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Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer: circulating tumor DNA analysis of a randomized phase 3 trial

Nature Medicine volume 31, pages 3662–3667 (2025)Cite this article

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Abstract

CDK4/6 inhibitors (CDK4/6i) improve outcome in patients with advanced estrogen receptor-positive, HER2− breast cancer. The phase 3 SONIA trial compared the addition of CDK4/6i to first- versus second-line endocrine therapy for time to disease progression after second-line treatment (progression-free survival after two lines of treatment (PFS2)), as well as for secondary outcomes overall survival, PFS after one line of treatment (PFS1), health-related quality of life (HRQOL), toxicity and cost-effectiveness. No significant difference in PFS2 was observed; however, on an individual patient level this may be different. Using prespecified circulating tumor DNA analyses, we performed an exploratory study to evaluate whether pretreatment circulating tumor DNA (ctDNA) levels in plasma can identify patients that benefit from CDK4/6i during their first-line treatment. Cell free DNA before start of first-line treatment from 409 female patients participating in SONIA was analyzed with the modified fast aneuploidy screening test-sequencing system. This assay yields a genome-wide aneuploidy score, indicative of ctDNA levels. Cox proportional hazard analyses for PFS1 and PFS2 were performed separately for the ctDNA high group (aneuploidy score ≥ 5) and the ctDNA low group (aneuploidy score < 5). In total, 141 of the 409 included patients had a high genome-wide aneuploidy score at baseline. PFS2 in the first- compared to the second-line CDK4/6i strategy showed hazard ratios of 0.58 (95% confidence interval 0.38–0.88) and 1.36 (95% confidence interval 0.95–1.96) in the high and low aneuploidy group, respectively. A significant interaction was demonstrated between treatment strategy and aneuploidy score for PFS2 (P = 0.004). In conclusion, this study demonstrated that pretreatment ctDNA levels can be used to identify patients that benefit from first-line CDK4/6i treatment. ClinicalTrials.gov registration: NCT03425838.

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Fig. 1: Overview of included patients and aneuploidy score.
Fig. 2: Kaplan–Meier curves of PFS1 and PFS2 by treatment and aneuploidy score.

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Data availability

De-identified mFast-SeqS and patient clinical data underlying the results reported in this article will be made available to other researchers on reasonable request for academic use, within the limitations of the informed consent and the study’s consortium agreement. A detailed data proposal is required and will be considered on a case-by-case basis. Requests should be directed to BOOG study Center (info@boogstudycenter.nl) and will be reviewed by the study’s principal investigators. A response will be provided within 90 days. A signed data access agreement with the sponsor is required before accessing shared data.

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Acknowledgements

We thank all participating patients and their families as well as the entire SONIA Study Consortium and the Dutch Breast Cancer research Group (BOOG) for their support and sponsorship. This study was funded by the Dutch Cancer Society (KWF grant 12039; A.J.) and Breast Cancer Now’s Catalyst Program (grant reference number 2018NovPCC100; S.M.W.). The latter is supported by funding from Pfizer. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Elisabeth M. Jongbloed, Noor Wortelboer.

Authors and Affiliations

  1. Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands

    Elisabeth M. Jongbloed, Noor Wortelboer, Vanja de Weerd, Corine M. Beaufort, Kirsten Ruigrok-Ritstier, Mai N. Van, Jaco Kraan, Esther Oomen-de Hoop, John W. M. Martens, Agnes Jager & Saskia M. Wilting

  2. Department of Medical Oncology, Amstelland Hospital, Amstelveen, the Netherlands

    Annette A. van Zweeden

  3. Department of Internal Medicine, Maasstad Hospital, Rotterdam, the Netherlands

    Annemieke van der Padt-Pruijsten

  4. Department of Medical Oncology, Frisius MC Leeuwarden, Leeuwarden, the Netherlands

    Lisanne C. Hamming

  5. Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands

    Inge R. Konings

  6. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands

    Gabe S. Sonke

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Contributions

E.M.J. and N.W. had full access to all the study data, and take responsibility for the integrity of the data and the accuracy of the data analyses. I.R.K., G.S.S., J.W.M.M., A.J. and S.M.W created the study concept and design. A.A.v.Z., A.v.d.P.-P., L.C.H., I.R.K., G.S.S. and A.J. were responsible for data acquisition. V.d.W., C.M.B., K.R.-R., M.N.V. and J.K. were responsible for administrative, technical or material support. E.M.J. and E.O.-d. H. carried out statistical analysis. The paper was drafted by E.M.J., N.W., J.W.M.M., A.J. and S.M.W and all authors were responsible for the critical revision of the paper.

Corresponding author

Correspondence to Saskia M. Wilting.

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Competing interests

Institutional research grant support was received from the following: Novartis (I.R.K. and G.S.S.); Gilead (I.R.K.); Agendia and AstraZeneca (G.S.S. and A.J.); Merck (G.S.S. and J.W.M.M.); Roche and Seasgen (G.S.S.); Bayer, Menarini and Tzu Genomics (J.W.M.M.) and Pfizer (A.J. and S.M.W.). Consultancy was received from Biovica, Novaratis and Seagen (G.S.S.) and Novartis (J.W.M.M.). Participation on the advisory board of AstraZeneca (A.J.). The other authors declare no competing interests.

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Nature Medicine thanks Luc Cabel, Andrew Davis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Table 1 Baseline characteristics and survival outcomes of patients in the ctDNA cohort vs. the non-evaluated patients in the SONIA trial
Full size table
Extended Data Table 2 Subgroup analysis of PFS2 in the ctDNA cohort patient population
Full size table
Extended Data Table 3 Sensitivity analysis excluding patients where blood samples were collected after treatment start
Full size table

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Jongbloed, E.M., Wortelboer, N., de Weerd, V. et al. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer: circulating tumor DNA analysis of a randomized phase 3 trial. Nat Med 31, 3662–3667 (2025). https://doi.org/10.1038/s41591-025-03935-w

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