The inter- and intra-tumor heterogeneity of triple negative breast cancers (TNBC), which is reflected in diverse drug responses, interplays with tumor evolution. Here, we developed a preclinical experimental and analytical framework using treatment-naive TNBC patient-derived tumor xenografts (PDTX) to test their predictive value in personalized cancer treatment approaches. Patients and their matched PDTX exhibited concordant drug responses to neoadjuvant therapy using two trial designs and dosing schedules. This platform enabled analysis of non-genetic mechanisms involved in relapse dynamics. Treatment resulted in permanent phenotypic changes with functional and therapeutic consequences. High throughput drug screening methods in ex vivo patient derived tumor xenograft cells (PDTCs) revealed patient-specific drug response changes dependent on first-line therapy. This was validated in vivo, as exemplified by a change in olaparib sensitivity in tumors previously treated with clinically relevant cycles of standard-of-care chemotherapy. In summary, PDTXs provide a robust tool to test patient drug responses and therapeutic regimens and to model evolutionary trajectories. However, high inter-model variability and permanent non-genomic transcriptional changes constrain their use for personalized cancer therapy. This work highlights important considerations associated with preclinical drug response modeling and potential uses of the platform to identify efficacious and preferential sequential therapeutic regimens.

中文翻译：

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使用患者来源的异种移植物对药物反应和进化动力学进行建模，揭示三阴性乳腺癌的精准医学策略


三阴性乳腺癌 （TNBC） 的肿瘤间和肿瘤内异质性反映在不同的药物反应中，与肿瘤演变相互作用。在这里，我们开发了一个临床前实验和分析框架，使用初治 TNBC 患者来源的肿瘤异种移植物 （PDTX） 来测试它们在个性化癌症治疗方法中的预测价值。使用两种试验设计和给药方案，患者及其匹配的 PDTX 对新辅助治疗表现出一致的药物反应。该平台能够分析涉及复发动力学的非遗传机制。治疗导致永久性表型变化，具有功能和治疗后果。离体患者来源的肿瘤异种移植细胞 （PDTC） 中的高通量药物筛选方法揭示了依赖于一线治疗的患者特异性药物反应变化。这在体内得到了验证，例如先前接受临床相关标准化疗周期治疗的肿瘤中奥拉帕尼敏感性的变化。总之，PDTX 为测试患者的药物反应和治疗方案以及模拟进化轨迹提供了一种强大的工具。然而，高模型间变异性和永久性非基因组转录变化限制了它们用于个性化癌症治疗。这项工作强调了与临床前药物反应建模相关的重要考虑因素以及该平台在确定有效和优先序贯治疗方案方面的潜在用途。