S-1 versus capecitabine as first-line chemotherapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer in the era of cyclin-dependent kinase 4/6 inhibitors: a retrospective cohort study

Oral fluoropyrimidines, including capecitabine and S-1, are widely used for treating hormone receptor-positive, HER2-negative (HR + /HER2 − ) metastatic breast cancer (MBC). In the modern era, defined by standard-of-care cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, evidence on their comparative effectiveness and the effect of prior CDK4/6 inhibitor exposure is limited. This study evaluated the survival outcomes of capecitabine versus S-1 as first-line chemotherapy and assessed whether prior CDK4/6 inhibitor use affected these outcomes. We conducted a retrospective cohort study of patients with HR + /HER2 − MBC who received capecitabine or S-1 as first-line chemotherapy between 2015 and 2023. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan–Meier method and Cox proportional hazards models. Outcomes were compared according to prior CDK4/6 inhibitor exposure and chemotherapeutic regimen. This study enrolled 123 patients. In the overall cohort, the median PFS and OS were 7.6 and 34.7 months, respectively. Eighty-five patients (69%) had prior CDK4/6 inhibitor exposure, which did not significantly affect survival. The median PFS was 7.3 months in patients with and 10.1 months in those without prior exposure ( p = 0.64), while the median OS was 34.8 and 34.7 months, respectively ( p = 0.59). S-1 showed a longer OS compared with capecitabine, although the PFS was similar between the two regimens. The median PFS was 6.7 months in patients receiving capecitabine ( n = 43) and 8.7 months in those receiving S-1 ( n = 80) ( p = 0.19). The median OS was 40.1 versus 24.0 months with S-1 and capecitabine, respectively ( p = 0.010); multivariate analysis revealed that S-1 was an independent favorable prognostic factor for OS (HR 0.39, 95% CI 0.24–0.66, p < 0.001). The rates of treatment discontinuation due to adverse events were similar between the two regimens. First-line oral fluoropyrimidines remain effective for HR + /HER2 − MBC in the modern era of CDK4/6 inhibitors. Prior CDK4/6 inhibitor exposure did not adversely affect survival outcomes. Although the PFS was similar between capecitabine and S-1, S-1 was associated with a significantly longer OS. These findings necessitate further investigation to elucidate the mechanisms underlying the observed survival difference.