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Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4857 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.2019
Predictive Value of Microsatellite Instability-High Remains ControversialMayo Clinic, Jacksonville, FL
National Surgical Breast and Bowel Project Operations and Biostatistical Centers, Pittsburgh, PA
Amgen Inc, Seattle, WA
National Surgical Breast and Bowel Project Operations and Biostatistical Centers, Pittsburgh, PA; and the University of Florida, Gainesville, FL
National Surgical Breast and Bowel Project Operations and Biostatistical Centers; and the Allegheny General Hospital, Pittsburgh, PA To the Editor: In his editorial, Dr Boland raises several issues that deserve additional comment. One is the issue of patient selection. Although it is true that retrospective analyses have inherent biases, because adjuvant chemotherapy has been the standard of care since the late 1980s, specimens from surgery-only patients are and will continue to be available to us only from archived tissue banks. Prospective analyses of microsatellite instability-high (MSI-H) patients treated with surgery alone, the essential control group, compared directly to MSI-H patients treated with chemotherapy, are no longer possible. Despite the potential for bias, the inclusion of the surgery-alone treated subset of patients is a strength of our study. Dr Boland also highlights additional patient selection flaws that are ironically present in the large study1 cited as able to "correct prior errors." In particular, that study represents a collection of patient samples from different trials, different countries, different times of patient enrollment, and varying fluorouracil (FU) regimens. In contrast, the National Surgical Breast and Bowel Project specimens used in our analysis were from the tissue bank of an established cooperative group that used the same FU/leucovorin (FULV) regimen across the studies. A critical issue that remains is whether the present body of information supports a change in the use of adjuvant chemotherapy for colon cancer patients. More specifically, based on the available data, can mismatch repair status be used to predict benefit from the use of adjuvant chemotherapy? Our study failed to identify an interaction between MSI status and FULV therapy, suggesting that patients benefit equally from the use of adjuvant fluoropyrimidine-based chemotherapy regardless of mismatch repair status. Our data support the conclusion that patients with MSI-H should not be managed differently from those with microsatellite stability (MSS) with respect to the relative benefit from adjuvant fluoropyrimidine-based chemotherapy. An additional important issue is whether these analyses are applicable to the use of other agents including oxaliplatin and, potentially, bevacizumab or cetuximab. Preclinical data suggest that MSI-H cells are sensitive to oxaliplatin yet resistant to the majority of platinums.2 Intriguingly, an interim analysis from an adjuvant trial with an irinotecan-containing regimen, reported that the MSI-H patients surprisingly benefited more than did those with MSS.3 An immediate answer is not available, but the researchers in two large national trials—National Surgical Breast and Bowel Project C-08 (oxaliplatin, fluorouracil, and folinic acid ± bevacizumab) and North Central Cancer Treatment Group N0147 (oxaliplatin, fluorouracil, and folinic acid ± cetuximab—plan to investigate whether MSI-H patients do better or worse than MSS patients. These results will remain entangled in whether it is the prognostic or predictive characteristic of MSI-H that results in improved survival, as no comparative surgery-alone arm is available. The unfortunate reality is that, despite a laudable effort by numerous investigators, the existing body of work does not currently support the use of MSI testing to predict benefit from the use of adjuvant chemotherapy. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Carmen Allegra, Almac Diagnostics (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
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 349:247-257, 2003 2. Zdraveski ZZ, Mello JA, Farinelli CK, et al: MutS preferentially recognizes cisplatin- over oxaliplatin-modified DNA. J Biol Chem 277:1255-1260, 2002 3. Bertagnolli MM, Compton CC, Niedzwiecki D, et al: Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, 5-fluorouracil and leucovorin in stage III colon cancer. J Clin Oncol 24:541s, 2006 (abstr 10003)
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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