Abstract 1054: Genomic representation of metastatic breast cancer patients by commercially available cell lines
Authors: Nicoletti Rick , Shaw Pamela , Salimi Naghmeh , Agoston Agoston T. , Agoston Elin S. 
Published: August 2018

We probed the clinicopathologic context of commercially available cell lines using sequencing data from the recently released Metastatic Breast Cancer (MBC) Project. Additionally, we identified cohorts in the MBC with similar profiles to the Wood cell model we recently derived and investigated alignment between clinicopathologic characteristics of these patients and the patient from which the model was derived.

Using a validated cancer panel, we analyzed 592 genes in the Wood cell model detecting mutations and CNAs. We then accessed mutation and CNA data from 1) the MBC Project for 103 primary and metastatic samples from 78 patients and 2) the Cancer Cell Line Encyclopedia (CCLE) database for 56 breast cancer cell lines. We performed unsupervised clustering on the 159 total specimens, incorporating both mutation and copy number data in the clustering analysis by labeling genes either altered or unaltered. MBC patient specimens were grouped based on the clustering results and assessed for trends across multiple clinicopathologic data categories. Specimens representing metastatic sites and the primary site from the same patient were both included in the analysis.

Clustering analysis revealed three major groups representing high, medium and low alteration levels (means of 237, 104 and 29 panel genes altered). The High mutation load group had 34 cell lines and 6 patient samples, the Medium group had 15 cell lines and 71 patent samples, and the Low group had 7 cell lines (including Wood) and 26 patient samples. The 6 patient specimens in the High group represented 5.8% of the MBC data, yet were represented by a majority (60.7%) of CCLE breast cancer lines. All patients in the High group self-reported extraordinary response to treatment; the other two groups had even distribution. None of the specimens in the High group had evidence of DCIS reported in the path report, whereas observed DCIS was distributed equally outside of the High group. Expectedly, markers of aggressiveness of disease were lower in the Low group compared to the rest of the MBC patients, including histologic grade (p=0.00072) and Ki67 percentage (p=0.026). The Low group MBC samples were more likely to be HER2(-) (p=0.02) and ER(+) (p=0.037), consistent the Wood patient. The eight patients clustering most closely with the Wood cell model had low N-stage disease when compared to the rest (p=0.036) which was consistent with the Wood patient N0 status.

CCLE breast cancer cell lines over-represent a small MBC patient subset with a very high load of genomic alterations that also trends toward exceptionally good response to treatment- consistent with the notion that cancer cell lines over-predict drug efficacy. Complete lack of DCIS in the High group is an interesting observation that may describe a disease progression resulting in absent or minimal DCIS precursor. As more MBC patient data are released, these analyses will be repeated to increase statistical power.

Citation Format: Rick Nicoletti, Pamela Shaw, Naghmeh Salimi, Agoston T. Agoston, Elin S. Agoston. Genomic representation of metastatic breast cancer patients by commercially available cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1054.