Abstract 5599: Noninvasive genomic profiling of cerebral spinal fluid in breast cancer patient with leptomeningeal disease

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.5599-5599
• Main Authors: Oikawa, Masahiro, Ramesh, Naveen, Sei, Emi, Bai, Shanshan, Hu, Min, John, de Groot F., Rshmi, Murthy, O'Brien, Barbara, Navin, Nicholas
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-5599

Leptomeningeal disease (LMD) involves the dissemination of tumor cells from the primary breast tumors into the membranes surrounding the central nervous system and spinal cords. LMD occurs in about 5% of breast cancer patients and is associated with very poor survival. The genomic evolution of LMD in breast cancer patients has remained difficult to study, in part due to technical challenges in collecting longitudinal biopsy samples from the central nervous system. Liquid biopsies of the cerebral spinal fluid (CSF) may provide a unique opportunity to profile circulating tumor DNA (ctDNA) and has not been compared directly to non-invasive monitoring of ctDNA in blood samples. Furthermore, most non-invasive ctDNA profiling methods are limited to a targeted set of genes and have not allowed unbiased whole-genome profiling. To address these limitations, we developed an unbiased method for ctDNA analysis called PEGASUS (Plasma Exome and Genome Analysis by Size-selection and Unbiased Sequencing) that enables whole-genome sequencing of copy number aberrations and somatic mutations from ctDNA. We applied PEGASUS to sequence matched blood samples and CSF from 10 breast cancer patients with LMD. Quantitation of ctDNA levels showed that ctDNA was detected in CSF samples from 9/10 patients, while blood ctDNA was detected in only 1 LMD patient with extensive metastatic disease. Whole-genome copy number profiling at 220kb resolution and mutational profiling of a 2000 cancer gene panel of the matched CSF and blood samples was performed in 10 LMD patients using PEGASUS. Our data identified aneuploid copy number aberrations and somatic mutations (range: 11-25) in the CSF of 7 patients, including mutations in known driver genes such as BRAF, RB1, TP53 and amplifications of MYC and ERBB2. In contrast the matched blood samples showed only diploid copy number profiles and no detectable somatic mutations in 9/10 LMD patients. In one patient with extensive cranial metastatic disease with matched CSF and blood ctDNA, we found a high concordance in copy number profiles (R= 0.75) and modest concordance of somatic mutations (59.5%), but also additional CNAs and mutations that were specific to the CSF. Collectively, these data show that genomic profiling of ctDNA in CSF is technically feasible for patients with LMD, and provides a major advantage over blood ctDNA which cannot be detected in mostcases. Citation Format: Masahiro Oikawa, Naveen Ramesh, Emi Sei, Shanshan Bai, Min Hu, de G