Editor’s Note: ESR1 mutation is a major mechanism of acquired resistance during first-line endocrine therapy for HR+/HER2− advanced breast cancer. At this year’s ESMO Breast Cancer Congress, Professor François Clément Bidard from Institut Curie presented screening-phase data from the SERENA-6 study (Abstract No. 419RO).The study prospectively monitored the emergence of ESR1 mutations using dynamic ctDNA surveillance during treatment with aromatase inhibitors (AI) plus CDK4/6 inhibitors. Results showed that the ESR1 mutation detection rate was approximately 10% at first testing, rising cumulatively to 20% after one year of continued monitoring. Most mutations were concentrated in specific hotspot regions within exons 5 and 8, supporting the feasibility of lower-cost targeted assays such as ddPCR.
These findings provide strong support for implementing routine ESR1 monitoring in clinical practice and for adjusting treatment strategies before overt disease progression occurs. Oncology Frontier invited Professor François Clément Bidard to further discuss the screening-phase findings of SERENA-6 and their clinical implications.
Study Overview
Background
The SERENA-6 trial previously demonstrated that switching to camizestrant while continuing CDK4/6 inhibitor therapy after ctDNA detection of ESR1 mutations—but before radiologic disease progression—significantly improved progression-free survival (PFS) compared with continuing AI plus CDK4/6 inhibitor therapy.
The current analysis focused specifically on the ESR1 mutation monitoring phase of SERENA-6 in patients receiving first-line AI plus CDK4/6 inhibitor treatment.
Study Design
Patients could enroll at any point during first-line treatment, provided they had already received AI plus CDK4/6 inhibitor therapy for at least six months.
Initial ESR1 mutation testing was performed using Guardant360® CDx. Patients whose first test was negative underwent repeat testing every two to three months alongside routine clinical evaluations. ESR1 monitoring continued until the predefined randomization target was reached.
Study Results
Between June 2021 and June 2024, patients were screened at 264 centers across 23 countries. A total of 3,256 patients underwent at least one ESR1 mutation test during first-line treatment.
At the end of screening:
- 1,949 patients remained under monitoring without ESR1 mutation detection or disease progression
- 548 patients tested positive for ESR1 mutations during surveillance
After excluding patients still undergoing surveillance, the estimated overall ESR1 mutation detection rate was 42%.
At first ESR1 testing:
- Patients tested between 6 and 24 months after starting AI plus CDK4/6 inhibitor therapy had an ESR1 mutation rate of 8.0%
- Those tested between >24 and 60 months had a rate of 11.9%
- Patients treated for more than 60 months had a rate of 6.3%
For patients whose initial test was negative, ongoing monitoring every two to three months identified additional ESR1-positive cases. Within five sequential testing rounds, the cumulative ESR1 mutation incidence reached 19.6%.
Among randomized patients (n=315), 94% carried at least one of four major ESR1 hotspot mutations:
- D538G (48%)
- Y537S (38%)
- Y537N (17%)
- E380Q (10%)
Other mutations—including Y537C, L536H, L536P, L536R, V422del, and S463P—were relatively uncommon, each occurring in 5% or fewer patients.
Notably, 18% of patients harbored more than one ESR1 mutation variant.
The study also found that the median variant allele frequency (VAF) among randomized patients was relatively low, consistent with the study’s strategy of detecting ESR1 mutations before radiographic progression becomes clinically apparent.
Study Conclusions
Although ESR1 mutations were frequently detected during initial screening in SERENA-6, continued monitoring identified substantially more ESR1-positive patients over time, supporting the need for serial testing rather than one-time assessment alone.
The findings suggest that all patients receiving AI plus CDK4/6 inhibitor therapy should undergo ESR1 mutation testing regardless of treatment duration. Furthermore, patients with initially negative results should continue regular surveillance alongside routine clinical assessments until either ESR1 mutation emergence or disease progression occurs.
Investigator Commentary
Professor François Clément Bidard explained that SERENA-6 was designed as an innovative clinical trial aimed at tracking the emergence of ESR1 mutations over time in patients receiving first-line aromatase inhibitor plus CDK4/6 inhibitor therapy.
He noted that the screening-phase data demonstrated an approximately 10% ESR1 mutation detection rate at the time of first testing among previously untested patients. However, when patients continued undergoing serial monitoring over approximately one year, the cumulative mutation rate rose to roughly 20%, indicating that ESR1 mutations are relatively common and continue to emerge over time.
Professor François Clément Bidard also highlighted that most mutations clustered within hotspot regions in exons 5 and 8. This finding is particularly important because it opens the possibility of using lower-cost targeted testing approaches, such as droplet digital PCR (ddPCR), which can effectively detect nearly all clinically relevant ESR1 mutations by focusing on these hotspot regions alone.
Another important observation was the low median variant allele frequency detected in randomized patients. According to Professor François Clément Bidard, this aligns closely with the central concept of SERENA-6: intercepting disease evolution before overt clinical or radiographic progression develops.
He emphasized that the goal of the study is to identify resistance early enough to modify therapy before patients develop symptoms associated with disease progression.
Professor François Clément Bidard summarized the key clinical messages as follows:
- A single ESR1 test detects mutations in approximately 10% of patients
- Continued monitoring over one year increases detection to roughly 20%
- Ultimately, 30%–40% of patients may develop ESR1 mutations over time
Importantly, these mutations are relatively easy to detect because most occur within two hotspot regions and can be identified using either next-generation sequencing (NGS) or more targeted ddPCR-based approaches.
Professor François Clément Bidard
