三陰性乳腺癌的雌激素受體、孕激素受體、HER2均為陰性，占全部乳腺癌的15%～20%，對傳統(tǒng)的內(nèi)分泌治療和HER2靶向治療無效，術(shù)后主要依靠化療，與其他乳腺癌相比，早期遠處復發(fā)風險較高，免疫治療問世之前，即使術(shù)后進行標準化療，仍有高達30%的早期患者3年內(nèi)復發(fā)。該嚴峻的臨床現(xiàn)實迫切需要有效延長術(shù)后治療以改善長期療效，尤其對于缺乏靶向治療方案的三陰性乳腺癌患者。

5年前，國際四大醫(yī)學期刊之一《美國醫(yī)學會雜志》創(chuàng)刊百余年來首次發(fā)表中國乳腺癌研究：SYSUCC-001。該研究5年隨訪結(jié)果表明，對于已完成術(shù)后標準治療的早期三陰性乳腺癌患者，將每天2次口服低劑量化療藥物卡培他濱1年作為延長術(shù)后化療方案，與僅僅觀察相比，5年無病生存率提高9.8%（82.8%比73.0%），病變或死亡風險降低36%（風險比：0.64，95%置信區(qū)間：0.42～0.95）。此前，CREATE-X研究已證實高風險三陰性乳腺癌術(shù)后完成標準治療再用常規(guī)劑量卡培他濱治療有效，對于術(shù)前化療后殘留病灶患者，5年無病生存率絕對提高10.7%，EA1131研究也證實對于三陰性乳腺癌基底細胞樣亞型術(shù)前化療后殘留浸潤癌患者，術(shù)后鉑類不敵稍低劑量卡培他濱，但是GEICAM/2003-11_CIBOMA/2004-01研究未能證實三陰性乳腺癌術(shù)后完成標準治療再用常規(guī)劑量卡培他濱繼續(xù)治療有效。雖然術(shù)后術(shù)后卡培他濱延長化療已被寫入指南，但是仍有兩個關(guān)鍵問題阻礙臨床應用：缺乏成熟的總生存數(shù)據(jù)、缺乏識別最有可能對卡培他濱獲益患者的生物學標志物，第二個問題使治療決策缺乏生物學原理的指導。

三陰性乳腺癌生物學研究最新進展為解決上述問題提供了途徑，基因轉(zhuǎn)錄因子FOXC1過表達于40%～60%的三陰性乳腺癌，既是治療耐藥介質(zhì)，也是潛在生物學預測標志物。FOXC1作為三陰性乳腺癌基底樣亞型標志物，可調(diào)控腫瘤侵襲、轉(zhuǎn)移和DNA損傷修復通路，這些機制可以直接拮抗卡培他濱療效。臨床前研究表明，F(xiàn)OXC1過表達可增強DNA損傷同源重組修復，從而促進腫瘤對卡培他濱等DNA損傷藥物耐藥。此前對常規(guī)劑量卡培他濱方案的回顧分析表明，F(xiàn)OXC1低表達腫瘤療效較好；不過，F(xiàn)OXC1對術(shù)后低劑量延長化療以持續(xù)抗腫瘤血管生成和腫瘤免疫調(diào)節(jié)效果的預測作用尚未被研究。

2025年11月24日，英國《柳葉刀》腫瘤學分冊在線發(fā)表中山大學腫瘤防治中心、廣東省人民醫(yī)院、廉江市人民醫(yī)院、哈爾濱醫(yī)科大學附屬腫瘤醫(yī)院、廣州市第一人民醫(yī)院、廣東省中醫(yī)院、廣州醫(yī)科大學附屬第二醫(yī)院、?？谑腥嗣襻t(yī)院、中山大學附屬第一醫(yī)院、廣東省婦幼保健院的SYSUCC-001研究10年隨訪結(jié)果和事后探索性生物學標志物分析，以確定卡培他濱作為延長術(shù)后化療方案的長期生存結(jié)局，并評價FOXC1預測價值。本次分析整合成熟的生存數(shù)據(jù)和方案預設(shè)生物學標志物檢測，將有力推動早期三陰性乳腺癌患者的治療標準和精準醫(yī)療策略，此類患者以前往往只能接受一刀切的治療方案。

該多中心非盲隨機對照三期臨床研究于2010年4月23日至2016年12月31日從全國13家醫(yī)院入組三陰性乳腺癌病理證實腫瘤大于5毫米無論淋巴結(jié)是否轉(zhuǎn)移且臨床未發(fā)現(xiàn)遠處轉(zhuǎn)移完成標準術(shù)后治療患者443例，按1比1隨機分為2組：其中222例每天2次按每平方米體表面積口服卡培他濱650毫克（常規(guī)1250毫克）連續(xù)1年，其余221例僅僅接受觀察。該研究預設(shè)主要終點為無病生存，次要終點包括總生存、遠處無病生存、局部區(qū)域無復發(fā)生存。此外，采用免疫組織化學法對基線腫瘤樣本FOXC1進行探索性生物學標志物分析。

• SYSUCC-001 (NCT01112826): Efficacy of Capecitabine Metronomic Chemotherapy to Triple-negative Breast Cancer

• Official Title: Phase III Study of Adjuvant Capecitabine Metronomic Chemotherapy in Triple-negative Operable Breast Cancer

結(jié)果，卡培他濱組221例和觀察組213例完成研究，各有1例和8例中途退出。截至2025年3月31日，其中420例（97%）獲得全部隨訪數(shù)據(jù)，中位隨訪116.0個月，四分位96.0至134.8個月。

卡培他濱組與觀察組相比：

• 10年無病生存率：78.1%比66.6%

• 病變或死亡風險：降低39%（風險比：0.61，95%置信區(qū)間：0.43～0.88，P=0.0074）

• 10年總生存率：82.4%比73.7%

• 總死亡風險：降低33%（風險比：0.67；95%置信區(qū)間：0.45～1.01，P=0.058）

• 10年遠處無病生存率：78.1%比66.5%

• 遠處病變或死亡風險：降低39%（風險比：0.61，95%置信區(qū)間：0.43～0.88，P=0.0075）

• 10年局部區(qū)域無復發(fā)生存率：81.6%比69.9%

• 局部區(qū)域復發(fā)或死亡風險：降低40%（風險比：0.60，95%置信區(qū)間：0.40～0.89，P=0.011）

獲得338例（78%）患者FOXC1檢測結(jié)果，171例（51%）來自卡培他濱組，167例（49%）來自觀察組。

149例（44%）患者FOXC1高表達，卡培他濱與觀察相比：

• 病變或死亡風險：降低67%（風險比：0.33，95%置信區(qū)間：0.16～0.68，P=0.0027）

• 總死亡風險：降低75%（風險比：0.25，95%置信區(qū)間：0.10～0.62，P=0.0028）

189例（56%）患者FOXC1低表達，卡培他濱與觀察相比，未見顯著獲益。

患者對卡培他濱治療總體耐受性良好，2級和3級手足綜合征發(fā)生率分別為19.0%和7.7%，未見其他≥3級毒性反應。

因此，該研究長期分析結(jié)果表明，對于早期三陰性乳腺癌患者，每天口服低劑量卡培他濱與僅僅觀察相比，10年無病生存、遠處無病生存、局部區(qū)域無復發(fā)生存顯著獲益，總生存獲益雖然無統(tǒng)計學顯著意義，但是總死亡風險降低33%有臨床意義。對于不到半數(shù)的FOXC1高表達患者，每天口服低劑量卡培他濱與僅僅觀察相比，總生存獲益顯著，不過該探索性生物學標志物分析屬于事后驗證，應謹慎解讀該結(jié)果，如果該結(jié)果獲得進一步前瞻研究驗證，那么根據(jù)FOXC1表達水平對患者進行篩選，可能有助于優(yōu)化卡培他濱治療效果。

對此，美國布朗大學沃倫阿爾珀特醫(yī)學院羅德島婦嬰醫(yī)院腫瘤內(nèi)科專家威廉·西科夫發(fā)表同期評論：早期三陰性乳腺癌術(shù)后卡培他濱治療？可以，但是適用于哪些患者？

Lancet Oncol. 2025 Nov 24;26(12):1575-1583. IF: 35.9

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.

Jing Yuan, Xi-Wen Bi, Xin Hua, Heng Huang, Li Cai, Li Zhao, Qian-Jun Chen, Xin-Xin Chen, Xu-Lin Wang, Ying Lin, An-Qing Zhang, Yong-Yi Zhong, Fei Xu, Jia-Jia Huang, Xin An, Yan-Xia Shi, Xi Wang, Shu-Sen Wang, Cong Xue, Zhong-Yu Yuan.

Sun Yat-sen University Cancer Center, Guangzhou, China; Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; Lianjiang People's Hospital, Lianjiang, China; Harbin Medical University Cancer Hospital, Harbin, China; Guangzhou First People's Hospital, Guangzhou, China; Traditional Chinese Medicine Hospital of Guangdong Province, Guangzhou, China; The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Haikou People's Hospital, Haikou, China; The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Maternal and Child Health Care Hospital of Guangdong Province, Guangzhou, China.

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.

DOI: 10.1016/S1470-2045(25)00545-5

Lancet Oncol. 2025 Nov 24;26(12):1515-1517. IF: 35.9

Adjuvant capecitabine in early-stage triple-negative breast cancer? Yes, but for whom?

William M Sikov.

Women and Infants Hospital of Rhode Island and Warren Alpert Medical School of Brown University, Providence, USA.

In The Lancet Oncology, Jing Yuan and colleagues present updated results from the SYSUCC-001 trial, evaluating extended adjuvant endocrine therapy with a year of twice daily (metronomic) capecitabine compared with observation in early-stage triple-negative breast cancer following standard chemotherapy. This post-hoc analysis includes data from 420 of the 434 patients in the trial. The findings confirm the benefit of extended adjuvant capecitabine compared with observation, with statistically significant, double-digit improvements in disease-free survival, distant disease-free survival, and locoregional recurrence-free survival at 10 years. While the difference in overall survival was not statistically significant (p=0.058), the improvement would be considered clinically meaningful by many clinicians. Treatment was generally well tolerated; among 221 patients receiving capecitabine, 42 (19.0%) developed grade 2 and 17 (7.7%) grade 3 hand-foot syndrome and there were no other common grade 3 or worse toxicities, as described in the primary report. In an exploratory analysis described in the present report, the subgroup of patients whose tumours expressed high levels of FOXC1 showed a much larger benefit from capecitabine treatment in terms of outcomes, while those with low levels of expression received no benefit.

DOI: 10.1016/S1470-2045(25)00621-7

來源：SIBCS

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