Biotechnology Healthcare - June 2008 - (Page 40) A team at the Netherlands Cancer Institute in Amsterdam developed the 70-gene signature on which MammaPrint is based. Now marketed by Agendia, in Amsterdam, MammaPrint is a microarray-based prognostic assay for use in patients younger than age 53 with stage 1 or 2 primary, lymph node- negative breast cancer. MammaPrint is the first assay cleared by the U.S. Food and Drug Administration as an in vitro diagnostic multivariate index assay device. Diagnostic device approvals are handled by the FDA’s devices branch, the Center for Devices and Radiological Health, which is charged with verifying that a device is safe, analytically valid, and does what the sponsor claims. CDRH is not responsible, however, for demonstrating that use of the device improves clinical outcomes. “MammaPrint does not have FDA approval,” Hayes emphasizes. “Agendia has FDA clearance to sell MammaPrint in the United States. When we deliberate in ASCO, we aren’t influenced by whether the FDA has cleared a marker, because that doesn’t indicate a change in patient outcomes at all. The devices branch has a very different set of criteria than the [Center for Drug Evaluation and Research], which approves a drug as safe an effective.” In other words, ASCO evaluated MammaPrint strictly on its data quality and the design of the clinical studies that generated that data. “In some of those studies, some patients were treated with systemic therapy and some were not,” Hayes says. “In the so-called ‘validation study,’ GENESEARCH BREAST PROGNOSTIC ASSAY The 76-gene microarray-based Rotterdam Signature was developed at the Daniel den Hoed Cancer Center, Erasmus Medical Center, in Rotterdam. Not yet commercially available, the Rotterdam Signature is being developed by Veridex, a Johnson & Johnson company. “When we defined this 76-gene signature, we used retrospective patient cohorts who had received surgery alone, without adjuvant chemotherapy or hormonal therapy, because we wanted to define a pure prognostic test that can accurately and reliably determine the patients with low and high risk of disease recurrence,” says Yixin Wang, PhD, executive director of research and development at Veridex, in Warren, N.J., and an early colTumor marker research laborator with the Rotterdam and development efforts team. Veridex is developing the Rotterdam Signature under the • The Breast Cancer Intergroup is conname of GeneSearch Breast ducting a study to evaluate whether Prognostic Assay. women with mid-range Oncotype DX In a 2005 article in The Recurrence Scores benefit from Lancet, Wang and colleagues chemotherapy. reported that the 76-gene ex• According to Wang, at Veridex, a pression profile identified pamulti-center study validating the tients who went on to develop GeneSearch Breast Prognostic Assay in tamoxifen-treated ER-positive distant metastases within 5 patients has been completed but not years with 93 percent sensitivyet published. ity and 48 percent specificity. • Multiple study results presented at Multicenter validation studies December’s San Antonio Breast Canof the 76-gene signature also cer Symposium suggest that Oncoappeared in the Journal of type DX may be clinically useful for Clinical Oncology and Clinical certain node-positive patients treated Cancer Research. with chemohormonal therapy followed In a clear reference to Onby tamoxifen, and that estrogen recotype DX, a Veridex news receptor (ER) expression may be proglease announcing the 2005 nostic in ER-positive and ER-negative Lancet paper noted “currently patients. available tools are generally re• Genomic Health is working on genetic stricted to patients with a speexpression assays for colon, prostate, cific ER status, or to patients renal, and lung cancers, along with already taking tamoxifen.” melanoma. That may not be the only pothey actually used a percentage of the samples from their development set.” Hayes also is cautious about microarray-based gene expression signatures, but for a different reason than Simon. “Oncotype DX was developed not with microarrays but with RTPCR,” Hayes explains. “One reason that’s important is that there is concern that those arrays have not been technically validated in regard to reproducibility. I have not seen a paper showing that you can take the same sample and get the same result three times, although FDA clearance suggests that these data must have been generated.” 40 BIOTECHNOLOGY HEALTHCARE · MAY/JUNE 2008
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