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Observational Study
. 2020 May 28;22(1):56.
doi: 10.1186/s13058-020-01290-x.

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  1   2 , Anne Perdrix  3   4 , Ludivine Beaussire  3 , Justine Lequesne  5 , Christelle Lévy  6 , George Emile  6 , Michael Bubenheim  7 , Sigrid Lacaille  3 , Céline Calbrix  4 , Laetitia Augusto  8 , Cécile Guillemet  8 , Cristina Alexandru  8 , Maxime Fontanilles  8   3 , David Sefrioui  3 , Lucie Burel  5 , Sabine Guénot  5 , Doriane Richard  5 , Nasrin Sarafan-Vasseur  3 , Frédéric Di Fiore  8   3
Affiliations
Observational Study

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 et al. Breast Cancer Res. .

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).

Keywords: Aromatase inhibitor; Breast cancer; CA-15.3; Cell-free DNA; Circulating DNA; ESR1 mutation.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Correlation between biomarker variations and time to progression. For each biomarker, the number of patients with a biomarker event (biomarker increase or mutation emergence) according to the time of progression (PD) is reported
Fig. 2
Fig. 2
Overall survival according to ESR1 mutation status at progression disease. p value was determined using a log-rank test
Fig. 3
Fig. 3
Overall survival according to CA-15.3 level at progression disease. p value was determined using a log-rank test or a Cox model
Fig. 4
Fig. 4
Overall survival according to cfDNA level at progression disease. p value was determined using a log-rank test or a Cox model
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