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Pancreatic Neoplasms: HELP
Articles by Alan P. Venook
Based on 12 articles published since 2009
(Why 12 articles?)
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Between 2009 and 2019, Alan Venook wrote the following 12 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Borderline resectable pancreatic cancer: need for standardization and methods for optimal clinical trial design. 2013

Katz, Matthew H G / Marsh, Robert / Herman, Joseph M / Shi, Qian / Collison, Eric / Venook, Alan P / Kindler, Hedy L / Alberts, Steven R / Philip, Philip / Lowy, Andrew M / Pisters, Peter W T / Posner, Mitchell C / Berlin, Jordan D / Ahmad, Syed A. ·Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. mhgkatz@mdanderson.org ·Ann Surg Oncol · Pubmed #23435609.

ABSTRACT: BACKGROUND: Methodological limitations of prior studies have prevented progress in the treatment of patients with borderline resectable pancreatic adenocarcinoma. Shortcomings have included an absence of staging and treatment standards and pre-existing biases with regard to the use of neoadjuvant therapy and the role of vascular resection at pancreatectomy. METHODS: In this manuscript, we review limitations of studies of borderline resectable PDAC reported to date, highlight important controversies related to this disease stage, emphasize the research infrastructure necessary for its future study, and present a recently-approved Intergroup pilot study (Alliance A021101) that will provide a foundation upon which subsequent well-designed clinical trials can be performed. RESULTS: We identified twenty-three studies published since 2001 which report outcomes of patients with tumors labeled as borderline resectable and who were treated with neoadjuvant therapy prior to planned pancreatectomy. These studies were heterogeneous in terms of the populations studied, the metrics used to characterize therapeutic response, and the indications used to select patients for surgery. Mechanisms used to standardize these and other issues that are incorporated into Alliance A021101 are reviewed. CONCLUSIONS: Rigorous standards of clinical trial design incorporated into trials of other disease stages must be adopted in all future studies of borderline resectable pancreatic cancer. The Intergroup trial should serve as a paradigm for such investigations.

2 Clinical Trial The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation. 2018

Innocenti, Federico / Owzar, Kouros / Jiang, Chen / Etheridge, Amy S / Gordân, Raluca / Sibley, Alexander B / Mulkey, Flora / Niedzwiecki, Donna / Glubb, Dylan / Neel, Nicole / Talamonti, Mark S / Bentrem, David J / Seiser, Eric / Yeh, Jen Jen / Van Loon, Katherine / McLeod, Howard / Ratain, Mark J / Kindler, Hedy L / Venook, Alan P / Nakamura, Yusuke / Kubo, Michiaki / Petersen, Gloria M / Bamlet, William R / McWilliams, Robert R. ·UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, United States of America. · Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, United States of America. · Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, United States of America. · North Shore University Health System, Evanston, IL, United States of America. · Northwestern University, Chicago, IL, United States of America. · University of California at San Francisco, San Francisco, CA, United States of America. · Moffitt Cancer Center, Tampa, FL, United States of America. · University of Chicago, Chicago, IL, United States of America. · Center for Genomic Medicine, RIKEN, Yokohama, Japan. · Mayo Clinic, Rochester, MN, United States of America. ·PLoS One · Pubmed #30107003.

ABSTRACT: PURPOSE: Advanced pancreatic cancer is a highly refractory disease almost always associated with survival of little more than a year. New interventions based on novel targets are needed. We aim to identify new genetic determinants of overall survival (OS) in patients after treatment with gemcitabine using genome-wide screens of germline DNA. We aim also to support these findings with in vitro functional analysis. PATIENTS AND METHODS: Genome-wide screens of germline DNA in two independent cohorts of pancreatic cancer patients (from the Cancer and Leukemia Group B (CALGB) 80303 and the Mayo Clinic) were used to select new genes associated with OS. The vitamin D receptor gene (VDR) was selected, and the interactions of genetic variation in VDR with circulating vitamin D levels and gemcitabine treatment were evaluated. Functional effects of common VDR variants were also evaluated in experimental assays in human cell lines. RESULTS: The rs2853564 variant in VDR was associated with OS in patients from both the Mayo Clinic (HR 0.81, 95% CI 0.70-0.94, p = 0.0059) and CALGB 80303 (HR 0.74, 0.63-0.87, p = 0.0002). rs2853564 interacted with high pre-treatment levels of 25-hydroxyvitamin D (25(OH)D, a measure of endogenous vitamin D) (p = 0.0079 for interaction) and with gemcitabine treatment (p = 0.024 for interaction) to confer increased OS. rs2853564 increased transcriptional activity in luciferase assays and reduced the binding of the IRF4 transcription factor. CONCLUSION: Our findings propose VDR as a novel determinant of survival in advanced pancreatic cancer patients. Common functional variation in this gene might interact with endogenous vitamin D and gemcitabine treatment to determine improved patient survival. These results support evidence for a modulatory role of the vitamin D pathway for the survival of advanced pancreatic cancer patients.

3 Clinical Trial Preoperative Modified FOLFIRINOX Treatment Followed by Capecitabine-Based Chemoradiation for Borderline Resectable Pancreatic Cancer: Alliance for Clinical Trials in Oncology Trial A021101. 2016

Katz, Matthew H G / Shi, Qian / Ahmad, Syed A / Herman, Joseph M / Marsh, Robert de W / Collisson, Eric / Schwartz, Lawrence / Frankel, Wendy / Martin, Robert / Conway, William / Truty, Mark / Kindler, Hedy / Lowy, Andrew M / Bekaii-Saab, Tanios / Philip, Philip / Talamonti, Mark / Cardin, Dana / LoConte, Noelle / Shen, Perry / Hoffman, John P / Venook, Alan P. ·Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston. · Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, Minnesota. · Department of Surgery, University of Cincinnati, Cincinnati, Ohio. · Department of Radiation Oncology, Johns Hopkins University, Baltimore, Maryland. · Department of Medical Oncology, NorthShore University HealthSystem, University of Chicago, Chicago, Illinois. · Department of Medical Oncology, University of California-San Francisco, San Francisco. · Department of Radiology, Columbia University, New York, New York. · Department of Pathology, Ohio State University, Columbus. · Department of Surgery, University of Louisville, Louisville, Kentucky. · Department of Surgery, Ochsner Medical Center, New Orleans, Louisiana. · Department of Surgery, Mayo Clinic, Rochester, Minnesota. · Department of Medical Oncology, University of Chicago, Chicago, Illinois. · Department of Surgery, University of California, San Diego. · Department of Medical Oncology, Ohio State University, Columbus. · Department of Medical Oncology, Karmanos Cancer Center, Detroit, Michigan. · Department of Surgery, NorthShore University HealthSystem, University of Chicago, Chicago, Illinois. · Department of Medical Oncology, Vanderbilt University, Nashville, Tennessee. · Department of Medical Oncology, University of Wisconsin-Madison, Madison, Wisconsin. · Department of Surgery, Wake Forest University, Winston Salem, North Carolina. · Department of Surgery, Fox Chase Cancer Center, Philadelphia, Pennsylvania. ·JAMA Surg · Pubmed #27275632.

ABSTRACT: IMPORTANCE: Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported. OBJECTIVE: To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting. DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014. INTERVENTIONS: Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan hydrochloride, 400 mg/m2 of leucovorin calcium, and then 2400 mg/m2 of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2 orally twice daily) prior to pancreatectomy. MAIN OUTCOMES AND MEASURES: Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate. RESULTS: The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration. CONCLUSIONS AND RELEVANCE: The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial's completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01821612.

4 Clinical Trial A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma. 2016

Ko, Andrew H / LoConte, Noelle / Tempero, Margaret A / Walker, Evan J / Kate Kelley, R / Lewis, Stephanie / Chang, Wei-Chou / Kantoff, Emily / Vannier, Michael W / Catenacci, Daniel V / Venook, Alan P / Kindler, Hedy L. ·From the *Division of Hematology/Oncology, University of California San Francisco, San Francisco, CA; †Division of Hematology/Oncology, University of Wisconsin, Madison, WI; ‡Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; and §Department of Radiology and ∥Division of Hematology/Oncology, University of Chicago, Chicago, IL. ·Pancreas · Pubmed #26390428.

ABSTRACT: OBJECTIVES: In mouse models of pancreatic cancer, IPI-926, an oral Hedgehog inhibitor, increases chemotherapy delivery by depleting tumor-associated stroma. This multicenter phase Ib study evaluated IPI-926 in combination with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) in patients with advanced pancreatic cancer. METHODS: Patients were treated with once-daily IPI-926 plus FOLFIRINOX. A 3 + 3 dose escalation design was used, with cohort expansion at the maximum tolerated dose. A subset of patients underwent perfusion computed tomography to assess changes in tumor perfusion. RESULTS: The maximum tolerated dose was identified 1 dose level below standard FOLFIRINOX. Common treatment-related adverse events included liver function test abnormalities, neuropathy, nausea/vomiting, and diarrhea. Objective response rate was high (67%), and patients receiving IPI-926 maintenance showed further declines in CA19-9 levels even after FOLFIRINOX discontinuation. Treatment did not result in consistent increases in tumor perfusion. The study closed early when a separate phase II trial of IPI-926 plus gemcitabine indicated detrimental effects of this combination. CONCLUSIONS: This is the first study to demonstrate the feasibility of using FOLFIRINOX as the chemotherapeutic backbone in a clinical trial design. Although robust antitumor activity and acceptable safety were observed with the addition of IPI-926 to this regimen, future development of Hedgehog inhibitors in pancreatic cancer seems unlikely.

5 Clinical Trial A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma. 2016

Ko, Andrew H / Bekaii-Saab, Tanios / Van Ziffle, Jessica / Mirzoeva, Olga M / Joseph, Nancy M / Talasaz, AmirAli / Kuhn, Peter / Tempero, Margaret A / Collisson, Eric A / Kelley, R Kate / Venook, Alan P / Dito, Elizabeth / Ong, Anna / Ziyeh, Sharvina / Courtin, Ryan / Linetskaya, Regina / Tahiri, Sanaa / Korn, W Michael. ·Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. andrewko@medicine.ucsf.edu. · Ohio State University Comprehensive Cancer Center, Columbus, Ohio. · Department of Pathology, University of California San Francisco, San Francisco, California. · Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. · Guardant Health, Inc., Redwood City, California. · University of Southern California, Los Angeles, California. ·Clin Cancer Res · Pubmed #26251290.

ABSTRACT: PURPOSE: On the basis of preclinical evidence of synergistic activity between MEK and EGFR inhibitors in pancreatic ductal adenocarcinoma (PDAC), we evaluated the safety and efficacy of selumetinib, a MEK1/2 inhibitor, plus erlotinib in patients with previously treated advanced PDAC. EXPERIMENTAL DESIGN: In this single-arm phase II trial, eligible patients received the combination of erlotinib 100 mg plus selumetinib 100 mg daily in 3-week cycles. Study assessments included measurement of clinical outcomes, with a primary endpoint of overall survival, and exploration of potential molecular predictors of treatment benefit. RESULTS: Forty-six patients were enrolled and received a median of two cycles (range, 1-7). Although no objective responses were observed, 19 patients (41%) showed evidence of stable disease for ≥6 weeks, and 13 of 34 patients (38%) had a CA19-9 decline ≥50%. Median progression-free survival was 1.9 months [95% confidence interval (CI), 1.4-3.3 months], with a median overall survival of 7.3 months (95% CI, 5.2-8.0 months). Common adverse events included rash, diarrhea, and nausea/vomiting. Patients with tumors exhibiting an epithelial phenotype (demonstrated by a high level of E-cadherin expression) were more likely to be sensitive to study treatment. Tumor-derived DNA was detectable in plasma from the majority of patients using next-generation digital DNA sequencing, and its relative abundance correlated with tumor burden. CONCLUSIONS: A therapeutic strategy of dual targeted inhibition of the MEK and EGFR pathways shows modest antitumor activity in pancreatic cancer. Specific molecular subtypes may derive greatest benefit from this combination. Further exploration, both with more potent MEK inhibitors and in molecularly enriched patient subsets, is warranted.

6 Clinical Trial Optimizing the administration of fixed-dose rate gemcitabine plus capecitabine using an alternating-week schedule: a dose finding and early efficacy study in advanced pancreatic and biliary carcinomas. 2012

Ko, Andrew H / Espinoza, Anne M / Jones, Kimberly A / Venook, Alan P / Bergsland, Emily K / Kelley, Robin K / Dito, Elizabeth / Ong, Anna / Hanover, Cherry S / Coakley, Fergus V / Tempero, Margaret A. ·Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. andrewko@medicine.ucsf.edu ·Am J Clin Oncol · Pubmed #21552099.

ABSTRACT: OBJECTIVES: This multisite study sought to optimize the dosing, schedule, and administration of fixed-dose rate (FDR) gemcitabine plus capecitabine for advanced pancreatic and biliary tract cancers using an alternating-week dose schedule of both agents. METHODS: Patients with previously untreated advanced pancreatic and biliary tract cancers with Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. For the dose-finding portion, a standard 3+3 dose-escalation schema was used, with the gemcitabine dose kept at 1000 mg/m(2) administered by FDR (10 mg/m(2)/min) on day 1 of each 14-day cycle, and capecitabine given on days 1 to 7 at doses ranging from 800 to 1500 mg/m(2) twice daily. Primary study objective was determination of maximum tolerated dose (MTD). The cohort at MTD was expanded for further efficacy assessment. RESULTS: A total of 45 patients (median age 61 y; 93% pancreatic/7% biliary; 84% with metastatic disease) were enrolled. Median number of cycles received was 11.5. The MTD using this dose schedule was FDR gemcitabine 1000 mg/m(2) plus capecitabine 1000 mg/m(2) bid, due to a high incidence of late hand-foot syndrome observed at the next higher dose level. Most common nonhematologic adverse events related to treatment included nausea/vomiting (overall rate, 64%; all grade 1/2) and hand-foot syndrome (overall rate, 60%; grade 3, 22%). The incidence of grade 3/4 hematologic adverse events was 24%. Six of 41 evaluable patients (14.6%) had a partial response; 18 of 31 patients (58%) with elevated baseline CA 19-9 level had ≥50% biomarker decline during treatment. Estimated median time to tumor progression and overall survival were 5.5 and 9.8 months, respectively (5.5 and 10.1 mo in the metastatic pancreatic cancer cohort). CONCLUSIONS: This dosing schedule of FDR gemcitabine plus capecitabine is active in patients with advanced pancreatobiliary cancers. Given its favorable toxicity profile and convenience, this regimen represents an appropriate front-line option for this patient population and may serve as the foundation on which new investigational agents are added in future trial design.

7 Clinical Trial A phase II study of bevacizumab plus erlotinib for gemcitabine-refractory metastatic pancreatic cancer. 2010

Ko, Andrew H / Venook, Alan P / Bergsland, Emily K / Kelley, R Kate / Korn, W Michael / Dito, Elizabeth / Schillinger, Brian / Scott, Janet / Hwang, Jimmy / Tempero, Margaret A. ·University of California at San Francisco Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, 4th Floor, Box 1705, San Francisco, CA 94115, USA. andrewko@medicine.ucsf.edu ·Cancer Chemother Pharmacol · Pubmed #20130876.

ABSTRACT: PURPOSE: No standard of care exists for patients with metastatic pancreatic cancer following progression on first-line chemotherapy. Based on potential for additive or synergistic activity by concurrent inhibition of VEGF and EGFR, we conducted a phase II study evaluating the combination of bevacizumab plus erlotinib in this patient population. METHODS: Patients with metastatic pancreatic adenocarcinoma, ECOG performance status 0-1, and previous exposure to 1-3 systemic therapies (at least one gemcitabine-based) were eligible. Treatment consisted of bevacizumab 15 mg/kg every 21 days plus erlotinib 150 mg daily. RESULTS: Thirty-six patients were enrolled, including eight who had previously received VEGF-targeted therapy and nine prior erlotinib. Median number of treatment cycles was 2 (range, 1-7). Common toxicities included rash (72%), diarrhea (25%), venous thromboembolic events (15%), and hypertension (11%). One patient demonstrated partial response and seven others stable disease for >2 cycles. CA19-9 decline ≥25% was observed in 4/26 patients with baseline levels >2x ULN. Estimated median time to progression was 40 days (95% CI, 35-41 days) and median survival 102 days (95% CI, 74-117 days), with a 6-month survival rate of 22%. Baseline concentration of circulating endothelial cells (CD45(-)/CD34(+)/CD31(+)) was inversely associated with overall survival. CONCLUSIONS: The combination of bevacizumab and erlotinib is safe but relatively ineffective in patients with gemcitabine-refractory metastatic pancreatic cancer. Future studies should focus on refining subsets of patients in this challenging population likely to benefit from treatment beyond first-line.

8 Article Generalizability of trial results to elderly Medicare patients with advanced solid tumors (Alliance 70802). 2015

Lamont, Elizabeth B / Schilsky, Richard L / He, Yulei / Muss, Hyman / Cohen, Harvey Jay / Hurria, Arti / Meilleur, Ashley / Kindler, Hedy L / Venook, Alan / Lilenbaum, Rogerio / Niell, Harvey / Goldberg, Richard M / Joffe, Steven / Anonymous320813. ·Massachusetts General Hospital Cancer Center, Boston, MA (EL) · Departments of Medicine, and Health Care Policy, Harvard Medical School, Boston, MA (EL, YH, AM) · American Society of Clinical Oncology, Alexandria, VA (RLS) · Department of Medicine, University of North Carolina, Chapel Hill, NC (HM) · Department of Medicine, Duke University, Durham, NC (HJC) · City of Hope, Duarte, CA (AH) · Department of Medicine, University of Chicago, Chicago, IL (HLK) · Department of Medicine, University of California San Francisco, San Francisco, CA (AV) · Yale Cancer Center, New Haven, CT (RL) · Department of Medicine, the University of Tennessee, Memphis, TN (HN) · Department of Medicine, Ohio State University, Columbus, OH (RMG) · Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (SJ). ·J Natl Cancer Inst · Pubmed #25432408.

ABSTRACT: BACKGROUND: In the United States, patients who enroll in chemotherapy trials seldom reflect the attributes of the general population with cancer, as they are often younger, more functional, and have less comorbidity. We compared survival following three chemotherapy regimens according to the setting in which care was delivered (ie, clinical trial vs usual care) to determine the generalizability of clinical trial results to unselected elderly Medicare patients. METHODS: Using SEER-Medicare data, we estimated survival for elderly patients (ie, age 65 years or older, n = 14097) with advanced pancreatic or lung cancer following receipt of one of three guideline-recommended first-line chemotherapy regimens. We compared their survival to that of similarly treated clinical trial enrollees, without age restrictions, with the same diagnosis and stage (n = 937). All statistical tests were two-sided. RESULTS: Trial patients were 9.5 years younger than elderly Medicare patients. Medicare patients were more often white and tended to live in areas of greater educational attainment than trial enrollees. For each tumor type, Medicare patients who were 75 years or older had median survivals that were six to eight weeks shorter than those of trial patients (4.3 vs 5.8 months following treatment with single agent gemcitabine for advanced pancreatic cancer, P = .03; 7.3 vs 8.9 months following treatment with carboplatin and paclitaxel for stage IV non-small cell lung cancer, P = .91; 8.2 vs 10.2 months following treatment with CDDP/ VP16 for extensive stage small cell lung cancer, P ≤ .01), whereas younger Medicare patients had survival times that were similar to those of trial patients. CONCLUSIONS: Results of clinical trials for advanced pancreatic cancer and lung cancers tended to correctly estimate survival for Medicare patients aged 65 to 74 years, but to overestimate survival for older Medicare patients by six to eight weeks. These estimates of Medicare patients' survival may aid subsequent patients and their oncologists in treatment decision-making.

9 Article 25-Hydroxyvitamin D levels and survival in advanced pancreatic cancer: findings from CALGB 80303 (Alliance). 2014

Van Loon, Katherine / Owzar, Kouros / Jiang, Chen / Kindler, Hedy L / Mulcahy, Mary F / Niedzwiecki, Donna / O'Reilly, Eileen M / Fuchs, Charles / Innocenti, Federico / Venook, Alan P / Anonymous5350802. ·Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA (KVL, APV); Department of Biostatistics and Bioinformatics, Duke University, Durham, NC (KO, DN); Alliance Statistics and Data Center, Duke University, Durham, NC (KO, CJ, DN); The University of Chicago Medical Center, Chicago, IL (HLK); Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL (MFM); Memorial Sloan-Kettering Cancer Center, New York, NY (EMO); Dana-Farber Cancer Institute, Boston, MA (CF); University of North Carolina Institute for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, NC (FI) katherine.vanloon@ucsf.edu. · Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA (KVL, APV); Department of Biostatistics and Bioinformatics, Duke University, Durham, NC (KO, DN); Alliance Statistics and Data Center, Duke University, Durham, NC (KO, CJ, DN); The University of Chicago Medical Center, Chicago, IL (HLK); Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL (MFM); Memorial Sloan-Kettering Cancer Center, New York, NY (EMO); Dana-Farber Cancer Institute, Boston, MA (CF); University of North Carolina Institute for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, NC (FI). ·J Natl Cancer Inst · Pubmed #25099612.

ABSTRACT: BACKGROUND: Data from animal and cell-line models suggest that vitamin D metabolism plays an important role in pancreatic tumor behavior. Although vitamin D deficiency has been implicated in numerous cancers, the vitamin D status of patients with advanced pancreatic cancer and the effect of baseline vitamin D levels on survival are unknown. METHODS: Participants in this correlative study (CALGB 151006) were enrolled in CALGB 80303, which was a randomized trial of patients with advanced pancreatic cancer that demonstrated no difference in overall survival (OS) among patients treated with gemcitabine plus placebo vs gemcitabine plus bevacizumab. We measured baseline serum 25-hydroxyvitamin D (25[OH]D) levels and examined associations between baseline 25(OH)D levels and progression-free survival and OS using the Cox rank score test. All statistical tests were two-sided. RESULTS: Of 256 patients with available serum, the median 25(OH)D level was 21.7ng/mL (range 4 to 77). 44.5% of patients were vitamin D deficient (25[OH]D <20ng/mL), and 32.4% were insufficient (25[OH]D ≥20 and <30ng/mL). 25(OH)D levels were lower in black patients compared with white patients, and patients of other/undisclosed race (10.7 vs 22.4 vs 20.9ng/mL, P < .001). Baseline 25(OH)D levels were not associated with PFS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .60) or OS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .95). CONCLUSION: Vitamin D deficiency was highly prevalent among patients with a new diagnosis of advanced pancreatic cancer. Black patients had statistically significantly lower 25(OH)D levels than white patients. In this cohort of patients with advanced pancreatic cancer receiving gemcitabine-based chemotherapy, baseline 25(OH)D levels were not associated with PFS or OS.

10 Article Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (Alliance). 2013

Nixon, Andrew B / Pang, Herbert / Starr, Mark D / Friedman, Paula N / Bertagnolli, Monica M / Kindler, Hedy L / Goldberg, Richard M / Venook, Alan P / Hurwitz, Herbert I / Anonymous3240771. ·Authors' Affiliations: Division of Medical Oncology; Alliance Statistics and Data Center, Duke University Medical Center; Durham, North Carolina; Section of Hematology/Oncology, University of Chicago Cancer Research Center; Chicago, Illinois; Department of Surgery, Brigham and Women's Hospital & Harvard Medical School; Boston, Massachusetts; Department of Internal Medicine, Ohio State University; Columbus, Ohio; and Division of Medical Oncology, University of California, San Francisco, California. ·Clin Cancer Res · Pubmed #24097873.

ABSTRACT: PURPOSE: CALGB80303 was a phase III trial of 602 patients with locally advanced or metastatic pancreatic cancer comparing gemcitabine/bevacizumab versus gemcitabine/placebo. The study found no benefit in any outcome from the addition of bevacizumab to gemcitabine. Blood samples were collected and multiple angiogenic factors were evaluated and then correlated with clinical outcome in general (prognostic markers) and with benefit specifically from bevacizumab treatment (predictive markers). EXPERIMENTAL DESIGN: Plasma samples were analyzed via a novel multiplex ELISA platform for 31 factors related to tumor growth, angiogenesis, and inflammation. Baseline values for these factors were correlated with overall survival (OS) using univariate Cox proportional hazard regression models and multivariable Cox regression models with leave-one-out cross validation. Predictive markers were identified using a treatment by marker interaction term in the Cox model. RESULTS: Baseline plasma was available from 328 patients. Univariate prognostic markers for OS were identified including: Ang2, CRP, ICAM-1, IGFBP-1, TSP-2 (all P < 0.001). These prognostic factors were found to be highly significant, even after adjustment for known clinical factors. Additional modeling approaches yielded prognostic signatures from multivariable Cox regression. The gemcitabine/bevacizumab signature consisted of IGFBP-1, interleukin-6, PDGF-AA, PDGF-BB, TSP-2; whereas the gemcitabine/placebo signature consisted of CRP, IGFBP-1, PAI-1, PDGF-AA, P-selectin (both P < 0.0001). Finally, three potential predictive markers of bevacizumab efficacy were identified: VEGF-D (P < 0.01), SDF1 (P < 0.05), and Ang2 (P < 0.05). CONCLUSION: This study identified strong prognostic markers for pancreatic cancer patients. Predictive marker analysis indicated that plasma levels of VEGF-D, Ang2, and SDF1 significantly predicted for benefit or lack of benefit from bevacizumab in this population.

11 Article Lymph node sampling rates and predictors of nodal metastasis in pancreatic neuroendocrine tumor resections: the UCSF experience with 149 patients. 2012

Parekh, Justin R / Wang, Sam C / Bergsland, Emily K / Venook, Alan P / Warren, Robert S / Kim, Grace E / Nakakura, Eric K. ·Division of Surgical Oncology, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA. ·Pancreas · Pubmed #22781907.

ABSTRACT: OBJECTIVES: The decision to perform pancreas-preserving procedures or standard resections for pancreatic neuroendocrine tumors (PNETs) is often based on the perceived risk of malignancy, including potential nodal involvement. We sought to identify clinicopathological factors that predict nodal disease. METHODS: This is a retrospective review of pathology database for PNET resections from January 1, 1988, to March 15, 2010. Univariate analysis and multivariate logistic regression were used to identify predictors of nodal metastasis. RESULTS: A total of 149 patients were identified. Enucleations had lower lymph node sampling rates compared to major resections. Excluding enucleations, 23% of patients had no lymph nodes sampled. For patients who did have lymph nodes evaluated, a median of 5 lymph nodes were examined. On multivariate analysis, only distant disease predicted nodal metastasis (odds ratio = 3.80, P = 0.02); tumor size did not (P = 0.48). One third of patients with lymph node metastasis had tumors less than 3 cm. CONCLUSIONS: Lymph nodes are not evaluated in many major pancreatic resections for PNET, and preoperative prediction of nodal metastasis is difficult, even when tumor size is considered. Consequently, many patients may be understaged and undergo potentially inadequate resection. Inconsistent lymph node sampling may explain conflicting conclusions in the literature regarding the prognostic value of lymph node involvement in PNET patients.

12 Article Identification of potential prognostic biomarkers in patients with untreated, advanced pancreatic cancer from a phase 3 trial (Cancer and Leukemia Group B 80303). 2012

Roberts, Andrew S / Campa, Michael J / Gottlin, Elizabeth B / Jiang, Chen / Owzar, Kouros / Kindler, Hedy L / Venook, Alan P / Goldberg, Richard M / O'Reilly, Eileen M / Patz, Edward F. ·Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA. ·Cancer · Pubmed #21713765.

ABSTRACT: BACKGROUND: Patients with advanced stage adenocarcinoma of the pancreas have a poor prognosis. The identification of prognostic and/or predictive biomarkers may help stratify patients so that therapy can be individualized. METHODS: Serum samples from patients enrolled in the Cancer and Leukemia Group B 80303 phase 3 trial, "Randomized Study of Gemcitabine With Versus Without Bevacizumab in Patients With Locally Advanced or Metastatic Adenocarcinoma of the Pancreas" were used to discover novel biomarkers. For the discovery phase, 40 sera were selected based on length of survival and type of therapy, and subjected to liquid chromatography coupled to tandem mass spectrometry analysis (LC-MS-MS). The top features (proteins) were then further selected for validation by enzyme-linked immunosorbent assay (ELISA). RESULTS: Quantification by nano-LC-MS-MS resulted in 1452 peptides mapping to 156 proteins across all 40 samples, 92 of which had 2 or more peptides. After curation of the data, the authors selected 1 putative prognostic protein, alpha 1-antichymotrypsin (AACT), and 2 putative predictive proteins, histidine-rich glycoprotein (HRG) and complement factor H (CFH), for validation by ELISA. AACT was found to be negatively correlated with overall survival (τ = -0.30 [-0.38, -0.22]; P < .00001). There was no evidence for interaction with bevacizumab and HRG, but there was some evidence for a weak positive correlation of HRG with overall survival (τ = 0.11 [0.03, 0.19]; P < .01). CFH was found to be neither a predictive nor a prognostic factor for overall survival. CONCLUSIONS: AACT may be a useful prognostic marker in patients with advanced stage pancreatic carcinoma, although additional validation studies are needed.