Pharmacogenomics and Pharmacoepidemiology
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
- surgical technique
- access to care
- 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.