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Breast Cancer

Commercialized Multigene Predictors of Clinical Outcome for Breast Cancer

^aDepartment of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA; ^bNuvera Biosciences, Woburn, Massachusetts, USA; ^cDepartment of Pathology and ^dDepartment of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Key Words. Breast cancer • oncotype DX • MammaPrint • Rotterdam signature • Invasiveness signature • Two-gene expression ratio

Correspondence: Correspondence: Jeffrey S. Ross, M.D., Department of Pathology and Laboratory Medicine, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208, USA. Telephone: 518-262-5461; Fax: 518-262-3663; e-mail: rossj{at}mail.amc.edu

Received December 19, 2007; accepted for publication March 10, 2008.

Disclosure: C.H. is employed by, owns stock in, and discloses receipt of intellectual property rights/patent holder in Nuvera Biosciences (Nuvoselect). G.N.H. discloses that except for oncotype DX^TM and MammaPrint®, all predictors described in the article are investigational and the indications are evolving. L.P. is a founder and stockholder of Nuvera Biosciences (Nuvoselect test), has acted as a consultant for Roche, Dako, Bristol-Myers Squibb, and Pfizer, and discloses that the article discusses the Affymetrix U133 GeneChip® System (Affymetrix Corporation) for potential use as a diagnostic test. W.F.S. has ownership and intellectual property in Nuvera BioSciences (Nuvoselect test) and he discloses that the article discusses prognostic/predictive genomic signatures by Genomic Health, Inc, Agendia, and Nuvera Biosciences for breast cancer diagnostics.

In the past 5 years, a number of commercialized multigene prognostic and predictive tests have entered the complex and expanding landscape of breast cancer companion diagnostics. These tests have used a variety of formats ranging from the familiar slide-based assays of immunohistochemistry and fluorescence in situ hybridization to the nonmorphology-driven molecular platforms of quantitative multiplex real-time polymerase chain reaction and genomic microarray profiling. In this review, 14 multigene assays are evaluated as to their scientific validation, current clinical utility, regulatory approval status, and estimated cost–benefit ratio. Emphasis is placed on two tests: oncotype DX^TM and MammaPrint®. Current evidence indicates that the oncotype DX^TM test has the advantages of earlier commercial launch, wide acceptance for payment by third-party payors in the U.S., ease of use of formalin-fixed paraffin-embedded tissues, recent listing by the American Society of Clinical Oncology Breast Cancer Tumor Markers Update Committee as recommended for use, continuous scoring system algorithm, ability to serve as both a prognostic test and predictive test for certain hormonal and chemotherapeutic agents, demonstrated cost-effectiveness in one published study, and a high accrual rate for the prospective validation clinical trial (Trial Assigning Individualized Options for Treatment). The MammaPrint® assay has the advantages of a 510(k) clearance by the U.S. Food and Drug Administration, a larger gene number, which may enhance further utility, and a potentially wider patient eligibility, including lymph node–positive, estrogen receptor (ER)-negative, and younger patients being accrued into the prospective trial (Microarray in Node-Negative Disease May Avoid Chemotherapy). A number of other assays have specific predictive goals that are most often focused on the efficacy of tamoxifen in ER-positive patients, such as the two-gene ratio test and the cytochrome P450 CYP2D6 genotyping assay.