Abstract P2-10-17: SET index predicts response to endocrine therapy rather than prognosis independently of other genomic signatures in a blinded validation study.
Authors: Karn T , Hatzis C , Symmans F , Pusztai L , Ruckhäberle E , Schmidt M , Müller V , Hanker L , Heinrich T , Holtrich U , Kaufmann M , Rody A 
Published: August 2014

Background: A genomic index for sensitivity to endocrine therapy (SET) was previously derived from genes strongly positively and negatively coexpressed with estrogen receptor (Symmans et al. 2010, JCO 28:4111). This SET index has been reported to predict survival benefit from adjuvant endocrine therapy independently of prognosis.

Materials and Methods: Affymetrix gene expression profiling was performed on 307 ER positive primary breast cancers from a retrospective cohort treated solely with endocrine therapy. In a blinded study the SET index' ability to predict survival was analyzed in this previously unpublished dataset. Affymetrix profiles (CEL files) were anonymized and provided to the developers of SET index (Nuvera Biosciences) without any clinical information. The 261 profiles that passed QC were categorized into SET classes based on the published prespecified cutoffs. Samples categorized as ER negative based on gene expression were excluded. Subsequently classifications were unblinded and clinical associations analyzed according to a predefined protocol. Exploratory analyses were performed on the relationship of SET index to other genomic signatures. We also assessed a potential pure prognostic value of SET index in an additional dataset of 164 node negative ER positive patients that did not receive any adjuvant treatment.

Results: A lower SET index significantly correlated with higher grade (p = 0.009) and negative PgR status (p = 0.016). We detected no significant differences for age, tumor size, lymph node status, and HER2 status between patients with high, intermediate, and low SET index. 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 index. In contrast, we found no prognostic value of SET index in lymph node positive patients (n = 95). In multivariate analyses of LNN patients including SET, age, tumor size, histological grade, and PgR status, only SET was significantly associated with DFS (HR 3.37, 95% CI 1.25–9.01; p = 0.016) and DMFS (HR 3.03, 95% CI 1.08–8.55; p = 0.036). In exploratory analyses SET index was not correlated to other genomic signatures related to proliferation (as Recurrence Score, GGI, and NKI70) or immune response (e.g. 7IGS, SDPP). When we included all these genomic signatures as continous scores in a multivariate stepwise Cox regression model in the LNN endocrine treated cohort, only SET remained as significant (p = 0.025) while Recurrence Score displayed a strong trend (p = 0.054). We also verified that SET had no pure prognostic value in an additional dataset of 164 ER positive patients that did not receive any adjuvant treatment.

Conclusions: In a blinded analysis the predictive ability of SET index was prospectively validated in an independent cohort of node-negative patients. Our exploratory analysis demonstrates that SET index is unrelated to other genomic signatures and delivers independent information on the response of patients to endocrine therapy rather than prognosis.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-17.