Abstract
BackgroundThe presence of multiple molecular aberrations in patients with breast cancer may correlate with worse outcomes.Case PresentationsWe performed in-depth molecular analysis of patients with estrogen receptor-positive, HER2-negative, hormone therapy-refractory breast cancer, who achieved partial or complete responses when treated with anastrozole and everolimus. Tumors were analyzed using a targeted next generation sequencing (NGS) assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. Patients received anastrozole (1 mg PO daily) and everolimus (5 or 10 mg PO daily). Thirty-two patients with breast cancer were treated on study and 5 (16 %) achieved a partial or complete response. Primary breast tissue was available for NGS testing in three of the responders (partial response with progression free survival of 11 and 14 months, respectively; complete response with progression free survival of 9+ months). The following molecular aberrations were observed: PTEN loss by immunohistochemistry, CCDN1 and FGFR1 amplifications, and PRKDC re-arrangement (NGS) (patient #1); PIK3CA and PIK3R1 mutations, and CCDN1, FGFR1, MYC amplifications (patient #2); TP53 mutation, CCNE1, IRS2 and MCL1 amplifications (patient #3). Some (but not all) of these aberrations converge on the PI3K/AKT/mTOR pathway, perhaps accounting for response.ConclusionsPatients with estrogen receptor-positive breast cancer can achieve significant responses on a combination of anastrozole and everolimus, even in the presence of multiple molecular aberrations. Further study of next generation sequencing-profiled tumors for convergence and resistance pathways is warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1439-y) contains supplementary material, which is available to authorized users.
Highlights
IntroductionThe presence of multiple molecular aberrations in patients with breast cancer may correlate with worse outcomes
The presence of multiple molecular aberrations in patients with breast cancer may correlate with worse outcomes.Case Presentations: We performed in-depth molecular analysis of patients with estrogen receptor-positive, HER2negative, hormone therapy-refractory breast cancer, who achieved partial or complete responses when treated with anastrozole and everolimus
We present an in-depth analysis of three patients with advanced, refractory breast cancer who attained remarkable responses despite the fact that their tumors harbored multiple gene alterations (Additional file 1: Table S1)
Summary
The presence of multiple molecular aberrations in patients with breast cancer may correlate with worse outcomes. Case Presentations: We performed in-depth molecular analysis of patients with estrogen receptor-positive, HER2negative, hormone therapy-refractory breast cancer, who achieved partial or complete responses when treated with anastrozole and everolimus. Thirty-two patients with breast cancer were treated on study and 5 (16 %) achieved a partial or complete response. Case Presentations At the time of analysis, 32 patients with advanced breast cancer were treated with anastrozole and everolimus, Wheler et al BMC Cancer (2015) 15:442 and five attained PR or CR with PFS of at least nine months [12]. In depth analysis was performed using NGS on three responders with available tissue (number of prior therapies = 2, 4, and 7, respectively, in the metastatic setting) (Table 1)
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