Problems with Using Biomarkers as Surrogate End Points for Cancer: A Cautionary Tale

  • Arthur Schatzkin
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 166)


Investigations employing surrogate cancer end points are especially attractive because they may be smaller, shorter, and cheaper than comparable studies with explicit cancer outcomes. For many potential surrogate end points—epithelial cell proliferation will be taken as an example—inferences are problematic because of the existence of alternative causal pathways to cancer that bypass the surrogate end point. Evaluating potential surrogates requires information on the following three questions: (1) What is the relation of the surrogate end point to cancer? (2) What is the relation of the intervention (or exposure) to the surrogate? (3) To what extent does the surrogate end point mediate the relation between intervention (exposure) and cancer? Data for these questions may derive from animal experiments, human metabolic studies, observational epidemiologic investigations (including ecologic studies), and randomized trials. Inferences to cancer from such downstream markers as colorectal adenomatous polyps and persistent human papillomavirus infection of the cervix are strong, though not absolutely unassailable. For all but these very-close-to-cancer markers, considerable caution is warranted in extrapolating from surrogate effects or associations to cancer.


Breast Cancer Risk Human Papilloma Virus Mammographic Density Colorectal Adenoma Advanced Adenoma 
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  1. 1.
    Reichman ME, Judd JT, Longcope C, Schatzkin A, Nair PP, Campbell WS, Clevidence BA, Taylor PR (1993) Effects of moderate alcohol consumption on plasma and urinary hormone concentrations in premenopausal women. J Natl Cancer Inst 85:722–727PubMedGoogle Scholar
  2. 2.
    Hamajima N, Hirose K, Tajima K, Rohan T, Calle EE, Heath CW Jr, et al (2002) Alcohol, tobacco and breast cancer—collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 87:1234–1245PubMedGoogle Scholar
  3. 3.
    Davey-Smith G, Ebrahim S (2003) ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 32:1–22PubMedGoogle Scholar
  4. 4.
    Little J, Sharp L, Duthie S, Narayanan S (2003) Colon cancer and genetic variation in folate metabolism: the clinical bottom line. J Nutr 133:3758S–3766SPubMedGoogle Scholar
  5. 5.
    Shaheen NJ, Silverman LM, Keku T, Lawrence LB, Rohlfs EM, Martin CF, Galanko J, Sandler RS (2003) Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer. J Natl Cancer Inst 95:154–159PubMedGoogle Scholar
  6. 6.
    Kipnis V, Subar AF, Midthune D, Freedman LS, Ballard-Barbash R, Troiano R, Bingham S, Schoeller DA, Schatzkin A, Carroll RJ (2003) The structure of dietary measurement error: results of the OPEN biomarker study. Am J Epidemiol 158:14–21PubMedGoogle Scholar
  7. 7.
    New drug, antibiotic and biological drug product regulations: accelerated approval (1992) Proposed Rule. 57: Federal Register 13234–13232Google Scholar
  8. 8.
    Rothman KJ, Greenland S (1998) Modern epidemiology. Lippincott-Raven, PhiladelphiaGoogle Scholar
  9. 9.
    Schiffman MH, Schatzkin A (1994) Test reliability is critically important to molecular epidemiology: an example from studies of human papillomavirus infection and cervical neoplasia. Cancer Res 54: S1944–S1947Google Scholar
  10. 10.
    Key TJ, Appleby PN, Reeaves GK, Roddam A, Dorgan JF, Longcope C, et al (2003) Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 95:1218–1226PubMedGoogle Scholar
  11. 11.
    Fleming T, DeMets DL (1996) Surrogate end points in clinical trials: are we being misled? Ann Intern Med 125:605–613PubMedGoogle Scholar
  12. 12.
    McTiernan A, Kooperberg C, White E, Wilcox S, Coates R, Adams-Campbell LL, Woods N, Ockene J (2003) Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women’s Health Initiative Cohort Study. JAMA 290:1331–1336PubMedCrossRefGoogle Scholar
  13. 13.
    Key TJ (1999) Serum oestradiol and breast cancer risk. Endocr Relat Cancer 6:175–180PubMedCrossRefGoogle Scholar
  14. 14.
    Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • Arthur Schatzkin
    • 1
  1. 1.Nutritional Epidemiology Branch, Division of Cancer Epidemiology and GeneticsNational Cancer InstituteRockvilleUSA

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