Abstract S1-01: TransCONFIRM: The correlative analysis of breast tumors from patients with advanced hormone receptor positive disease identifies a genetic signature associated with decreased benefit from single agent fulvestrant
Authors: Jeselsohn Rinath M , Barry William T , Zhao Jin , Buchwalter Gilles , Guarducci Cristina , Migliaccio Ilenia , Biagioni Chiara , Bonechi Martina , Laing Naomi , Rukazenkov Yuri , Winer Eric P , Brown Myles , Di Leo Angelo , Malorni Luca 
Published: May 2015

Abstract
Introduction: Several multi-gene expression based assays have been developed to assess the prognosis and predict response to endocrine treatments in early stage hormone receptor positive (HR+) breast cancer. Although a significant number of patients with metastatic ER+ disease will not respond to endocrine treatments, molecular assays to predict response in this setting are limited. In addition, tissue specimens of metastatic lesions for molecular studies are not always available. In this study we sought to identify a molecular profile in the primary tumors of patients who developed disease recurrence that could predict response to endocrine treatment in metastatic disease.
Methods: We used the primary breast tumor samples from a subgroup of patients participating in the randomized phase III CONFIRM trial, which compared 500mg versus 250mg of fulvestrant in post-menopausal women with HR+ advanced breast cancer. Formalin- fixed paraffin embedded tumors were collected from 130 of the participants and were centrally reviewed for ER, PR, HER2 and Ki67. RNA was sufficient for gene expression profiling in 112 of the cases using the NuGEN Ovation FFPE WTA System and Affymetrix HTA 2.0 GeneChip. The majority of the patients in this analysis developed metastatic disease during adjuvant endocrine treatment (N=55) or had de-novo metastatic disease (N=39) versus relapse after adjuvant treatment (N=18). The association between gene expression and progression free survival (PFS) was investigated using a multivariate Cox proportional hazard model adjusting for statistically significant clinicopatholgical factors. In addition we performed pathway-level analysis and evaluated the PAM50 subtype predictor and Risk of Relapse (ROR) score.
Results: The median PFS was 8 months in our cohort. HER2 level by immunohistochemistry above 1+, high PR level, defined as Allred score of above 6, and Ki67 of above 50% were significantly associated with PFS and were included in the multivariate model. Dose of fulvestrant was not associated with PFS in this cohort. We identified a signature of 25 genes that is inversely associated with PFS on fulvestrant treatment (FDR 20%). When compared to other published datasets of breast cancer tumors, these genes are enriched in tumors with poor outcome and triple negative cancers. Pathway analysis revealed an association between activation of the EGFR pathway and decreased PFS (P=0.01). PAM50 subtypes varied with the luminal subtype being the most common (65%) and were generally concordant with the clinical subtype. However, we did not detect a significant trend between PAM50 subtype or ROR score and PFS or overall survival.
Conclusions: In this cohort of patients with early and de-novo metastatic disease we identified a gene signature in the primary tumors that is associated with decreased response to fulvestrant treatment in metastatic disease. This signature warrants further validation to determine it’s predictive value and potential to assist in treatment decision making for patients with HR+ metastatic disease.
Citation Format: Rinath M Jeselsohn, William T Barry, Jin Zhao, Gilles Buchwalter, Cristina Guarducci, Ilenia Migliaccio, Chiara Biagioni, Martina Bonechi, Naomi Laing, Yuri Rukazenkov, Eric P Winer, Myles Brown, Angelo Di Leo, Luca Malorni. TransCONFIRM: The correlative analysis of breast tumors from patients with advanced hormone receptor positive disease identifies a genetic signature associated with decreased benefit from single agent fulvestrant [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S1-01.