CHICAGO — ESR1 mutations detected in plasma circulating tumor DNA were identified in a high percentage of patients with hormone receptor-positive metastatic breast cancer, confirming an important role in endocrine resistance, according to an analysis of data from the phase 3 PALOMA-3 reported at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting.1

The ESR1 mutations were detected in 27% of baseline plasma samples in the PALOMA-3 trial, results of which were presented at ASCO last year and published simultaneously in the New England Journal of Medicine. The study compared fulvestrant with and without palbociclib in 521 premenopausal and postmenopausal women with hormone receptor-positive/HER2-negative metastatic breast cancer who had progressed on prior endocrine therapy.

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The results also showed that “ESR1 mutations were strongly associated with acquired resistance to prior aromatase inhibitors” and that treatment with palbociclib “offers high efficacy regardless of ESR1 mutation status,” said Nicholas C. Turner, Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom. “The combination of palbociclib and fulvestrant presents an attractive treatment option for patients previously treated with aromatase inhibitors,” he added.

The goal of the analysis was to identify baseline factors that are associated with detection of ESR1 mutations in plasma; to assess the impact of these mutations on the efficacy of fulvestrant and palbociclib; and to assess the reproducibility of plasma ESR1 mutation analysis by digital PCR.

From the total PALOMA-3 cohort, 396 baseline plasma samples were collected. Using the QIAamp Circulating Nucleic Acid Kit, DNA was extracted from 2 mL aliquots, and 12 ESR1 ligand-binding domain mutations were analyzed in exons 5, 7, and 8 by Sysmex Inostics BEAMing digital PCR. “To assess reproducibility of ESR1 mutation analysis, separate samples were analyzed by droplet digital PCR,” he reported.

Of the 395 plasma samples tested, ESR1 mutations were detected in 106 (26.8%). Most frequent were D538G (14.1%), E380Q (8.1%), Y537S (7.3%), and Y537N (4.5%), and the mutations were polyclonal in 38% of mutation-positive patients.

All 106 patients with ESR1 mutations had previously been treated with an aromatase inhibitor. In those previously treated with tamoxifen only, no ESR1 mutations were identified.

Median progression-free survival was 5.7 months (95% confidence interval [CI], 3.7-9.4) for patients with the ESR1 mutations vs 9.2 months (95% CI, 7.5-10.9) for those without the mutations (hazard ratio [HR], 1.33; 95% CI, 0.99-1.80; 2-sided P = .0572).

Median progression-free survival was significantly longer in the fulvestrant plus palbociclib group compared with the fulvestrant plus placebo group in patients both without a detectable ESR1 mutation (9.5 vs 3.8 months; HR, 0.44 [95% CI, 0.31-0.62], 1-sided P < .0001) and with an ESR1 mutation (9.4 vs 4.1 months; HR, 0.52 [95% CI, 0.32-0.87], 1-sided P = .0052).

Compared with those with the ESR1 mutation, the clinical benefit rate was significantly higher among those without the mutation, 40.7% vs 33.3% (P < .0001).

In the 353 of 395 samples independently tested by droplet digital PCR, the concordance between the two assays was 94.1% (Kappa = 0.84), which was statistically significant (P < .0001).



1. Turner NC, Jiang Y, Ben O’Leary B, et al. Efficacy of palbociclib plus fulvestrant (P+F) in patients (pts) with metastatic breast cancer (MBC) and ESR1 mutations (mus) in circulating tumor DNA (ctDNA). Oral presentation at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago, IL.