中国三阴性乳腺癌术后化疗“新”白金方案
大约15%～20%的乳腺癌为三阴性乳腺癌，雌激素、孕激素、HER2三大受体均为阴性，对抗激素治疗和抗HER2治疗效果不佳，全身治疗主要依靠化疗。以前，三阴性乳腺癌化疗方案金标准主要包括环磷酰胺＋氟尿嘧啶＋蒽环类→紫杉类。近年来，对于三阴性乳腺癌的晚期患者和早期术前患者，卡铂等铂类化疗方案的效果已被若干随机对照研究证实。不过，对于三阴性乳腺癌的早期术后患者，此前的铂类辅助化疗方案随机对照研究仅取得非劣效结果。
2020年8月13日，《美国医学会杂志》肿瘤学分册在线发表复旦大学附属肿瘤医院余科达、叶富贵、贺敏、范蕾、马丁、莫淼、吴炅、柳光宇、狄根红、侯意枫、沈镇宙、邵志敏、重庆大学附属肿瘤医院曾晓华、上海交通大学附属第六人民医院何萍青、复旦大学附属妇产科医院吴克瑾、上海交通大学附属国际和平妇幼保健院王杰、上海交通大学附属第九人民医院黄浦分院汪成、同济大学附属第一妇婴保健院庄志刚、福建医科大学附属协和医院宋传贵、同济大学附属杨浦医院林晓燕等学者的PATTERN研究报告，对紫杉醇＋卡铂方案与环磷酰胺＋氟尿嘧啶＋表柔比星→多西他赛标准方案辅助治疗中国早期三阴性乳腺癌术后患者的有效性、安全性、遗传学指标进行了比较。
PATTERN (Adjuvant Platinum and Taxane in Triple-negative Breast Cancer): A Prospective, Randomized, Open-label, Multicentric, phase III Clinical Trial Compared With PC and CEF100 Followed by Docetaxel as Adjuvant Chemotherapy Regimen for Chinese Primary Triple Negative Breast Cancer Patients (NCT01216111)
该多中心非盲随机对照三期临床研究于2011年7月1日～2016年4月30日从全国9家医院入组三阴性乳腺癌尚未转移、非局部晚期、术前尚未接受抗癌治疗、术后经病理证实区域淋巴结阳性或淋巴结阴性但肿瘤直径大于1厘米、年龄18～70岁（中位51岁，四分位44～57岁，范围23～70岁）女性647例，按1∶1的比例随机分为两组：
卡铂方案组325例：6轮紫杉醇＋卡铂（每28天的第1、8、15天紫杉醇80mg/m²＋卡铂AUC=2）
标准方案组322例：3轮环磷酰胺＋表柔比星＋氟尿嘧啶（每3周环磷酰胺500mg/m²＋表柔比星100mg/m²＋氟尿嘧啶500mg/m²）→3轮多西他赛（每3周多西他赛100mg/m²）
数据分析于2019年12月1日～2020年1月31日，主要终点为无病生存，次要终点包括总生存、无远处病变生存、无复发生存、毒性反应。此外，对乳腺癌易感基因BRCA等12种DNA同源重组修复相关基因（ATM、ATR、BARD1、BRCA1、BRCA2、BRIP1、CHEK2、FANCM、PALB2、RAD51C、RAD51D、RECQL）突变患者的无病生存进行亚组分析。BRCA是重要的抑癌基因，大约11.2%的三阴性乳腺癌患者存在BRCA致病突变，容易引起DNA同源重组修复异常和DNA不稳定，而铂类的主要作用机制即破坏细胞DNA。
结果，中位随访62个月，卡铂方案与标准方案相比：
5年无病生存比例：86.5%比80.3%，病变或死亡风险低35%（风险比：0.65，95%置信区间：0.44～0.96，P=0.03）
5年无远处病变生存比例：92.6%比87.9%，远处病变或死亡风险低41%（风险比：0.59，95%置信区间：0.35～0.999，P=0.05）
5年无复发生存比例：91.2%比84.4%，复发或死亡风险低46%（风险比：0.54，95%置信区间：0.34～0.88，P=0.01）
5年总生存比例：93.4%比89.8%，总死亡风险低29%（风险比：0.71，95%置信区间：0.42～1.22，P=0.22）
根据亚组分析，卡铂方案与标准方案相比：
BRCA突变患者：病变或死亡风险低56%（风险比：0.44，95%置信区间：0.15～1.31，P=0.14）
同源重组修复相关基因突变患者：病变或死亡风险低61%（风险比：0.39，95%放置信区间：0.15～0.99，P=0.04）
安全性数据与相关药物的已知安全性一致。
因此，该研究结果首次表明，对于三阴性乳腺癌术后患者，紫杉醇＋卡铂方案与环磷酰胺＋氟尿嘧啶＋表柔比星→多西他赛标准方案相比，是更有效的辅助化疗选择，尤其对于同源重组修复相关基因突变患者，故有必要对紫杉醇＋卡铂敏感的三阴性乳腺癌同源重组修复相关基因突变亚组患者开展进一步研究。
不过，并非任何紫杉类＋铂类方案都能获取得优效结果。与此前仅取得非劣效结果的紫杉类＋铂类方案不同之处是，该方案采用了肾脏毒性和恶心呕吐较轻的卡铂而非顺铂、采用了周疗较有效的紫杉醇而非多西他赛、采用了分3周给药而非每3周给药（缩短给药间隔、减少单次剂量、提高总剂量的密集化疗方案相对于标准化疗方案而言，本身可提高有效性和耐受性）从而首次对三阴性乳腺癌术后患者获得优效结果，故可称之为“新”白金方案。而且，该研究方案制定于10年之前，随着新的紫杉类和新的铂类不断问世、给药方案不断优化，该研究将为更多的“新”白金方案奠定基础。
相关链接
JAMA Oncol. 2020 Aug 13. Online ahead of print.
Effect of Adjuvant Paclitaxel and Carboplatin on Survival in Women With Triple-Negative Breast Cancer: A Phase 3 Randomized Clinical Trial.
Ke-Da Yu; Fu-Gui Ye; Min He; Lei Fan; Ding Ma; Miao Mo; Jiong Wu; Guang-Yu Liu; Gen-Hong Di; Xiao-Hua Zeng; Ping-Qing He; Ke-Jin Wu; Yi-Feng Hou; Jie Wang; Cheng Wang; Zhi-Gang Zhuang; Chuan-Gui Song; Xiao-Yan Lin; Angela Toss; Francesco Ricci; Zhen-Zhou Shen; Zhi-Ming Shao.
Fudan University Shanghai Cancer Center, Shanghai, China; Chongqing Cancer Hospital, Chongqing University, Chongqing, China; Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China; Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China; The International Peace Maternity & Child Health Hospital of China Welfare Institute, Shanghai Jiao Tong University, Shanghai, China; Shanghai Ninth People's Hospital Huangpu Branch, Shanghai Jiao Tong University, Shanghai, China; Shanghai First Maternity and Infant Hospital, Shanghai Tongji University, Shanghai, China; Fujian Medical University Union Hospital, Fuzhou, China; Tongji University School of Medicine Yangpu Hospital, Shanghai, China; University Hospital of Modena, Modena, Italy; Institute Curie, Paris & Saint-Cloud, France.
This randomized phase 3 clinical trial evaluates the effect of a carboplatin-plus-paclitaxel regimen on survival, compared with a standard-dose regimen of cyclophosphamide, epirubicin, and fluorouracil followed by docetaxel, in women with operable triple-negative breast cancer in China.
QUESTION: Does a paclitaxel-plus-carboplatin (PCb) as adjuvant treatment in women with operable triple-negative breast cancer offer superior benefit compared with a standard-dose CEF-T regimen (cyclophosphamide, epirubicin, and fluorouracil followed by docetaxel)?
FINDINGS: In this randomized phase 3 clinical trial conducted at 9 cancer centers and hospitals in China and including 647 patients, after a median follow-up of 62 months, 5-year disease-free survival rate was statistically significantly higher in the PCb group compared with the CEF-T group.
MEANING: Results of this study suggest that a paclitaxel-plus-carboplatin regimen may be an alternative adjuvant chemotherapy choice for patients with operable triple-negative breast cancer.
IMPORTANCE: The value of platinum-based adjuvant chemotherapy in patients with triple-negative breast cancer (TNBC) remains controversial, as does whether BRCA1 and BRCA2 (BRCA1/2) germline variants are associated with platinum treatment sensitivity.
OBJECTIVE: To compare 6 cycles of paclitaxel plus carboplatin (PCb) with a standard-dose regimen of 3 cycles of cyclophosphamide, epirubicin, and fluorouracil followed by 3 cycles of docetaxel (CEF-T).
DESIGN, SETTING, AND PARTICIPANTS: This phase 3 randomized clinical trial was conducted at 9 cancer centers and hospitals in China. Between July 1, 2011, and April 30, 2016, women aged 18 to 70 years with operable TNBC after definitive surgery (having pathologically confirmed regional node-positive disease or node-negative disease with tumor diameter >10 mm) were screened and enrolled. Exclusion criteria included having metastatic or locally advanced disease, having non-TNBC, or receiving preoperative anticancer therapy. Data were analyzed from December 1, 2019, to January 31, 2020, from the intent-to-treat population as prespecified in the protocol.
INTERVENTIONS: Participants were randomized to receive PCb (paclitaxel 80 mg/m2 and carboplatin [area under the curve = 2] on days 1, 8, and 15 every 28 days for 6 cycles) or CEF-T (cyclophosphamide 500 mg/m2, epirubicin 100 mg/m2, and fluorouracil 500 mg/m2 every 3 weeks for 3 cycles followed by docetaxel 100 mg/m2 every 3 weeks for 3 cycles).
MAIN OUTCOMES AND MEASURES: The primary end point was disease-free survival (DFS). Secondary end points included overall survival, distant DFS, relapse-free survival, DFS in patients with germline variants in BRCA1/2 or homologous recombination repair (HRR)-related genes, and toxicity.
RESULTS: A total of 647 patients (mean [SD] age, 51 [44-57] years) with operable TNBC were randomized to receive CEF-T (n = 322) or PCb (n = 325). At a median follow-up of 62 months, DFS time was longer in those assigned to PCb compared with CEF-T (5-year DFS, 86.5% vs 80.3%, hazard ratio [HR] = 0.65; 95% CI, 0.44-0.96; P = .03). Similar outcomes were observed for distant DFS and relapse-free survival. There was no statistically significant difference in overall survival between the groups (HR = 0.71; 95% CI, 0.42-1.22, P = .22). In the exploratory and hypothesis-generating subgroup analyses of PCb vs CEF-T, the HR for DFS was 0.44 (95% CI, 0.15-1.31; P = .14) in patients with the BRCA1/2 variant and 0.39 (95% CI, 0.15-0.99; P = .04) in those with the HRR variant. Safety data were consistent with the known safety profiles of relevant drugs.
CONCLUSIONS AND RELEVANCE: These findings suggest that a paclitaxel-plus-carboplatin regimen is an effective alternative adjuvant chemotherapy choice for patients with operable TNBC. In the era of molecular classification, subsets of TNBC sensitive to PCb should be further investigated.
ClinicalTrials.gov: NCT01216111
DOI: 10.1001/jamaoncol.2020.2965