File Danielle, Curigliano Giuseppe, Carey Lisa A
University of North Carolina at Chapel Hill, Chapel Hill, NC.
European Institute of Oncology, IRCCS, University of Milano, Milano, Italy.
Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-11. doi: 10.1200/EDBK_100023.
Untreated, HER2+ disease is the most aggressive breast cancer phenotype; however, the development of multiple highly effective HER2-targeting drugs has transformed treatment and survival. These drugs include the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab; small molecule inhibitors lapatinib, neratinib, and tucatinib; and antibody-drug conjugates trastuzumab emtansine (T-DM1) and now trastuzumab deroxtecan. More complex regimens using these drugs continue to improve outcomes, but the incremental benefits of these advances are often modest. Improved outcomes came from the addition of HER2-targeted therapies to conventional chemotherapy, beginning with trastuzumab, then pertuzumab added to trastuzumab, or with neratinib given for the year after trastuzumab. Neoadjuvant, or preoperative, administration of chemotherapy plus HER2-targeting allows surgical deescalation and tailoring treatment by pathologic complete response (pCR) to therapy. Patients with pCR after conventional therapy have excellent outcomes; what we now know is that the poorer outcomes associated with residual disease can be ameliorated with adjuvant T-DM1. However, as we have developed more complex, effective, and expensive therapy to maximize outcomes, it is also true that we are overtreating many patients. In stage I HER2+ breast cancer, there are excellent outcomes with paclitaxel plus trastuzumab or T-DM1 alone. Higher clinical stage HER2+ disease is still treated aggressively, although intrinsic subtype or activated immune tumor microenvironment may identify those with augmented treatment response or better outcome. It is likely that future strategies to escalate and de-escalate treatment with less chemotherapy, fewer anti-HER2 drugs, or shorter duration will depend upon integrated clinical and genomic modeling.
未经治疗的HER2阳性疾病是最具侵袭性的乳腺癌表型；然而，多种高效的HER2靶向药物的研发改变了治疗方式并提高了生存率。这些药物包括抗HER2单克隆抗体曲妥珠单抗和帕妥珠单抗；小分子抑制剂拉帕替尼、来那替尼和图卡替尼；以及抗体药物偶联物曲妥珠单抗 emtansine（T-DM1），现在还有曲妥珠单抗德鲁替康。使用这些药物的更复杂方案持续改善治疗结果，但这些进展带来的增量益处往往不大。改善治疗结果源于在传统化疗基础上加用HER2靶向治疗，首先是曲妥珠单抗，然后是帕妥珠单抗加曲妥珠单抗，或者在曲妥珠单抗治疗后给予来那替尼一年。新辅助（即术前）化疗加HER2靶向治疗可实现手术降期，并根据病理完全缓解（pCR）情况调整治疗方案。传统治疗后达到pCR的患者预后良好；我们现在知道，辅助使用T-DM1可改善与残留疾病相关的较差预后。然而，随着我们开发出更复杂、有效且昂贵的治疗方法以最大化治疗效果，确实也存在过度治疗许多患者的情况。在I期HER2阳性乳腺癌中，单独使用紫杉醇加曲妥珠单抗或T-DM1就有很好的治疗效果。更高临床分期的HER2阳性疾病仍进行积极治疗，尽管内在亚型或激活的免疫肿瘤微环境可能有助于识别那些治疗反应增强或预后更好的患者。未来，减少化疗、减少抗HER2药物或缩短治疗时间的治疗升级和降级策略可能将依赖于综合临床和基因组建模。
