三阴性乳腺癌由于三大常见靶点均为阴性，故异质性极大，患者的生存结局也千差万别，可谓有人住高楼、有人在深沟、有人光万丈、有人一身锈。虽然三阴性乳腺癌的其他靶点和其他靶向疗法不计其数，而且几乎每天都有新靶点和新疗法被发现，但是大多尚未进入人体临床研究阶段，或是尚未进入市场，或是尚未进入中国内陆市场，或是价格昂贵，如同镜花水月，遥不可及。因此，靶点万千种，浮云莫去求，疗法若彩虹，遇上方知有。切实可行、切合实际的办法，就是对现有化疗方案进行优化。对于早期三阴性乳腺癌患者，目前标准的术后化疗方案包括紫杉类和蒽环类，如果同时加入口服化疗药物卡培他滨可能提高疗效。不过，既往研究数据主要来自欧美晚期乳腺癌患者，缺乏有说服力的中国早期乳腺癌患者研究数据。
2019年第42届美国圣安东尼奥乳腺癌论坛全体大会和2020年美国临床肿瘤学会《临床肿瘤学杂志》先后发表中国乳腺癌临床研究协作组CBCSG 010研究5年随访结果，探讨了将卡培他滨加入中国早期三阴性乳腺癌患者术后标准化疗方案的有效性和安全性。该研究结果表明，对于早期三阴性乳腺癌术后患者，紫杉类＋蒽环类化疗标准方案±口服卡培他滨相比，5年无病生存率显著提高5.9%。
CBCSG010 (NCT01642771): Comparative Study on Two Post-operative Adjuvant Chemotherapy Regimens for Treating Triple-negative Breast Cancer (A Prospective, Randomized, Open, Multi-center Phase III Clinical Study Comparing Efficacy and Safety of Sequential T-FEC and TX-XEC as Post-operative Adjuvant Chemotherapy Options for the Treatment of Triple-negative Breast Cancer)
CBCSG010研究开展同时，复旦大学附属肿瘤医院还对中国三阴性乳腺癌进行了大规模多组学生物标志物分析，并于2019年美国《细胞》旗下《癌细胞》发表三阴性乳腺癌复旦分型，将三阴性乳腺癌进一步分为四种类型，实现分型施策和个体化精准治疗。那么，利用三阴性乳腺癌复旦分型治疗策略，能否确定哪些患者对联合卡培他滨口服化疗获益更大？
2024年10月17日，美国《国家综合癌症网络杂志》在线发表复旦大学附属肿瘤医院吴文雅、杨云松、杨文涛、李俊杰✉️、邵志敏✉️、哈尔滨医科大学附属肿瘤医院庞达、河北医科大学第四医院刘运江、海军军医大学第一附属医院盛湲、山西省肿瘤医院李炘正、苏州市立医院俞士尤、南昌市第三医院曹亚丽、苏州大学附属第二医院蒋国勤、中国医科大学附属第一医院金锋、新疆医科大学附属肿瘤医院马斌林等学者的CBCSG010研究生物标志物分析，进一步探索了中国早期三阴性乳腺癌患者术后标准化疗方案加入卡培他滨口服化疗的疗效预测指标。
该探索性回顾分析首先对CBCSG010研究三阴性乳腺癌患者肿瘤组织基因转录分子进行测序，随后进行单样本基因集富集分析和生存分析，以确定三阴性乳腺癌微环境分子特征，并评定免疫相关基因表达水平或者免疫细胞计数与卡培他滨治疗效果的关系。此外，对福尔马林固定石蜡包埋标本进行2个免疫标志物PD-L1和CD8的免疫组织化学染色和基质肿瘤浸润淋巴细胞的苏木精伊红染色，验证生物信息学分析结果，以阐明疗效差异原因，并探索可能对术后卡培他滨联合免疫治疗获益的潜在人群。
结果发现，三阴性乳腺癌免疫浸润程度较高（免疫热肿瘤）患者，联合卡培他滨治疗的5年无病生存率显著较高。
免疫热肿瘤的定义：肿瘤细胞和免疫细胞的PD-L1阳性评分总和≥25、间质肿瘤浸润淋巴细胞阳性率≥10%、CD8阳性细胞≥10%。
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发病或死亡风险：低87%（风险比：0.13；95%置信区间：0.03～0.52；P=0.049）
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发病或死亡风险：低89%（风险比：0.11；95%置信区间：0.04～0.29；P=0.028）
因此，该研究结果表明，三阴性乳腺癌免疫热肿瘤患者更有可能对术后联合卡培他滨口服化疗获益，并且免疫治疗联合化疗可能对免疫热肿瘤患者更有效，故有必要进一步开展前瞻研究进行验证。
J Natl Compr Canc Netw. 2024 Oct 17;22(8):528-536. IF: 14.8
Tailoring Escalation Adjuvant Therapy for Early-Stage Triple-Negative Breast Cancer in the CBCSG010 Clinical Trial Biomarker Analysis.
Wu W, Yang Y, Yang W, Pang D, Liu Y, Sheng Y, Li X, Yu S, Cao Y, Jiang G, Jin F, Ma B, Li J, Shao Z.
Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Fudan University Shanghai Cancer Center, Shanghai, China; The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; The Fourth Clinical Medical College of Hebei Medical University, Shijiazhuang, Hebei, China; Changhai Hospital of Shanghai, Shanghai, China; Shanxi Cancer Hospital, Taiyuan, Shanxi, China; Eastern Hospital of Suzhou Municipal Hospital, Suzhou, Jiangsu, China; The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; The First Hospital of China Medical University, Shenyang, Liaoning, China; Xinjiang Cancer Hospital, Wulumuqi, Xinjiang, China.
BACKGROUND: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. The CBCSG010 trial is a prospective and multicenter phase III clinical trial confirming that adding adjuvant capecitabine significantly improved the 5-year disease-free survival (DFS) rate in patients with TNBC by 5.9%. In this study, we attempted to identify the specific population that benefited from adjuvant therapy.
METHODS: In this retrospective exploratory analysis, we performed RNA sequencing of tumor tissues from patients with TNBC in the CBCSG010 clinical trial. A single-sample gene set enrichment analysis algorithm and survival analysis were performed to characterize the intrinsic molecular features of the TNBC microenvironment and assess the associations between immune-related gene expression levels or immune cell counts with capecitabine treatment efficacy. Additionally, we performed immunohistochemical staining of 2 markers, PD-L1 and CD8, and hematoxylin-eosin staining of stromal tumor-infiltrating lymphocytes (sTILs) on formalin-fixed, paraffin-embedded specimens to validate findings from bioinformatics analyses.
RESULTS: We found that patients with TNBC with high immune-infiltration treated with capecitabine were more likely to have a better prognosis. We used a cutoff of ≥25 combined positive score (CPS) of PD-L1, ≥10% positive sTILs, and ≥10% positive cells of CD8 to define the “immune-hot” patients. Among immune-hot patients, Kaplan-Meier curves showed that 5-year DFS rates were 96.9% and 79.4% in the capecitabine and control groups, respectively (hazard ratio, 0.13; 95% CI, 0.03-0.52; P=.049 in favor of capecitabine). In the capecitabine group, the 5-year DFS rate was higher for immune-hot patients than for immune-cold patients (96.9% vs 76.4%; hazard ratio, 0.11; 95% CI, 0.04-0.29; P=.028).
CONCLUSIONS: Our study suggested that immune-hot patients with TNBC are more likely to benefit from adjuvant capecitabine, and that combining immunotherapy with chemotherapy may be expected to be more effective in immune-hot patients.
DOI: 10.6004/jnccn.2024.7032
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