Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) in combination with endocrine therapy are the current standard of care for the first-line treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (aBC). However, most patients’ disease will progress within a few years, and there have been limited insights into which patients are at higher risk for early relapse using this therapy approach. Development of sensitive genetic testing methodologies for liquid biopsies has allowed for a window into the ongoing dynamics of breast cancer. Circulating tumor DNA (ctDNA), a component of cell-free DNA shed by tumor cells into the bloodstream, has emerged as a potentially powerful tool for noninvasive genomic profiling and dynamic treatment monitoring. The phase IIIb BioItaLEE trial (Bianchini et al, Clin Cancer Res) was designed to prospectively evaluate the prognostic and predictive value of baseline and early ctDNA dynamics in postmenopausal patients with HR+, HER2− aBC treated with first-line ribociclib plus letrozole.
BioItaLEE was a multicenter, open-label, single-arm study conducted in Italy (NCT03439046; N =287). Postmenopausal patients with HR+, HER2− aBC—locoregionally recurrent or metastatic—in the first-line setting received ribociclib 600 mg orally daily on a 3-weeks-on/1-week-off schedule in combination with letrozole 2.5 mg orally once daily. Serial blood samples for ctDNA analysis were collected at baseline, cycle 1 day 15 (C1D15), and cycle 2 day 1 (C2D1), and at the time of first imaging assessment, progression, and/or study treatment discontinuation. The primary objective was to identify and track the evolution of baseline ctDNA genomic alterations during treatment and evaluate their potential association with progression-free survival (PFS).
At baseline, detectable ctDNA mutations were identified in 43% of biomarker-evaluable patients (n = 104), with the most frequently altered genes being PIK3CA (22.1%) and TP53 (15.5%). Across the full study population at a median follow-up of 26.9 months, median PFS was 23.4 months. The objective response rate was 35.9% and clinical benefit rate at 24 weeks was 72.3%, with median duration of response not reached. The safety profile of ribociclib plus letrozole was consistent with prior experience; 15.7% of patients discontinued ribociclib due to adverse events, and 6.3% experienced severe adverse events.
Alterations in TP53, MYC, and HER-pathway and CDK4/6-pathway genes were associated with early progression. In this population, patients without a detectable mutation at baseline (n = 150, 57%) had significantly better outcomes, with a median PFS that was not estimable vs 16.6 months in those with detectable mutations at baseline (hazard ratio = 0.41). Among patients with a baseline-detectable mutation, early ctDNA clearance was observed in 47.1% at C1D15 and 52.4% at C2D1, and clearance at either time point was associated with meaningfully improved median PFS: 21.85 versus 12.09 months for patients without ctDNA clearance at C1D15 (hazard ratio = 0.51; P = .0228), and 22.11 vs 12.32 months at C2D1 (hazard ratio = 0.44).
These results establish both pretreatment ctDNA status and early ctDNA dynamics as promising biomarkers in this setting, with potential implications for oncologists across practice environments.
High Level
The BioItaLEE data provide important correlative data showing the potential of ctDNA monitoring for prognostic and early predictive insights in HR+, HER2− aBC. The association between early clearance (detectable as soon as C1D15, just 2 weeks into treatment) and higher PFS raises a compelling question regarding the clinical utility of early ctDNA kinetics as a pharmacodynamic surrogate for treatment efficacy, potentially identifying patients unlikely to derive durable benefit. Further studies are needed to determine if closer monitoring or changing the therapeutic approach on the basis of the lack of ctDNA clearance could improve outcomes in such patients. The identification of TP53, MYC, and CDK4/6-pathway alterations as drivers of early progression also warrants additional validation, as these have potential utility as study enrollment or stratification criteria in clinical trials for first-line treatment of HR+, HER2– aBC. Additional areas for future investigation may include identification of potential “rescue” approaches to delay clinical progression in patients in whom ctDNA is not cleared and the role of later ctDNA testing (beyond C2 and first imaging) to identify predictive biomarkers or resistance mechanisms contributing to disease progression. Future studies could expand to include additional treatments beyond letrozole and ribociclib, such as other endocrine and targeted therapy approaches.
Ground Level
For community oncologists managing care for patients with HR+, HER2− aBC, the BioItaLEE trial sets up a potential role for early ctDNA testing in first-line treatment. This study reported that patients without detectable mutations at baseline had substantially better PFS. Among those with detectable mutations, clearance of ctDNA within the first 2 weeks of treatment closely correlated with improved outcomes. While ctDNA monitoring is not an established standard of care, and further validation is needed, it might have some utility in specific settings currently. For example, in patients for whom regular imaging is not feasible (eg, due to frailty or costs), ctDNA testing at baseline and in early cycles of first-line endocrine therapy might provide insights into early progression risk. These findings support the growing interest in liquid biopsy for follow-up for patients on endocrine and CDK4/6 inhibitor-based therapy, and further investigation into the potential of ctDNA to guide therapy decisions is warranted.