Circulating Tumor DNA Markers for Early Progression on Fulvestrant with or without Palbociclib in ER+ Advanced Breast Cancer

Ben O'leary, Rosalind J. Cutts, Xin Huang, Sarah Hrebien, Yuan Liu, Fabrice André, Sibylle Loibl, Sherene Loi, Isaac Garcia-Murillas, Massimo Cristofanilli, Cynthia Huang Bartlett, Nicholas C. Turner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Background: There are no established molecular biomarkers for patients with breast cancer receiving combination endocrine and CDK4/6 inhibitor (CDK4/6i). We aimed to determine whether genomic markers in circulating tumor DNA (ctDNA) can identify patients at higher risk of early progression on fulvestrant therapy with or without palbociclib, a CDK4/6i. Methods: PALOMA-3 was a phase III, multicenter, double-blind randomized controlled trial of palbociclib plus fulvestrant (n = 347) vs placebo plus fulvestrant (n = 174) in patients with endocrine-pretreated estrogen receptor-positive (ER+) breast cancer. Pretreatment plasma samples from 459 patients were analyzed for mutations in 17 genes, copy number in 14 genes, and circulating tumor fraction. Progression-free survival (PFS) was compared in patients with circulating tumor fraction above or below a prespecified cutoff of 10% and with or without a specific genomic alteration. All statistical tests were 2-sided. Results: Patients with high ctDNA fraction had worse PFS on both palbociclib plus fulvestrant (hazard ratio [HR] = 1.62, 95% confidence interval [CI] = 1.17 to 2.24; P =. 004) and placebo plus fulvestrant (HR = 1.77, 95% CI = 1.21 to 2.59; P =. 004). In multivariable analysis, high-circulating tumor fraction was associated with worse PFS (HR = 1.20 per 10% increase in tumor fraction, 95% CI = 1.09 to 1.32; P <. 001), as was TP53 mutation (HR = 1.84, 95% CI = 1.27 to 2.65; P =. 001) and FGFR1 amplification (HR = 2.91, 95% CI = 1.61 to 5.25; P <. 001). No interaction with treatment randomization was observed. Conclusions: Pretreatment ctDNA identified a group of high-risk patients with poor clinical outcome despite the addition of CDK4/6 inhibition. These patients might benefit from inclusion in future trials of escalating treatment, with therapies that may be active in these genomic contexts.

Original languageEnglish (US)
Pages (from-to)309-317
Number of pages9
JournalJournal of the National Cancer Institute
Issue number3
StatePublished - Mar 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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