Abstract 3942: Evolution of genomic alterations in breast tumors
Authors: Gaba Anu G. , Landsverk Megan , Weiss Jennifer L. , Thompson Paul , Chan Chun-Hung , Powell Steven F. , Black Lora J. , Ford James M. 
Published: July 2017

Abstract
Cancer therapy exerts a strong selection pressure that shapes tumor evolution. Recent studies have demonstrated high rates of concordance between primary tumor and recurrences. The main objective of our study was to demonstrate the molecular evolution of breast cancer using next-generation sequencing (NGS) across various time points during treatment.
Methods: We conducted a retrospective analysis of 3 patients with metastatic breast cancer. Specimens from patients undergoing 1 or more lines of treatment in the metastatic setting (met2) were tested using Foundation One, evaluating 343 genes and select rearrangements by NGS. Archival tumor specimens from primary and first metastases (met1) were subsequently obtained and tested using the same assay. Each sample was analyzed independently at the time of submission over a period of two years and results were compared across all time points.
Results: Functional variants in patient 1 were concordant at all time points. Patient 2 was hormonal receptor positive and Her-2 negative at diagnosis and at met1 and 2. A known variant in PIK3CA was detected at all three time points. She developed an EGFR variant of unknown significance (VUS) at met1 which was retained in met2 where she also gained a variant in ESR1, coinciding with development of resistance to hormonal therapy. Patient 3 was triple negative at diagnosis and at repeat analysis. A known PIK3CA variant was also detected at all time points. Her primary tumor sample was positive for an amplification of RUNX1T1 which was not detected at met1 or 2. At met1 she developed an amplification of CCNE1 which persisted through met2 in which an ERBB3 variant also arose. Additional discordances in all three patients were due to technical or interpretive differences at the time of analysis. All three patients had VUSs reported in primary and met1 time points that were not present at met2. However, expanded gene bait set was implemented between the submission of met2 samples and the primary and met1 samples. Therefore, full concordance of all genes across all samples could not be determined. Patient 2 had a variant in CHD1 initially classified to have therapeutic implications based on literature and databases at the time of analysis. More recent data indicated that it was likely a benign germline variant and was downgraded to a VUS in subsequent reports. Classification of ROS1 amplification as significant or a VUS also varied.
Conclusion: In our samples, the majority of genomic alterations showed concordance throughout the course of breast cancer. There are key actionable genes which make their presence later on in the metastatic setting. Repeat tumor assessment by methods such as biopsies or ctDNA should be a part of breast cancer management as it may lead to changes in therapy. However, since the methodology and classification of variants may change over time, reanalysis of all data at each time point is warranted. We have initiated a prospective larger trial to study the spectrum of breast cancer evolution.
Citation Format: Anu G. Gaba, Megan Landsverk, Jennifer L. Weiss, Paul Thompson, Chun-Hung Chan, Steven F. Powell, Lora J. Black, James M. Ford. Evolution of genomic alterations in breast tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3942. doi:10.1158/1538-7445.AM2017-3942