Prognostic and Predictive Value of the 21-Gene Recurrence Score Assay in Postmenopausal Women with Node-Positive, Estrogen- Receptor-Positive Breast Cancer.

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Prognostic and Predictive Value of the 21-Gene Recurrence Score Assay in Postmenopausal Women with Node-Positive, Estrogen- Receptor-Positive Breast Cancer on Chemotherapy: A Retrospective Analysis of a Randomised Trial Albain KS et al. Lancet Oncol 2010;11(1):55-65. San Antonio Breast Cancer Symposium 2009;Abstract 112.

Introduction A low 21-gene recurrence score (RS) in postmenopausal patients with ER-positive, node-negative breast cancer predicts a lack of benefit from the addition of chemotherapy to tamoxifen (T) treatment (JCO 2006;24:3726). The value of the 21-gene recurrence score assay in patients with ER-positive, node-positive breast cancer that are treated with T alone is unknown. Current study objectives: Assess prognostic value of the 21-gene recurrence score in patients with node-positive breast cancer treated only with T. Assess whether 21-gene recurrence assay allows for the prediction of a node-positive subset of patients who do not benefit from anthracycline-based chemotherapy. Albain KS et al. Lancet Oncol 2010;11(1):55-65.

SWOG-8814: Parent Trial Schema Tamoxifen (T) Tamoxifen 20 mg PO QD x 5 yrs Eligibility (n=1,477) Postmenopausal ER or PR positive Axillary lymph node positive R CAF-T CAF x 6 Cycles  T x 20 mg PO QD x 5 yrs CAFT* CAF x 6 Cycles Concurrent T 20 mg PO QD x 5 yrs CAF = Doxorubicin 30 mg/m2 day 1, day 8 Cyclophosphamide 100 mg/m2 PO days 1-14 5-FU 500 mg/m2 day 1, day 8; Cycle repeated q 28 days * Excluded from analysis due to inferior efficacy Albain KS et al. Lancet Oncol 2010;11(1):55-65.

SWOG-8814: Translational Study 1,477 patients randomly assigned to trial 664 tumor samples available from central banking 601 samples analyzed by RT PCR: 148 T alone; 219 CAF  T; 234 CAFT 367 final samples for this analysis (Tamoxifen and CAF-T groups only; CAFT group excluded due to inferior efficacy) Primary analysis: Cox regression model using continuous RS Secondary analysis: RS categories, low (<18), intermediate (18-30) and high (≥31) Albain KS et al. Lancet Oncol 2010;11(1):55-65.

Ten-Year Disease-Free Survival (DFS) and Overall Survival (OS) in Tamoxifen Alone Group RS Group 10-year DFS p-value* OS Low (<18) 60% 0.017 77% 0.003 Intermediate (18-30) 49% 68% High (≥31) 43% 51% *Log-rank p-value stratified according to the number of positive nodes (1-3 vs ≥4 positive nodes). Albain KS et al. Lancet Oncol 2010;11(1):55-65.

Hazard Ratio: Ten-Year DFS, T versus CAF-T Groups RS Group HR (95% CI) p-value* Low (<18) 1.02 (0.54-1.93) 0.97 Intermediate (18-30) 0.72 (0.39-1.31) 0.48 High (≥31) 0.59 (0.35-1.01) 0.033 Entire RS sample — 0.054 *Log-rank p-value stratified according to the number of positive nodes (1-3 vs ≥4 positive nodes); HR = hazard ratio. Albain KS et al. Lancet Oncol 2010;11(1):55-65.

Conclusions The RS is prognostic for patients with node-positive breast cancer treated with tamoxifen alone. A high RS score predicts an improved DFS in patients with node-positive breast cancer treated with anthracyline-based chemotherapy followed by tamoxifen compared to tamoxifen alone. A low RS score identifies women with node-positive breast cancer who may not benefit from the addition of anthracycline-based chemotherapy to tamoxifen treatment. Albain KS et al. Lancet Oncol 2010;11(1):55-65.

Conclusions (Continued) “Prospective studies with larger sample sizes are essential to establish who benefits most from modern endocrine therapy plus chemotherapy, and whether use of multigene assays affects survival.” - KS Albain Albain KS et al. Lancet Oncol 2010;11(1):55-65.

Fondazione Michelangelo Phase III Trial in HER2-Negative Conventionally High-Risk Patients (Node-Positive and/or T2-T3) Oncotype DX Recurrence Score Study One Higher risk (RS > 18) Study Two Lower risk (RS ≤ 18) R *Randomized by RS >11 vs ≤18 R * Ixabepilone  CMF FEC AT  CMF AT  CMF Endocrine therapy Endocrine therapy (if ER- and/or PR-positive) Gianni L. Personal Communication. December 2009; Gianni L. Presentation. Research To Practice Satellite Symposium, San Antonio Breast Cancer Symposium 2009; www.fondazionemichelangelo.org.