Lapatinib (L) plus trastuzumab (T), with endocrine therapy for estrogen receptor (ER)+ tumors, but without chemotherapy, yielded meaningful response in HER2+ breast cancer (BC) neoadjuvant trials. The irreversible/pan-HER inhibitor neratinib (N) has proven more potent than L. However, the efficacy of N+T in comparison to pertuzumab (P) + T or L + T (without chemotherapy) remains less studied. To address this, mice bearing HER2+ BT474-AZ (ER+) cell and BCM-3963 patient-derived BC xenografts were randomized to vehicle, N, T, P, N+T, or P+T, with simultaneous estrogen deprivation for BT474-AZ. Time to tumor regression/progression and incidence/time to complete response (CR) were determined. Changes in key HER pathway and proliferative markers were assessed by immunohistochemistry and western blot of short-term-treated tumors. In the BT474-AZ model, while all N, P, T, N + T, and P + T treated tumors regressed, N + T-treated tumors regressed faster than P, T, and P + T. Further, N + T was superior to N and T alone in accelerating CR. In the BCM-3963 model, which was refractory to T, P, and P + T, while N and N + T yielded 100% CR, N + T accelerated the CR compared to N. Ki67, phosphorylated (p) AKT, pS6, and pERK levels were largely inhibited by N and N + T, but not by T, P, or P + T. Phosphorylated HER receptor levels were also markedly inhibited by N and N + T, but not by P + T or L + T. Our findings establish the efficacy of combining N with T and support clinical testing to investigate the efficacy of N + T with or without chemotherapy in the neoadjuvant setting for HER2+ BC.

拉帕替尼（L）加曲妥珠单抗（T）联合内分泌治疗雌激素受体（ER）+肿瘤，但不进行化疗，在 HER2+ 乳腺癌（BC）新辅助试验中产生了有意义的反应。不可逆/泛 HER 抑制剂来那替尼 (N) 已被证明比 L 更有效。然而，与帕妥珠单抗 (P) + T 或 L + T（无化疗）相比，N+T 的疗效仍较少研究。为了解决这个问题，携带 HER2+ BT474-AZ (ER+) 细胞和 BCM-3963 患者来源的 BC 异种移植物的小鼠被随机分配至媒介物、N、T、P、N+T 或 P+T，同时剥夺 BT474- 的雌激素。 AZ。确定肿瘤消退/进展的时间和发生率/完全缓解（CR）的时间。通过短期治疗肿瘤的免疫组织化学和蛋白质印迹评估关键 HER 通路和增殖标志物的变化。在 BT474-AZ 模型中，虽然所有 N、P、T、N + T 和 P + T 治疗的肿瘤均消退，但 N + T 治疗的肿瘤消退速度快于 P、T 和 P + T。此外，N + T在加速 CR 方面优于单独使用 N 和 T。在 BCM-3963 模型中，T、P 和 P + T 耐药，而 N 和 N + T 产生 100% CR，与 N 相比，N + T 加速 CR。Ki67、磷酸化 (p) AKT、pS6 ，pERK 水平在很大程度上被 N 和 N + T 抑制，但不被 T、P 或 P + T 抑制。磷酸化 HER 受体水平也被 N 和 N + T 显着抑制，但不被 P + T 或 L + 抑制。 T。我们的研究结果确立了 N 与 T 相结合的疗效，并支持临床测试，以研究 N + T 联合或不联合化疗在 HER2+ BC 新辅助治疗中的疗效。