Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA
Abstract
Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection. Repeat biopsies to study genomic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity. Recent studies have shown that genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy. Here we report sequencing of cancer exomes in serial plasma samples to track genomic evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1-2 years. For each case, exome sequencing was performed on 2-5 plasma samples (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel; a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin; a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab, and following subsequent treatment with lapatinib, a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient; and a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) following treatment with gefitinib. These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal evolution in human cancers.
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Proof of principle has been established that ctDNA analysis could complement tumor biopsy and provide an early warning of acquired resistance.
“however, the proof of principle that such an approach could complement tumor biopsy and provide an early warning of acquired resistance has been established [38, 41, 136].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [136]
Since introduction of third generation EGFR TKIs requires monitoring the occurrence of T790M mutation for the pianification of treatment at resistance, this noninvasive approach will be useful for the clinical practice treatment at resistance.
“Since introduction of third generation EGFR TKIs requires monitoring the occurrence of T790M mutation for the pianification of treatment at resistance, this noninvasive approach will be useful for the clinical practice treatment at resistance.53 56”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [56]
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- Authors
- Murtaza, M., Dawson, S.-J., Tsui, D. W. Y., Gale, D., Forshew, T., Piskorz, A. M., Parkinson, C., Chin, S.-F., Kingsbury, Z., Wong, A. S. C., Marass, F., Humphray, S., Hadfield, J., Bentley, D., Chin, T. M., Brenton, J. D., Caldas, C., & Rosenfeld, N.
- Affiliations
- University of Cambridge (GB)
- Illumina (United Kingdom) (GB)
- National University Cancer Institute, Singapore (SG)
- National University of Singapore (SG)
- Corresponding author
- Brenton, James D.
- Caldas, Carlos
- Rosenfeld, Nitzan
- ORCID
- Venue
- Nature
- Published
- 2013-04-07
- Volume
- 497
- Issue
- 7447
- Pages
- 108-112
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2067904749
- Cited by
- 1,624
- References
- 8
- Citations by year
- 2026: 44 · 2025: 61 · 2024: 61 · 2023: 65 · 2022: 110 · 2021: 102 · 2020: 132 · 2019: 187 · 2018: 159 · 2017: 181 · 2016: 168 · 2015: 173 · 2014: 125 · 2013: 55
- FWCI
- 61.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Cancer Research UK (15601, 11906, 16942, 22310)
- National Institute for Health and Care Research (NF-SI-0611-10154)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- circulating tumor DNA, liquid biopsy, acquired drug resistance, plasma DNA, clonal evolution, metastatic breast cancer, lung cancer, ovarian cancer, PIK3CA mutation, RB1 mutation, T790M mutation, cisplatin resistance, tamoxifen resistance, gefitinib resistance, allele fraction
- MeSH terms
- Growth Arrest-Specific Protein 6, Alleles, Antineoplastic Agents, Breast Neoplasms, Carcinoma, Non-Small-Cell Lung, DNA Mutational Analysis, DNA, Neoplasm, Female, Humans, Lung Neoplasms, Neoplasms, Ovarian Neoplasms, Plasma, Genome, Human, Retinoblastoma Protein, Drug Resistance, Neoplasm, Evolution, Molecular, Phosphatidylinositol 3-Kinases, Genomics, Intercellular Signaling Peptides and Proteins, Mediator Complex Subunit 1, Class I Phosphatidylinositol 3-Kinases, Exome, ErbB Receptors
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