Abstract 1209: Next generation sequencing demonstrates multiple gene amplifications and mutations in 3 patients with estrogen receptor-positive breast cancer with responses to treatment with combination aromatase and PI3K/AKT/mTOR pathway inhibition

Background: Gene amplifications in breast cancer may indicate poor prognosis disease, particularly for patients with multiple amplifications. Endocrine response and resistance in breast cancer maybe revealed to PI3K/AKT/mTOR pathway activation. Patients and Methods: We analyzed tissue with next generation sequencing (NGS) from 3 patients with estrogen receptor (ER)-positive breast cancer treated on a dose escalation study with anastrozole, an aromatase inhibitor, and everolimus, an mTOR inhibitor. Genomic libraries were captured for 3230 exons in 182 cancer related genes plus 37 introns from 14 genes, often rearranged in cancer (Foundation Medicine, Cambridge, MA). Results: Twelve of 50 evaluable patients with ER-positive breast and gynecologic tumors treated with anastrozole (1mg PO daily) and everolimus (either 5mg PO daily or 10mg PO daily) had SD ≥ 6 months/PR/CR. NGS analysis on 3 of the 12 patients tumors demonstrated multiple amplifications, including: CCND1, CCNE1, FGFR1, MYC, IRS2 and MCL1. One patient had a complete response (CR) and two patients achieved partial responses (PR) with an 80% decrease in disease in one patient and a 38% decrease in disease in the other. All 3 patients had ER-positive breast cancer and previously experienced progression of disease while receiving hormone therapy. These amplifications seen have all been linked to hormone therapy resistance in ER-positive breast cancers. Two of these patients also had direct alterations in the PI3K/AKT/mTOR pathway: PIK3CA and PIK3R1 mutations in one patient and PTEN loss in another. Conclusions: Molecular profiling of 3 patients with ER-positive breast cancer with PR/CR on treatment with anastrozole/everolimus revealed multiple genetic alterations. Among these alterations were amplifications that may be associated with resistance to hormone therapies. Further exploration of combination hormonal therapies and correlative molecular profiling is warranted. Citation Format: Ralph Zinner, Johnique T. Atkins, Filip Janku, Stacy Moulder, Phil Stephens, Roman Yelensky, Robert Wolff, Razelle Kurzrock, Jennifer J. Wheler. Next generation sequencing demonstrates multiple gene amplifications and mutations in 3 patients with estrogen receptor-positive breast cancer with responses to treatment with combination aromatase and PI3K/AKT/mTOR pathway inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philade