12O_PR Independent Blinded Validation of the Genomic Index of Sensitivity to Endocrine Therapy (Set)

Abstract

ABSTRACT Background The SET index of ER-related transcription has been reported to predict survival benefit from adjuvant endocrine therapy independently of prognosis (Symmans et al. 2010; J Clin Oncol 28:4111). Materials and methods We set up a blinded study to prospectively validate SET index’ ability to predict survival in an unpublished retrospective cohort of 307 ER positive primary breast cancers treated solely with endocrine therapy. Affymetrix profiles (CEL files) were anonymized and provided to the developers of SET (Nuvera Biosciences) without any clinical information. The 261 profiles that passed QC were categorized into SET classes based on the published prespecified cutoffs. Subsequently classifications were unblinded and clinical associations analyzed according to a predefined protocol. Exploratory analyses were performed on the relationship of SET to other genomic signatures. Results Age, tumor size, lymph node, and HER2 status were not significantly different between patients with high, intermediate, and low SET. However, lower SET significantly correlated with higher grade (P = 0.009) and negative PgR status (P = 0.016). In the lymph node negative (LNN) cohort (n = 120) we observed a significant difference in DFS (5yr DFS 77.1 ± 10.2% vs 94.4 ± 2.2%; HR 4.20, 95% CI 1.72-10.2; P = 0.002) and DMFS (HR 3.18, 95% CI 1.20-8.47; P = 0.020) for patients with low SET. We found no prognostic value of SET in lymph node positive patients (n = 95). In multivariate analyses of LNN patients including age, tumor size, and grade only SET was significantly associated with DFS (HR 3.97, 95% CI 1.54-10.20; P = 0.004) and DMFS (HR 3.03, 95% CI 1.08-8.55; P = 0.036). In exploratory analyses SET was not correlated to other genomic signatures related to proliferation (Recurrence Score, GGI, NKI70) or immune response and remained as best independent predictor in stepwise cox regression (P = 0.025). SET had no pure prognostic value in 164 additional ER positive patients that did not receive any adjuvant treatment. Conclusions The predictive ability of SET index was prospectively validated in an independent cohort of node-negative patients. Exploratory analysis suggested that SET is unrelated to other prognostic signatures. Disclosure C. Hatzis: Employment or Leadership Position: Nuvera Biosciences (Compensated) Stock Ownership: Nuvera Biosciences. W.F. Symmans: Consultant or Advisory Role: Nuvera Biosciences (Uncompensated). Stock Ownership: Nuvera Biosciences. All other authors have declared no conflicts of interest.