对于HER2基因扩增或过表达的早期乳腺浸润癌患者，曲妥珠单抗可以减少术后辅助化疗的复发和死亡风险。不过，在具有里程碑意义的曲妥珠单抗辅助治疗研究中，当地免疫组化法检测HER2为阳性但是集中原位杂交法检测HER2为阴性的亚组患者，似乎可能对曲妥珠单抗获益。
2019年12月10日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表美国NRG肿瘤学组（NSABP + GOG + RTOG）、加利福尼亚凯萨医疗集团、匹兹堡大学、休斯顿卫理公会癌症中心、东南临床肿瘤学研究协作组、国家癌症研究所、普莱诺肿瘤医院、马克桑格迈斯特中心、明尼苏达社区肿瘤研究联盟、科罗拉多大学丹佛分校、佛罗里达大学奥兰多癌症中心、洛约拉大学、乔治城大学、爱尔兰肿瘤研究协作组、爱尔兰癌症研究中心、都柏林大学圣文森特医院、加拿大麦吉尔大学、拉瓦尔大学、蒙特利尔大学、韩国延世大学的NSABP B-47研究报告，探讨了曲妥珠单抗能否改善HER2免疫组化法弱阳性而原位杂交法阴性高风险早期乳腺浸润癌术后辅助化疗的无浸润病变生存。
NSABP B-47: Chemotherapy With or Without Trastuzumab After Surgery in Treating Women With Invasive Breast Cancer: A Randomized Phase III Trial of Adjuvant Therapy Comparing Chemotherapy Alone (Six Cycles of Docetaxel Plus Cyclophosphamide or Four Cycles of Doxorubicin Plus Cyclophosphamide Followed by Weekly Paclitaxel) to Chemotherapy Plus Trastuzumab in Women With Node-Positive or High-Risk Node-Negative HER2-Low Invasive Breast Cancer (NCT01275677)
该多中心随机对照三期临床研究于2011年2月8日～2015年2月10日入组HER2免疫组化法评分1+或2+、原位杂交法比值<2.0或HER2基因拷贝数<4.0的高风险早期乳腺浸润癌女性3270例，按1∶1随机分入两组进行术后辅助化疗±12个月曲妥珠单抗。化疗方案为多西他赛＋环磷酰胺或多柔比星和环磷酰胺→每周紫杉醇12周。
结果中位随访46个月时化疗±曲妥珠单抗相比：
5年无浸润病变生存率相似（89.8%比89.2%，风险比：0.98，95%置信区间：0.76～1.25，P=0.85）无论HER2免疫组化法表达水平、淋巴结转移或激素受体状态如何
5年无远处复发生存率相似（92.7%比93.6%，风险比：1.10，95%置信区间：0.81～1.50，P=0.55）
5年总生存期率相似（94.8%比96.3%，风险比：1.33，95%置信区间：0.90～1.95，P=0.15）
毒性反应相似
因此，该研究结果表明，对于HER2未过表达的高风险早期乳腺浸润癌女性，曲妥珠单抗并未改善术后辅助化疗的无浸润病变生存、无远处复发生存率或总生存。曲妥珠单抗对于未达到免疫组化法评分3+或原位杂交法比值扩增的乳腺癌女性并未获益。
J Clin Oncol. 2019 Dec 10. [Epub ahead of print]
NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2+.
Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N.
NRG Oncology, Pittsburgh, PA; Kaiser Permanente Oncology Clinical Trials Northern CA, Novato, CA; University of Pittsburgh, Pittsburgh, PA; Houston Methodist Cancer Center, Houston, TX; University of Pittsburgh Cancer Institute, Pittsburgh, PA; Southeast Clinical Oncology Research-National Cancer Institute Community Oncology Research Program, Richmond, VA; Irish Cooperative Oncology Research Group/Cancer Trials Ireland, Dublin, Ireland; St Vincent's University Hospital, Dublin, Ireland; Kaiser Permanente Southern California, San Diego, CA; McGill University, Montréal, Québec, Canada; Université Laval, Québec City, Québec, Canada; US Oncology Plano, Plano, TX; The Mark H. Zangmeister Center, Columbus, OH; Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; Minnesota Community Oncology Research Consortium, St Louis Park, MN; University of Colorado Denver, Denver, CO; Loyola University, Maywood, IL; Georgetown University Medical Center, Washington, DC; Yonsei University College of Medicine, Seoul, Korea; Orlando Health UF Health Cancer Center, Orlando, FL.
PURPOSE: Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer.
METHODS: A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) < 2.0 or, if ratio was not performed, HER2 gene copy number < 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks.
RESULTS: At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab [CRxT] v 89.2% with CRx alone; hazard ratio [HR], 0.98; 95% CI, 0.76 to 1.25; P = .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50; P = .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95; P = .15). There were no unexpected toxicities from the addition of trastuzumab to CRx.
CONCLUSION: The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2-overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.
PMID: 31821109
DOI: 10.1200/JCO.19.01455
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