三阴性乳腺癌的雌激素受体ER、孕激素受体PR和人类表皮生长因子受体HER2均为阴性，大约占全部乳腺浸润癌的15%至20%，与其他乳腺癌相比，早期复发和死亡风险较高。对于早期三阴性乳腺癌，术后蒽环类＋紫杉类化疗是标准治疗方法，但是大约20%至40%的患者仍然复发。因此，迫切需要更有效的策略对三阴性乳腺癌术后治疗进行优化。三阴性乳腺癌从基因DNA转录到RNA再翻译为蛋白质的各种分子特征相差极大，导致现有治疗方法对不同患者的效果和结局也千差万别。大规模并行测序技术的进步，促使各种多基因特征分析技术被研发，包括21基因、70基因和27基因特征分析技术，可用于预测激素受体阳性或HER2阳性乳腺癌患者结局并指导术后治疗，但是缺乏针对三阴性乳腺癌的多基因特征分析技术，并且缺乏前瞻临床研究验证。
复旦大学附属肿瘤医院于2016年发表的单中心前瞻观察研究首先自主研发出整合3种信使RNA和2种长链非编码RNA的多基因预后分类方法，可以准确地将三阴性乳腺癌患者复发风险划分为高低两组。初步数据表明，高风险患者对紫杉类化疗获益较少。该结果支持将非交叉耐药铂类药物加入高风险患者标准术后化疗的想法。由于顺铂与吉西他滨具有协同作用的强有力临床前证据，并且晚期三阴性乳腺癌三期临床试验观察到该两药联合一线治疗的客观缓解率显著提高，利用复旦多基因预后分类方法划分的高风险早期三阴性乳腺癌患者，可能对术后治疗将吉西他滨和顺铂加入蒽环类＋紫杉烷方案获益。
因此，复旦大学附属肿瘤医院牵头成立的乳腺肿瘤精准治疗协作组自主发起全国多中心随机对照三期临床研究BCTOP-T-A01，对复旦多基因预后分类方法确定的高风险早期三阴性乳腺癌术后患者，比较了强化治疗方案（多西他赛＋表柔比星＋环磷酰胺→吉西他滨＋顺铂）与标准治疗方案（表柔比星＋环磷酰胺→多西他赛）的有效性和安全性，并且前瞻验证了该分类方法对患者接受标准治疗方案的预后价值。
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BCTOP-T-A01 (NCT02641847): TA(E)C-GP Versus A(E)C-T for the High Risk TNBC Patients and Validation of the mRNA-lncRNA Signature
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Official Title: Efficacy and Safety Study of TA(E)C-GP Versus A(E)C-T for the High Risk Triple-negative Breast Cancer Patients Predicted by the Messenger RNA (mRNA)-Long Non-coding RNA (lncRNA) Signature and Validation of the Signature’s Efficacy
2024年10月23日，国际四大医学期刊之一、创刊于1840年的英国医学会官方期刊《英国医学杂志》在线发表复旦大学附属肿瘤医院贺敏、江一舟、龚悦、范蕾、刘西禹、刘引、汤立晨、莫淼、侯意枫、狄根红、柳光宇、余科达、吴炅、严霞、王中华、邵志敏✉️、重庆大学附属肿瘤医院曾晓华、苏北人民医院符德元、福建省肿瘤医院宋传贵、上海市第一妇婴保健院庄志刚、复旦大学附属妇产科医院吴克瑾、中国福利会国际和平妇幼保健院王杰等学者的BCTOP-T-A01研究中位随访45.1个月结果，这是《英国医学杂志》创刊184年以来首次发表三阴性乳腺癌研究成果。
该多中心非盲随机对照三期临床研究于2016年1月3日至2023年7月17日从全国7家医院入组年龄18至70岁女性早期三阴性乳腺癌术后患者504例，采用复旦多基因特征分析进行风险分层，其中高风险患者336例、低风险患者168例，按1∶1∶1随机分为3组：
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A组166例高风险：强化治疗（4个周期多西他赛＋表柔比星＋环磷酰胺→4个周期吉西他滨＋顺铂）
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B组170例高风险：标准治疗（4个周期表柔比星＋环磷酰胺→4个周期多西他赛）
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C组168例低风险：标准治疗（4个周期表柔比星＋环磷酰胺→4个周期多西他赛）
主要终点为意向治疗分析A组与B组的无病生存。次要终点包括C组与B组的无病生存、无复发生存、总生存和安全性。
结果，498例入组患者接受了研究治疗，中位随访45.1个月。
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3年无病生存率：90.9%比80.6%（风险比：0.51，95%置信区间：0.28～0.95；P=0.03）
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3年无复发生存率：92.6%比83.2%（风险比：0.50，95%置信区间：0.25～0.98；P=0.04）
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3年总生存率：98.2%比91.3%（风险比：0.58，95%置信区间：0.22～1.54；P=0.27）
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3年无病生存率：90.1%比80.6%（风险比：0.57，95%置信区间：0.33～0.98；P=0.04）
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3年无复发生存率：94.5%比83.2%（风险比：0.42，95%置信区间：0.22～0.81；P=0.007）
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3年总生存率：100%比91.3%（风险比：0.14，95%置信区间：0.03～0.61；P=0.002）
因此，该多中心前瞻临床研究结果证实，针对三阴性乳腺癌的首个多基因特征分析技术获得成功，可被用于指导精准化疗和预测结局，利用该多基因特征分析技术为可手术三阴性乳腺癌患者量身定制术后化疗方案。对于高风险患者，将吉西他滨和顺铂加入蒽环类和紫杉类的强化方案与标准方案相比，无病生存率提高10.3个百分点，发病或死亡风险降低49%，且毒性可控。对于低风险患者，标准治疗的3年总生存率达100%，可以避免不必要的强化治疗。
对此，澳大利亚新南威尔士大学圣文森特临床医学院加文医学研究所和克里斯奥布莱恩癌症中心肿瘤内科医师发表同期编者述评：早期三阴性乳腺癌的风险预测，认为经过验证的复旦多基因特征分析技术以及预后分类方法可以促进早期三阴性乳腺癌术后治疗决策，或许还可指导术前化疗选择，例如蒽环类和铂类以及新疗法，希望该方法和其他方法能够为将来治疗这种难治性乳腺癌亚型患者提供更加个体化、更有针对性的治疗方案，减少对传统细胞毒性化疗的依赖。
BMJ. 2024 Oct 23;387:e079603. IF: 93.6
Intensive chemotherapy versus standard chemotherapy among patients with high risk, operable, triple negative breast cancer based on integrated mRNA-lncRNA signature (BCTOP-T-A01): randomised, multicentre, phase 3 trial.
He M, Jiang YZ, Gong Y, Fan L, Liu XY, Liu Y, Tang LC, Mo M, Hou YF, Di GH, Liu GY, Yu KD, Wu J, Yan X, Zeng XH, Fu DY, Song CG, Zhuang ZG, Wu KJ, Wang J, Wang ZH, Shao ZM.
Fudan University Shanghai Cancer and Key Laboratory of Breast Cancer in Shanghai, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Fudan University Shanghai Cancer Center, Shanghai, China; Chongqing Cancer Hospital, Chongqing University, Chongqing, China; Northern Jiangsu People’s Hospital, Yangzhou, Jiangsu, China; Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China; Shanghai First Maternity and Infant Hospital, Shanghai Tongji University, Shanghai, China; Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China; The International Peace Maternity and Child Health Hospital of China Welfare Institute, Shanghai Jiao Tong University, Shanghai, China.
OBJECTIVE: To evaluate the feasibility of using a multigene signature to tailor individualised adjuvant therapy for patients with operable triple negative breast cancer.
DESIGN: Randomised, multicentre, open label, phase 3 trial.
SETTING: 7 cancer centres in China between 3 January 2016 and 17 July 2023.
PARTICIPANTS: Female patients aged 18-70 years with early triple negative breast cancer after definitive surgery.
INTERVENTIONS: After risk stratification using the integrated signature, patients at high risk were randomised (1:1) to receive an intensive adjuvant treatment comprising four cycles of docetaxel, epirubicin, and cyclophosphamide followed by four cycles of gemcitabine and cisplatin (arm A; n=166) or a standard treatment of four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (arm B; n=170). Patients at low risk received the same adjuvant chemotherapy as arm B (arm C; n=168).
MAIN OUTCOME MEASURES: The primary endpoint was disease-free survival in the intention-to-treat analysis for arm A versus arm B. Secondary endpoints included disease-free survival for arm C versus arm B, recurrence-free survival, overall survival, and safety.
RESULTS: Among the 504 enrolled patients, 498 received study treatment. At a median follow-up of 45.1 months, the three year disease-free survival rate was 90.9% for patients in arm A and 80.6% for patients in arm B (hazard ratio 0.51, 95% confidence interval (CI) 0.28 to 0.95; P=0.03). The three year recurrence-free survival rate was 92.6% in arm A and 83.2% in arm B (hazard ratio 0.50, 95% CI 0.25 to 0.98; P=0.04). The three year overall survival rate was 98.2% in arm A and 91.3% in arm B (hazard ratio 0.58, 95% CI 0.22 to 1.54; P=0.27). The rates of disease-free survival (three year disease-free survival 90.1% v 80.6%; hazard ratio 0.57, 95% CI 0.33 to 0.98; P=0.04), recurrence-free survival (three year recurrence-free survival 94.5% v 83.2%; 0.42, 0.22 to 0.81; P=0.007), and overall survival (three year overall survival 100% v 91.3%; 0.14, 0.03 to 0.61; P=0.002) were significantly higher in patients in arm C than in those in arm B with the same chemotherapy regimen. The incidence of grade 3-4 treatment related adverse events were 64% (105/163), 51% (86/169), and 54% (90/166) for arms A, B, and C, respectively. No treatment related deaths occurred.
CONCLUSIONS: The multigene signature showed potential for tailoring adjuvant chemotherapy for patients with operable triple negative breast cancer. Intensive regimens incorporating gemcitabine and cisplatin into anthracycline/taxane based therapy significantly improved disease-free survival with manageable toxicity.
TRIAL REGISTRATION: ClinicalTrials.gov NCT02641847
DOI: 10.1136/bmj-2024-079603
BMJ. 2024 Oct 23;387:q2088. IF: 93.6
Risk prediction in early triple negative breast cancer.
Chris O’Brien Lifehouse, Sydney, NSW, Australia; Garvan Institute of Medical Research, St Vincent’s Healthcare Clinical Campus UNSW Sydney, Sydney, NSW, Australia.
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