Correlation of Oncotype DX Recurrence Score with Cyclin D1 and ErbB2.
Authors: Misra D. , Adelson K. , Halpern M. , Jaffer S. , Nagi C. , Bleiweiss I. , Mandeli J. , Raptis G. , Germain D. 
Published: December 2010

Background: The Oncotype DX assay predicts the risk of recurrence in patients with stage I-II ER+, node negative breast cancer treated with tamoxifen. It is not understood if the Oncotype DX assay predicts the natural aggressiveness of an individual breast cancer or if it identifies a subtype of tamoxifen resistant breast cancer. In clinical practice, a high recurrence score (RS) on Oncotype DX is interpreted as a more aggressive tumor and is used to justify the use of chemotherapy. However, if the RS was actually predictive of tamoxifen resistance, patients may benefit from the use of an aromatase inhibitor, and chemotherapy may be unnecessary. Cyclin D1 and ErbB2 are two biomarkers shown to predict tamoxifen resistance.Cyclin D1 is overexpressed in approximately 35% of breast cancers. The Austrian Breast and Colorectal Cancer Study Group assessed expression of Cyclin D1 in patients taking tamoxifen within the ABCSG trial 05 and ABCSG trial 06. In both trials, Cyclin D1 overexpression correlated with a lower relapse free survival and overall survival compared to patients without Cyclin D1 overexpression.Erb2 is overexpressed in 15-30% of breast cancers. In the Gruppo Universitario Napoletano 1 trial, ER+ patients with early stage node negative breast cancer who overexpressed ErbB2 had no improvement in progression free survival and overall survival with 2 years of adjuvant tamoxifen therapy. Additional retrospective studies have supported initial reports of an association between overexpression of ErbB2 and tamoxifen resistance.Methods: 69 patients who had the Oncotype DX assay performed and had unstained pathology slides available were assessed for ErbB2 and Cyclin D1 expression. ErbB2 overexpression status was also obtained in another 74 patients who had the Oncotype DX assay performed. ErbB2 overexpression was determined from a review of medical records where ErbB2 was defined as being positive if immunohistochemical (IHC) staining intensity was 3+ with &gt;90% of cells expressing ErbB2 or FISH revealed an amplification of &gt;2.0. IHC analysis of Cyclin D1 was performed according to standard protocol and using commercially available antibodies. Scoring of slides for Cyclin D1 staining were performed by blinded pathologists who assessed both extent and intensity of nuclear staining for Cyclin D1.Results: The median Oncotype Dx RS within ErbB2+ patients was significantly higher than ErbB2- patients (36.5 vs. 18 p&lt;0.0001), and approximately 50% of patients within each RS grouping (high, intermediate, and low) overexpressed cyclin D1.Conclusion: ErbB2 overexpression among high RS patients suggests the Oncotype DX assay may predict tamoxifen resistance and other markers for tamoxifen resistance need to be correlated with the RS. Although preliminary analysis of the IHC staining for Cyclin D1 does not correlate with a high RS, high Cyclin D1 expression among patients within the low RS subgroup is concerning since this subgroup may have an increased likelihood of disease relapse when treated with adjuvant tamoxifen alone.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3035.