R Varnier 1, D Pérol 2, W Jacot 3, A Mailliez 4, V Diéras 5, F Dalenc 6, A Gonçalves 7, C Levy 8, M Arnedos 9, J-S Frenel 10, C Bailleux 11, V Massard 12, E Brain 13, B Sauterey 14, A-M Savoye 15, L Bosquet 16, J-C Thery 17, T Petit 18, T Bachelot 2, T Grinda 19, I Ray-Coquard 20
Affiliations Expand
PMID: 40967066
PMCID: PMC12478084
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.
