Correspondence
Microsatellite Instability in Colon Cancer
N Engl J Med 2003; 349:1774-1776October 30, 2003
- Article
To the Editor:
Ribic et al. (July 17 issue)1 investigated microsatellite instability as a predictor of a benefit from adjuvant chemotherapy in patients with stage II or stage III colon cancer, and their findings confirm that microsatellite instability portends a better prognosis than microsatellite-stable cancer.1-3 However, this research differs from that of Elsaleh et al., in which patients whose stage III colorectal cancer demonstrated microsatellite instability derived the greatest benefit from adjuvant chemotherapy.4 In contrast, Ribic et al. found that patients with microsatellite instability did not benefit from adjuvant chemotherapy and may have been harmed by it (P=0.01). We wish to bring attention to a National Cancer Institute–National Surgical Adjuvant Breast and Bowel Project (NCI–NSABP) collaborative investigation involving 542 patients with stage II or III colon cancer (173 of whom underwent surgery only and 369 of whom received adjuvant therapy). Patients with microsatellite instability (18 percent) and patients with microsatellite-stable cancers were found to benefit equally from the use of adjuvant chemotherapy. Thus, although the described investigations consistently show that adjuvant chemotherapy benefits patients with microsatellite-stable colon cancer, the relation between microsatellite instability and adjuvant chemotherapy differs among studies. We agree with Ribic et al. that the microsatellite-instability status should not be used in making therapeutic decisions outside of clinical trials at the present time.
4 ReferencesCarmen J. Allegra, M.D.
National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA 15212
callegra@nmcr.com George Kim, M.D.
Mayo Clinic Jacksonville, Jacksonville, FL 32224Ilan R. Kirsch, M.D.
National Cancer Institute, Bethesda, MD 208891
Ribic CM ,Sargent DJ ,Moore MJ , et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349:247-257
Full Text | Web of Science | Medline2
Watanabe T ,Wu T-T ,Catalano PJ , et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 2001;344:1196-1206
Full Text | Web of Science | Medline3
Gryfe R ,Kim H ,Hsieh ETK , et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000;342:69-77
Full Text | Web of Science | Medline4
Elsaleh H ,Joseph D ,Grieu F ,Zeps N ,Spry N ,Iacopetta B . Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 2000;355:1745-1750
CrossRef | Web of Science | Medline
To the Editor:
Ribic et al. report that patients with stage II or III colorectal cancer do not benefit from adjuvant chemotherapy if their tumors show microsatellite instability, in contrast with our findings in patients with stage III disease1 and the findings of others in patients with stage IV disease.2 A possible explanation for these discrepancies might be that tumors with microsatellite instability have different properties, including prognosis and response to chemotherapy, depending on the underlying cause of their microsatellite-instability phenotype. Patients with sporadic colorectal cancer in whom microsatellite instability is caused by MLH1 gene-promoter methylation are on average 18 years older than patients with microsatellite instability who do not have methylation of this gene.3 A variety of mechanisms that are not related to methylation cause microsatellite instability in the majority of younger patients, including germ-line and somatic mutations and the loss of heterozygosity of mismatch-repair genes.4 The patients studied by Ribic et al. were enrolled in clinical trials and hence were considerably younger than those in our population-based series.1 We suggest that it may be premature to discount the predictive value of microsatellite instability without further characterization of tumors with this phenotype, particularly in terms of their DNA-methylation status.
4 ReferencesBarry Iacopetta, Ph.D.
University of Western Australia, Nedlands 6009, Australia
bjiac@cyllene.uwa. edu. au Hany Elsaleh, M.B., B.S., Ph.D.
University of California, Los Angeles, Los Angeles, CA 90095-6951Nik Zeps, Ph.D.
Sir Charles Gairdner Hospital, Nedlands 6009, Australia1
Elsaleh H ,Joseph D ,Grieu F ,Zeps N ,Spry N ,Iacopetta B . Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 2000;355:1745-1750
CrossRef | Web of Science | Medline2
Liang JT ,Huang KC ,Lai HS , et al. High-frequency microsatellite instability predicts better chemosensitivity to high-dose 5-fluorouracil plus leucovorin chemotherapy for stage IV sporadic colorectal cancer after palliative bowel resection. Int J Cancer 2002;101:519-525
CrossRef | Web of Science | Medline3
Malkhosyan SR ,Yamamoto H ,Piao Z ,Perucho M . Late onset and high incidence of colon cancer of the mutator phenotype with hypermethylated hMLH1 gene in women. Gastroenterology 2000;119:598-598
CrossRef | Web of Science | Medline4
Yuen ST ,Chan TL ,Ho JW , et al. Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers. Oncogene 2002;21:7585-7592
CrossRef | Web of Science | Medline
To the Editor:
Microsatellite instability helps predict the treatment response in patients with colorectal carcinoma.1-3 In our studies of microsatellite instability, we found that intratumor heterogeneity for a given marker may bias the stratification of patients. In analyzing 90 sporadic colorectal adenocarcinomas for microsatellite instability and MLH1MSH2 expression according to the topographic compartment of the tumor, we found significant differences between the superficial compartment (tumor cells above the muscularis propria) and the deep compartment (tumor cells infiltrating the muscularis propria), with down-regulation of protein expression and increased microsatellite instability in the deep compartment. At least one third of tumors that are unstable in the deep compartment can be expected to be stable in the superficial compartment.
3 ReferencesJuan J. Jimenez, M.D., Ph.D.
Alfredo Blanes, M.D., Ph.D.
University of Malaga School of Medicine, 29071 Malaga, SpainSalvador J. Diaz-Cano, M.D., Ph.D.
Barts and the London NHS Trust, London E1 1BB, United Kingdom
s.j. diaz-cano@qmul. ac. uk 1
Ribic CM ,Sargent DJ ,Moore MJ , et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349:247-257
Full Text | Web of Science | Medline2
Watanabe T ,Wu T-T ,Catalano PJ , et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 2001;344:1196-1206
Full Text | Web of Science | Medline3
Barratt PL ,Seymour MT ,Stenning SP , et al. DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study. Lancet 2002;360:1381-1391
CrossRef | Web of Science | Medline
Author/Editor Response
Our findings that patients who have stage II or stage III colon cancer with high-frequency microsatellite instability do not benefit from and may be harmed by fluorouracil-based adjuvant chemotherapy were based on analyses of tumors from patients who were randomly assigned prospectively to surgery alone or to fluorouracil-based adjuvant chemotherapy after surgery. In contrast, the unpublished results described by Allegra and colleagues were derived through the comparison of patients participating in two NSABP trials (trials C-01 and C-02) who had undergone surgical resection with patients from two other NSABP trials (C-03 and C-04) who were assigned to surgery plus fluorouracil-based adjuvant chemotherapy.1 The observations of Iacopetta and colleagues were derived from a nonrandomized, hospital-based cohort study2 in which the choice of whether to deliver adjuvant treatment was made by the physician. Age, coexisting conditions, and performance status were all possible factors in determining whether patients were offered or accepted adjuvant chemotherapy after surgery. Thus, the findings described by both Allegra et al. and Iacopetta et al. are susceptible to measurable and unmeasurable differences in the treated and untreated patients among the study populations they analyzed. In addition, the findings of Elsaleh et al.2 regarding differential efficacy of treatment according to sex and the location of the cancer within the colon have recently been contradicted by a pooled analysis of data from more than 3300 patients, raising additional issues about the representativeness of the population of patients they studied.3 Nonetheless, we agree that further studies are needed before the current recommendations for the use of fluorouracil-based adjuvant chemotherapy in patients with colon cancer are changed.
The observations, described by Jimenez and colleagues, of topographic differences in high-frequency microsatellite-instability status within cancer specimens are interesting but appear to be inconsistent with the presence of high-frequency microsatellite instability in the benign lesions that are precursors to colorectal cancer: aberrant crypt foci and adenomatous polyps.4,5 Furthermore, the consistent association of distinct clinicopathological phenotypes with colorectal cancers with high-frequency microsatellite instability (right-sided predominance, exophytic growth, poor differentiation, lymphocytic infiltrates, and “pushing” margins of invasion)6 and the routine use of tumor microsatellite instability to identify patients with hereditary nonpolyposis colorectal cancer argue that microsatellite instability does indeed reflect a reliable tumor genotype, as defined by most investigators, and is probably not influenced by methodologic factors.
We agree that the tumor-methylation status or the specific mismatch-repair deficiency present in any cancer may further influence the observed response to chemotherapy. We hope that large, multicenter, collaborative efforts or meta-analyses will soon be able to address these important issues in order to optimize the care of patients with colon cancer.
6 ReferencesRobert Gryfe, M.D., Ph.D.
Christine M. Ribic, M.Sc.
Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
gryfe@mshri.on. ca Daniel J. Sargent, Ph.D.
Mayo Foundation, Rochester, MN 559051
Allegra CJ ,Paik S ,Colangelo LH , et al. Prognostic value of thymidylate synthase, Ki-67, and p53 in patients with Dukes' B and C colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project collaborative study. J Clin Oncol 2003;21:241-250
CrossRef | Web of Science | Medline2
Elsaleh H ,Joseph D ,Grieu F ,Zeps N ,Spry N ,Iacopetta B . Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 2000;355:1745-1750
CrossRef | Web of Science | Medline3
Gill S ,Loprinzi CL ,Sargent DJ , et al. Using a pooled analysis to improve the understanding of adjuvant therapy (AT) benefit for colon cancer (CC). Prog Proc Am Soc Clin Oncol2003;253-253 abstract.4
Heinen CD ,Shivapurkar N ,Tang Z ,Groden J ,Alabaster O . Microsatellite instability in aberrant crypt foci from human colons. Cancer Res 1996;56:5339-5341
Web of Science | Medline5
Ricciardiello L ,Goel A ,Mantovani V , et al. Frequent loss of hMLH1 by promoter hypermethylation leads to microsatellite instability in adenomatous polyps of patients with a single first-degree member affected by colon cancer. Cancer Res 2003;63:787-792
Web of Science | Medline6
Kim H ,Jen J ,Vogelstein B ,Hamilton SR . Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994;145:148-156
Web of Science | Medline
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Hamed Kargozaran, Morton Kahlenberg, Vijay P. Khatri. (2008) The Implications of Colorectal Cancer Molecular Biology in Clinical Practice. Surgical Oncology Clinics of North America 17:2, 341-355
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J Rubio, A Blanes, J J Sanchez-Carrillo, S J Diaz-Cano. (2007) Microsatellite abnormalities and somatic down-regulation of mismatch repair characterize nodular-trabecular muscle-invasive urothelial carcinoma of the bladder. Histopathology 51:4, 458-467
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E. Casado, J. Castro, C. Belda-Iniesta, P. Cejas, J. Feliu, M. Sereno, M. González-Barón. (2007) Molecular markers in colorectal cancer: genetic bases for a customised treatment. Clinical and Translational Oncology 9:9, 549-554
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L Pozo, JJ Sanchez-Carrillo, A Martinez, A Blanes, SJ Diaz-Cano. (2007) Differential kinetic features by tumour topography in cutaneous small-cell neuroendocrine (Merkel cell) carcinomas. Journal of the European Academy of Dermatology and Venereology 0:0, 070802021952008-???
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Daniel B Longley, Wendy L. Allen, Patrick G. Johnston. (2006) Drug resistance, predictive markers and pharmacogenomics in colorectal cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1766:2, 184-196
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Wendy L Allen, Patrick G Johnston. (2005) Have we made progress in pharmacogenomics? The implementation of molecular markers in colon cancer. Pharmacogenomics 6:6, 603-614
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M Kruhøffer, J L Jensen, P Laiho, L Dyrskjøt, R Salovaara, D Arango, K Birkenkamp-Demtroder, F B Sørensen, L L Christensen, L Buhl, J-P Mecklin, H Järvinen, T Thykjaer, F P Wikman, F Bech-Knudsen, M Juhola, N N Nupponen, S Laurberg, C L Andersen, L A Aaltonen, T F Ørntoft. (2005) Gene expression signatures for colorectal cancer microsatellite status and HNPCC. British Journal of Cancer 92:12, 2240-2248
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Luis A. Diaz. (2005) The current clinical value of genomic instability. Seminars in Cancer Biology 15:1, 67-71
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