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Electronic letters published:
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Author's response to letter from Bernard
Reaction to Systematic Review: Gene Expression Profiling Assays in Early-Stage Breast Cancer
Letter to the Editor
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Steven N. Goodman, MD, MHS, PhD Johns Hopkins, Luigi Marchionni and Antonio C. Wolff
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sgoodman{at}jhmi.edu Steven N. Goodman, et al.
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To the Editor: We appreciate the points made by the authors of this letter, which underscore messages of our article [1] and those of Simon [2]. The authors are correct that the populations on which the two tests were validated differed in terms of pretreatment. They also differed by estrogen receptor (ER) status; the 70-gene test was validated on a mixed population of ER positive and negative patients, whereas all of the Oncotype patients were ER positive. While there may be an explanation for the reported differences, these are the numbers reported from the validation studies upon which women have to base decisions, and they point out the difficulty of interpreting numbers for populations that may have mixed prognoses (ER positive and negative) and a mix of therapeutic choices (estrogen therapy and/or chemotherapy). With respect to the choice of endpoint it must be noted that the claim that the tests would predict similar risks in the short term in the same patients is based on a series of assumptions, required because of the mixed validation population and broader indications of the Mammaprint test. While it is true that chemotherapy has its greatest effect on early relapses, we believe most women are interested in their long-term prospects, and if the probability of long-term relapse is very low, this puts a bound on how much benefit could be gained through therapy. If the indices indeed predict approximately equally in the short term and one predicts better in the long term, it is hard to see how they could be of equal clinical value. Finally, we must respectfully disagree that the measure of clinical utility is whether a test is superior to existing predictors. Whether superior predictions translate into clinical benefit depends on a.) whether the prediction would justify a change in a therapeutic decision, and b.) whether the change the therapeutic decision would result in net therapeutic benefit (from reduced morbidity and mortality from treatment or disease). Our conclusion remains that for Mammaprint, the evidence for the decision making element still needs strengthening (by evaluation in prognostically and therapeutically homogeneous populations to avoid the kinds of calculations that the letter's authors are forced to make), and the direct evidence for therapeutic benefit is absent. 1. Marchionni L, Wilson RF, Wolff AC, et al. Systematic review: gene expression profiling assays in early-stage breast cancer. Ann Intern Med. 2008;148(5):358-69. 2. Simon R. Development and evaluation of therapeutically relevant predictive classifiers using gene expression profiling. J Natl Cancer Inst. 2006;98:1169-1171. Conflict of Interest:None declared |
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Rene Bernards, PhD Agendia BV, Emiel J.T. Rutgers MD PhD Lajos Puszta MD PhD
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r.bernards{at}nki.nl Rene Bernards, et al.
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The recent review “Gene Expression Profiling Assays in Early-Stage Breast Cancer” (1), which compares several multi-gene signature for breast cancer prognosis, states that for the MammaPrint 70-gene test “Fifteen percent of patients with the good-prognosis signature had recurrence by 10 years, demonstrating that when the 70-gene signature is used alone in this mixed population, the long-term risk in the good-prognosis group may not be low enough to justify forgoing chemotherapy”. At first glance, this recurrence rate (14.7%) indeed appears high when compared to the OncotypeDX test, which had only a 6.8% rate of recurrence by 10 years in the low risk group (2). However, this direct comparison is flawed due to the fact that the patients analyzed by the OncotypeDX test were all treated with tamoxifen, whereas the patients analyzed with the MammaPrint test were mostly untreated (3). Since tamoxifen is known to reduce the rate of recurrences by some 30-50% (4-6), this explains, at least in part, the differences in percentage recurrences between the two tests. A related question also directly relevant to this issue is whether, in comparing the performance of these tests, one should focus on the recurrence rates after 10 years, as is generally done. These tests are generally performed to help assess whether a patient requires adjuvant systemic chemotherapy. Meta-analyses of breast cancer have demonstrated that adjuvant chemotherapy almost exclusively reduces the rate of recurrences in the first five years (6). Importantly, both MammaPrint and Oncotype DX are better in predicting early (< 5 year) recurrences than late (> 5 year) recurrences (2, 7), which incidentally is also the group that benefits most from adjuvant chemotherapy (6). Thus, for the question who should receive adjuvant chemotherapy, it is most relevant to identify the patients that relapse in the first five years after surgery. If a comparison is made between MammaPrint and OncotypeDX low risk groups for recurrence rates at 5 years post surgery, the following numbers emerge: OncotypeDX: recurrence rate 2.5% (2); MammaPrint: 5.3% (3). Since 95% of the MammaPrint cohort did not receive any adjuvant therapy, tamoxifen-treatment of the MammaPrint low risk ER-positive patients would have resulted in a further reduction in recurrences by 30-50%, from 5.3% to 2.7 - 3.7%. Thus, at the more relevant endpoint of 5-year survival, MammaPrint and OncotypeDX appear to perform very similarly. If these low- risk groups would be given chemotherapy in addition to tamoxifen, the predicted benefit would be a further reduction of approximately 10% in recurrence. Such a marginal benefit from polychemotherapy is, in most countries considered to be insufficient to warrant giving a large patient group a toxic therapy. The most relevant consideration for clinical utility is whether a test is superior to what we use today to assess risk of recurrence. In two large studies, MammaPrint was superior to the NIH and the St. Gallen criteria and the Adjuvant! Online tool (3, 8). In about one in three patients, risk assessment using Adjvant! was discordant with MammaPrint in a large multicenter study (8). This is important and justifies in our opinion the use of this assay in the clinic. References 1. Marchionni L, Wilson RF, Wolff AC, et al. Systematic review: gene expression profiling assays in early-stage breast cancer. Ann Intern Med. 2008;148(5):358-69. 2. 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. 2004;351(27):2817-26. 3. 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. 2002;347(25):1999-2009. 4. Ravdin PM. Overview of randomized trials of systemic adjuvant therapy. Cancer Treat Res. 2000;103:157-81. 5. Group EBCTC. Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998;351(9114):1451-67. 6. Group EBCTC. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-717. 7. Cardoso F, Van't Veer L, Rutgers E, Loi S, Mook S, Piccart-Gebhart MJ. Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 2008;26(5):729-35. 8. 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. 2006;98(17):1183-92. Conflict of Interest:Employee and shareholder of Agendia |
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Lawrence C. Panasci, M.D. Sir Mortimer B. Davis Jewish General Hospital, Victor Cohen, M.D.
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lpanasci{at}hotmail.com Lawrence C. Panasci, et al.
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I would like to congratulate Dr. Marchionni et al (1) on the excellent review of gene expression profiling in early breast cancer. As concerns the Oncotype DX test you state that the greatest contribution of the test may be in reclassifying patients from high to low risk as compared to the adjuvant on line test. The test of adjuvant on line that was utilized as a comparison in 2004 did not include Her-2/neu in the adjuvant on line. Perhaps the Oncotype DX test is largely detecting patients that are Her-2 negative and are placing them in a lower risk which you could do just with the Her-2 testing alone. Can you comment on this? Conflict of Interest:None declared |
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