Limited evolution of the actionable metastatic cancer genome under therapeutic pressure

Joris van de Haar, Louisa R. Hoes, Paul Roepman, Martijn P. Lolkema, Henk M. W. Verheul, Hans Gelderblom, Adrianus J. de Langen, Egbert F. Smit, Edwin Cuppen, Lodewyk F. A. Wessels, Emile E. Voest*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

37 Citations (Scopus)


Genomic profiling is critical for the identification of treatment options for patients with metastatic cancer, but it remains unclear how frequently this procedure should be repeated during the course of the disease. To address this, we analyzed whole-genome sequencing (WGS) data of 250 biopsy pairs, longitudinally collected over the treatment course of 231 adult patients with a representative variety of metastatic solid malignancies. Within the biopsy interval (median, 6.4 months), patients received one or multiple lines of (mostly) standard-of-care (SOC) treatments, with all major treatment modalities being broadly represented. SOC biomarkers and biomarkers for clinical trial enrollment could be identified in 23% and 72% of biopsies, respectively. For SOC genomic biomarkers, we observed full concordance between the first and the second biopsy in 99% of pairs. Of the 219 biomarkers for clinical trial enrollment that were identified in the first biopsies, we recovered 94% in the follow-up biopsies. Furthermore, a second WGS analysis did not identify additional biomarkers for clinical trial enrollment in 91% of patients. More-frequent genomic evolution was observed when considering specific genes targeted by small-molecule inhibitors or hormonal therapies (21% and 22% of cases, respectively). Together, our data demonstrate that there is limited evolution of the actionable genome of treated metastases. A single WGS analysis of a metastatic biopsy is generally sufficient to identify SOC genomic biomarkers and to identify investigational treatment opportunities.
Original languageEnglish
Pages (from-to)1553-1563
Number of pages11
JournalNature Medicine
Issue number9
Early online date9 Aug 2021
Publication statusPublished - Sept 2021

Bibliographical note

Funding Information:
We acknowledge the Hartwig Medical Foundation and the Center of Personalised Cancer Treatment (CPCT) for providing the data used in this the study. This work was supported by funding from the Josephine Nefkens Foundation and the Oncode Institute.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.


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