MammaPrint™ 70-gene Signature: Another Milestone in Personalized Medical Care for Breast Cancer Patients

Elzbieta A. Slodkowska; Jeffrey S. Ross


Expert Rev Mol Diagn. 2009;9(5):417-422. 

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The MammaPrint™ assay (Agendia BV, The Netherlands; and Agendia, Inc., CA, USA) was the first fully commercialized multivariate predictive test to employ a microarray-based multigene assay to determine the risk of relapse for newly diagnosed breast cancer patients. The 70 genes that comprise the MammaPrint assay are focused primarily on proliferation, with additional genes associated with invasion, metastasis, stromal integrity and angiogenesis. This test is currently designed as a pure prognostic assay and has received 510(k) clearance from the US FDA. It is offered as a prognostic test for women under the age of 61 years with either estrogen receptor (ER)-positive or ER-negative, lymph node-negative breast cancer. The test was also the first assay to be approved by the FDA's in vitro diagnostic multivariate index assay (IVDMIA) classification.[101] This test cannot currently be performed on formalin-fixed, paraffin-embedded tissues and requires either freshly frozen tumor samples or tissues collected into an RNA preservative solution. The test has been marketed in the USA since early 2008. To date, Agendia BV, Inc. reports on its website that more than 12,000 MammaPrint tests have been performed.[102]

MammaPrint was originally developed at The Netherlands Cancer Institute in Amsterdam using the Rosetta Inpharmatics DNA microarray system (Merck and Co., NJ, USA) and then commercialized on the Agilent microarray platform (Agilent Technologies, DE, USA). The 70-gene signature was derived originally from a set of 231 genes that were differentially expressed in tumors that metastasized versus those that did not and identified by gene expression profiling on 78 patients less than 55 years of age with sporadic, lymph node-negative breast cancer. Patients were divided into a good prognosis group (n = 44; disease free after 5 years) and a poor prognosis group (n = 34; metastatic disease within 5 years). The odds ratio for patients in the poor prognostic group to develop metastatic disease was 15 (95% CI: 4–56; p < 0·0001), which was higher than that for other clinicopathological prognostic factors.

The signature was also found in a multivariate analysis to be an independent prognostic factor.[11] It is offered as a centralized assay for lymph node-negative patients independent of hormone receptor status in Europe where the extracted mRNA from primary breast cancers is shipped for the custom microarray profiling. The test results are dichotomous, with reports indicating either a high or low risk of disease recurrence. MammaPrint results are reported dichotomously as either low or high risk. When the assay is low risk the likelihood that the patient will progress to metastatic disease is low. However, for high-risk patients, the prediction of metastatis progression is not nearly as accurate in that, at 5 years, only approximately 25% of these high-risk patients will actually progress. It should also be noted that most hormone receptor-negative breast cancers score a high risk on the MammaPrint assay. The sensitivity in predicting 10-year cancer death was comparable with that of Adjuvant! Online (0.84 vs 0.82), while specificity was significantly higher (0.42 vs 0.29 by Adjuvant! Online), reflecting the potential of MammaPrint for the detection of patients with a good prognosis who appear unlikely to benefit from potentially cytotoxic chemotherapy.[12] It is being further investigated if the assay can also predict sensitivity to various treatment modalities. The list price of the test in the USA is US$4250 and €2675.

In addition, in late 2008, Agendia BV announced the launch of a companion assay, TargetPrint™, which measures the gene-expression levels of the ER, progesterone receptor (PR) and HER2 in freshly preserved breast cancer tumor biopsies. The TargetPrint assay determines the ER, PR and HER2 mRNA levels using eight subarrays on Agendia's new High-Density Microarray Chip. The TargetPrint assay has been validated against FDA-approved immunohistochemistry assays, but has not itself been cleared by the FDA. The Agilent High Density Microarray Chip itself received FDA clearance in August 2008.


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