SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.
Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of ER+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including the development of ESR1 (Estrogen Receptor gene alpha) mutations.
Background
The SERENA-6 trial is the first global registrational Phase 3 study to evaluate a ctDNA-guided approach for the early detection and treatment of ESR1 mutations in HR+, HER2-negative advanced breast cancer. ESR1 mutations, which promote ligand independent Estrogen Receptor activation, are a common mechanism of acquired resistance to estrogen deprivation therapies such as Aromatase Inhibitors (AIs) plus CDK4/6 inhibitors (CDK4/6i). ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, has been associated with shorter Overall Survival. ESR1 mutations are typically absent at diagnosis but emerge during AI therapy. Detecting ESR1 mutations through circulating tumor DNA (ctDNA) provides a non-invasive method to identify molecular progression prior to radiographic evidence.
Camizestrant is an oral, next-generation Selective Estrogen Receptor Degrader (SERD) with antagonist activity against both wild-type and mutant estrogen receptors. SERENA-6 evaluated whether switching to Camizestrant plus continued CDK4/6i upon ctDNA detection of ESR1 mutations, but before radiographic progression, can improve outcomes, compared to continuing the standard AI-based regimen.
Study Design and Results
SERENA-6 is a randomized, double-blind, Phase 3 trial in which 3,256 patients with HR+/HER2-negative advanced breast cancer who had received 6 or more months of first-line AI + CDK4/6 inhibitor (Palbociclib, Ribociclib, or Abemaciclib) were surveilled for ESR1 mutations using ctDNA performed every 2-3 months alongside routine imaging. Upon ESR1 mutations detection without clinical progression, 315 eligible patients (N=315) who were found to have an ESR1 mutation during ctDNA surveillance were randomized were randomized 1:1 to Switch to Camizestrant (75 mg daily) + continued CDK4/6i + placebo for AI (N=157) or continue AI + CDK4/6i + placebo for Camizestrant (N=158). Both treatment groups were well balanced. Stratification included visceral disease status, timing of ESR1 mutation detection, prior duration of therapy, and CDK4/6 inhibitor type. The Primary endpoint was Investigator-assessed Progression-Free Survival (PFS).
At the prespecified interim analysis, about 50% had ESR1mutations detected on the first ctDNA test. The median PFS was significantly longer with Camizestrant – 16.0 vs 9.2 months; HR=0.44, P<0.00001. This PFS benefit was consistent across all subgroups. The 12-month PFS rates were 60.7% in the Camizestrant group vs 33.4% in the control group. The 24-month PFS rates: 29.7% vs 5.4%. Overall survival (OS) data remains immature. Patients in the Camizestrant arm had a quality of life that was maintained longer than the AI group.
Treatment discontinuation due to adverse events were low at 1.3% for the Camizestrant, and 1.9% for the Aromatase Inhibitor group.
Clinical Implications
SERENA-6 demonstrated that early, ctDNA-guided switching from AI to Camizestrant in patients with emergent ESR1 mutations significantly prolonged PFS without added toxicity. This trial is the first to validate a molecular response–guided treatment strategy in HR+/HER2-negative advanced breast cancer, potentially redefining first-line management.
However, questions remain regarding long-term Overall Survival benefits and the cost-effectiveness and logistical feasibility of serial ctDNA monitoring. Additional follow-up and Real-World Data will be crucial to determine the broader clinical utility of this approach.
Conclusion
Camizestrant in combination with CDK4/6 inhibition, guided by ctDNA detected ESR1 mutations emergence, offers a promising new treatment paradigm for HR+/HER2-negative advanced breast cancer. SERENA-6 paves the way for incorporating precision molecular monitoring into routine first-line management.
Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2– advanced breast cancer (ABC): Phase 3, double-blind ctDNA-guided SERENA-6 trial. Turner N, Mayer E, Park YH, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA4).
