PurposeTo assess the prognostic and predictive value of circulating ESR1 mutation and its kinetics before and after progression on aromatase inhibitor (AI) treatment.Patients and methodsESR1 circulating D538G and Y537S/N/C mutations were retrospectively analyzed by digital droplet PCR after first-line AI failure in patients treated consecutively from 2010 to 2012 for hormone receptor-positive metastatic breast cancer. Progression-free survival (PFS) and overall survival (OS) were analyzed according to circulating mutational status and subsequent lines of treatment. The kinetics of ESR1 mutation before (3 and 6 months) and after (3 months) AI progression were determined in the available archive plasmas.ResultsCirculating ESR1 mutations were found at AI progression in 44/144 patients included (30.6%). Median follow-up from AI initiation was 40 months (range 4-94). The median OS was decreased in patients with circulating ESR1 mutation than in patients without mutation (15.5 versus 23.8 months, P=0.0006). The median PFS was also significantly decreased in patients with ESR1 mutation than in patients without mutation (5.9 vs 7 months, P=0.002). After AI failure, there was no difference in outcome for patients receiving chemotherapy (n = 58) versus non-AI endocrine therapy (n=51) in patients with and without ESR1 mutation. ESR1 circulating mutations were detectable in 75% of all cases before AI progression, whereas the kinetics 3 months after progression did not correlate with outcome.ConclusionESR1 circulating mutations are independent risk factors for poor outcome after AI failure, and are frequently detectable before clinical progression. Interventional studies based on ESR1 circulating status are warranted.

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)

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.

No abstract

No abstract

No abstract

Si la présence de cellules tumorales circulantes (CTC) et d’ADN tumoral circulant (ADNtc) est connue de longue date, seuls les progrès technologiques récents ont permis d’évaluer l’intérêt de cette approche dans le cancer du sein. La détection de CTC, tant pour les cancers du sein localisés que métastatiques, est un facteur de mauvais pronostic établi, mais qui ne permet pas de proposer de prise en charge spécifique. L’usage de l’ADNtc nécessite des validations prospectives, mais semble particulièrement prometteur pour la recherche demaladie résiduelle ou l’identification de clones tumoraux porteurs de mutations (PI3KCA, ESR1) permettant de prédire l’efficacité ou la résistance thérapeutique.

e12534 Background: Circulating cell free DNA (cfDNA), CA 15.3 and circulating tumor DNA (ctDNA) have been associated with survival in MBC. These 3 biomarkers have never been compared. Methods: We retrospectively included all patients treated in our center between 2010 and 2012 for a HR+ MBC, who had clinical progression during the first line of aromatase inhibitor (AI) and available plasma samples. CfDNA level (ng/mL), CA 15.3 level (U/mL) and ESR1 circulating mutation level (Y537N, Y537S, Y537C and D538G, identified by ddPCR) were determined at time of clinical progression (Tp) and 3 months before (Tp-3). Biomarkers values at Tp and Tp-3 as well as their variations were analyzed according to clinical progression and overall survival (OS). Results: 91 patients were analyzed. CA 15.3 was elevated ( > 30 U/mL) in 71/91 (78%) at Tp and 62/91 (68%) at Tp-3. Higher CA 15.3 was associated with worse OS, especially at Tp (HR = 1.0006/unit at both times, p = 0.009 at Tp; p = 0.08 at Tp-3). Higher cfDNA was associated with worse OS, both at Tp and Tp-3 (HR = 1.006/unit, p < 0.0001 and HR = 1.007/unit, p = 0.02, respectively). An ESR1 mutation was detected in 14/91 at Tp-3 (15%) and 28/91 at Tp (31%). ESR1 mutation detection was strongly correlated with OS both at Tp and Tp-3 (HR = 2.4, p = 0.0005 and HR = 1.97, p = 0.03, respectively). Between Tp-3 and Tp, overall median CA 15.3 and ESR1 mutation level increased (p < 0.0001 and p = 0.007, respectively) and were related to poorer OS (HR = 1.007/unit, p = 0.0002 and HR = 3.1, p = 0.05). In contrast, CfDNA was not correlated at all with clinical progression (36/91 increase, 36/91 decrease, and 19/91 stable cfDNA). ROC curve analysis identified a 59% CA 15.3 increase as the best cut-off for predicting progression, but with poor performance (AUC = 0.64). Multivariate analysis showed that CA 15.3 at Tp (HR = 1.0006/unit, p = 0.006), cfDNA at Tp (HR = 1.005/unit, p = 0.01), ESR1 detection at Tp (HR = 2.7, p = 0.0002) and CA 15.3 increase between Tp-3 and Tp (HR = 1.006/unit, p = 0.003) were associated with poor OS. Conclusions: All 3 biomarkers are correlated with OS in MBC treated with AI. CfDNA variation is poorly related to clinical progression while CA 15.3 variation or ESR1 mutation detection are much more reliable. Overall the better performance is observed with ESR1 mutation detection.