% decrease in SUV(max)(36%). Evaluation for OS & PFS is ongoing. Conclusions: Findings from our interim analysis suggests that mFOLFIRINOX, given along with prophylactic pegfilgrastim is associated with a similar RR and improved tolerability compared to full dose FOLFIRINOX in advanced PC. In pts with LAPC, neoadjuvant FOLFIRINOX appears to have substantial activity with 46% of evaluable pts undergoing resection. Accrual will continue to reach a goal of 70 pts. Clinical trial information: NCT01523457.
A phase II study of vismodegib, a hedgehog (Hh) pathway inhibitor, combined with gemcitabine and nab-paclitaxel (nab-P) in patients (pts) with untreated metastatic pancreatic ductal adenocarcinoma (PDA).
Authors: De Jesus-Acosta Ana , O'Dwyer Peter J. , Ramanathan Ramesh K. , Von Hoff Daniel D. , Maitra Anirban , Rasheed Zeshaan , Zheng Lei , Rajeshkumar N. V. , Le Dung T. , Hoering Antje , Bolejack Vanessa , Yabuuchi Shinichi , Laheru Daniel A.
Published: February 2017

257

Background: The Hh pathway is overexpressed in PDA tumors. Pre-clinically, Hh inhibitors have demonstrated a reduction in pancreatic cancer stem cells (pCSC) and stroma. Vismodegib, an oral small-molecule antagonist of the Hh pathway, has previously been safely combined with Gemcitabine chemotherapy. Methods: Pts with untreated, metastatic PDA were treated with Gemcitabine (1000 mg/m2) + nab-P (125 mg/m2) on days 1, 8 and 15 of 28 days cycle. Vismodegib (150mg PO daily) was started on the second cycle. All drugs were continued until disease progression or unacceptable toxicities. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), response rate (RR), and toxicity. Pre and post treatment tumor biopsies were obtained from primary or metastatic lesions. Results: 59 patients have been enrolled at 3 sites. Median age 60 (range 42-86); ECOG PS 0/1: 23 (40%)/ 34 (60%); male/female 32 (54%)/ 27 (46%). Estimated median PFS and OS in ITT population was 5.5 and 10 mo respectively (95% CI: 5.2-5.9 / 7.3-11). Of the 49 pts evaluable for response to date, 1 (2%) had CR, 20 (41%) had PR, 21 (43%) had SD and 7 (14%) had PD. Common Gr ≥3 toxicities: neutropenia 37.5% (n=21), anemia 21.4% (n=12), neuropathy 16.1% (n=9) and fatigue 9.4% (n=5). All patients with partial response had response within the primary pancreatic tumor. CA19-9 declines of >70% occurred in 57% of patients with measurable levels. Conclusions: Addition of Vismodegib to Gemcitabine/nab-P is well tolerated in patients with untreated PDA. This trial is ongoing to complete 80 patients. Blood and tumor tissue biomarker analyses for stem cells, Hh signaling and stromal activity are ongoing and will be reported in ASCO GI 2014. Clinical trial information: NCT01088815.
A prospective study of repeat endoscopic biopsy to identify HER2-positive tumors following an initial HER2-negative biopsy in unresectable or metastatic gastric cancer: Gasther-1.
Authors: Kang Yoon-Koo , Park Sook Ryun , Park Young Soo , Lee Jeong Hoon , Ryoo Baek-Yeol , Woo Chang Gok , Lee Gin Hyug , Jung Hwoon-Yong , Ryu Min-Hee
Published: February 2017

27

Background: The intratumoral heterogeneity of HER2 expression in gastric cancer (GC) is a major challenge for identifying patients (pts) who would benefit from anti-HER2 therapy. The aim of this study is to evaluate the significance of re-evaluation of the HER2 status by repeat endoscopic biopsy in pts with HER2-negative GC on initial endoscopic biopsy. Methods: Pts with unresectable or metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma who would receive 1st line chemotherapy were eligible if the HER2 was negative on the initial endoscopic biopsy. HER2 positivity was defined as IHC 3+ or IHC 2+/FISH+ using the GC scoring system. A repeat endoscopic biopsy was performed in ≥6 different primary tumor sites immediately after obtaining initial HER2-negative results. Results: From May 2011 to April 2013, a total of 183 pts were enrolled. Baseline characteristics at the time of the initial biopsy were as follows: tumor location, GEJ~fundus/body~antrum/diffuse stomach = 22 (12.0%)/115 (62.9%)/46 (25.1%); Lauren classification, intestinal/diffuse/mixed = 53 (29.0%)/111 (60.7%)/19 (10.4%); and HER2 IHC score, 0/1/2 = 149 (81.4%)/26 (14.2%)/8 (4.4%). The median number of biopsy pieces was 5 (range, 1-15) and 10 (1-15) in the initial and repeat biopsy, respectively (p<0.0001). As HER2 positive tumor was identified in 16 pts, HER2 positivity rate on repeat biopsy was 8.7% (95% CI 4.6-12.8%). The detection of HER2 positivity on repeat biopsy was associated with tumor location (diffuse stomach vs others = 0% vs 11.7%, p=0.013), Bormann type (IV vs others = 0% vs 11.7%, p=0.013), and the HER2 IHC score on the initial biopsy (0 vs 1/2 = 6.7% vs 18.2%, p=0.045). In multivariate analysis, the HER2 IHC score (1/2 vs 0, OR = 3.30; p=0.041) was an independent predictor of HER2 positivity in repeat biopsy. Conclusions: In pts with metastatic or unresectable GC, repeat endoscopic biopsy could detect HER2-positive GC which initial biopsy had missed. As anti-HER2 therapy improves the survival of pts with HER2 positive GC, in pts who showed HER2 negativity on initial biopsy, repeat biopsy should be considered subsequently.
A phase 1b study of the anticancer stem cell agent demcizumab (DEM) and gemcitabine (GEM) with or without paclitaxel protein bound particles (nab-paclitaxel) in patients with pancreatic cancer.
Authors: Gracian Antonio Cubillo , Jameson Michael B. , Grande Enrique , Cooray Prasad , Parnis Francis , Grimison Peter , Jeffery Mark , Stagg Robert J. , Dupont Jakob , Tebbutt Niall C.
Published: February 2017

279

Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway. DEM is a humanized IgG2anti-DLL4 antibody that inhibits tumor growth and decreases cancer stem cell (CSC) frequency in minimally passaged human xenograft models. In addition, DEM has been shown to have an antiangiogenic effect and showed synergistic activity when combined with GEM and nab-paclitaxel in human pancreatic tumor-derived xenograft models. Methods: Pts with 1st line stage pancreatic cancer received DEM (2.5 every 2 or 4 wks or 5 mg/kg every 4 wks) and GEM 1000 mg/m27 of 8 wks, then 3 of every 4 wks. The primary objective was to determine the MTD of DEM. Other objectives were safety, efficacy, immunogenicity, PK and biomarkers of Notch signaling and CSCs. Results: Twenty four pts were enrolled; 8 received 2.5 mg/kg every 2 wks, 8 received 2.5 mg/kg every 4 wks & 8 received 5 mg/kg every 4 wks of DEM. Three (12.5%) and 21 (87.5%) pts had stage III and IV disease, respectively. Related AEs (all grades) in > 15% of pts were: fatigue (29%), hypertension (29%), vomiting (29%), nausea (25%), thrombocytopenia (21%) and decreased appetite (21%). The hypertension was managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. One pt who received 5 mg/kg developed reversible pulmonary hypertension and heart failure on study day 143. As a result, the duration of DEM will be limited to 70 days in subsequent cohorts. Four of 16 (25%) pts had a RECIST partial response and 7 had stable disease. The median PFS for the 5 mg/kg cohort was 5.9 months. The PK and immunogenicity data will also be presented. Conclusions: DEM plus GEM were generally well tolerated with fatigue, hypertension, and vomiting being the most common drug related AEs. Encouraging early clinical activity was observed. The duration of DEM is being limited to 70 days and nab-paclitaxel is also being given in subsequent cohorts. The first cohort of pts receiving GEM, nab-paclitaxel, and DEM has been enrolled and > 100 days of follow-up on these pts will be presented. Clinical trial information: NCT01189929.
Neoadjuvant chemotherapy with gemcitabine and S-1 for resectable and borderline pancreatic ductal adenocarcinoma: A prospective, multi-institutional, phase II trial.
Authors: Mizuma Masamichi , Motoi Fuyuhiko , Ishida Kazuyuki , Fujishima Fumiyoshi , Ottomo Shigeru , Oikawa Masaya , Okada Takaho , Shimamura Hiromune , Takemura Shinichi , Ono Fuminori , Akada Masanori , Nakagawa Kei , Katayose Yu , Egawa Shinichi , Unno Michiaki
Published: February 2017

283

Background: Although surgical resection is the only curative treatment for pancreatic ductal adenocarcinoma (PDAC), recurrence rates are very high even if complete resection is performed. Accordingly, a new therapeutic strategy against PDAC is needed. Combination with gemcitabine and S-1 (GS) as first line chemotherapy is promising. The purpose of this study is to evaluate the feasibility and efficacy of GS for resectable and borderline PDAC in the neoadjuvant chemotherapy (NAC). Methods: This study is a prospective, multi-institutional, single-arm, phase II trial. Neoadjuvant chemotherapy with gemcitabine and S-1(NAC-GS) for resectable and borderline PDAC was performed as follows. Gemcitabine was given at a dose of 1,000 mg/m2 on days 1 and 8 of each cycle. S-1 was administered orally at a dose of 40 mg/m2 twice daily for the first 14 consecutive days followed by a 7-day rest. Each cycle was repeated every 21 days. The primary endpoint was the 2-year survival rate. Secondary endpoints were feasibility, resection rate, pathological effect, recurrence-free survival and tumor marker status. Results: 36 patients were enrolled between 2008 and 2010. 35 were eligible for participation in this trial. The most common toxicity was neutropenia in response to 90% of the relative dose intensity. Radiological tumor shrinkage and decreases of CA19-9 levels were seen in 69% and 89%, respectively. R0 resection rate was 87%, and the morbidity rate (40%) was acceptable. The 2-year survival rate of the total cohort was 45.7%. Patients undergoing surgical resection without distant metastases after NAC-GS (n=27) showed an increased median overall survival (34.7 months), compared with 10.0 months for resection with distant metastases or non-resection (p=0.0017). Conclusions: NAC-GS is safe and well tolerated in a multi-institutional setting. NAC-GS is encouraging patients with resectable and borderline PDAC because of better outcomes. Clinical trial information: UMIN-000001504.
Multicenter phase I trial of sorafenib (S) in high-risk hepatocellular carcinoma (HCC) patients after liver transplantation (LT).
Authors: Siegel Abby B. , El-Khoueiry Anthony B. , Finn Richard S. , Goyal Abhishek , Blanke Charles David , Brown Robert S.
Published: February 2017

285

Background: LT offers excellent long-term survival for HCC patients within the Milan criteria. For those outside Milan, recurrence rates are higher. No known treatments have been shown to decrease risk of recurrence post-transplant. Methods: Subjects had pathologically proven HCC that was outside Milan (pre- or post-transplant), was poorly differentiated, or had vascular invasion. We used a standard 3+3 design, beginning drug between 4 and 16 weeks after LT, with planned duration of treatment of 24 weeks. Cohort dosages were: 1) 200 mg q day, 2) 200 mg BID, 3) 200 mg/400 mg q day. Correlative studies included circulating endothelial cells (CECs-Veridex) and plasma biomarkers (VEGF, sVEGFR1, sVEGFR2, IL-6 and HGF) collected prior to treatment, at 1 month, and at recurrence. Results: We enrolled 14 patients; 93% were men. Median age was 63; 71% had underlying HCV, 21% HBV, and 21% ETOH. 57% were outside Milan on preoperative imaging. On explant, 29% had poorly-differentiated tumors, and 36% had vascular invasion. MTD was 200 mg BID; only 43% of patients received >80% of planned dose. DLTs included liver function abnormalities (1), transplant rejection leading to death (1), and grade 3 hypertension (1). Grade 3-4 toxicities seen in >10% of subjects included: leukopenia (29%), LFT abnormalities (21%), hypertension (14%), hand-foot syndrome (14%) and diarrhea (14%). Over a median follow-up of 836 days, 1 patient died and 4 recurred (median time to recurrence=716 days). Two recurrences were in subjects with limited exposure to S. Median CEC number at baseline was 16 cells/4 ml for those who recurred, and 42 cells/4 ml for those who did not (p=0.10). Median sVEGFR2 levels decreased after 1 month on S (p=0.09), but did not predict recurrence. Conclusions: To our knowledge, this is the first multicenter phase I trial of S completed in the post-transplant setting for high-risk HCC. MTD of S was 200 mg PO BID. Post-transplant S was feasible. Exploratory biomarker data suggest that low CECs at baseline were potentially associated with a higher recurrence rate. Time to recurrence was promising compared with historic controls, but needs to be further explored and validated in a larger study. Clinical trial information: NCT00997022.
A phase I trial of cixutumumab (C) (IMC-A12) and sorafenib (S) for treatment of advanced hepatocellular carcinoma (HCC).
Authors: El-Khoueiry Anthony B. , O'Donnell Robert , Mack Philip C , Blanchard Suzette , Bahary Nathan , Jiang Yixing , Yen Yun , Wright John Joseph , Chen Helen , Lenz Heinz-Josef , Gandara David R.
Published: February 2017

293

Background: The insulin growth factor (IGF) pathway is activated in hepatocarcinogenesis. C is a monoclonal antibody against human insulin-like growth factor-1 receptor (IGF-1R). In vivo HCC models show activated IGF signaling and antitumor effects due to C. Given the cross-talk between the IGF and VEGF pathways, the combination of C and S was chosen for study. Methods: This study evaluated the safety of C (2, 4 or 6 mg/kg) IV weekly with standard doses of S (400 mg po bid) in patients (pts) with HCC without standard curative options. Eligibility criteria included: no prior systemic therapy, Child-Pugh score of A or B7, ECOG 0 or 1, platelets > 75,000/mm3, and albumin > 2.8 g/dl. The study used a standard 3+3 design. One cycle was 28 days. Results: A total of 21 pts (17 males and 4 females) were enrolled; mean age was 63 years (43-85); 10 Asian, 4 Hispanic, 5 White, 1 Black, and 1 Native American. There were 3 dose limiting toxicities (DLTs); grade 3 hyperglycemia, grade 3 hypophosphatemia, and grade 5 peritonitis (table). The maximum tolerated dose (MTD) was C 4 mg/Kg and S 400 mg BID. Eighteen of 21 (86%) pts had ≥ grade 3 toxicities attributable to treatment. Grade 3 adverse events that occurred in ≥ 2 pts were: diarrhea (4; 19%), hypertension (4; 19%), thrombocytopenia (3; 14%), palmar-plantar erythrodysesthesia (2; 10%), hyperglycemia (2; 10%), and fatigue (2; 10%). There was one grade 4 colonic perforation and one grade 5 peritoneal infection in the same pt. The median number of cycles completed was 4 (0-19 cycles). Sixteen of the 21 pts completed 2 cycles and were evaluated for response. Thirteen of the sixteen (81%) (95% CI: 54%-96%) achieved stable disease. The median event-free survival was 3.8 months (95%CI: 1.9, 11.3). The median OS was 13.1 months (95% CI: 7.6, undefined). Conclusions: The majority of adverse events in pts treated with the combination of C and S were typical of sorafenib toxicity. There was preliminary evidence of efficacy as seen in the median OS. Analysis of biomarker correlative data is on-going. Clinical trial information: NCT01008566. [Table: see text]