Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Apr;43(16):1214-1222.
doi: 10.1038/s41388-024-02986-6. Epub 2024 Feb 27.

Fulvestrant and everolimus efficacy after CDK4/6 inhibitor: a prospective study with circulating tumor DNA analysis

Antoine Vasseur  1   2 , Luc Cabel  1 , Caroline Hego  2 , Wissam Takka  2 , Olfa Trabelsi Grati  3 , Benjamin Renouf  4 , Florence Lerebours  1 , Delphine Loirat  1 , Etienne Brain  1 , Paul Cottu  1 , Marie-Paule Sablin  1 , Jean-Yves Pierga  1   5 , Céline Callens  3 , Shufang Renault #  6 , François-Clément Bidard #  7   8   9
Affiliations

Fulvestrant and everolimus efficacy after CDK4/6 inhibitor: a prospective study with circulating tumor DNA analysis

Antoine Vasseur et al. Oncogene. 2024 Apr.

Abstract

In a prospective study (NCT02866149), we assessed the efficacy of fulvestrant and everolimus in CDK4/6i pre-treated mBC patients and circulating tumor DNA (ctDNA) changes throughout therapy. Patients treated with fulvestrant and everolimus had their ctDNA assessed at baseline, after 3-5 weeks and at disease progression. Somatic mutations were identified in archived tumor tissues by targeted NGS and tracked in cell-free DNA by droplet digital PCR. ctDNA detection was then associated with clinicopathological characteristics and patients' progression-free survival (PFS), overall survival (OS) and best overall response (BOR). In the 57 included patients, median PFS and OS were 6.8 (95%CI [5.03-11.5]) and 38.2 (95%CI [30.0-not reached]) months, respectively. In 47 response-evaluable patients, BOR was a partial response or stable disease in 15 (31.9%) and 11 (23.4%) patients, respectively. Among patients with trackable somatic mutation and available plasma sample, N = 33/47 (70.2%) and N = 19/36 (52.8%) had ctDNA detected at baseline and at 3 weeks, respectively. ctDNA detection at baseline and PIK3CA mutation had an adverse prognostic impact on PFS and OS in multivariate analysis. This prospective cohort study documents the efficacy of fulvestrant and everolimus in CDK4/6i-pretreated ER + /HER2- mBC and highlights the clinical validity of early ctDNA changes as pharmacodynamic biomarker.

PubMed Disclaimer

Conflict of interest statement

This work was supported by SIRIC 3 Curie (grant INCa-DGOS-INSERM-ITMO Cancer_18000). FC Bidard received research support and honoraria for advisory board from AstraZeneca and Novartis. F Lerebours reports consulting for AstraZeneca, Eisai, Genomic Health, Eli Lilly, Laboratories Pierre Fabre, and Roche; and travel support from AstraZeneca, Eisai, Novartis, Pfizer, Roche, and Laboratories Pierre Fabre; and lecture fees from AstraZeneca, Eisai, Eli Lilly, Novartis, and Laboratories Pierre Fabre. MP Sablin reports lecture fees from Servier. JY Pierga reports consulting for AstraZeneca, Eisai, Eli Lilly, MSD, Gilead, Daiichy Sankyo, Novartis, Pfizer and travel support from AstraZeneca, MSD, Novartis, Pfizer, Gilead, Seagen, and lecture fees from AstraZeneca, MSD, Eli Lilly, Novartis, Gilead, Veracyte. No other potential conflicts of interest were reported.

Figures

Fig. 1
Fig. 1. Workflow of the study.
ER + : estrogen receptor positive; mBC: metastatic breast cancer; NGS: next-sequencing generation; ddPCR: droplet digital PCR.
Fig. 2
Fig. 2. Progression-free survival and overall survival in patients treated with everolimus and fulvestrant.
In the whole population (A, B) and according to previous palbociclib treatment duration (above or under/equal to median PFS (C, D)). PFS progression-free survival, OS overall survival.
Fig. 3
Fig. 3. ctDNA detection at different time points.
A ctDNA levels at different time points quantified by ddPCR. Each dot represents the level of ctDNA of a patient measured. Mann–Whitney test was used to compare ctDNA levels at different time points. B Swimmer plot showing the dynamic changes of ctDNA levels, best overall response and timing of clinical relapse. Each bar represents one patient. Red circles indicate ctDNA detection and blue circles indicate no ctDNA detection. The black triangle indicates disease progression (PD). *SD ≥ 6 months. Bsl: baseline; 3–5 W: 3–5 weeks, PD progressive disease, PR partial response, SD stable disease, NA not available.
Fig. 4
Fig. 4. Prognostic value of ctDNA detection at different time points.
Progression-free survival and overall survival according to ctDNA detection at baseline (A, B) and 3 weeks (C, D). PFS progression-free survival, OS overall survival.
Fig. 5
Fig. 5. Tumor response and prognostic value of early ctDNA variations.
Tumor response according to ctDNA change from baseline (A). *SD ≥ 6 months. Progression-free survival and overall survival according to early ctDNA variation (B, C) and ctDNA clearance (D, E). PD progressive disease, PR partial response, SD stable disease, PFS progression-free survival; OS: overall survival.
See this image and copyright information in PMC

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. doi: 10.3322/caac.21660. - DOI - PubMed
    1. Finn RS, Martin M, Rugo HS, Jones S, Im S-A, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925–36. doi: 10.1056/NEJMoa1607303. - DOI - PubMed
    1. Hortobagyi GN, Stemmer SM, Burris HA, Yap Y-S, Sonke GS, Paluch-Shimon S, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375:1738–48. doi: 10.1056/NEJMoa1609709. - DOI - PubMed
    1. Johnston S, Martin M, Di Leo A, Im S-A, Awada A, Forrester T, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019;5:5. doi: 10.1038/s41523-018-0097-z. - DOI - PMC - PubMed
    1. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21:2101–9. doi: 10.1200/JCO.2003.04.194. - DOI - PubMed

MeSH terms

LinkOut - more resources