Pernas Sonia, Tolaney Sara M
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medical Oncology-Breast Cancer Unit, Institut Catala d'Oncologia (ICO)-H.U. Bellvitge-IDIBELL, Barcelona, Spain.
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Ther Adv Med Oncol. 2019 Mar 19;11:1758835919833519. doi: 10.1177/1758835919833519. eCollection 2019.
The introduction of anti-HER2 therapies to the treatment of patients with HER2-positive breast cancer has led to dramatic improvements in survival in both early and advanced settings. Despite this breakthrough, nearly all patients with metastatic HER2-positive breast cancer eventually progress on anti-HER2 therapy due to or acquired resistance. A better understanding not only of the underlying mechanisms of HER2 therapy resistance but of tumor heterogeneity as well as the host and tumor microenvironment is essential for the development of new strategies to further improve patient outcomes. One strategy has focused on inhibiting the HER2 signaling pathway more effectively with dual-blockade approaches and developing improved anti-HER2 therapies like antibody-drug conjugates, new anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors that might replace or be used in addition to some of the current anti-HER2 treatments. Combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors, CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are also being extensively evaluated in clinical trials. These add-on strategies of combining optimized targeted therapies could potentially improve outcomes for patients with HER2-positive breast cancer but may also allow de-escalation of treatment in some patients, potentially sparing some from unnecessary treatments, and their related toxicities and costs.
将抗HER2疗法引入HER2阳性乳腺癌患者的治疗中，已使早期和晚期患者的生存率得到显著提高。尽管有这一突破，但几乎所有转移性HER2阳性乳腺癌患者最终都会因原发性或获得性耐药而在抗HER2治疗中出现疾病进展。更好地了解HER2治疗耐药的潜在机制、肿瘤异质性以及宿主和肿瘤微环境，对于制定进一步改善患者预后的新策略至关重要。一种策略聚焦于通过双重阻断方法更有效地抑制HER2信号通路，并研发改良的抗HER2疗法，如抗体药物偶联物、新型抗HER2抗体、双特异性抗体或新型酪氨酸激酶抑制剂，这些可能会取代当前的一些抗HER2治疗或与之联合使用。抗HER2疗法与其他药物（如免疫检查点抑制剂、CDK4/6抑制剂和PI3K/AKT/mTOR抑制剂）的联合应用也正在临床试验中得到广泛评估。这些优化靶向治疗联合应用的附加策略可能会改善HER2阳性乳腺癌患者的预后，但也可能使部分患者的治疗方案降级，从而有可能使一些患者避免不必要的治疗及其相关毒性和费用。
