Journal of the National Cancer Institute Advance Access originally published online on June 17, 2009
JNCI Journal of the National Cancer Institute 2009 101(13):902-903; doi:10.1093/jnci/djp163
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2009. Published by Oxford University Press.
EDITORIALS |
Are We Getting Closer to Molecular Population Screening for Colorectal Cancer?
Affiliations of author: Clalit National Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion, Haifa, Israel
Correspondence to: Gad Rennert, MD, PhD, Clalit National Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center, 7 Michal St, Haifa 34362, Israel (e-mail: rennert{at}tx.technion.ac.il).
The best methods to bring about a reduction in the incidence and mortality of colorectal cancer in the world have been the subject of much debate in recent years. Colorectal cancer is highly preventable through behavioral changes in diet and physical activity; still, much effort has been invested in developing efficient screening technologies for secondary prevention.
Public health theory stresses a number of requirements that must be met before screening for a disease can be initiated (1). This line of thought differs from the usual clinical situation in which symptomatic patients present themselves to the health system in search of medical help. The screening setting refers to very large populations that are usually symptom free and at a very low probability of having the disease of interest at any given round of screening. The disease of concern needs to be clinically significant in terms of incidence, prevalence, mortality, or suffering and have a natural history that can be influenced by a timely intervention. Screening technologies need to have proven and substantial efficacy. Specificity takes priority over sensitivity, contrary to the case when diagnosing symptomatic patients. Efficacy is best proven through randomized controlled trials that show disease-specific mortality reduction. Studies that are designed in a nonrandomized manner are prone to major biases, such as length bias, lead-time bias, and selection bias (1), all of which can seriously diminish the validity of the results in terms of the direction and the magnitude of the effect. The screening technology needs to be as simple as possible, easy to perform, cheap, and, most importantly, acceptable to the population, that is, noninvasive and with an overall balance of more benefit than harm.
Clinical practice, however, often strays from these rules, which leads to unjustified, unnecessary, and sometimes risky screening recommendations and behavior.
Colorectal cancer fulfills a number of the basic requirements for suitability for screening. It is common, with a lifetime probability of approximately 6% in Western countries, and is responsible for substantial mortality (it is the second leading cause of cancer death in the United States) with a relative 5-year survival rate of only 67% (2,3). Its clinical natural history is suitable for screening because there is a long precancerous phase that is identifiable in the form of polyps or adenomas (4). This cancer precursor enables the screening efforts to be directed not only toward early detection but also toward primary prevention.
A plethora of technologies is currently suggested as possible tools for screening for colorectal cancer. Several policy statements appeared last year on the role of various screening tools for colorectal cancer (5,6), statements that unfortunately only partially adhered to the classical and important rules of screening decision making outlined above.
Tests that detect occult blood in the stool have repeatedly been shown to lead to a statistically significant reduction in mortality from colorectal cancer in randomized controlled trials (7–10). Despite these findings, the low sensitivity of the first generation of these tests made them distasteful to clinicians, mainly those in the United States. However, their simplicity, low cost, noninvasiveness, and efficacy led to their incorporation as the tests of choice in the vast majority of Western countries that have a public policy of organized population screening (11,12). Newer generations of these fecal occult blood tests, such as Hemoccult SENSA (Beckman Coulter, Inc, Fullerton, CA) or immunological tests, have demonstrated vast improvements in test sensitivity, thus leading to very high detection rates with acceptable rates of false-positive results (13–15).
Endoscopic techniques are considered by some as state of the art for colorectal cancer detection, although no well-designed randomized controlled trial has ever shown the true magnitude of their efficacy. Several publications have shown that the sensitivity of endoscopic techniques is less than perfect when compared with findings in radiology-based colonography (16) and that the true mortality reduction potential is far from clear (17,18). In addition, these techniques are invasive, costly, and frequently involve the removal of an extremely large number of benign tumors that probably would never have become malignant. A lower-than-expected mortality reduction coupled with a relatively high rate of complications (18) when performed outside of a study setting precludes the use of these techniques as suitable screening tools for most of the world's population. Colonography is a relatively recent addition to the arsenal of screening technologies that has the advantage of being practically noninvasive and has similar detection qualities to optic colonoscopy and minor rates of complications in expert hands (16,19). Nevertheless, this technology is also still awaiting demonstration of its overall level of efficacy and involves exposure to radiation, as well as requiring the distasteful bowel preparation disliked by so many.
With the evolving field of molecular medicine, interest in testing for genetic fingerprints of shed tumor cells in the stool as a means to detect tumors was inevitable. Such efforts have been in practice for more than a decade. Although the original studies, which relied on known genetic markers in the Wnt pathway and in the microsatellite instability pathway, were less successful than anticipated (20,21), a new generation of tests incorporating detection of methylated markers is more promising (22), with clinical evaluations of vimentin gene methylation and methylation of other genes currently underway (23–25).
In this issue of the Journal, Melotte et al. (26) report on a promising biomarker of colorectal cancer, N-Myc downstream-regulated gene 4 (NDRG4). Methylation of the promoter of this tumor suppressor gene, which leads to inactivation of gene expression, was shown to be highly prevalent in colorectal cancers and very uncommon in noncancerous colon mucosa. When NDRG4 promoter methylation was tested in small groups of colorectal cancer patients and healthy control subjects, it was found to have a sensitivity rate, although not yet optimal, that was higher than that previously reported for genetic stool tests. This sensitivity was achieved with very high specificity in both training and validation sets. Adding this marker to a panel with other promising markers previously shown to be of relevance may further improve the precision of this type of technology for colorectal cancer screening.
As the practice of medicine at large is moving away from invasive diagnostic technologies to sophisticated and advanced noninvasive technologies, so is the forefront of cancer screening. Genetic diagnosis of colorectal cancers and meaningful adenomas has now reached a new phase that, when further fine-tuned, may carry the promise of becoming a suitable and affordable means of prevention and early detection of colorectal cancer in the general population.
REFERENCES
1. Miller AB, ed. Screening for Cancer (1985) Orlando, FL: Academic Press Inc. 9–13, 16–18.
2. American Cancer Society. Cancer Facts and Figures 2008 (2008) Atlanta, GA: American Cancer Society.
3. Cancer of the Colon and Rectum (Invasive) Survival Rates, by Race, Sex, Diagnosis Year, Age and Stage at Diagnosis. http://seer.cancer.gov/csr/1975_2006/browse_csr.php?section=6&page=sect_06_table.11.html. Accessed May 1, 2009.
4. Tanaka T. Colorectal carcinogenesis: review of human and experimental animal studies. J Carcinog (2009) 8:5.[CrossRef][Medline]
5. Levin B, Lieberman DA, McFarland B, et al, American Cancer Society Colorectal Cancer Advisory Group; US Multi-Society TaskForce; American College of Radiology Colon Cancer Committee. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology [published online ahead of print March 5, 2008]. CA Cancer J Clin (2008) 58(3):130–160.
6. Whitlock EP, Lin JS, Liles E, Beil TL, Fu R. Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive Services Task Force [published online ahead of print October 6, 2008]. Ann Intern Med (2008) 149(9):638–658.
7. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med (1993) 328(19):1365–1371. Erratum in: N Engl J Med. 1993;329(9):672.
8. Mandel JS, Church TR, Bond JH, et al. The effect of fecal occult-blood screening on the incidence of colorectal cancer. N Engl J Med (2000) 343(22):1603–1607.
9. Scholefield JH, Moss S, Sufi F, Mangham CM, Hardcastle JD. Effect of faecal occult blood screening on mortality from colorectal cancer: results from a randomised controlled trial. Gut (2002) 50(6):840–844.
10. Jørgensen OD, Kronborg O, Fenger C. A randomised study of screening for colorectal cancer using faecal occult blood testing: results after 13 years and seven biennial screening rounds. Gut (2002) 50(1):29–32.
11. Inventory of Colorectal Cancer Screening Activities in ICSN Countries, May 2008. http://appliedresearch.cancer.gov/icsn/colorectal/screening.html. Accessed May 1, 2009.
12. Benson VS, Patnick J, Davies AK, Nadal MR, Smith RA, Atkin WS, on behalf of the International Colorectal Cancer Screening Network. Colorectal cancer screening: a comparison of 35 initiatives in 17 countries. Int J Cancer (2008) 122(6):1357–1367.[CrossRef][Web of Science][Medline]
13. Rennert G, Rennert HS, Miron E, Peterburg Y. Population colorectal cancer screening with fecal occult blood test. Cancer Epidemiol Biomarkers Prev (2001) 10(11):1165–1168.
14. van Rossum LG, van Rijn AF, Laheij RJ, et al. Random comparison of guaiac and immunochemical fecal occult blood tests for colorectal cancer in a screening population [published online ahead of print March 25, 2008]. Gastroenterology (2008) 135(1):82–90.[CrossRef][Web of Science][Medline]
15. Allison JE, Sakoda LC, Levin TR, et al. Screening for colorectal neoplasms with new fecal occult blood tests: update on performance characteristics [published online ahead of print September 25, 2007]. J Natl Cancer Inst (2007) 99(19):1462–1470.
16. Pickhardt PJ, Choi JR, Hwang I, et al. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults [published online ahead of print December 1, 2003]. N Engl J Med (2003) 349(23):2191–2200.
17. Baxter NN, Goldwasser MA, Paszat LF, Saskin R, Urbach DR, Rabeneck L. Association of colonoscopy and death from colorectal cancer [published online ahead of print December 15, 2008]. Ann Intern Med (2009) 150(1):1–8.
18. Ransohoff DF. How much does colonoscopy reduce colon cancer mortality? [published online ahead of print December 15, 2008]. Ann Intern Med (2009) 150(1):50–52.
19. Kim DH, Pickhardt PJ, Taylor AJ, et al. CT colonography versus colonoscopy for the detection of advanced neoplasia. N Engl J Med (2007) 357(14):1403–1412.
20. Imperiale TF, Ransohoff DF, Itzkowitz SH, Turnbull BA, Ross ME, Colorectal Cancer Study Group. Fecal DNA versus fecal occult blood for colorectal cancer screening in an average-risk population. N Engl J Med (2004) 351(26):2704–2714.
21. Rennert G, Kislitsin D, Brenner DE, Rennert HS, Lev Z. Detecting K-ras mutations in stool from fecal occult blood test cards in multiphasic screening for colorectal cancer [published online ahead of print March 8, 2007]. Cancer Lett (2007) 253(2):258–264.[CrossRef][Web of Science][Medline]
22. Zou H, Harrington JJ, Shire AM, et al. Highly methylated genes in colorectal neoplasia: implications for screening. Cancer Epidemiol Biomarkers Prev (2007) 16(12):2686–2696.
23. Chen WD, Han ZJ, Skoletsky J, et al. Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J Natl Cancer Inst (2005) 97(15):1124–1132.
24. Ahlquist DA, Sargent DJ, Loprinzi CL, et al. Stool DNA and occult blood testing for screen detection of colorectal neoplasia. Ann Intern Med (2008) 149(7):441–450.
25. Brenner DE, Rennert G. Fecal DNA biomarkers for the detection of colorectal neoplasia: attractive, but is it feasible? J Natl Cancer Inst (2005) 97(15):1107–1109.
26. Melotte V, Lentjes MHFM, van den Bosch SM, et al. N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer. J Natl Cancer Inst (2009) 101(13):916–927.
Related Articles in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2009 101: 901.
J Natl Cancer Inst 2009 101: 901.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||