Metronomic capecitabine as extended adjuvant chemotherapy for early triple-negative breast cancer (SYSUCC-001): updated 10-year outcomes and post-hoc exploratory biomarker analysis from a randomised, phase 3 trial

Background: In the primary report of the SYSUCC-001 trial, 1 year of metronomic capecitabine improved 5-year disease-free survival in patients with operable triple-negative breast cancer. Here, we provide updated 10-year disease-free survival and overall survival data from extended follow-up, together with an exploratory analysis of FOXC1 as a potential predictive biomarker.

Methods: This post-hoc, long-term analysis of an open-label, multicentre, phase 3 trial was conducted at 13 centres in China. Eligible women with stage T1b-3 N0-3c M0 triple-negative breast cancer who had completed standard adjuvant therapy were randomly assigned (1:1) to receive oral metronomic capecitabine 650 mg/m2 twice daily for 1 year or observation. Here, we report 10-year follow-up data, including all of the original prespecified trial endpoints: disease-free survival (primary outcome), overall survival, distant disease-free survival, and locoregional recurrence-free survival analysed in the full analysis set. Exploratory biomarker analysis of FOXC1 was undertaken using immunohistochemistry on baseline tumour samples. This trial is registered with ClinicalTrials.gov, NCT01112826, and is complete.

Findings: Between April 23, 2010, and Dec 31, 2016, 443 participants were enrolled and randomly assigned, of whom 434 initiated the intervention as assigned and were included in the primary analysis (221 in the capecitabine group, 213 in the observation group). As of data cutoff for this analysis (March 31, 2025), 420 (97%) participants had available follow-up data and the median duration of follow-up was 116·0 months (IQR 96·0-134·8). The updated 10-year disease-free survival was significantly higher in the capecitabine group than in the observation group (78·1% vs 66·6%; hazard ratio [HR] 0·61; 95% CI 0·43-0·88; p=0·0074). 10-year overall survival was not significantly different between the two groups (82·4% vs 73·7%; HR 0·67; 95% CI 0·45-1·01; p=0·058). The 10-year distant disease-free survival rates were 78·1% versus 66·5% (HR 0·61; 95% CI 0·43-0·88; p=0·0075) and 10-year locoregional recurrence-free survival rates were 81·6% versus 69·9% (0·60; 0·40-0·89; p=0·011). The FOXC1 biomarker cohort comprised 338 (78%) patients (171 [51%] from the capecitabine group, 167 [49%] from the observation group). In FOXC1-high patients (n=149), capecitabine conferred superior disease-free survival (HR 0·33; 95% CI 0·16-0·68; p=0·0027) and overall survival (0·25; 0·10-0·62; p=0·0028) compared with observation, whereas the FOXC1-low subgroup (n=189) showed no benefit with capecitabine versus observation.

Interpretation: In this exploratory, long-term analysis, extended adjuvant metronomic capecitabine provided durable disease-free survival benefit in early triple-negative breast cancer, although the findings should be interpreted with caution given the post-hoc nature of the analysis. Patients with FOXC1-high tumours showed a survival advantage with capecitabine versus observation; if this finding is validated, FOXC1-driven patient selection might be useful to optimise therapeutic responses.

Funding: National Natural Science Foundation of China and Guangdong Esophageal Cancer Institute Science and Technology Program.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.