ER+/HER2+乳腺癌患者在经过双重HER2阻断化疗后比ER-/HER2+乳腺癌患者更难达到病理完全缓解（pCR） 。内分泌治疗加曲妥珠单抗对晚期ER+/HER2+乳腺癌有效。抑制CDK4/6和HER2可导致协同的细胞增殖减少。我们将帕博西尼布、来曲唑和曲妥珠单抗（PLT）组合成一种化疗节省方案。我们评估了新辅助PLT在早期ER+/HER2+乳腺癌中的应用。主要终点是在16个星期后的pCR。进行实验活检以进行全外显子和RNA测序、PAM50亚型分型和Ki67评估，以进行完全细胞周期阻滞（CCCA：Ki67≤2.7%）。26名患者后，由于无效性而停止发展。pCR（残留癌负荷-RCB 0）为7.7％，RCB 0/I为38.5％。19例中出现了G3/4治疗相关不良事件。其中，G3/4粒细胞减少症为50％，高血压为26.9％，白细胞减少症为7.7％。分析表明，在C1D15时有85％的CCCA，而在停用帕博西尼布后的手术后为27％。基线PAM50亚型分型鉴定了31.2％ HER2-E，43.8％Luminal B和25％ Luminal A。比较C1D15和基线的161个基因差异表达。MKI67，TK1，CCNB1，AURKB和PLK1是下调的基因，与C1D15的CCCA一致。分子特征数据库基因集分析表明，C1D15时涉及增殖，ER和mTORC1信号和DNA损伤修复的进程被下调，与研究药物的作用机制一致。新辅助PLT显示出7.7％的pCR和38.5％的RCB 0/I率。RNA测序和Ki67数据表明，研究治疗具有强烈的抗增殖作用。ClinicalTrials.gov- NCT02907918。©2023年作者。

Patients with ER+/HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after chemotherapy with dual HER2 blockade than ER-/HER2+ BC. Endocrine therapy plus trastuzumab is effective in advanced ER+/HER2+ BC. Inhibition of CDK4/6 and HER2 results in synergistic cell proliferation reduction. We combined palbociclib, letrozole, and trastuzumab (PLT) as a chemotherapy-sparing regimen. We evaluated neoadjuvant PLT in early ER+/HER2+ BC. Primary endpoint was pCR after 16 weeks. Research biopsies were performed for whole exome and RNA sequencing, PAM50 subtyping, and Ki67 assessment for complete cell cycle arrest (CCCA: Ki67 ≤ 2.7%). After 26 patients, accrual stopped due to futility. pCR (residual cancer burden-RCB 0) was 7.7%, RCB 0/I was 38.5%. Grade (G) 3/4 treatment-emergent adverse events occurred in 19. Among these, G3/4 neutropenia was 50%, hypertension 26.9%, and leucopenia 7.7%. Analysis indicated CCCA in 85% at C1 day 15 (C1D15), compared to 27% at surgery after palbociclib was discontinued. Baseline PAM50 subtyping identified 31.2% HER2-E, 43.8% Luminal B, and 25% Luminal A. 161 genes were differentially expressed comparing C1D15 to baseline. MKI67, TK1, CCNB1, AURKB, and PLK1 were among the genes downregulated, consistent with CCCA at C1D15. Molecular Signatures Database gene-sets analyses demonstrated downregulated processes involved in proliferation, ER and mTORC1 signaling, and DNA damage repair at C1D15, consistent with the study drug's mechanisms of action. Neoadjuvant PLT showed a pCR of 7.7% and an RCB 0/I rate of 38.5%. RNA sequencing and Ki67 data indicated potent anti-proliferative effects of study treatments. ClinicalTrials.gov- NCT02907918.© 2023. The Author(s).