双药？单药？乳腺癌术前靶向治疗选择
对于HER2阳性早期乳腺癌的术前（新辅助）治疗，虽然NeoALTTO、NSABP B-41、CHER-LOB、CALGB 40601、EORTC 10054、LPT109096等研究已证实曲妥珠单抗＋拉帕替尼双药靶向治疗优于曲妥珠单抗或拉帕替尼单药靶向治疗，但是仅NeoALTTO和CHER-LOB研究获得统计学显著差异。因此，有必要对HER2阳性早期乳腺癌术前靶向治疗期间的病理学和分子学变化进行分析，以发现双药或单药靶向治疗效果的影响因素和早期预测指标。
2020年11月17日，英国《自然》旗下《自然通讯》在线发表美国洛杉矶加利福尼亚大学、斯坦福大学、哈佛大学、亚圣玛丽亚癌症治疗中心、迈阿密大学、贝克斯菲尔德综合癌症中心、佛罗里达癌症中心、内华达综合癌症中心、希望之城综合癌症中心、圣路易斯奥比斯保癌症中心、西达赛奈医疗中心、基因泰克、南加利福尼亚大学的美国肿瘤学转化研究协作组（TRIO-US）B07研究报告，对HER2阳性早期乳腺癌术前新辅助治疗期间的病理学和分子学变化进行了全程检测，对治疗效果的影响因素和早期预测指标进行了探讨。该研究第一作者为美国洛杉矶加利福尼亚大学萨拉·贺维茨教授，她也是廖宁教授周三见国际会诊团队专家之一。该研究总监为HER2发现者和曲妥珠单抗研发者之一、美国洛杉矶加利福尼亚大学丹尼斯·约瑟夫·史莱门教授，2008年好莱坞蹭将其研究历程拍摄成电影《拥爱奇迹》。
TRIO-US B07 (NCT00769470): Docetaxel, Carboplatin, and Trastuzumab and/or Lapatinib in Treating Women With Stage I, Stage II, or Stage III Breast Cancer That Can Be Removed by Surgery (A Multicenter, Open Label, Randomized Phase II Trial of Presurgical Treatment With Single-Agent Trastuzumab or Lapatinib or the Combination of Trastuzumab and Lapatinib, Followed by Six Cycles of Docetaxel and Carboplatin With Trastuzumab or Lapatinib or the Combination of Trastuzumab and Lapatinib in Patients With HER2/Neu-Amplified Operable Breast Cancer)
该多中心非盲随机对照二期临床研究于2008年12月22日～2012年12月20日从美国13个癌症中心入组HER2阳性早期乳腺癌可手术患者128例，按1∶1∶2的比例随机分为3组进行1轮HER2靶向治疗，随后6轮标准联合化疗＋HER2靶向治疗。其中，曲妥珠单抗组34例、拉帕替尼组36例、曲妥珠单抗＋拉帕替尼组58例。主要研究终点为手术时的病理完全缓解率。
结果，全部入组患者的病理完全缓解率：
曲妥珠单抗组：47%（95%置信区间：30%～65%）
拉帕替尼组：25%（95%置信区间：13%～43%）
曲妥珠单抗＋拉帕替尼组：52%（95%置信区间：38%～65%）
术前完成研究方案指定治疗的患者比例：
曲妥珠单抗组：100%
拉帕替尼组：69%
曲妥珠单抗＋拉帕替尼组：74%
如有可能，对肿瘤或肿瘤床组织进行采集和分子学检测，其中治疗前110例、第1轮HER2靶向治疗后89例、手术时59例。病理完全缓解率较高的分子学因素包括：HER2高水平扩增、激素受体阴性。
第1轮HER2靶向治疗后，肿瘤、免疫和基质的基因表达发生很大变化。此时，与病理完全缓解率相反，拉帕替尼与曲妥珠单抗相比，增殖显著减少。此时，各组免疫基因表达都增加，手术时又减少。
因此，该研究结果表明，分子学检测可早期评定HER2靶向治疗的敏感性，尤其免疫微环境对HER2靶向药物具有重要作用。
Nat Commun. 2020 Nov 17;11(1):5727.
Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2-positive breast cancer (TRIO-US B07).
Sara A. Hurvitz, Jennifer L. Caswell-Jin, Katherine L. McNamara, Jason J. Zoeller, Gregory R. Bean, Robert Dichmann, Alejandra Perez, Ravindranath Patel, Lee Zehngebot, Heather Allen, Linda Bosserman, Brian DiCarlo, April Kennedy, Armando Giuliano, Carmen Calfa, David Molthrop, Aruna Mani, Hsiao-Wang Chen, Judy Dering, Brad Adams, Eran Kotler, Michael F. Press, Joan S. Brugge, Christina Curtis, Dennis J. Slamon.
David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Stanford University School of Medicine, Stanford, CA, USA; Harvard Medical School, Boston, MA, USA; Central Coast Medical Oncology, Santa Maria, CA, USA; University of Miami Miller School of Medicine, Miami, FL, USA; Comprehensive Blood & Cancer Center, Bakersfield, CA, USA; Florida Cancer Specialists & Research Institute, Orlando, FL, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA; City of Hope Comprehensive Cancer Center, Duarte, CA, USA; FCPP Hematology/Oncology, San Luis Obispo, CA, USA; Cedars-Sinai Medical Center, Los Angeles, CA, USA; Genentech, South San Francisco, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer (N=128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N=34), lapatinib (L; N=36), or both (TL; N=58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30-65%) and TL (52%, 95% CI 38-65%), and a lower pCR rate with L (25%, 95% CI 13-43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment (N=110), after one cycle of HER2-targeted therapy alone (N=89), and at time of surgery (N=59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents.
DOI: 10.1038/s41467-020-19494-2