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

Elisabeth M. Jongbloed; Noor Wortelboer; Vanja de Weerd; Corine M. Beaufort; Kirsten Ruigrok-Ritstier; Mai N. Van; Jaco Kraan; Annette A. van Zweeden; Annemieke van der Padt-Pruijsten; Lisanne C. Hamming; Inge R. Konings; Gabe S. Sonke; Esther Oomen-de Hoop; John W.M. Martens; Agnes Jager; Saskia M. Wilting

doi:10.1038/s41591-025-03935-w

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

Elisabeth M. Jongbloed
, Noor Wortelboer
, Vanja de Weerd
, Corine M. Beaufort
, Kirsten Ruigrok-Ritstier
, Mai N. Van
, Jaco Kraan
, Annette A. van Zweeden
, Annemieke van der Padt-Pruijsten
, Lisanne C. Hamming
, Inge R. Konings
, Gabe S. Sonke
, Esther Oomen-de Hoop
, John W.M. Martens
, Agnes Jager
, Saskia M. Wilting^*

^*Corresponding author for this work

Medical Oncology

Research output: Contribution to journal › Article › Academic › peer-review

4 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3662-3667
Number of pages	6
Journal	Nature Medicine
Volume	31
Issue number	11
DOIs	https://doi.org/10.1038/s41591-025-03935-w
Publication status	Published - Nov 2025

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Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1038/s41591-025-03935-w

Cite this

Jongbloed, E. M., Wortelboer, N., de Weerd, V., Beaufort, C. M., Ruigrok-Ritstier, K., Van, M. N., Kraan, J., van Zweeden, A. A., van der Padt-Pruijsten, A., Hamming, L. C., Konings, I. R., Sonke, G. S., Oomen-de Hoop, E., Martens, J. W. M., Jager, A., & Wilting, S. M. (2025). Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer: circulating tumor DNA analysis of a randomized phase 3 trial. Nature Medicine, 31(11), 3662-3667. https://doi.org/10.1038/s41591-025-03935-w

@article{ccb05afd558a498885b8648c6155a671,

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

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.",

author = "Jongbloed, \{Elisabeth M.\} and Noor Wortelboer and \{de Weerd\}, Vanja and Beaufort, \{Corine M.\} and Kirsten Ruigrok-Ritstier and Van, \{Mai N.\} and Jaco Kraan and \{van Zweeden\}, \{Annette A.\} and \{van der Padt-Pruijsten\}, Annemieke and Hamming, \{Lisanne C.\} and Konings, \{Inge R.\} and Sonke, \{Gabe S.\} and \{Oomen-de Hoop\}, Esther and Martens, \{John W.M.\} and Agnes Jager and Wilting, \{Saskia M.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.",

year = "2025",

month = nov,

doi = "10.1038/s41591-025-03935-w",

language = "English",

volume = "31",

pages = "3662--3667",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

number = "11",

}

Jongbloed, EM, Wortelboer, N, de Weerd, V, Beaufort, CM, Ruigrok-Ritstier, K , Van, MN , Kraan, J, van Zweeden, AA, van der Padt-Pruijsten, A, Hamming, LC, Konings, IR, Sonke, GS, Oomen-de Hoop, E , Martens, JWM , Jager, A & Wilting, SM 2025, 'Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer: circulating tumor DNA analysis of a randomized phase 3 trial', Nature Medicine, vol. 31, no. 11, pp. 3662-3667. https://doi.org/10.1038/s41591-025-03935-w

TY - JOUR

T1 - Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer

T2 - circulating tumor DNA analysis of a randomized phase 3 trial

AU - Jongbloed, Elisabeth M.

AU - Wortelboer, Noor

AU - de Weerd, Vanja

AU - Beaufort, Corine M.

AU - Ruigrok-Ritstier, Kirsten

AU - Van, Mai N.

AU - Kraan, Jaco

AU - van Zweeden, Annette A.

AU - van der Padt-Pruijsten, Annemieke

AU - Hamming, Lisanne C.

AU - Konings, Inge R.

AU - Sonke, Gabe S.

AU - Oomen-de Hoop, Esther

AU - Martens, John W.M.

AU - Jager, Agnes

AU - Wilting, Saskia M.

PY - 2025/11

Y1 - 2025/11

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105015502370

U2 - 10.1038/s41591-025-03935-w

DO - 10.1038/s41591-025-03935-w

M3 - Article

C2 - 40908356

AN - SCOPUS:105015502370

SN - 1078-8956

VL - 31

SP - 3662

EP - 3667

JO - Nature Medicine

JF - Nature Medicine

IS - 11

ER -

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

Abstract

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