Currently, clinical characterization of metastatic breast cancer is based on tissue samples taken at time of diagnosis. However, tissue biopsies are invasive and tumors are continuously evolving, which indicates the need for minimally invasive longitudinal assessment of the tumor. Blood-based liquid biopsies provide minimal invasive means for serial sampling over the course of treatment and the opportunity to adjust therapies based on molecular markers. Here, we aim to identify cellular changes that occur in breast cancer over the lifespan of an affected patient through single-cell proteomic and genomic analysis of longitudinally sampled solid and liquid biopsies. Three solid and 17 liquid biopsies from peripheral blood of an ER+ /HER2− metastatic breast cancer patient collected over 4 yr and eight treatment regimens were analyzed for morphology, protein expression, copy-number alterations, and single-nucleotide variations. Analysis of 563 single morphometrically similar circulating tumor cells (CTCs) and 13 cell-free DNA (cfDNA) samples along with biopsies of the primary and metastatic tumor revealed progressive genomic evolution away from the primary tumor profiles, along with changes in ER expression and the appearance of resistance mutations. Both the abundance and the genomic alterations of CTCs and cfDNA were highly correlated and consistent with genomic alterations in the tissue samples. We demonstrate that genomic evolution and acquisition of drug resistance can be detected in real time and at single-cell resolution through liquid biopsy analytes and highlight the utility of liquid biopsies to guide treatment decisions.
| Authors | Lisa Welter1, Liya Xu1, Dillon McKinley1, Angel E. Dago2, Rishvanth K. Prabakar1, Sara Restrepo-Vassalli1, Kevin Xu1, Mariam Rodriguez-Lee1, Anand Kolatkar1, Rafael Nevarez1, Carmen Ruiz1, Jorge Nieva3, Peter Kuhn1,3,4, and James Hicks1 |
| Affiliations | 1. Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, California 90089, USA, 2. The Scripps Research Institute, La Jolla, California 92037, USA, 3. Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA, 4. Viterbi School of Engineering, University of Southern California, Los Angeles, California 90089, USA |
| Journal | Cold Spring Harbor Molecular Case Studies |
| Publication URL | http://molecularcasestudies.cshlp.org/ |
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| Brief Description of Data Available | low-pass copy number alternation (CNA) data from single cells and cell-free DNA (cfDNA), targeted sequencing of cfDNA, whole-exome sequencing and Sanger sequencing of the primary breast tissue and metastatic bone and liver biopsies, single-cell Sanger sequencing |
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| Condition | Metastatic Breast Cancer |
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| Websites |
fastq files of low pass whole genome sequencing data for copy number alteration (CNA) analysis of FFPE tissue, cfDNA and single cells
13 bam files of cfDNA samples sequenced using the ThermoFisher Oncomine Breast cfDNA Assay v2
ab1 trace files of FFPE tissue from primary breast, bone metastasis and liver metastasis for ESR1; ab1 trace files of single CTCs for ESR1 and PIK3CA
fastq files of paired-end whole exome sequencing runs. 2 separate runs per sample. Sample types are primary breast tissue, bone metastasis tissue and liver metastasis tissue