Varnier R, Pérol D, Jacot W, Mailliez A, Diéras V, Dalenc F, Gonçalves A, Levy C, Arnedos M, Frenel JS, Bailleux C, Massard V, Brain E, Sauterey B, Savoye AM, Bosquet L, Thery JC, Petit T, Bachelot T, Grinda T, Ray-Coquard I.
ESMO Open. 2025 Oct;10(10):105803.
PMID: 40967066
DOI: 10.1016/j.esmoop.2025.105803
Abstract
Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have improved the prognosis of hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), but their impact on the efficacy of second-line treatments remains poorly described.
Materials and methods: This retrospective study included patients from the Epidemiological Strategy and Medical Economics database who initiated endocrine therapy ± CDK4/6i as first-line treatment for HR-positive/HER2-negative MBC between 2008 and 2019 across 18 French cancer centres and subsequently received second-line therapy. Objectives were to describe treatment patterns, time to progression (TTP), and post-progression survival after CDK4/6i, and to compare chemotherapy efficacy between CDK4/6i-exposed and historical CDK4/6i-naive patients, using propensity score adjustments.
Results: Among 13 577 HR-positive/HER2-negative MBC patients, 538 received CDK4/6i and 4030 received endocrine therapy alone as first-line treatment. Following CDK4/6i exposure, 47% of patients received chemotherapy as first subsequent treatment {median TTP 5.94 months [95% confidence interval (CI) 5.23-7.10 months]; 5.00 months (95% CI 3.68-6.63 months) for taxanes, 6.43 months (95% CI 3.87-12.29 months) for anthracyclines, 7.62 months (95% CI 6.13-8.30 months) for fluoropyrimidines}, 26% received endocrine therapy alone [6.14 months (95% CI 4.43-10.03 months)], 16% received phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors [5.16 months (95% CI 3.90-6.48 months)], and 9% underwent CDK4/6i rechallenge [9.57 months (95% CI 6.0 months-not applicable)]. In the comparative analysis, chemotherapy appeared slightly less effective in CDK4/6i-exposed patients than in CDK4/6i-naive patients, with a median TTP of 5.77 months (95% CI 5.13-6.67 months) versus 7.77 months (95% CI 7.428.07 months), respectively. This difference remained significant after adjusting for patient characteristics (hazard ratio 1.26, P = 0.003), except for comparison with fluoropyrimidine-based regimens, which showed comparable efficacy across groups.
Conclusions: This study highlights the variability in second-line treatment strategies following CDK4/6i and suggests the presence of cross-resistance reducing the efficacy of subsequent chemotherapy.
Keywords: CDK4/6 inhibitor; breast cancer; cross-resistance; second-line therapy; treatment patterns.
