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Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 2057-2058 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.5614
Reaction to American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast CancerAgendia BV; Slotervaart Medical Center, Amsterdam, the Netherlands To the Editor: The American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer1 contains for the first time a recommendation on "multiparameter gene expression analysis for breast cancer." Two such tests, both predicting recurrence in early stage breast cancer, are commercially available today. They belong to a new category of molecular diagnostic tests, in vitro diagnostic multigene index assays (IVDMIAs), which the US Food and Drug Administration (FDA) intends to regulate.2 The newly published recommendations conclude that the Oncotype DX (Genomic Health Inc, Redwood City, CA) test "can be used to predict the risk of recurrence," whereas the clinical utility of the second test, MammaPrint (Agendia BV, Amsterdam, the Netherlands), is "under investigation." I was surprised to read that this evaluation by the expert group resulted in a recommendation to use Oncotype DX, but not MammaPrint, given that MammaPrint represents the only FDA 510(k)-cleared IVDMIA for breast cancer. It would be unthinkable that a group of doctors would recommend the use of a non–FDA-approved drug over an FDA-approved equivalent for the same indication. But in the area of diagnostics this appears to be possible. Four factually incorrect assumptions about MammaPrint have led the expert panel to reach this conclusion. First, Oncotype DX validation has not reached level 2 evidence, as the National Surgical Adjuvant Breast and Bowel Project (NSABP) 14 and 20 validation studies did not have validation of Oncotype DX as a primary or secondary end point, and the material used for the validation was collected retrospectively. Moreover, not all samples of these trials were used for the validation of Oncotype DX. As such, Oncotype DX has only reached level 3 evidence, as formulated by Hayes et al,3 which is also the case for MammaPrint. Second, the expert group does not seem to appreciate that FDA clearance of MammaPrint includes an accurate description of the "clinical utility" of the product. The expert group writes: "The precise clinical utility and appropriate application for other multiparameter assays, such as the MammaPrint assay, the so-called Rotterdam Signature, and the Breast Cancer Gene Expression Ratio are under investigation."1 FDA clearance of an IVDMIA includes close scrutiny of the validation studies and severely restricts the claims of clinical utility. One cannot find a more precise description of clinical utility than those that have been granted by the FDA. Third, the panel writes that "only the Oncotype DX and the MammaPrint assays are available commercially, and the laboratory that performs the Oncotype DX has been certified by the Clinical Laboratory Improvement Amendments [CLIA] to perform the test for clinical use."1 This statement suggests that the MammaPrint test is performed in a laboratory that does not have such CLIA certification, which is incorrect. Agendia's laboratories were granted the even more strict CLIA accreditation status and also acquired accreditation of the College of American Pathologist in January of this year. Fourth, the panel comments on the tissue handling required for a MammaPrint test: "the tissue handling requirements for MammaPrint make this assay challenging in current clinical practice: tumor specimens were snap-frozen in liquid nitrogen within 1 hour after surgery; in addition, at present, all data have been generated with whole sections, not with core biopsies."1 The FDA has issued a second 510(k) clearance for MammaPrint on June 22, 2007, in which fresh biopsies can be shipped at ambient temperature in an RNA-preserving solution, bypassing the need to freeze the sample. Most importantly, we believe that the quality of the test result critically depends on the availability of intact RNA, which cannot be obtained from the formalin-fixed, paraffin-embedded (FFPE) tissue blocks used for the Oncotype DX test. FFPE tissue fixation was never designed for RNA analysis and many different protocols are used. The proof of technical validity for FFPE samples in the context of RNA measurements is still outstanding. Do the authors really want to suggest that we should prefer convenience over accuracy in cancer diagnostics? In conclusion, the level of validation of both tests is similar, and there are no reasons to issue a different recommendation for these two tests. On the contrary: if there is a choice between an FDA-cleared test and a "home brew" alternative, is there really a choice? AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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: Rene Bernards, Agendia (C); Consultant or Advisory Role: none Stock Ownership: Rene Bernards, Agendia Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Harris L, Fritsche H, Mennel R, et al: American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. J Clin Oncol 25:5287-5312, 2007 2. US Food and Drug Administration: Draft Guidance for Industry, Clinical Laboratories, and FDA Staff In Vitro Diagnostic Multivariate Index Assays. http://www.fda.gov/cdrh/oivd/guidance/1610.pdf 3. Hayes DF, Bast RC, Desch CE, et al: Tumor marker utility grading system: A framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst 88:1456-1466, 1996
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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