Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation

Slide 1 of 14: Cancer Pharmacogenomics Workshop Panel Discussion

Cornelia Ulrich, M.S., Ph.D.
Full Member/Associate Professor
Fred Hutchinson Cancer Research Center
University of Washington, Seattle

July 21, 2009


Slide 2 of 14: 3 Key Discussion Points

  • Integration of Health Behaviors
    • Why we shouldn’t ignore supplement use and other nutritional factors
  • Necessity of a Transdisciplinary Approach to Cancer Prognosis
  • Value of new Patient Cohorts

Slide 3 of 14: Vitamin Supplement Use is High

  • Review of 32 studies addressing vitamin and mineral supplement use among US adult cancer patients:
    • 64-81% any vitamin or mineral supplements
    • 14%-32% of survivors initiate supplement use after diagnosis
    • Physicians commonly unaware of use

[Image] showing graph of increase in use of folic-acid containing supplements with diagnosis, Colon CFR patients (n = 971).

Source: Velicer and Ulrich. JCO. 2008; 26(4): 665-73.


Slide 4 of 14: Folate-Mediated One-Carbon Metabolism

[Image] depicting folate metabolism, including the folic acid from supplements, fortified foods, methotrexate, and 5-FU treatment.


Slide 5 of 14: Can Folate’s Role in Providing Nucleotides be Harmful?

  • Tumors have greater folate and nucleotide requirements to support their growth:
    • Antifolates are used in cancer chemotherapy
    • Tumors frequently upregulate folate receptors
  • High folate intakes in rodents with early neoplastic lesions foster tumor growth (Kim 1996, Song 2000, Song 2000, Leu 2000)

Aspirin/Folate Polyp Prevention Trial shows increased risk of advanced and multiple adenoma with folic acid administration

Source: Cole 2007, Ulrich 2007


Slide 6 of 14: Unanswered Questions – Folic Acid in Cancer Patients

  • Do tumors differ depending on folic acid supplementation?
    • Differences in folate receptors, or gene expression? → altering treatment efficacy?
  • Do treatment effects (5-FU, MTX) differ with folic acid supplementation?
  • Are there gene-diet interactions in determining response?
  • Does growth of micrometastases and risk of recurrence differ with folic acid supplementation?

Slide 7 of 14: Folate Status and Colon Cancer Prognosis – a Paradigm for Transdisciplinary Research

[Image] depicting how folic acid supplements pre-diagnosis and genetic polymorphisms can affect tumor characteristics (gene expression, methylome). Additionally pre- and post-diagnosis folic acid supplements can affect survival. Survival can also be influenced by 5-FU based treatment, which in turn can be affected by folate status.


Slide 8 of 14: Women's Intervention Nutrition Study (WINS) Trial

  • n=2437 women with resected early stage breast cancer
  • low-fat diet intervention reduces relapse events
  • Major improvement (42%) in relapse-free survival with low-fat diet among ER- patients

[Image] of graph showing the percent of patients with relapse events consuming the intervention diet compared to the control diet as published by Chlebowski et al. JNCI. 2006; 94(16): 1247-9. Reprinted by permission of Oxford University Press.


Slide 9 of 14: Herbal Drugs Can Affect Chemotherapeutic Pharmacokinetics

  • St. John’s wort:
    • Widely used herbal supplement for mild forms of depression
    • Can induce the expression of CYP3A4
  • Irinotecan is eliminated via CYP3A4 and has a narrow therapeutic range
  • St. John’s wort for 18 days significantly reduced plasma levels of SN-38 and drug efficacy

[Image] of graph showing effect of St. John’s Wort on plasma concentration of the active irinotecan metabolite SN-38 over time.

Sources: Markowitz JS et al. JAMA. 2003; 290 (11): 1519-20. Mathijsen R et al. JNCI. 2002; 94(16): 1247-9. Reprinted by permission of Oxford University Press.


Slide 10 of 14: Cancer Prognosis - a Multifactorial Outcome

[Image] of multiple factors which can affect cancer prognosis, including:

  • genetic factors
  • tumor biology
  • treatment
  • surgical technique
  • access to care
  • race/ethnicity
  • lifestyle factors
  • psychosocial factors
  • energy balance
  • nutritional status

Slide 11 of 14: What Research Designs are Needed?

  • Cancer patients change health behaviors after their diagnosis & during treatment
  • Assessments prior to diagnosis are inadequate to draw conclusions
  • Randomized trials are not appropriate when harm is a possibility
  • Potential for confounding in observational cohorts
  • What is needed?
    • Both observational patient cohorts, with exposure assessment at diagnosis and afterwards at defined intervals
    • Randomized trials where possible

Slide 12 of 14: Clinical Trial Vs. Prospective Patient Cohorts

  • Clinical Trial
    • Select population & treatment
    • Uniform treatment
    • Excellent outcome assessment
    • Limited assessment of health behaviors
    • Multicenter (many)
    • Logistic challenges?
    • Many sites, COG setting
  • Population-based patient cohort
    • General population & real-world Tx
    • Heterogenous Tx
    • Variable outcome assessment
    • Excellent assessment of health behaviors
    • Single or multicenter
    • Logistic challenges?
    • HIPAA regulations
    • Multiple hospital

Slide 13 of 14: New Patient Cohorts Can "Get it Right"

  • Collect data and biospecimens in a high-quality, standardized manner
  • Obtain *all* transdisciplinary pieces of information
    • Health behaviors and epidemiologic data
    • Clinical exposures & outcomes
    • Biospecimens (tumor, blood, urine, stool…)
  • Get data and specimens repeatedly at critical time intervals
    • What happens after diagnosis and during treatment?
    • Understudied and not feasible in existing cohorts

Slide 14 of 14: Colocare Study Design

[Image] showing Colocare study design to collect diagnosis and treatment information, biospecimen and questionnaire collection, and measurement of outcomes.

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