Escalating and De-escalating Therapy for Early-Stage HER2-Positive Breast Cancer.
Escalating and De-escalating Therapy for Early-Stage HER2-Positive Breast Cancer.
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DOI：
10.1200/edbk_100023
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发表时间：
2020-03-01
期刊：
影响因子：
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通讯作者：
Carey, Lisa A
中科院分区：
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作者：
File, Danielle;Curigliano, Giuseppe;Carey, Lisa A
未经治疗，HER2+疾病是最具侵袭性的乳腺癌表型；然而，多种高效her2靶向药物的发展已经改变了治疗和生存。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、纳拉替尼和图卡替尼；抗体-药物偶联曲妥珠单抗emtansine （T-DM1）和曲妥珠单抗deroxtecan。使用这些药物的更复杂的方案继续改善结果，但这些进步的增量效益往往是有限的。改善的结果来自于在常规化疗中加入her2靶向治疗，从曲妥珠单抗开始，然后在曲妥珠单抗中加入帕妥珠单抗，或者在曲妥珠单抗后一年给予奈拉替尼。新辅助或术前化疗加her2靶向治疗可通过病理完全反应（pCR）对治疗进行手术降级和定制治疗。经常规治疗的pCR患者预后良好；我们现在知道的是，与残留疾病相关的较差结果可以通过辅助T-DM1得到改善。然而，当我们开发出更复杂、更有效、更昂贵的治疗方法来最大化结果时，我们对许多患者的过度治疗也是事实。在I期HER2+乳腺癌中，紫杉醇联合曲妥珠单抗或T-DM1单独治疗有很好的结果。更高临床阶段的HER2+疾病仍在积极治疗中，尽管内在亚型或激活的免疫肿瘤微环境可能识别出那些治疗反应增强或预后更好的患者。未来通过更少的化疗、更少的抗her2药物或更短的持续时间来升级或降级治疗的策略可能取决于综合临床和基因组模型。
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.