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Published on: July 25, 2020
Fulvestrant and everolimus efficacy after CDK4/6 inhibitor: a prospective study with circulating tumor DNA analysis
Antoine Vasseur1,2, Luc Cabel1, Caroline Hego2
1Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud, France.
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.
Insights
Fulvestrant and everolimus show efficacy in pre-treated metastatic breast cancer (mBC). Early circulating tumor DNA (ctDNA) detection predicts poorer outcomes, validating ctDNA as a biomarker.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Metastatic breast cancer (mBC) patients pre-treated with CDK4/6 inhibitors (CDK4/6i) require effective therapeutic options.
- Understanding treatment response and resistance mechanisms is crucial for improving patient outcomes.
Purpose of the Study:
- To assess the efficacy of fulvestrant plus everolimus in CDK4/6i-pretreated ER+/HER2- mBC patients.
- To evaluate the utility of circulating tumor DNA (ctDNA) dynamics as a pharmacodynamic biomarker throughout therapy.
Main Methods:
- Prospective cohort study (NCT02866149) of 57 mBC patients.
- Somatic mutations identified via targeted next-generation sequencing (NGS) in tumor tissue.
- ctDNA tracked in cell-free DNA using droplet digital PCR at baseline, 3-5 weeks, and disease progression.
Main Results:
- Median progression-free survival (PFS) was 6.8 months; median overall survival (OS) was 38.2 months.
- Partial response or stable disease observed in 31.9% and 23.4% of response-evaluable patients, respectively.
- ctDNA detection at baseline (70.2%) and 3 weeks (52.8%) was associated with adverse prognostic impact on PFS and OS.
Conclusions:
- Fulvestrant and everolimus demonstrate efficacy in CDK4/6i-pretreated ER+/HER2- mBC.
- Early ctDNA changes serve as a valid pharmacodynamic biomarker, correlating with clinical outcomes.
