Optimal Strategy and Benefit of Pulsed Therapy Depend On Tumor Heterogeneity and Aggressiveness at Time of Treatment Initiation.
Optimal Strategy and Benefit of Pulsed Therapy Depend On Tumor Heterogeneity and Aggressiveness at Time of Treatment Initiation.
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DOI：
10.1158/1535-7163.mct-21-0574
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发表时间：
2022-05-04
影响因子：
5.7
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中科院分区：
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治疗耐药是癌症治疗的根本障碍。最初对治疗有反应的肿瘤可能具有预先存在的耐药亚克隆或在治疗过程中获得耐药性，理论上复发是不可避免的。在这里，我们使用数学模型研究可能延迟复发的治疗策略。我们发现，对于单一药物治疗，脉冲治疗（短时间、升高剂量，然后完全中断治疗）与在一段时间内使用相同总剂量的连续治疗相比，可以延迟复发。对于使用一种以上药物治疗的肿瘤，连续联合治疗仅有时比序贯治疗更好，而脉冲联合治疗或简单地以规定的时间间隔交替使用两种疗法可延迟最长的复发。这些结果与健身成本或阻力收益无关，并且对噪声具有鲁棒性。模拟的机器学习分析表明，治疗开始时的初始肿瘤反应和异质性足以确定脉冲或交替治疗策略相对于连续治疗的益处。对纪念斯隆凯特琳癌症中心治疗的乳腺癌患者的八个肿瘤负荷轨迹的分析表明，该模型可以利用对治疗的初始反应和估计的先前存在的耐药人群来预测耐药时间。该模型计算出脉冲治疗可以延迟所有八个病例的复发。总体而言，我们的结果支持通过数学模型优化的脉冲治疗可以延迟治疗耐药性。
Therapeutic resistance is a fundamental obstacle in cancer treatment. Tumors that initially respond to treatment may have a preexisting resistant subclone or acquire resistance during treatment, making relapse theoretically inevitable. Here, we investigate treatment strategies that may delay relapse using mathematical modeling. We find that for a single-drug therapy, pulse treatment—short, elevated doses followed by a complete break from treatment—delays relapse compared with continuous treatment with the same total dose over a length of time. For tumors treated with more than one drug, continuous combination treatment is only sometimes better than sequential treatment, while pulsed combination treatment or simply alternating between the two therapies at defined intervals delays relapse the longest. These results are independent of the fitness cost or benefit of resistance, and are robust to noise. Machine-learning analysis of simulations shows that the initial tumor response and heterogeneity at the start of treatment suffice to determine the benefit of pulsed or alternating treatment strategies over continuous treatment. Analysis of eight tumor burden trajectories of breast cancer patients treated at Memorial Sloan Kettering Cancer Center shows the model can predict time to resistance using initial responses to treatment and estimated preexisting resistant populations. The model calculated that pulse treatment would delay relapse in all eight cases. Overall, our results support that pulsed treatments optimized by mathematical models could delay therapeutic resistance.