Molecular Analysis of Esophageal Cancer Survival

Summary

Principal Investigator: Matthew H Kulke
Abstract: DESCRIPTION (provided by applicant): The candidates long-term objective is to become an independent investigator, focusing on the use of biological markers to guide and improve the treatment of patients with gastrointestinal malignancies. In this proposal, he plans to perform a molecular analysis of survival in a large, prospectively collected cohort of patients with esophageal cancer. Under the mentorship of David Christiani, MD, the candidate will achieve the specific aims of examining the association between overall survival and the presence of specific genetic polymorphisms (GSTP1, GSTM1, GSTT1, CYP1A1, CYP3A5, p53, XRCC1 and ERCC2) in patients with esophageal cancer. In addition, he will examine the association between overall survival and the expression of molecular markers (p53, p21, COX-2, VEGF, and TS) in tissue biopsy specimens from these patients. The research design makes use of a prospective cohort of over 600 patients with esophageal cancer, collected as part of a larger project undertaken by the candidate's mentor examining esophageal cancer risk factors. The methods include the collection of blood samples and clinical data from each of the patients (with patient consent). DNA extracted from each of these blood specimens will be tested for the presence of specific genetic polymorphisms. In addition, stored paraffin-embedded tissue specimens for each of the patients will be retrieved and evaluated for the expression of specific molecular markers. The presence of specific polymorphisms and tissue markers will be correlated with overall survival, after adjustment for possible confounding variables. The project has important health relatedness: in the year 2002, there will be an estimated 13,100 new cases of esophageal cancer in the United States. Among all patients who develop esophageal cancer, 12,600 (96%) will develop metastatic disease and will ultimately die from their malignancy. Recent studies have suggested that the genetic polymorphisms being examined in this study affect the metabolism of both carcinogens and agents used as systemic chemotherapy, and therefore may significantly affect prognosis. Similarly, the expression of specific molecular markers in tumor tissue may affect biologic behavior and prognosis. A better understanding of the association between genetic polymorphisms, expression of tumor molecular markers, and prognosis may lead to better treatment strategies and improved survival rates for patients with esophageal cancer.
Funding Period: 2003-07-03 - 2008-06-30
more information: NIH RePORT

Top Publications

  1. pmc The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas
    Jonathan R Strosberg
    Department of Gastrointestinal Oncology, H Lee Moffitt Cancer Center, Tampa, FL, USA
    Pancreas 39:799-800. 2010
  2. pmc NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas
    Matthew H Kulke
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston MA 02115, USA
    Pancreas 39:735-52. 2010
  3. pmc Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes
    Penelope A Bradbury
    Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada
    Pharmacogenet Genomics 19:613-25. 2009
  4. pmc p53 Arg72Pro and MDM2 T309G polymorphisms, histology, and esophageal cancer prognosis
    David W Cescon
    Department of Medical Biophysics, Princess Margaret Hospital, University of Toronto, Canada
    Clin Cancer Res 15:3103-9. 2009
  5. pmc A prospective phase II study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors
    Matthew H Kulke
    Dana Farber Cancer Institute, Boston, MA 02115, USA
    Cancer Chemother Pharmacol 68:293-300. 2011
  6. pmc Phase II study of pemetrexed in patients with advanced neuroendocrine tumors
    Jennifer A Chan
    Department of Medical Oncology, Dana Farber Cancer Institute, Dana 1220, Boston, MA, 02115, USA
    Cancer Chemother Pharmacol 66:961-8. 2010
  7. pmc O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors
    Matthew H Kulke
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA
    Clin Cancer Res 15:338-45. 2009
  8. ncbi Gastrointestinal neuroendocrine tumors: a role for targeted therapies?
    Matthew H Kulke
    Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Dana Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
    Endocr Relat Cancer 14:207-19. 2007
  9. ncbi Selective lymphopenia and opportunistic infections in neuroendocrine tumor patients receiving temozolomide
    Abraham B Schwarzberg
    Harvard Medical School, Boston, Massachusetts, USA
    Cancer Invest 25:249-55. 2007
  10. ncbi Clinical presentation and management of carcinoid tumors
    Matthew H Kulke
    Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115 0684, USA
    Hematol Oncol Clin North Am 21:433-55; vii-viii. 2007

Scientific Experts

  • Matthew Kulke
  • Eileen Regan
  • Thomas E Clancy
  • Andrew X Zhu
  • Abraham B Schwarzberg
  • Penelope A Bradbury
  • Jonathan R Strosberg
  • Jennifer A Chan
  • Geoffrey Liu
  • Thomas J Lynch
  • Clement Ma
  • Ariela L Marshall
  • David C Christiani
  • Kofi Asomaning
  • Wei Xu
  • John C Wain
  • Wei Zhou
  • Rihong Zhai
  • Li Su
  • David W Cescon
  • Keith Stuart
  • Carolyn Casey
  • Pankaj Bhargava
  • Jeffrey W Clark
  • Gregory A Wiseman
  • David S Klimstra
  • Alexandria T Phan
  • Craig C Earle
  • Domenico Coppola
  • Larry K Kvols
  • Frances A Shepherd
  • Susanne M Hooshmand
  • Rebecca Suk Heist
  • Rebecca S Heist
  • Jessica Hopkins
  • Zhaoxi Wang

Detail Information

Publications18

  1. pmc The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas
    Jonathan R Strosberg
    Department of Gastrointestinal Oncology, H Lee Moffitt Cancer Center, Tampa, FL, USA
    Pancreas 39:799-800. 2010
    ..In patients with localized tumors undergoing surgical resection, adjuvant treatment (chemotherapy with or without radiation) is warranted in most cases...
  2. pmc NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas
    Matthew H Kulke
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston MA 02115, USA
    Pancreas 39:735-52. 2010
    ..We provide an overview of well-differentiated NETs of the stomach and pancreas and describe consensus guidelines for the treatment of patients with these malignancies...
  3. pmc Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes
    Penelope A Bradbury
    Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada
    Pharmacogenet Genomics 19:613-25. 2009
    ..We investigated the potential predictive significance of functional NER single nucleotide polymorphisms in esophageal cancer patients treated with (n = 262) or without (n = 108) cisplatin...
  4. pmc p53 Arg72Pro and MDM2 T309G polymorphisms, histology, and esophageal cancer prognosis
    David W Cescon
    Department of Medical Biophysics, Princess Margaret Hospital, University of Toronto, Canada
    Clin Cancer Res 15:3103-9. 2009
    ....
  5. pmc A prospective phase II study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors
    Matthew H Kulke
    Dana Farber Cancer Institute, Boston, MA 02115, USA
    Cancer Chemother Pharmacol 68:293-300. 2011
    ..We performed a prospective, phase II study of 2ME2, administered in combination with bevacizumab, in patients with advanced carcinoid tumors...
  6. pmc Phase II study of pemetrexed in patients with advanced neuroendocrine tumors
    Jennifer A Chan
    Department of Medical Oncology, Dana Farber Cancer Institute, Dana 1220, Boston, MA, 02115, USA
    Cancer Chemother Pharmacol 66:961-8. 2010
    ..Pemetrexed is a multitargeted antifolate with activity in tumor types not significantly responsive to other antifolates. We evaluated the efficacy of pemetrexed in a phase II study of patients with advanced neuroendocrine tumors...
  7. pmc O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors
    Matthew H Kulke
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA
    Clin Cancer Res 15:338-45. 2009
    ..We evaluated the prevalence of MGMT deficiency in neuroendocrine tumors and correlated MGMT deficiency with treatment response to temozolomide-based regimens...
  8. ncbi Gastrointestinal neuroendocrine tumors: a role for targeted therapies?
    Matthew H Kulke
    Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Dana Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
    Endocr Relat Cancer 14:207-19. 2007
    ..Ongoing randomized studies should help better define the role these and other targeted agents will play in the future treatment of patients with this disease...
  9. ncbi Selective lymphopenia and opportunistic infections in neuroendocrine tumor patients receiving temozolomide
    Abraham B Schwarzberg
    Harvard Medical School, Boston, Massachusetts, USA
    Cancer Invest 25:249-55. 2007
    ..Prophylaxis for Pneumocystis jiroveci pneumonia and varicella-zoster, as well as cytomegalovirus monitoring, should be considered in patients receiving temozolomide-based treatment...
  10. ncbi Clinical presentation and management of carcinoid tumors
    Matthew H Kulke
    Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115 0684, USA
    Hematol Oncol Clin North Am 21:433-55; vii-viii. 2007
    ..Preliminary reports of activity associated with agents targeting the vascular endothelial growth factor pathway suggest that such strategies may play a role in the future treatment of patients who have this disease...
  11. ncbi New developments in the treatment of gastrointestinal neuroendocrine tumors
    Matthew H Kulke
    Department of Medical Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA
    Curr Oncol Rep 9:177-83. 2007
    ..Continued investigation of these agents should render a better understanding of their efficacy in patients with advanced neuroendocrine tumors...
  12. ncbi Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors
    Matthew H Kulke
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA
    J Clin Oncol 24:3555-61. 2006
    ..We therefore performed a multicenter phase II study of rhEndostatin in patients with carcinoid or pancreatic neuroendocrine tumors...
  13. ncbi A phase II trial of irinotecan and cisplatin in patients with metastatic neuroendocrine tumors
    Matthew H Kulke
    Department of Medical Oncology, Dana Institute, Boston, Massachusetts, USA
    Dig Dis Sci 51:1033-8. 2006
    ..4 months. We conclude that while the combination of irinotecan and cisplatin may have activity in aggressive neuroendocrine tumor subtypes, this combination is inactive in patients with well-differentiated neuroendocrine tumors...
  14. ncbi A phase II study of doxorubicin, cisplatin, and 5-fluorouracil in patients with advanced adenocarcinoma of the stomach or esophagus
    Matthew H Kulke
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
    Cancer Invest 24:229-34. 2006
    ..The use of doxorubicin as an alternative to epirubicin in the ECF regimen has not been evaluated...
  15. ncbi Phase I and pharmacokinetic study of S-1 administered for 14 days in a 21-day cycle in patients with advanced upper gastrointestinal cancer
    Andrew X Zhu
    Massachusetts General Hospital, 100 Blossom Street, Cox 640, Boston, MA 02114, USA
    Cancer Chemother Pharmacol 59:285-93. 2007
    ....
  16. ncbi A Phase II trial of vinorelbine in patients with advanced gastroesophageal adenocarcinoma
    Matthew H Kulke
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
    Cancer Invest 24:346-50. 2006
    ..9 months and the median overall survival time was 7.8 months. We conclude that vinorelbine has minimal toxicity but only minor antitumor activity in patients with advanced gastroesophageal adenocarcinoma...
  17. ncbi Alkaline phosphatase predicts survival in patients with metastatic neuroendocrine tumors
    Thomas E Clancy
    Department of Surgery, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Dig Dis Sci 51:877-84. 2006
    ..Close monitoring of alkaline phosphatase levels may be useful when considering initiation or changes of therapy in patients with metastatic neuroendocrine tumors...
  18. ncbi Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors
    Matthew H Kulke
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA
    J Clin Oncol 24:401-6. 2006
    ..We evaluated the efficacy of an oral regimen of temozolomide and thalidomide in patients with metastatic carcinoid, pheochromocytoma, or pancreatic neuroendocrine tumors...