Approximately 70% of breast cancers are hormone receptor–positive (HR-positive) and HER2-negative. First-line treatment typically combines a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) with an aromatase inhibitor (AI) to suppress estrogen-driven tumor growth. However, about 40% of patients develop acquired mutations in the ESR1 gene during AI therapy, leading to ligand-independent activation of estrogen receptor alpha (ERα) and treatment resistance. As resistance to both endocrine therapy and CDK4/6 inhibitors emerges, treatment options become limited, and prognosis worsens—only 35% of patients with advanced disease are expected to survive beyond five years.

In HR+/HER2- breast cancer, the phase III SERENA-6 trial (Abstract LBA4) is the most talked-about abstract at ASCO 2025 because it challenges the conventional treatment approach that suggests waiting for evident disease progression before changing treatment. Instead, SERENA-6 investigates the proactive therapy switching approach when circulating tumor DNA (ctDNA) in the blood shows estrogen receptor 1 mutation (ESR1m) mutations, which show resistance to standard endocrine drugs, even before scans confirm progression.

The researchers screened more than 3,300 patients at 264 different clinical sites in 23 countries,  for ESR1m using circulating tumor DNA (ctDNA) until 315 eligible patients were randomized to switch to camizestrant (n = 157) or continue with an aromatase inhibitor (n = 158). All patients remained on the same CDK4/6i. Approximately 50% of randomized patients had ESR1m detected at the first ctDNA test. Baseline characteristics were well balanced between treatments. 

After 171 progression-free survival (PFS) events, the hazard ratio for progression-free survival was 0.44 (95% confidence interval (CI) 0.31 – 0.60,  p < 0.00001; median progression-free survival 16.0 vs. 9.2 months). The PFS benefit was consistent across subgroups. The PFS rate at 12 months was 60.7% (95% confidence interval 51.1–69.0) vs 33.4% (95% confidence interval 24.9–42.2), and at 24 months was 29.7% (95% confidence interval 19.0–41.2) vs. 5.4% (95% confidence interval 0.7–18.2). Second PFS (PFS2) hazard ratio was 0.52 (95% confidence interval 0.33–0.81; 27% maturity). Overall survival (OS) is immature (12%). 

Camizestrant plus CDK4/6i was well tolerated with safety consistent with the known profiles of camizestrant and each CDK4/6 inhibitor. Rates of treatment discontinuation due to adverse events were 1.3% for camizestrant and 1.9% for the aromatase inhibitor.

KOL insights: 

“Patients with advanced breast cancer have an urgent need for new treatments that delay disease progression on first-line endocrine-based therapies. Treatment switching at molecular progression based on a blood test for ctDNA rather than on seeing the cancer get worse on a scan is novel. It takes advantage of both our knowledge of cancer resistance and the ability to find the resistance markers in the blood before the cancer can get worse.”– Expert Opinion

“Monitoring patients for ESR1 mutations provided a ‘head start’ on the next treatment, enabling it to extend the time to anatomic progression compared with usual management.”– Expert Opinion

“While the immediate PFS benefit is exciting, caution that it’s crucial to assess if this translates to long-term benefits like overall survival (OS), and to rule out “lead time bias” – where earlier detection merely leads to an earlier switch in therapy without truly extending life.”– Expert Opinion

“SERENA-6 offers a “powerful glimpse into the future of precision oncology, where we don’t just react to cancer progression, we anticipate it,” representing a “bold, modern shift toward truly personalized, proactive care”– Expert Opinion

“The main message here is that liquid biopsy technology allows us to intervene sooner when the tumour burden is lower and the chance of a good outcome is higher,”– Expert Opinion

Conclusion: 

The Phase III SERENA-6 trial establishes a new paradigm in managing HR-positive, HER2-negative advanced breast cancer by demonstrating that ctDNA-guided treatment adaptation can significantly improve outcomes. Unlike the earlier PADA-1 study, which suggested benefit from switching therapy upon ESR1 mutation detection but lacked methodological rigor, SERENA-6 addressed these limitations with a randomized, double-blind, placebo-controlled design. Patients who switched early to camizestrant plus a CDK4/6 inhibitor following ESR1 mutation detection via ctDNA had a significantly longer progression-free survival (16.0 vs 9.2 months) compared to those who continued on an aromatase inhibitor. This supports the value of molecular monitoring to preempt clinical progression. Although overall survival data remain immature, the trial provides strong evidence that early intervention based on ctDNA may delay resistance and optimize first-line therapy. These findings underscore the clinical potential of serial ctDNA testing and position SERENA-6 as the first pivotal study to validate this precision-guided approach in breast cancer.