Plenary: The SERENA-6 Trial

During the plenary session of ASCO 2025, Professor Nicholas Turner presented the results from the Phase III SERENA-6 trial. Prof Michail Ignatiadis and Dr Elisa Agostinetto, both working at the Institut Jules Bordet, Hôpital Universitaire de Bruxelles, discussed these data. 

This phase III, double-blind trial evaluated the impact of switching endocrine therapy upon detection of ESR1 mutations via ctDNA monitoring in patients with hormone receptor-positive breast cancer. Patients receiving CDK4/6 inhibitors plus aromatase inhibitors for at least six months underwent serial ctDNA testing. Upon detection of ESR1 mutations in the absence of radiological progression, participants were randomised to continue standard therapy or switch to the oral SERD, camizestrant, while maintaining CDK4/6 inhibition.

The primary endpoint was PFS. Results demonstrated a significant improvement in PFS with the introduction of camizestrant compared to continued aromatase inhibitor therapy. Quality of life outcomes also favoured the camizestrant arm. Long-term endpoints such as OS and PFS after subsequent therapy remain immature. Notably, the study did not allow for crossover in the control arm for patients who progressed, which may impact the interpretation of OS outcomes. The lack of crossover may also influence PFS2, given differences in the number of treatment lines between study arms. The trial underscores the feasibility of early intervention targeting acquired resistance mechanisms detected via ctDNA.

While promising, these findings have not yet led to changes in clinical practice due to incomplete survival data and concerns about implementing intensive ctDNA monitoring in routine care. Ongoing studies aim to address these gaps, including those assessing ctDNA-guided treatment in the early breast cancer setting. ESR1 mutation detection at different times during therapy could indicate biological heterogeneity, although current data do not reveal clear subgroup differences.

The role of ctDNA as a biomarker to guide therapy change in endocrine-resistant breast cancer continues to evolve. Current efforts in related trials aim to confirm whether early molecular interventions can prevent distant relapse and improve survival.