Proliferation-, estrogen-, and T-cell-related metagenes to predict outcome after adjuvant/neoadjuvant chemotherapy for operable breast cancer in the ECTO trial.

Abstract

1014 Background: Predicting recurrence in operable breast cancer (BC) despite optimal chemotherapy would be relevant to new drug development and tailored treatments. Methods: A large series (n=3,154) of public Affymetrix gene-expression profiles (GEP) was used to define prognostic/predictive metagenes in different BC subtypes. In ER+/HER2- a proliferation and an ER-related metagene were combined to predict low, intermediate and high risk of recurrence. In TN and in HER2+ a T cell metagene was used to predict low, intermediate and high risk (higher expression associated with lower risk). The metagenes were validated in patients enrolled in the phase III ECTO trial (Gianni L. JCO 2009) and treated with the same taxane-anthracycline-CMF regimen as neoadjuvant or adjuvant therapy before endocrine therapy if indicated. The outcome was distant event free survival (DEFS). Results: 283 good quality GEPs were obtained (neoadjuvant n=121; adjuvant n=162) from 464 retrospectively collected samples. Median follow-up was 8.9 years. In ER+/HER2- tumors the 10-yrs DEFS was 92.3, 81.2 and 66.6% in low, intermediate and high risk groups, respectively [high vs low HR 4.38 (1.01-19.1) p=.048] according to proliferation and ER-related metagenes. In HER2+ and TN subgroup the 10-yrs DEFS was 97.2, 75.6 and 78.8% in low, intermediate and high risk groups, respectively [high vs low HR 8.73 (1.09-69.8) p=.041]. In TN tumors, the pCR rate was 20% in the high and 61.5% in the low risk group. By combining the predicted risk group in each molecular subtype the 10-yrs DEFS was 95.3, 79.2 and 71.5% in low (24.2%), intermediate (42.7%) and high (33.1%) risk group, respectively [logrank p=0.003; high vs low HR 6.22 (1.87-20.6) p=.002]. ER, PGR, Ki67 and lymphocyte infiltration (LI) by IHC underperformed compared to genomic predictors. Conclusions: BC patients at higher risk of relapse despite optimal standard treatment can be identified who should be spared ineffective and toxic therapy and considered for investigational new strategies. In TN and HER2+, high T cell metagene and to a lesser extent LI are prognostic/predictive and associated with an extremely low risk of DEFS after chemotherapy.