The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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6. Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer
Herberts, C., Annala, M., Sipola, J. et al. Nature. 608: 199-208. (2022).
doi: 10.1038/s41586-022-04975-9.
Summary of the findings
Deep whole genome sequencing (NGS) was performed on ctDNA from serial blood samples from patients with advanced prostate cancer. Subclonal populations derived from various metastatic deposits were reconstructed from bulk DNA based on features such as chromosomal instability or whole-chromosome alterations relative to expected ploidy. Clonal population dynamics were then inferred across treatment timelines highlighting new genomic and epigenetic mechanisms of treatment resistance acquisition.
Repeat metastatic biopsies were previously the only tool available to learn how tumours evolve over time, but are invasive, expensive to perform, and do not necessarily accurately reflect a patient’s overall disease. Circulating tumour DNA (ctDNA) represents a noninvasive strategy for molecular profiling of advanced cancers, but historical focus on low-resolution approaches meant that the full repertoire of clinico-genomic information captured by ctDNA remained unestablished. In this Nature paper, the authors applied deep whole-genome sequencing to serial ctDNA samples from patients with advanced prostate cancer. Using a bespoke subclonal reconstruction algorithm, the authors demonstrate that ctDNA is a patchwork of multiple clonal populations derived from metastatic deposits throughout a patient’s body. By analysing same-patient ctDNA collected over time, they show that standard Androgen Receptor (AR)-targeted therapies for metastatic prostate cancer actively change the composition of these cancer populations within the body, selecting for populations with AR alterations which often underlie clinical resistance. This work pinpoints new genomic and epigenomic mechanisms of resistance to the most common drugs for treating metastatic prostate cancer, and more broadly demonstrates how ctDNA profiling can enable the discovery of treatment resistance mechanisms to drugs across all cancers.
Future impact
This expansion of liquid biopsy technology will inform the next generation of comprehensive clinical ctDNA biomarker tests, helping clinicians choose treatments better tailored to their patients’ unique cancer biology. Beyond impacting patient care, the author’s research proposes ctDNA testing as a novel research modality to accelerate the discovery of treatment resistance mechanisms to common cancer drugs. This methodology can be applied to other cancer types to reveal new biological insight (e.g. how do tumours metastasize; how do tumours evade therapy?) but also help design new cancer therapies that more effectively target resistant disease.
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The Cancer Researcher is an online magazine for the cancer research community from the European Association for Cancer Research.
The EACR, a registered charity, is a global community for those working and studying in cancer research. Our mission is “The advancement of cancer research for the public benefit: from basic research to prevention, treatment and care.”
