Treatment response and tumor evolution: lessons from an extended series of multianalyte liquid biopsies in a metastatic breast cancer patient
- 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
- 1Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, California 90089, USA;
- 2The Scripps Research Institute, La Jolla, California 92037, USA;
- 3Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA;
- 4Viterbi School of Engineering, University of Southern California, Los Angeles, California 90089, USA
- Corresponding author: jameshic{at}usc.edu
Abstract
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 years 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.
Footnotes
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[Supplemental material is available for this article.]
- Received August 14, 2020.
- Accepted November 15, 2020.
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