Breast Cancer Research (May 2020)

Risk of early progression according to circulating ESR1 mutation, CA-15.3 and cfDNA increases under first-line anti-aromatase treatment in metastatic breast cancer

  • Florian Clatot,
  • Anne Perdrix,
  • Ludivine Beaussire,
  • Justine Lequesne,
  • Christelle Lévy,
  • George Emile,
  • Michael Bubenheim,
  • Sigrid Lacaille,
  • Céline Calbrix,
  • Laetitia Augusto,
  • Cécile Guillemet,
  • Cristina Alexandru,
  • Maxime Fontanilles,
  • David Sefrioui,
  • Lucie Burel,
  • Sabine Guénot,
  • Doriane Richard,
  • Nasrin Sarafan-Vasseur,
  • Frédéric Di Fiore

DOI
https://doi.org/10.1186/s13058-020-01290-x
Journal volume & issue
Vol. 22, no. 1
pp. 1 – 12

Abstract

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Abstract Background Endocrine therapy is recommended as a first-line treatment for hormone receptor-positive metastatic breast cancer (HR+MBC) patients. No biomarker has been validated to predict tumor progression in that setting. We aimed to prospectively compare the risk of early progression according to circulating ESR1 mutations, CA-15.3, and circulating cell-free DNA in MBC patients treated with a first-line aromatase inhibitor (AI). Methods Patients with MBC treated with a first-line AI were prospectively included. Circulating biomarker assessment was performed every 3 months. The primary objective was to determine the risk of progression or death at the next follow-up visit (after 3 months) in case of circulating ESR1 mutation detection among patients treated with a first-line AI for HR+MBC. Results Overall, 103 patients were included, and 70 (68%) had progressive disease (PD). Circulating ESR1 mutations were detected in 22/70 patients with PD and in 0/33 patients without progression (p < 0.001). Among the ESR1-mutated patients, 18/22 had a detectable mutation prior to progression, with a median delay of 110 days from first detection to PD. The detection of circulating ESR1 mutations was associated with a 4.9-fold (95% CI 3.0–8.0) increase in the risk of PD at 3 months. Using a threshold value of 25% or 100%, a CA-15.3 increase was also correlated with progression (p < 0.001 and p = 0.003, respectively). In contrast to ESR1, the CA-15.3 increase occurred concomitantly with PD in most cases, in 27/47 (57%) with a 25% threshold and in 21/25 (84%) with a 100% threshold. Using a threshold value of either 25% or 100%, cfDNA increase was not correlated with progression. Conclusion The emergence of circulating ESR1 mutations is associated with a 4.9-fold increase in the risk of early PD during AI treatment in HR+MBC. Our results also highlighted that tracking circulating ESR1 mutations is more relevant than tracking CA-15.3 or cfDNA increase to predict progression in this setting. Trial registration ClinicalTrials.gov, NCT02473120 . Registered 16 June 2015—retrospectively registered after one inclusion (first inclusion 1 June 2015)

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