Abstract S2-4: Final Results of a Prospectively Planned Biomarker Analysis: HER1-3 as Predictive Markers of Benefit from Early Treatment with Aromatase Inhibitors Versus Tamoxifen in the TEAM Pathology Sub-Study.

Abstract

Abstract Background: The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial included prospectively planned biomarker studies to identify predictive biomarkers for patients receiving endocrine therapy. Quantitative IHC data for ER/PgR, HER1, HER2, HER3 and FISH analysis of HER2 in all cases was available for the current analysis relative to outcome of estrogen receptor-positive (ER+) early breast cancer patients treated with exemestane versus tamoxifen. Patients & Methods: Pathology blocks from 4598 TEAM patients were collected and tissue microarrays constructed. Quantitative analysis of receptors (HER1/2/3) by conventional IHC, and FISH (for HER2 only) were analysed relative to disease-free survival and treatment on an intent to treat basis using survival data for the first 2.75 years of the TEAM trial. Results: Of 4595 eligible cases samples received, 16 were excluded, and 4010 had complete biomarker data for all markers (HER1/HER2 & HER3) for the final biomarker analysis, 3.5% were HER1 positive, 13% HER2 positive & 21% HER3 positive. 1248 (31%) cases were HER1or2or3 positive (HER1-3+ve). HER1-3 positivity was associated with poor outcome (HR=1.6 95%CI=1.3-2.0). In HER1-3 negative patients the hazard ratio (for risk of relapse on exemestane versus tamoxifen in the first 2.75 years) was 0.68 (95% CI = 0.52-0.89), for the HER1-3 positive cases the hazard ratio was 1.14 (95% CI = 0.83-1.56) with a significant treatment by marker interaction (HR=1.68 95%CI=1.1-2.5; p=0.0014 in multivariate analysis). Trends for similar effects were seen for HER1 negative (-ve) vs HER1 positive (+ve) (HRs 0.80, 95%CI=0.65-0.99 vs 1.63 95%CI=0.74-3.59), HER2-ve vs HER2+ve (HRs 0.71, 95%CI=0.57- 0.9 vs 1.69 95%CI=108-2.63) and HER3-ve vs HER3+ve (HRs 0.78 95%CI=0.62-0.99 vs 1.04 95%CI=0.67-1.62) breast cancers. Conclusion: Preferential exemestane versus tamoxifen treatment benefit was seen in HER1/2/3 negative cases, whilst HER1/2/3 positive cases had a poor prognosis in this endocrine treated population (suggesting a degree of resistance to endocrine therapy), and no evidence of additional benefit from AIs versus tamoxifen. These three Type I receptor tyrosine kinases appear to identify breast cancers with relative resistance to all forms of endocrine therapy. This prospectively planned and powered treatment by marker analysis provides high level scientific evidence which may assist clinicians and patients in determining optimal AI schedules for women with early breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S2-4.