Abstract 4591: Estrogen receptor-positive breast cancer: from genomic landscape to treatment approach
Authors: De Pradip , Williams Casey , Krie Amy , Williams Kirstin , Klein Jessica , Carlson Jennifer H. , Dey Nandini , Leyland-Jones Brian 
Published: July 2016

Background: Estrogen receptor (ER)-positive or luminal breast tumors represent around two-thirds of all breast cancers. Luminal breast cancer is a highly heterogeneous disease comprising different histologies, gene-expression profiles and mutational patterns, with very diverse clinical courses and responses to systemic treatment. Despite adjuvant endocrine therapy and chemotherapy treatment for patients at high risk of relapse, both early and late relapses still occur, a fact that highlights the unmet medical needs of these patients. A catalogue of molecular aberrations in ER+ breast cancer (BC) is critical for developing and deploying therapies that will improve patients’ lives. Methods: Comprehensive genomic profiling from 128 BC patients (February 2014 through October, 2015) were analyzed. Patients were biopsied after consultation and samples were characterized (ER, PR, and HER2 by IHC; FFPE samples for genomic [Foundation One] and proteomic analyses [Theranostics]). We also evaluated mutation distribution in cell free DNA via digital NGS using Guardant 360 panel. Results: Total 97 genes were altered in 83 ER+BC patients and most frequent genetic alterations are PIK3CA (40%), p53 (27.7%) and CCND1 (24%). The PI3K-AKT pathway specific genes (AK1, AKT2, PIK3CA, PIK3CB, PIK3R1, PTEN, MTOR, RICTOR, RAPTOR, TSC2, STK11, MDM2 and MDM4) were altered in 80% of patients. Analyzing the composite alterations in individual ER+BC patients, we observed that 20% of patients had alterations in two or more nodes of the PI3K pathway while alterations of cell cycle pathway genes (CCND1, CCNE1, CDK4, CDKN1B, CDKN2A/B and RB1) were observed in 36% of patients. Interestingly, concurrent alterations of both PI3K and cell cycle pathways were 24%. Hence we tested the anti-tumor efficacy of the combination of isoform-specific PI3K inhibitor (alpha or beta) and LEE011 using ER+ BC cell lines (PIK3CA mutated MCF7, T47D, & PTEN-null MDA-MB415 cells) based model. Data show a synergistic effect of PI3K alpha or beta inhibitor and CDK4/6 inhibitor as determined from the changes in proliferative and apoptotic signals as well as cell cycle arrest. Conclusion: Since a persistent expression of the CDK4-Cyclin D1 pathway activation enables tumor cells survival even in the presence of PI3K inhibitor (Cancer Cell 2014), results of our study demonstrated that the anti-tumor effect of isoform-specific PI3Ki and CDK4/6i be beneficial in RB wt ER+BC patients with a concurrent genetic alterations of these pathways.

Citation Format: Pradip De, Casey Williams, Amy Krie, Kirstin Williams, Jessica Klein, Jennifer H. Carlson, Nandini Dey, Brian Leyland-Jones. Estrogen receptor-positive breast cancer: from genomic landscape to treatment approach. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4591.