Circulating ESR1 mutations at the end of aromatase inhibitor adjuvant treatment and after relapse in breast cancer patients

Abstract

BackgroundDetection of circulating ESR1 mutations is associated with acquired resistance to aromatase inhibitor (AI) in metastatic breast cancer. Until now, the presence of circulating ESR1 mutations at the end of adjuvant treatment by AI in early breast cancer had never been clearly established. In this context, the aim of the present study was to evaluate the circulating ESR1 mutation frequency at the end of adjuvant treatment and after relapse.MethodsThis monocentric retrospective study was based on available stored plasmas and included all early breast cancer patients who completed at least 2 years of AI adjuvant treatment and experienced a documented relapse after the end of their treatment. Circulating ESR1 mutations (D538G, Y537S/N/C) were assessed by droplet digital PCR in plasma samples taken at the end of adjuvant treatment, at time of relapse and at time of progression under first line metastatic treatment.ResultsA total of 42 patients were included, with a median adjuvant AI exposure of 60 months (range 41–85). No circulating ESR1 mutation was detectable at the end of AI adjuvant therapy. At first relapse, 5.3% of the patients (2/38) had a detectable circulating ESR1 mutation. At time of progression on first-line metastatic treatment, 33% of the patients (7/21) under AI had a detectable circulating ESR1 mutation compared to none of the patients under chemotherapy (0/10). The two patients with a detectable ESR1 mutation at relapse were treated by AI and had an increase of their variant allele fraction at time of progression on first-line metastatic treatment.ConclusionsCirculating ESR1 mutation detection at the end of AI-based adjuvant treatment is not clinically useful. Circulating ESR1 mutation could be assessed as soon as first relapse to guide interventional studies.

The Emerging Role of ESR1 Mutations in Luminal Breast Cancer as a Prognostic and Predictive Biomarker of Response to Endocrine Therapy

“…However, Kuang et al observed higher rates of ESR1 mutations in patients treated with AI regardless of the treatment setting (adjuvant, metastatic or both) [39]. In line with the concept that ESR1 mutations are primarily acquired during aromatase inhibitors treatment, Allouchery et al have recently published findings from 42 patients with early BC treated with AI for at least 2 years, showing that ESR1 mutations were not found in any of the studied patients [40]. These data confirm prior observations that detecting ESR1 mutations in early BC is a rare event, ranging between 2 and 5% depending on the dataset [22].…”

Clinical Implications of Monitoring ESR1 Mutations by Circulating Tumor DNA in Estrogen Receptor Positive Metastatic Breast Cancer: A Pilot Study

“…Previous research showed that acquired ESR1 mutations in ctDNA are rare before adjuvant AI treatments, but are frequently selected by AI therapies for metastatic disease, which provide molecular mechanism of resistance to AI therapy [[16], [17], [18], [19], [20], [21], [22]]. It is worth noting that how long to detect ESR1 mutations after AI exposure would be clinically useful.…”

<p>Advances in the Detection Technologies and Clinical Applications of Circulating Tumor DNA in Metastatic Breast Cancer</p>

“…Allouchery et al found that the mutation frequency of ESR1 increased with the development of relapse and progression (5.3% and 33%, respectively), suggesting that detecting circulating ESR1 mutations should be focused on the metastatic setting. 86 A secondary analysis of the BOLERO-2 clinical trial by Chandarlapaty et al demonstrated that each of the ESR1 mutations was associated with shorter OS. 87 Paoletti et al found that patients with persistently elevated ESR1LBDm + ctDNA had worse PFS than patients who did not (P = 0.0007).…”