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Journal of Clinical Oncology, Vol 24, No 4 (February 1), 2006: pp. 721-722 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.6524
Molecular Forecasting of Breast Cancer: Time to Move Forward With Clinical TestingJules Bordet Institute, Brussels, Belgium
International Drug Development Institute (IDDI), Brussels, Belgium
Netherlands Cancer Institute, Amsterdam, the Netherlands
Jules Bordet Institute, Brussels, Belgium
Jules Bordet Institute, Brussels for the TRANSBIG consortium To the Editor: We read the recent review article by Brenton et al1 with interest and would like to make the following observations: The article "questions the feasibility of using existing signatures for prospective randomization of patients in clinical trials" and yet strongly supports "taking into account the new molecular subtypes of breast cancer when assessing predictive effects." This seems to suggest that the authors are endorsing the results of unsupervised microarray analyses over the supervised approaches that have undergone external validation. While the data reporting breast cancer subtypes are exciting, these classifications, generated by cluster analysis, still remain extremely unstable: there is no operational definition of what constitutes each subtype (ie, no diagnostic test with specific genes and no prespecified rules or cutoffs when applying the "intrinsic gene set" as described by Sorlie et al2,3). Indeed, as a demonstration of their instability, when more samples are added, as in a later article, the luminal C subtype disappears, and the luminal B class clusters with the estrogen-receptor (ER) negative samples—the basal and erbB2 subgroups.4 Furthermore, it can be argued that the other results do not give more information than what can be provided by ER-positive or negative receptor status and histologic grade.4 Similarly, the basal-like subtype has been the subject of much recent investigation; however, it is still unclear what exactly characterizes a basal-like breast cancer, apart from the high grade, ER-negative, erbB2- negative clinical surrogate, and its similarity to the phenotype of breast cancers associated with BRCA1 germline mutation carriers. The Microarray for Node-negative Disease Avoids Chemotherapy (MINDACT) trial, which will be run under the auspices of the TRANSBIG consortium (see last paragraph of this letter) and coordinated by the European Organisation for Research and Treatment of Cancer, will prospectively evaluate the added value of a prognostic gene signature5 over currently used best clinico-pathologic prognostic factors (the genomic signature will be compared against the Adjuvant! Online software, www.adjuvantonline.com). Since the publication of the initial results of the Amsterdam 70-gene prognostic signature, a number of authors have underlined critical issues in gene selection bias, error estimation, fragility of gene signatures, and overoptimistic performance estimation in the early validation studies due to model overfit.6,7 Therefore, TRANSBIG undertook the first independent, external validation (as defined by criteria a priori) of this gene signature in order to determine if it had real potential for better individualization of breast cancer treatment. In a population of 302 node-negative, systemically untreated early breast cancer patients from five European cancer centers (median follow-up: 13.6 years), we observed that the 70-gene signature significantly adds independent prognostic information to clinico-pathologic risk factors (Nottingham Prognostic Index, St Gallen and the Adjuvant! software)8 for the later, the adjusted hazard ratios were 2.13 (95% CI, 1.19 to 3.82) for time to distant metastases and 2.66 (95% CI, 1.46 to 4.84) for overall survival. This study was not just a comparison of prognostic indices, such as reported in a recent article.9 Another study assessing the prognostic value of the 70-gene profile using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) has also found similar results in 96 patients.10 Hence, despite previous methodological criticisms, the signal seems robust, the data reproducible, and its success (now level 3 evidence) justifies proceeding to a prospective study. A prospective randomized trial like MINDACT is essential, in our opinion, to determine in an unbiased way, the true value of the gene signature in clinical practice. Its potential to spare 10% to 20% of women adjuvant chemotherapy without sacrificing long-term outcome,11 and also to identify a group of women who require different targeted treatment strategies to overcome their poor prognosis is too compelling to be ignored, especially given the opportunity for over (and under)-treatment of women diagnosed with early breast cancer today. MINDACT will commence in early 2006 with a pilot study of 800 women in which the trial population characteristics and the compliance with randomization will be assessed. Undoubtedly, there are and will be many predictive and prognostic signatures derived from high-throughput technology reported in the future. It is clear that independent and external validation of gene signatures must occur before they proceed to prospective clinical assessment and widespread use. Furthermore, like all diagnostic approaches, refinements in knowledge may require modifications to the ultimate diagnostic gene signature in the future. However, in our opinion, the 70-gene signature is ready for clinical testing. The MINDACT and the similarly designed PACCT (US Intergroup Program for the Assessment of Clinical Cancer Tests) studies are the only way to provide level 1 evidence about the clinical relevance of genomicsignatures. Participation in these trials should be strongly encouraged so this question can be answered as soon as possible. Authors' Disclosures of Potential Conflicts of Interest The author or 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Acknowledgment TRANSBIG is a translational research network linked to the Breast International Group comprising of 39 partners in 21 countries. It was created in early 2004 to facilitate translational research incorporation into breast cancer clinical trials and is partially funded by the European Commission Framework VI program (for further information: http://www.breastinternationalgroup.org). REFERENCES
1. Brenton JD, Carey LA, Ahmed AA, et al: Molecular Classification and Molecular Forecasting of Breast Cancer: Ready for Clinical Application? J Clin Oncol 23:7350-7360, 2005 2. Sorlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of breast carcinomas distinguish tumour subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001 3. Sotiriou C, Neo SY, McShane LM, et al: Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A 10393-10398, 2003 4. Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breast tumour subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418-8423, 2003 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. Ransohoff DF: Rules of evidence for cancer molecular-marker discovery and validation. Nat Rev Cancer 4:309-314, 2004[CrossRef][Medline] 7. Jenssen TK, Hovig E: Gene-expression profiling in breast cancer. Lancet 365:634-635, 2005[Medline] 8. Piccart M, Loi S, Van'tVeer L, et al: Multi-center external validation study of the Amsterdam 70-gene prognostic signature in node negative untreated breast cancer: Are the results still outperforming the clinical-pathological criteria? 27th San Antonio Breast Cancer Symposium December, 2004 (abstr 38) 9. Eden P, Ritz C, Rose C, et al: "Good Old" clinical markers have similar power in breast cancer prognosis as microarray gene expression profilers. Eur J Cancer 40:1837-1841, 2004[CrossRef][Medline] 10. Espinosa E, Vara JA, Redondo A, et al: Breast cancer prognosis determined by gene expression profiling: A quantitative reverse transcriptase polymerase chain reaction study. J Clin Oncol 23:7278-7285, 2005 11. 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
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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