NEJM：在HER2阳性乳腺癌中的曲妥珠单抗辅助治疗
2011-10-15 MedSci原创 MedSci原创
丹尼斯·斯拉门（Slamon）等 乳腺癌国际研究组成员 背景 在人类表皮生长因子受体（HER）阳性乳腺癌的辅助治疗中，曲妥珠单抗可改善（患者的）生存情况，尽管采用基于蒽环类联合疗法的方案与心脏毒性相关。我们想对一种新的含曲妥珠单抗的非蒽环类治疗方案的有效性和安全性进行评估。 方法 我们将3222名有HER2阳性早期乳腺癌的妇女随机分为3组：第一组接受多
丹尼斯·斯拉门（Slamon）等 乳腺癌国际研究组成员
背景 在人类表皮生长因子受体（HER）阳性乳腺癌的辅助治疗中，曲妥珠单抗可改善（患者的）生存情况，尽管采用基于蒽环类联合疗法的方案与心脏毒性相关。我们想对一种新的含曲妥珠单抗的非蒽环类治疗方案的有效性和安全性进行评估。
方法 我们将3222名有HER2阳性早期乳腺癌的妇女随机分为3组：第一组接受多柔比星和环磷酰胺治疗，随后每3周进行1次多西他赛治疗（AC-T）；第二组接受相同的治疗方案加52周曲妥珠单抗治疗（AC-T加曲妥珠单抗）；第三组接受多西他赛和卡铂加52周曲妥珠单抗治疗（TCH）。主要研究终点是无病生存率。次要终点是总生存率和安全性。
结果 在随访中位数为65个月时，656个事件触发了该治疗方案规定的分析。5年时估计的无病生存率在接受 AC-T的患者中为75%，在接受AC-T加曲妥珠单抗的患者中为84%，以及在接受TCH的患者中为81%。估计的总生存率分别为87%、92%和 91%。我们发现有效性（无病生存或总生存）在两个曲妥珠单抗治疗方案之间无显著差异，而两种治疗方案均优于AC-T。充血性心力衰竭和心功能障碍的发生率在接受AC-T加曲妥珠单抗组显著高于TCH组(P<0.001)。报告的急性白血病病例有8例：在接受基于蒽环类治疗方案组有7例以及TCH组有1例（在接受TCH治疗后，该患者在该研究以外接受了1种蒽环类药物的治疗）。
结论 在有HER2阳性乳腺癌的妇女中，添加1年的曲妥珠单抗辅助治疗显著提高了无病生存率和总生存率。与AC-T加曲妥珠单抗相比，考虑到非蒽环类TCH治疗方案相似的有效性、较少的毒性效应以及较低的心脏毒性和白血病发生危险，危险益处比有利于非蒽环类TCH治疗方案。
（N Engl J Med 2011; 365:1273-83. October 6, 2011）
Background
Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab.
Methods
We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety.
Results
At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study.
Conclusions
The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk–benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials.gov number, NCT00021255.)
Supported by Sanofi-Aventis and Genentech; a Department of Defense Breast Cancer Innovator Award and funding from the Revlon/UCLA Women's Cancer Program and the Peter and Denise Wittich Breast Cancer Program (to Dr. Slamon); and grants (to Dr. Press) from the U.S. Army Medical Research and Development Command (DAMD-03-1-0626), the National Cancer Institute (CA 48780), and the California Breast Cancer Research Program (12IB-0155 and 14NB-0179) for studies of TOP2A.
Dr. Slamon reports receiving honoraria and reimbursement for travel expenses from Genentech and Sanofi-Aventis; Dr. Eiermann, receiving honoraria, lecture fees, and reimbursement for travel expenses from Roche and Sanofi-Aventis; Dr. Robert, receiving reimbursement for travel expenses from Fairfax Northern Virginia Hematology Oncology PC and that his institution has received grant support, honoraria, and payments for the development of educational presentations from Fairfax Northern Virginia Hematology Oncology PC on his behalf; Dr. Pienkowski, serving as a board member for Sanofi-Aventis and Roche, receiving honoraria from Roche and GlaxoSmithKline, and that he and his institution have received lecture fees and reimbursement for travel expenses from Roche and Sanofi-Aventis; Dr. Press, receiving consulting fees, honoraria, lecture fees, and reimbursement for travel expenses from Genentech; Dr. Mackey, receiving honoraria from Roche; Dr. Glaspy, receiving lecture fees from Genentech, Amgen, and Eli Lilly; Dr. Chan, serving on an advisory board for and receiving consulting fees, grant support, and honoraria from Roche and receiving reimbursement for travel expenses from Sanofi-Aventis; Dr. Pinter, receiving consulting and lecture fees from Roche; Dr. Valero, receiving honoraria and reimbursement for travel expenses from Roche; Dr. Sauter, receiving honoraria and reimbursement for travel expenses from Roche; Dr. von Minckwitz, receiving fees for expert testimony, lecture fees, and reimbursement for travel expenses from Roche and Sanofi-Aventis; Dr. Buyse, being an employee of and having an equity interest in the International Drug Development Institute; Dr. Bendahmane and Dr. Tabah-Fisch, being employees of Sanofi-Aventis; Dr. Tabah-Fisch, receiving stock options from Sanofi-Aventis; and Dr. Crown, receiving honoraria and reimbursement for travel expenses from Roche and Sanofi-Aventis and that his institution has also received grant support from Roche on his behalf.
NEJMoa0910383/suppl_file/nejmoa0910383_disclosures.pdf">Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
No other potential conflict of interest relevant to this article was reported.
We thank the staff of the Breast Cancer International Research Group for their assistance with all aspects of the conduct and reporting of this study; all participating patients who gave their consent to be included in the study; Dr. Sandra Swain, chair of the data and safety monitoring committee, as well as all committee members; and Dr. Jonathan Plehn, chair of the cardiac safety monitoring committee, as well as all committee members.
Source Information
The authors' affiliations are listed in the Appendix.
Address reprint requests to Dr. Slamon at the University of California–Los Angeles, 10945 Le Conte Ave., Suite 3360, Los Angeles, CA 90095-1678, or at dslamon@mednet.ucla.edu.
Additional investigators in the Breast Cancer International Research Group (BCIRG) 006 study are listed in the NEJMoa0910383/suppl_file/nejmoa0910383_appendix.pdf">Supplementary Appendix, available at NEJM.org.
Appendix
The authors' affiliations are as follows: the Jonsson Comprehensive Cancer Center, University of California–Los Angeles (D.S., J.G.) and the Norris Comprehensive Cancer Center, University of Southern California (M.P.) — both in Los Angeles; Frauenklinik vom Roten Kreuz, Munich (W.E.), the Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg (G.S.), and Zentrum für Frauenheilkunde, Frankfurt (G.M.) — all in Germany; U.S. Oncology Research (N.R.) and University of Texas M.D. Anderson Cancer Center (V.V.) — both in Houston; Maria Sklodowska-Curie Center, Warsaw, Poland (T. Pienkowski); Hospital Universitario San Carlos, Madrid (M.M.); the Department of Oncology, University of Alberta, Edmonton, Canada (J.M.); Mount Breast Group, Mount Hospital, Perth, Australia (A.C.); City Oncology Dispensary, St. Petersburg, Russia (M.P.); Petz Oktato Korhaz Onkoradiologia, Budapest, Hungary (T. Pinter); Sun Yat Sen Cancer Center, Taipei, Taiwan (M.-C.L.); National Breast Cancer Coalition, Washington, DC (F.V.); Breast Cancer International Research Group (V.B., M.-A.L., A.R.) and Sanofi-Aventis (B.B., I.T.-F.) — both in Paris; the International Drug Development Institute, Louvain-la-Neuve, Belgium (M.B.); and All Ireland Cooperative Oncology Research Group, St. Vincent's University Hospital, Dublin (J.C.).
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#曲妥珠#
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