Abstract 498: Meta-analysis of genomic aberrations identified in CTCs andctDNA in triple negative breast cancer
Authors: Howard Kellie , Austin Sharon , Lo Fang Yin , Ramirez Arturo , Boles Debbie , Pruitt John , Mahen Elisabeth , Collins Heather , Leonti Amanda , Maassel Lindsey , Subia Christopher , Saloranta Tuuli , Christopherson Nicole , Deutsch Kerry , Stilwell Jackie , Kaldjian Eric , Dorschner Michael , Blau Sibel , Blau Anthony , Eisenberg Marcia , Anderson Steven , Madan Anup 
Published: July 2016

Abstract
Technological innovation and scientific advances in understanding cancer at the molecular level have accelerated the discovery and development of both diagnostics and therapeutics. Circulating tumor cells (CTCs) and plasma circulating tumor DNA (ctDNA) are non-invasive prognostic markers that have been associated with metastatic and aggressive disease. Both CTCs and ctDNA allow molecular characterization of a tumor that is inaccessible or too risky to biopsy. The analysis of genomic aberrations in both sample types provides insights into drug resistance and can help determine appropriate, targeted cancer treatments. Mutations found in the primary or metastatic tumor can be identified in both CTCs and ctDNA as well as novel mutations that may reflect intratumoral and intermetastatic heterogeneity. When collected and evaluated over an extended period of time, changes in the CTC and/or ctDNA mutational profile can offer guidance into the effectiveness of a treatment, indicate the progression of disease, and detect recurrence of disease earlier.
We have performed whole exome sequencing of CTCs and ctDNA from a metastatic triple negative breast cancer (TNBC) patient to better understand the evolution of tumor heterogeneity during therapy. The patient was enrolled in the Intensive Trial of OMics in Cancer clinical Trial (ITOMIC-001) and initially received weekly cisplatin infusions followed by additional targeted therapy. Longitudinal peripheral blood samples were collected over a period of 272 days following enrollment in the clinical trial. CTCs were identified using the AccuCyte-CyteFinder system (RareCyte, Seattle WA).
We used next generation sequencing, and computational biology tools to analyze genomic DNA from multiple CTCs, white blood cells (WBCs) and ctDNA from various time points. We observed similar genomic aberrations in both CTCs and ctDNA that could be classified into three groups: a) a static group that remains unchanged during the course of therapy, b) a sample-specific group that is unique to each time point and c) an intermediate group that has variants that are short-lived but are present across multiple time points. Variants identified in the liquid biopsy samples were compared with variants observed in primary breast tumor, metastatic bone marrow tumor and publically available pan-cancer datasets. We then performed meta-analysis on somatic variants to identify changes in affected networks in response to therapy over time. Several key nodes were identified that could rationally have been targeted for therapy using compounds currently in clinical trials. We then compared and combined the perturbed networks obtained from the CTCs and ctDNA to better understand the etiology of TNBC. These studies represent the first step of a synergistic partnership between the genetic information obtained from the analysis of CTCs and ctDNA with innovative health care for patients with metastatic breast cancer.
Citation Format: Kellie Howard, Sharon Austin, Fang Yin Lo, Arturo Ramirez, Debbie Boles, John Pruitt, Elisabeth Mahen, Heather Collins, Amanda Leonti, Lindsey Maassel, Christopher Subia, Tuuli Saloranta, Nicole Christopherson, Kerry Deutsch, Jackie Stilwell, Eric Kaldjian, Michael Dorschner, Sibel Blau, Anthony Blau, Marcia Eisenberg, Steven Anderson, Anup Madan. Meta-analysis of genomic aberrations identified in CTCs andctDNA in triple negative breast cancer. [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 498.