Abstract SY37-02: Monitoring tumor evolution by whole-genome plasma sequencing

Abstract

Abstract The recent surge in high-throughput sequencing of cancer genomes is delivering cheaper and more accurate tumor genome information. It can be anticipated that patients will increasingly be treated by focusing on the genetic architecture of their particular tumor rather than on the tumor's location or histologic features. However, cancer genomes are unstable and prone to changes under selection pressures such as the application of therapies. Thus, molecularly targeted cancer therapies require serial monitoring of the tumor genome's makeup to establish the status of biomarkers or to determine whether novel predictive biomarkers are evolving. To this end, circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) offer a unique opportunity for serially monitoring tumor genomes in a non-invasive fashion from the peripheral blood in a cost-effective manner. As CTCs and ctDNAs are potential surrogates for the tumor itself, they are often referred to as “liquid biopsy”. The analyses and characterization of ctDNA and CTCs have tremendous potential for providing new biological insights into the pivotal steps in metastases. Furthermore, non-invasive monitoring of tumor genomes offers a unique opportunity for the identification of potential biomarkers at various time points during a disease course. This may result in an improvement of the clinical outcome of many cancer types, as patients can be given a drug tailored to the genetic makeup of their tumor. Our group has developed methods allowing the analysis of genome-wide copy number changes and mutations in a panel of genes by next-generation sequencing (NGS) from single CTCs and ctDNA. In order to make whole-genome analysis from plasma DNA amenable to clinical routine applications and we have developed an approach based on a benchtop high-throughput platform, i.e. Illuminas MiSeq instrument. We perform whole-genome sequencing from plasma at a shallow sequencing depth to establish a genome-wide copy number profile of the tumor at low costs within 2 days. In parallel we sequence a panel of high-interest genes and introns with frequent fusion breakpoints with high coverage. Furthermore, we have established bioinformatics tools facilitating pathway analysis and tumor genome stratification based on liquid biopsy data, which reduce the complexity of data and increase the biological and clinical interpretability. Our emphasis is on the analysis of liquid biopsies derived from breast, prostate, colon, and lung cancer. Altogether we have now analyzed several hundred plasma DNA samples and elucidated the plasticity of tumor genomes by serial monitoring. We present how mechanisms against given therapies (e.g. androgen-deprivation therapy in men with prostate cancer or anti-EGFR therapy in individuals with colorectal cancer) evolve and can be detected in plasma DNA. Furthermore, we provide estimates about the dynamics of clonal evolution of tumor genomes derived from plasma DNA analyses. Citation Format: Michael R. Speicher, Ellen Heitzer, Peter Ulz, Jochen B. Geigl. Monitoring tumor evolution by whole-genome plasma sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY37-02. doi:10.1158/1538-7445.AM2015-SY37-02