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Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 2058-2059 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.6638
Inconsistent Criteria Used in American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast CancerDepartment of Medical Oncology, Jules Bordet Institute, Brussels, Belgium
Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France
Department of Surgical Oncology, University of Dundee, Dundee, United Kingdom
Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands To the Editor: We read with much interest the new American Society of Clinical Oncology (ASCO) recommendations for the use of tumor markers in breast cancer published in the Journal of Clinical Oncology.1 We were, however, quite disappointed by the lack of consistency in the criteria used to evaluate some of the markers. Oncotype DX (Genomic Health Inc, Redwood City, CA) is recommended for use in adjuvant treatment decision making based on what we consider to be only level 3 evidence according to the definitions published by Hayes et al.2 According to these definitions, level 2 evidence is only achieved if a marker is validated in a prospective trial as a predefined secondary end point. This was not the case in either of the National Surgical Adjuvant Breast and Bowel Project trials (NSABP 14 and 20) used to validate retrospectively Oncotype DX.3,4 The analysis was planned and performed after the trials were closed and the results published, and validation of this marker was never a predefined, per-protocol secondary study objective. In addition, all biologic material from these trials used in the validation were collected retrospectively, and material from only some of the patients were included. Therefore, the validation of Oncotype DX can only be considered retrospective and of level 3 evidence. The same applies to MammaPrint (Agendia BV, Amsterdam, the Netherlands)5,6 which was validated retrospectively on biologic material, albeit collected prospectively, not linked to a clinical trial. Therefore, MammaPrint also bears level 3 evidence so far. The use of a clinical trial population for a validation has its pros and cons. It undoubtedly allows us to study a homogeneously treated population for which clinical data are uniformly collected. However, such a population is highly selected and caution is needed regarding the applicability of all clinical trial findings to the general population. The methodology used in the TRANSBIG validation of MammaPrint7 also presents paths and pitfalls. Although not linked to a specific clinical trial, predefined selection criteria were applied to study a homogeneous group of patients for whom material had been collected prospectively in the past. Moreover, quality assurance of the data was provided by an independent audit at all sites, combined with a central pathology review. But, as with all retrospective series, bias is unavoidable because samples were needed from patients who had not been treated with systemic therapy, who had had a long follow-up, and from whom frozen material had been collected. Nevertheless, these patients may be more representative of a general routine practice population. The bottom line is that both approaches are valid but not perfect, and they only provide level 3 evidence of clinical utility. Therefore, both markers, Oncotype DX and MammaPrint, should have the same level of acceptance by the ASCO panel. In our opinion, present data are insufficient to recommend their use in routine clinical practice outside of clinical trials. The St Gallen Consensus Guidelines8 have assigned Oncotype DX and MammaPrint the same level of evidence, considering them both as not yet ready for use outside clinical trials. However, because both are technically validated and MammaPrint has even US Food and Drug Administration clearance (which includes clinical utility as a criteria), these tests may provide physicians and patients with useful additional information for treatment decision making for certain difficult clinical cases. The way tests are performed and on what type of tumor specimen (fresh, frozen, or embedded in paraffin) is not relevant to its acceptance for clinical practice use, as long as the technical validity of sampling and logistics is demonstrated. As the panel is certainly aware, two very important, large, prospective trials are ongoing that aim to evaluate the clinical usefulness of both tools: the Microarray in Node-Negative Disease May Avoid Chemotherapy trial for MammaPrint, partially sponsored by the European Commission, and the Trial Assigning Individualized Options for Treatment trial for Oncotype DX, partially sponsored by the National Cancer Institute. Great efforts—human, economic, and otherwise—have been invested to set up and run these trials, which are without doubt the only correct way to prove the clinical value of these tools in today's patient populations. We are surprised to see that ASCO recommends the clinical use of a tool currently under evaluation in a trial sponsored by the National Cancer Institute that will enroll about 8,000 patients.
Another example of inconsistency in the criteria used to rate and recommend biomarkers for clinical use is the case of topoisomerase II The level of evidence presently existing for Topo II and the type of validation studies performed so far are similar to those performed for Oncotype DX, and hence the recommendation regarding their use in clinical practice should be similar. Furthermore, for Topo II, two important projects aiming to provide the necessary level 1 evidence before this biomarker can be used in clinical practice are ongoing: (1) a large meta-analysis of 4,500 patients from four large adjuvant prospective trials with a centralized evaluation of both human epidermal growth factor receptor 2 and Topo II status; and (2) a prospective, neoadjuvant trial, specifically designed to validate the biologic hypothesis that Topo II is a predictive marker of response to anthracyclines (the Trial of Principle trial). As a final note, we would like to respectfully suggest that ASCO consider including some of the many European experts on biomarker development and validation in the next panel for biomarker recommendations, similar to what is already done for other ASCO guideline panels and the St Gallen Consensus Panel, which is composed of both European and North American breast cancer experts. This may allow for broader and more consensual recommendations. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. 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. 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 3. Paik S, Tang G, Shak S, et al: Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor–positive breast cancer. J Clin Oncol 24:3726-3734, 2006 4. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004 5. van 't Veer LJ, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530-536, 2002[CrossRef][Medline] 6. van de Vijver MJ, He YD, van 't Veer LJ, et al: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999-2009, 2002 7. Buyse M, Loi S, van't Veer L, et al: Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst 98:1183-1192, 2006 8. Goldhirsch A, Wood WC, Gelber RD, at al: Progress and promise: Highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 18:1133-1144, 2007 9. Colozza M, Azambuja E, Cardoso F, et al: Proliferative markers as prognostic and predictive tools in early breast cancer: Where are we now? Ann Oncol 16:1723-1739, 2005 10. Press MF, Mass RD, Zhou JY, et al: Association of topoisomerase II alpha (TOP2A) gene amplification with responsiveness to anthracycline-containing chemotherapy among women with metastatic breast cancer entered in Herceptin H0648g pivotal clinical trial. J Clin Oncol 23:847s, 2005 (suppl; abstr 9543) 11. Di Leo A, Gancberg D, Larsimont D, et al: HER2 amplification and topoisomerase II alpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res 8:1107-1116, 2002 12. Tanner MM, Isola J, Wiklund T, et al: Topoisomerase II alpha gene amplification predicts favorable treatment response of tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER2/neu amplified breast cancer: Results from the randomized Scandinavian Breast Group Trial 9401. J Clin Oncol 24:1-9, 2006 13. Knoop AS, Knudsen H, Balslev E, et al: Retrospective analysis of topoisomerase IIalpha amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol, 23:7483-7490, 2005 14. Coon JS, Marcus E, Gupta-Burt S, et al: Amplification and overexpression of topoisomerase II alpha predict response to anthracycline-based therapy in locally advanced breast cancer. Clin Cancer Res 8:1061-1067, 2002 15. O'Malley FP, Chia S, Tu D, et al: Prognostic and predictive value of topoisomerase II alpha in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA. 5). J Clin Oncol 24:533, 2006 16. Slamon D, Eiermann W, Robert N, et al: BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC Related Reply
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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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(Topo II). The ASCO panel refers to the article by Colozza et al
T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC
