Previous studies have demonstrated that ESR1 mu is a mechanism for acquired endocrine resistance in metastatic breast cancer (mBC). The randomized, double-blind, phase III PALOMA-3 study compared the use of palbociclib plus fulvestrant (P+F) versus fulvestrant plus placebo (F+Pla) in pre- and postmenopausal women with hormone receptor positive (HR+)/hormone estrogen receptor 2 negative mBC who have progressed on prior endocrine therapy. The researchers presented the study at the ASCO Annual Meeting. The researchers assessed the relationship between circulating tumor DNA (ctDNA) ESR1 mu status and palbociclib sensitivity and the reproducibility of ESR1 ctDNA analysis. 

A total of 396 baseline plasma samples (395 were then tested) were collected from 521 patients, and DNA was extracted from 2 ml aliquots using the QIAamp Circulating Nucleic Acid Kit and 12 ESR1 ligand-binding domain mus were analyzed in exons 5, 7, and 8 by Sysmex Inostics. To assess reproducibility of ESR1 mu analysis, separate samples were analyzed by droplet digital polymerase chain reaction. 

In 26.8% of patients (n = 106), ESR1 mus were detected, most frequently occurring with 

  • D538G (14.1%) 
  • E380Q (8.1%) 
  • Y537S (7.3%) 
  • Y537N (4.5%). 

Mus were polyclonal in 10.1% of patients. All of the 106 patients were previously treated with an aromatase inhibitor, although no ESR1 mus were detected in patients previously treated with tamoxifen only.  

The median progression-free survival was 5.7 months for patients with ESR1 mus (95% confidence interval [CI] = 3.7–9.4) compared with 9.2 months for those without ESR1 mus (hazard ratio [HR] = 95% CI, 0.99–1.8; p = 0.0572).  

Median progression-free survival was significantly longer for those treated with P+F compared with those in the F+Pla group in patients without ESR1 mu (9.5 versus 3.8 months, respectively; HR = 0.44; 95% CI = 0.31–0.62; p < 0.0001) and those with ESR1 mu (9.4 versus 4.1 months, respectively; HR = 0.52; 95% CI = 0.32–0.87; p = 0.0052).  

A total of 353 samples were tested by droplet digital polymerase chain reaction, and the concordance between the two assays was 94.1%.  

The researchers concluded, “ESR1 mus, detected in plasma ctDNA, were identified in a high percentage of patients with HR+ mBC, confirming an important role in endocrine-resistance. P+F treatment provided significant benefit for mBC patients with and without ESR1 mus.”

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