高危早期乳腺癌术后辅助化疗方案对比
MINDACT三期随机对照临床研究已经证实，根据70基因复发风险评分，46%的早期乳腺癌患者虽然临床风险较高，但是基因组风险较低，可以安全地避免术后辅助化疗。不过，对于其余高风险早期乳腺癌患者，应该选择标准的蒽环类化疗方案，还是毒性较低的多西他赛＋卡培他滨化疗方案？
MINDACT (Microarray In Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid ChemoTherapy): A Prospective, Randomized Study Comparing the 70-Gene Signature With the Common Clinical-Pathological Criteria in Selecting Patients for Adjuvant Chemotherapy in Breast Cancer With 0 to 3 Positive Nodes (NCT00433589)
2020年2月21日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表法国癌症中心联盟、古斯塔夫·鲁西研究所、巴黎文理研究大学、居里学院、勒内·胡古宁医院、洛林癌症研究所、比利时布鲁塞尔自由大学朱尔·博代研究所、欧洲癌症研究与治疗组织、国际乳腺癌协作组、天主教鲁汶大学、荷兰癌症研究所、祖德兰医疗中心、耶罗恩·博斯医院、美国旧金山加利福尼亚大学海伦·迪勒家族综合癌症中心、德克萨斯大学圣安东尼奥健康科学中心、贝勒大学医学院、西班牙加泰罗尼亚生物医学研究所、瓦尔·德希布伦综合医院、纳瓦拉大学马德里医院、瑞士洛桑大学沃杜瓦中心医院、欧洲乳腺癌联盟、意大利米兰大学、欧洲肿瘤研究所、热那亚大学圣马蒂诺医院、德国埃森中心医院、西德研究协作组、多特蒙德圣若望医院、葡萄牙尚帕利莫基金会临床中心的研究报告，通过第二次随机分组，对蒽环类标准方案或多西他赛＋卡培他滨方案治疗临床和（或）基因组高风险早期乳腺癌的有效性和安全性进行了比较。
该研究患者总数6693例，化疗患者2832例，对其中1301例（45%）按1∶1的比例进行第二次随机分组：对照组649例，给予蒽环类±紫杉类的标准方案；实验组652例，每3周给予多西他赛75mg/m²静脉注射1次＋卡培他滨825mg/m²每天2次×14天，连续6个周期。主要终点为无病生存。次要终点包括总生存和安全性。
结果，其中97%的患者完成第二次随机分组治疗。对照组紫杉类化疗患者占29.6%，占淋巴结阴性患者的0.5%。
截至2016年3月1日，中位随访5.0年，发生无病生存事件148例，远远少于统计学效力所需422例。
多西他赛＋卡培他滨与蒽环类±紫杉类相比：
无病生存比例相似（90.7%比88.8%，95%置信区间：88%～92.8%、85.9%～91.1%）
发病死亡风险相似（风险比：0.83，95%置信区间：0.60～1.15，P=0.26）。
对于临床和基因组高风险亚组患者，多西他赛＋卡培他滨与蒽环类±紫杉类相比：
总体生存比例相似（96.3%比96.2%，95%置信区间：94.4%～97.6%、94.3%～97.4%）
全因死亡风险相似（风险比：0.91，95%置信区间：0.54～1.53，P=0.72）
无病生存比例相似（86.1%比88.1%，95%置信区间：84.3%～91.1%、82.1%～89.3%）
发病死亡风险相似（风险比：0.83，95%置信区间：0.58～1.21）
多西他赛＋卡培他滨与蒽环类±紫杉类相比，不良事件发生比例：
1级神经病变：27.1%比11.2%
2级手足综合征：28.5%比3.3%
2级腹泻：13.7%比5.8%
严重心脏事件：0.8%比0.6%
第二癌：3.3%比5.0%
白血病：0.2%比0.3%
治疗相关死亡：0.5%比0.3%
因此，该研究第二次随机分组结果表明，对于高风险早期乳腺癌，虽然统计学效力不足，但是多西他赛＋卡培他滨与蒽环类化疗方案相比，结局或安全性未见显著提高。
相关链接
J Clin Oncol. 2020 Feb 21. [Epub ahead of print]
Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial.
Delaloge S,, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY,, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium.
Gustave Roussy, Villejuif, France; Unicancer Breast Group, Paris, France; Institut Curie-Hopital Rene Huguenin, Saint-Cloud, France; Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; European Organization for Research and Treatment of Cancer, Brussels, Belgium; Breast International Group, Brussels, Belgium; Netherlands Cancer Institute, Amsterdam, the Netherlands; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA; Zuyderland Medisch Centrum, Heerlen-Geleen, the Netherlands; Institut Catala D'Oncologia-Institut d'Investigacio Biomedica de Bellvitge, L'Hospitalet, Barcelona, Spain; Hospital General Vall D'Hebron, Barcelona, Spain; Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Europa Donna-The European Breast Cancer Coalition, Milan, Italy; Kliniken Essen-Mitte, Westdeutsche Studiengruppe, Monchengladbach, Germany; St Johannes Hospital, Dortmund, Germany; Institut de Cancérologie de Lorraine, Vandoeuvre-Les-Nancy, France; Institut Curie Paris Sciences et Lettres, Université de Paris, Paris, France; The University of Texas Health Sciences Center, San Antonio, TX; Clinica Universidad de Navarra-Site Madrid, Madrid, Spain; Jeroen Bosch Ziekenhuis, 's-Hertogenbosch, the Netherlands; Baylor University College of Medicine, Houston, TX; University of Milan and European Institute of Oncology-Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; University of Genoa and Azienda Ospedaliera Universitaria San Martino, Genova, Italy; Centre Hospitalier Universitaire, Université Catholique de Louvain, Namur, Belgium; Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, Portugal.
PURPOSE: MINDACT demonstrated that 46% of patients with early breast cancer at high clinical but low genomic risk on the basis of MammaPrint may safely avoid adjuvant chemotherapy. A second random assignment (R-C) compared docetaxel-capecitabine with an anthracycline-based regimen.
PATIENTS AND METHODS: R-C randomly assigned patients 1:1 between standard anthracycline-based regimens, with or without taxanes (control) and experimental docetaxel 75 mg/m² intravenously plus oral capecitabine 825 mg/m² two times per day for 14 days (DC) every 3 weeks for 6 cycles. The primary end point was disease-free survival (DFS). Secondary end points included overall survival and safety.
RESULTS: Of 2,832 patients, 1,301 (45%) were randomly assigned, and 97% complied with R-C assignment. In the control arm, 29.6% only received taxanes (0.5% of N0 patients). DFS events (n = 148) were much less than required (n = 422) as a result of a lower-than-expected accrual and event rate. At 5 years of median follow-up, DFS was not different between DC (n = 652) and control (n = 649; 90.7% [95% CI, 88% to 92.8%] v 88.8% [95% CI, 85.9% to 91.1%]; hazard ratio [HR], 0.83 [95% CI, 0.60 to 1.15]; P = .26). Overall survival (HR, 0.91 [95% CI, 0.54 to 1.53]) and DFS in the clinical high and genomic high-risk subgroup (86.1% v 88.1%; HR, 0.83 [95% CI, 0.58 to 1.21]) were similar in both arms. DC led to more grade 1 neuropathy (27.1% v 11.2%) and more grade 2 hand/foot syndrome (28.5% v 3.3%) and diarrhea (13.7% v 5.8%). Serious cardiac events occurred in 9 patients (control, n = 4; DC, n = 5). Fifty-three patients developed second cancers (control, n = 32; DC, n = 21; leukemia: 2 v 1). Five treatment-related deaths occurred (control, 2 [0.3%]; DC, 3 [0.5%]).
CONCLUSION: Although underpowered, this second randomization in MINDACT did not show any improvement in outcome or safety with the use of DC compared with anthracycline-based chemotherapy.
PMID: 32083990
DOI: 10.1200/JCO.19.01371