© 2004 by Oxford University Press
© 2004 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability
Correspondence to: Asad Umar, PhD, DVM, National Cancer Institute, National Institutes of Health, 6130 Executive Blvd., EPN 2141, Bethesda, MD 20892 (e-mail: asad.umar{at}nih.gov)
Dr. Laghi proposes that all colorectal cancers be screened for microsatellite instability (MSI) using BAT26 as a marker rather than selecting patients based on family history for screening with the National Cancer Institute (NCI) panel of markers, as proposed in the revised Bethesda Guidelines (Table 1) (1). This issue—that using just one MSI marker might make analysis simple and relatively inexpensive and hence would allow all patients with colorectal cancers to be screened, regardless of recommended screening guidelines—has been discussed before (2), and it needs careful examination, similar to what it received during the adoption of the NCI panel of markers. Most of the clinical and translational research experts did not feel that use of a single marker, even after applying screening guidelines, would identify the true number of hereditary nonpolyposis colorectal cancer (HNPCC) cases. In this Workshop, it was recognized that although markers like BAT26 are effective at determining MSI, they are not 100% sensitive (no false-negatives) or 100% specific (no false-positives), as suggested by Dr. Laghi. For example, BAT26 revealed MSI in 73 of 494 colorectal cancer patients, but when five markers were used, the number of patients with MSI increased to 95 of 494 (3). Similarly, of 20 ovarian cancers with confirmed MSI, only five showed BAT26 instability (4), confirming results found in the literature for ovarian and endometrial cancers.
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Let us compare the cost-effectiveness of MSI screening using a single marker on all colorectal cancer patients versus screening based on family history and either the Amsterdam or the revised Bethesda Guidelines (Fig. 1). For instance, if all colorectal cancer cases [approximately 500 000 worldwide, and 147 000 in the United States (5)] are to be analyzed for MSI at approximately $300 per primer pair for MSI analysis using one marker (6), the cost will be approximately $13 million per year in the United States and $150 million per year worldwide. However, using a screening guideline to reduce the number of MSI analyses performed can reduce the cost by as much as one-third (or approximately $3 million in the United States) and one-fourth (approximately $50 million worldwide), according to rough estimates based on suspected HNPCC/MSI cases (Ramsey S: personal communication).
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The issue of cost-effectiveness of any marker panel boils down to the relative cost and sensitivity and specificity of each approach. Alternative markers must be at least as sensitive (at equal specificity) and cost less than screening with the NCI panel of markers to improve the cost-effectiveness of screening probands. This explains why it would not be a good idea to perform MSI analysis on all colorectal cancer patients and emphasizes the importance of using family history and a well thought-out set of guidelines [Amsterdam, Bethesda, or one of the newly developed Asian guidelines (7)] to ensure that the maximum number of individuals at risk of developing MSI colorectal cancer are screened.
NOTES
I greatly appreciate careful reading of this response and comments from Drs. Jeff Bacher, J. Richard Boland, Jeremy Jass, Noralene Lindor, Henry Lynch, Scott Ramsey, John I. Risinger, and Jonathan Terdiman.
REFERENCES
1 Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96:261–8.
2 Salovaara R, Loukola A, Kristo P, Kaariainen H, Ahtola H, Eskelinen M, et al. Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 2000;18:2193–200.
3 Loukola A, Eklin K, Laiho P, Salovaara R, Kristo P, Jarvinen H, et al. Microsatellite marker analysis in screening for hereditary nonpolyposis colorectal cancer (HNPCC). Cancer Res 2001;61:4545–9.
4 Sood AK, Holmes R, Hendrix MJ, Buller RE. Application of the National Cancer Institute international criteria for determination of microsatellite instability in ovarian cancer. Cancer Res 2001;61:4371–4.
5 World Health Organization. Incidence, mortality, and survival databases. Available at: http://www.who.int/cancer/resources/incidences/en/. [Last accessed: August 12, 2004.]
6 de la Chapelle A. Microsatellite instability phenotype of tumors: genotyping or immunohistochemistry? The jury is still out. J Clin Oncol 2002;20:897–9.
7 Umar A, Risinger JI, Hawk ET, Barrett JC. Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer 2004;4:153–8.[Web of Science][Medline]
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J Natl Cancer Inst 2004 96: 1402-1403.
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