Background
Exploratory biomarker analysis from the Phase III SONIA trial. N=409 (141 high ctDNA, 268 low ctDNA) with HR+/HER2- advanced breast cancer. Pretreatment circulating tumor DNA (ctDNA) assessed by modified fast aneuploidy screening test-sequencing (mFAST-seq).
Interventions and follow up
Arm A: First-line aromatase inhibitor + CDK4/6i (ctDNA-stratified)
Arm B: Second-line fulvestrant + CDK4/6i (ctDNA-stratified)
Primary endpoint: PFS after 2 lines (PFS2) stratified by ctDNA status
mFollow up: 58.5mo
Arm B: Second-line fulvestrant + CDK4/6i (ctDNA-stratified)
Primary endpoint: PFS after 2 lines (PFS2) stratified by ctDNA status
mFollow up: 58.5mo
Results
PFS2 (high ctDNA, aneuploidy ≥5): HR 0.58, 95% CI 0.38–0.88 — favors first-line CDK4/6i
PFS2 (low ctDNA, aneuploidy <5): HR 1.36, 95% CI 0.95–1.96 — favors second-line CDK4/6i
Interaction: P=.004
PFS2 (low ctDNA, aneuploidy <5): HR 1.36, 95% CI 0.95–1.96 — favors second-line CDK4/6i
Interaction: P=.004
Adverse events
Overall: higher grade 3–4 rates with first-line CDK4/6i in both ctDNA groups
Profile: consistent with the parent SONIA trial (neutropenia, anemia predominant)
Profile: consistent with the parent SONIA trial (neutropenia, anemia predominant)
Conclusions
Pretreatment ctDNA levels identified patients benefiting from first-line CDK4/6i (high ctDNA) versus second-line use (low ctDNA), demonstrating a potential ctDNA-driven treatment-timing strategy in HR+/HER2- MBC.
Key Limitations
Exploratory post hoc analysis (not prespecified); modest subgroup sample sizes; ctDNA testing not routinely available; requires prospective validation; aneuploidy score cutoff (≥5 vs <5) selected post hoc.
Clinical Context
Provides preliminary evidence for ctDNA-driven personalization of CDK4/6i timing. If validated prospectively, could inform precision-timing strategies that optimize benefit while limiting toxicity and cost in HR+/HER2- MBC.
References