HER2靶向治疗改善了HER2阳性乳腺癌患者的生存率，然而反应性差依然是一个主要的临床障碍。最近，无论DNA修复缺陷与否，HER2阳性乳腺癌细胞对poly-(ADP-ribose) polymerase (PARP) 抑制剂表现出了敏感性，同时对HER2靶向治疗具有耐药性。本研究旨在描述在曲妥珠单抗和PARP抑制剂治疗结合后细胞生存能力改变之前的生物因素。我们评估了HER2阳性和HER2阴性乳腺癌细胞对治疗的反应。此外，我们在HER2阳性患者来源的乳腺癌异种移植模型中评估了3'-脱氧-3'-[18F]-氟胸腺嘧啶正电子发射断层扫描([18F]FLT-PET)成像对早期治疗反应的评估价值。在体外实验中，我们观察到细胞存活能力下降。在体内实验中，与对照组和单药治疗组相比，组合治疗中观察到肿瘤生长抑制降低。早期细胞增殖的评估与最终细胞存活一致。标准摘要统计的[18F]FLT摄取对早期增殖变化不敏感。与此同时，[18F]FLT摄取的直方图分析指出了成像增殖生物标志物的潜在可转化性。本研究强调了联合曲妥珠单抗和PARP抑制剂在HER2阳性乳腺癌中的潜力，同时证明了在HER2阳性乳腺癌异质模型中优化[18F]FLT-PET定量的需求。

HER2-targeted treatments have improved survival rates in HER2+ breast cancer patients, yet poor responsiveness remains a major clinical obstacle. Recently, HER2+ breast cancer cells, both resistant and responsive to HER2-targeted therapies, have demonstrated sensitivity to poly-(ADP-ribose) polymerase (PARP) inhibition, independent of DNA repair deficiencies. This study seeks to describe biological factors that precede cell viability changes in response to the combination of trastuzumab and PARP inhibition. Treatment response was evaluated in HER2+ and HER2- breast cancer cells. Further, we evaluated the utility of 3'-Deoxy-3'-[18F]-fluorothymidine positron emission tomography ([18F]FLT-PET) imaging for early response assessment in a HER2+ patient derived xenograft (PDX) model of breast cancer. In vitro, we observed decreased cell viability. In vivo, we observed decreased inhibition in tumor growth in combination therapies, compared to vehicle and monotherapy-treated cohorts. Early assessment of cellular proliferation corresponds to endpoint cell viability. Standard summary statistics of [18F]FLT uptake from PET were insensitive to early proliferative changes. Meanwhile, histogram analysis of [18F]FLT uptake indicated the potential translatability of imaging proliferation biomarkers. This study highlights the potential of combined trastuzumab and PARP inhibition in HER2+ breast cancer, while demonstrating a need for optimization of [18F]FLT-PET quantification in heterogeneous models of HER2+ breast cancer.