Abstract No. 
2010 San Antonio Breast Cancer Symposium‐
December 8-12

A Genomic Predictor of Survival Following Taxane-Anthracycline Chemotherapy for Breast Cancer

Symmans WF, Hatzis C, Valero V, Booser DJ, Esserman L, Martin M, Vidaurre T, Holmes F, Souchon EA, Lluch A, Cotrina J, Gomez H, Hubbard R, Ferrer-Lozano, J, Dyer, R

Background: There is currently no predictive assay for patients with clinical Stage II-III breast cancer from which predicted sensitivity to treatment is associated with high probability of survival following chemotherapy.

Patients & Methods: We performed Affymetrix gene expression microarrays of prospectively collected tumor biopsies from 508 patients with newly diagnosed HER2-normal invasive breast cancer prior to neoadjuvant taxane-anthracycline chemotherapy followed by adjuvant endocrine therapy (if hormone receptor-positive). The predictor was developed from 310 samples (from MDACC & I-SPY) by combining: 1) a signature to predict sensitivity to endocrine therapy (SET); 2) estrogen receptor (ER)-stratified predictive signatures of resistance to chemotherapy, defined as extensive residual cancer burden (RCB-III) or relapse within 3 years; and 3) ER-stratified predictive signatures of response to chemotherapy, defined as pathologic complete response (pCR) or minimal RCB (RCB-I). The predictor classified tumors as treatment sensitive if high or intermediate SET, or if predicted to be responsive (and not resistant) to chemotherapy. Otherwise, tumors were classified as treatment insensitive. The predictor was then tested on an independent cohort (N= 198, 98% with clinical Stage II-III) who received neoadjuvant (N= 180) or adjuvant (N= 18) taxane-anthracycline chemotherapy (from MDACC, USO, GEICAM, Peru, LBJ). Distant relapse-free survival (DRFS) was evaluated at a 3-year median follow up using negative predictive value (NPV, absence of event if predicted to be sensitive), and absolute risk reduction (ARR) for those predicted to be sensitive (versus insensitive), with 95% confidence interval (CI). The independent predictive value was assessed in multivariate Cox regression analysis based on the likelihood ratio test (P≥0.05). Results: Patients in the independent validation cohort who were predicted to be treatment sensitive (28%) had excellent DRFS, with NPV 92% (CI 85-100) and significant absolute risk reduction (ARR 18%, CI 6-28) at 3 years, compared to those predicted to be insensitive. This was similar to the DRFS observed in patients who achieved pCR after they completed neoadjuvant chemotherapy (NPV 93%, CI 85-100). Predictions were accurate in each phenotypic subset: ER+/HER2- (30% predicted sensitive, NPV 97%, CI 91-100; ARR 11%, CI 0.1-21) and ER-/HER2- (26% predicted sensitive, NPV 83%, CI 68-100; ARR 26%, CI 4-28). Predicted treatment sensitivity (HR 0.20, CI 0.07-0.57), ER+ status (HR 0.32, CI 0.17-0.63), clinical tumor stage T3-4 (HR 2.04, CI 1.07-3.88) and age >50 (HR 0.50, CI 0.25-0.98) were significant in a multivariate model that also included clinical nodal status, grade, and type of taxane used.

Conclusion: We report validation results for the first molecular predictor of sensitivity to neoadjuvant/adjuvant systemic therapy for clinical Stage II-III breast cancer that is independently associated with excellent DRFS in those predicted to be sensitive. Predictions were accurate for both ER+/HER2- and ER-/HER2- invasive breast cancer.

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