昨天讲了淋巴结阴性HER2阳性早期乳腺癌术后治疗简化，今天继续讲淋巴结阳性HER2阴性早期乳腺癌术后治疗简化。
淋巴结阳性是早期乳腺癌患者不良结局的高风险因素，在手术治疗之后加用辅助化疗可以巩固疗效。自上世纪70年代，多项研究发现蒽环类化疗方案加入紫杉类可进一步改善患者的结局，提高乳腺癌的生存率，蒽环类＋紫杉类成为高风险乳腺癌术后化疗双王组合。不过，2008年美国圣安东尼奥乳腺癌大会公布的NSABP B-30研究结果表明，对于淋巴结阳性早期乳腺癌术后患者，4个周期多柔比星＋环磷酰胺→4个周期多西他赛（AC-T）方案与4个周期多柔比星＋多西他赛（AT）方案或4个周期多柔比星＋环磷酰胺＋多西他赛（ACT）方案相比，无进展生存显著较长，蒽环类＋紫杉类双王组合被“第三者”环磷酰胺拆散。目前，4个周期表柔比星＋环磷酰胺→4个周期紫杉醇（EC-P）是淋巴结阳性患者术后辅助治疗的标准方案，但是此方案治疗时间较长，可能导致放疗时机延误；剂量密集化疗方案不良反应较重，可能导致患者生活质量明显下降；另外，环磷酰胺毕竟属于氮芥类，毒性较大，对年轻女性生育功能也存在影响，临床应用有一定局限性。表柔比星＋紫杉醇（EP）方案对于远处转移或局部晚期乳癌疗效都达到60%～70%，耐受性较好，但是用于早期乳腺癌术后辅助治疗尚缺乏与标准方案的头对头比较，尤其对于亚洲患者。
2023年2月24日，《美国医学会杂志》网络开放版在线发表中国医学科学院肿瘤医院袁芃、康一坤、马飞、樊英、王佳玉、王雪、岳健、罗扬、张频、李青、中国工程院院士徐兵河等学者的CH-BC-006研究报告，首次对EP方案与EC-P方案辅助治疗淋巴结阳性HER2阴性早期乳腺癌术后患者的长期生存结局和安全性进行头对头比较。
CH-BC-006 (NCT01134523): Phase 3 Study of Regimens Comparison for Breast Cancers of Positive Lymph Nodes
该单中心非盲非劣效随机对照三期临床研究于2010年6月1日～2016年6月30日从中国医学科学院肿瘤医院入组年龄≥18岁、卡氏体力状态评分≥70分、女性、淋巴结阳性HER2阴性激素受体阳性原发乳腺浸润癌术前未放化疗或内分泌治疗且术后6周内患者813例，按1∶1随机分为两组：
主要结局指标为无病生存，定义为从随机分组至局部复发、区域复发、远处转移或全因死亡，不包括第二非乳腺浸润癌，末次随访时检查未发生任何预先定义事件的生存患者。次要结局指标包括总生存、远处无病生存、包括第二非乳腺浸润癌的无病生存、安全性。 结果，中位随访93.6个月（四分位：60.9～114.1）。两组意向治疗患者临床特征和病理学指标分布基本平衡。 随访期间共发生189例复发转移或死亡，EP组与EC-P组意向治疗人群相比：- （风险比：0.82，95%置信区间：0.62～1.10，非劣效P=0.001）
随访期间共发生77例全因死亡事件，EP组与EC-P组意向治疗人群相比：- （风险比：0.95，95%置信区间：0.61～1.49）
亚组分析表明，EP组与EC-P组意向治疗人群相比：- 患者全因死亡率：9.6%比9.4%（风险比：0.76，95%置信区间：0.28～2.03）
- 患者全因死亡率：6.5%比8.1%（风险比：0.85，95%置信区间：0.49～1.49）
安全性分析表明，两组治疗期间未发生治疗相关死亡，毒性反应主要包括3～4级白细胞减少、中性粒细胞减少、贫血、血小板减少、胃肠毒性、神经毒性、肝脏毒性、心脏毒性、脱发和疲劳。其中，EP组与EC-P组实际治疗人群相比，3～4级白细胞减少和中性粒细胞减少发生率较高，绝经前患者化疗相关绝经发生率较低。 因此，该单中心非盲非劣效随机对照三期临床研究结果表明，对于HER2阴性淋巴结阳性乳腺癌术后患者，EP方案与EC-P方案相比，蒽环类单次剂量减少、环磷酰胺退出、治疗时间缩短、长期生存结局并不逊色、化疗相关绝经发生率较低，是有效的辅助化疗方案。但是，医师在临床应用中应关注EP方案化疗的血液学不良反应，保证疗效的同时，提高患者的生活质量。 对此，复旦大学附属肿瘤医院余科达教授受邀发表一句话点评：雪藏20年的王炸组合（蒽环加紫杉），早年曾被一票否决（NSABP B-30），近年陈冤得雪，成为一种新选择。JAMA Netw Open. 2023 Feb 24;6(2):e230122. IF: 13.353Effect of Epirubicin Plus Paclitaxel vs Epirubicin and Cyclophosphamide Followed by Paclitaxel on Disease-Free Survival Among Patients With Operable ERBB2-Negative and Lymph Node-Positive Breast Cancer: A Randomized Clinical Trial.Yuan P, Kang Y, Ma F, Fan Y, Wang J, Wang X, Yue J, Luo Y, Zhang P, Li Q, Xu B.National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.This randomized clinical trial compares the long-term efficacy and toxic effects of epirubicin plus paclitaxel and the standard epirubicin and cyclophosphamide followed by paclitaxel regimen among women with ERBB2-negative, lymph node-positive breast cancer.QUESTION: Is long-term efficacy of adjuvant regimen epirubicin plus paclitaxel (EP) noninferior to the standard regimen epirubicin and cyclophosphamide followed by paclitaxel (EC-P) in operable ERBB2-negative, lymph node-positive breast cancer?FINDINGS: In this phase 3 randomized clinical trial of 813 patients with a median follow-up of 94 months, 5-year disease-free survival for patients receiving EP and EC-P was 86% and 81%, respectively. The 5-year overall survival was 95% and 95%, respectively.MEANING: In this study, the EP regimen was noninferior to the EC-P regimen and was an effective adjuvant chemotherapy regimen for women with ERBB2-negative breast cancer.IMPORTANCE: Adjuvant therapy is an important and effective treatment for breast cancer. However, there is a lack of head-to-head clinical trials comparing the regimens epirubicin plus paclitaxel (EP) vs epirubicin and cyclophosphamide followed by paclitaxel (EC-P) in breast cancer.OBJECTIVE: To evaluate the noninferiority of a cyclophosphamide-free (EP) regimen compared with the standard EC-P regimen for patients with operable hormone receptor-positive, ERBB2 (formerly HER2)-negative, lymph node-positive breast cancer.DESIGN, SETTING, AND PARTICIPANTS: This prospective, open-label, phase 3, noninferiority randomized clinical trial was conducted from June 1, 2010, to June 30, 2016, in the Cancer Hospital, Chinese Academy of Medical Sciences, Beijing. Patients with hormone receptor-positive, ERBB2-negative, lymph node-positive operable breast cancer were included and randomized into 2 treatment groups. Data were analyzed from June 30, 2016, to November 1, 2022.INTERVENTIONS: Patients received adjuvant epirubicin (75 mg/m2) and paclitaxel (175 mg/m2) every 3 weeks for 6 cycles (EP regimen) or epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks for 4 cycles followed by paclitaxel (175 mg/m2) every 3 weeks for 4 cycles (EC-P regimen) as the intention-to-treat (ITT) population.MAIN OUTCOMES AND MEASURES: The primary outcome was disease-free survival (DFS), and the secondary outcomes included overall survival (OS), distant DFS, and safety.RESULTS: A total of 900 patients were registered, and 813 eligible patients (median age, 48 [IQR, 41-56] years) were randomly assigned to the EP group (n = 407) or the EC-P group (n = 406) after the surgical procedure. Through a median follow-up of 93.6 (IQR, 60.9-114.1) months, the hazard ratio (HR) of DFS for EP vs EC-P was 0.82 (95% CI, 0.62-1.10; 5-year DFS, 86.0% vs 80.6%; noninferior P = .001). The 5-year OS for the ITT population treated with the EP or the EC-P regimen was 94.7% vs 95.0%, respectively (HR, 0.95 [95% CI, 0.61-1.49]). Patients in the EP group had more frequent toxic effect events than those in the EC-P group.CONCLUSIONS AND RELEVANCE: In this prospective, open-label, phase 3, randomized clinical trial, the EP regimen was noninferior to the EC-P regimen. These findings supported that the EP regimen could be an effective adjuvant chemotherapy regimen for women with ERBB2-negative breast cancer.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01134523DOI: 10.1001/jamanetworkopen.2023.0122
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