Multi-parametric 4-D Imaging Biomarkers for Neoadjuvant Treatment Response

 描述(申请人提供)：成像在评估肿瘤对治疗的反应中起着关键作用；然而，目前使用的方法仍然非常有限。例如，像RECIST这样的标准是主观的，不能用来充分描述不规则病变的特征；单靠肿瘤体积测量不能考虑详细的结构变化；来自选定肿瘤区域的特征，如“热点”峰值增强，不能捕捉整个肿瘤的信息。因此，目前的方法不能捕捉到治疗的多方面影响，包括表型肿瘤的异质性及其在治疗过程中的纵向变化，这越来越被认为是一个重要的预测指标。到目前为止，很少有研究探索使用更丰富的成像描述符，这可能会产生更强大的预测标记。此外，很少有人尝试将多模式生物标记物，如成像与组织病理学和分子标记物结合起来，为特定的肿瘤亚型和个别患者开发增强的预测模型。我们建议开发先进的计算工具，这些工具将能够：1)提取新的多参数成像信号；2)通过可变形图像配准准确地描述在新辅助治疗期间它们的纵向变化模式。因此，我们的方法是面向知识发现的，用于从量化成像提供的信息的许多可能方法中确定哪些成像参数具有最高的预测值。在SA1中，我们将开发基于相互显著原理的健壮的4D可变形图像配准方法，用于估计变换，这将使我们能够健壮地配准连续成像扫描，并获得由治疗引起的纵向组织效应的解剖上精确的时空参数图。在SA2中，我们将通过执行多参数特征提取来分析整个肿瘤和正常组织的效果，包括一组丰富的形态、纹理、运动和实质组织描述符，其中 结合注册将使我们能够全面捕获治疗期间动态演变的成像表型。在SA3中，我们将在一项重要的乳房成像研究中测试我们的方法，即I-SPY 1/ACRIN 6657试验。我们将应用机器学习工具来识别成像模式的高维关联，并结合组织病理学肿瘤亚型，最好地预测病理完全应答(PCR)和5年无病生存(DFS)。在SA4中，我们将使用I-SPY 2/ACRIN 6698试验独立测试我们的模型，在该试验中，我们还将评估我们的功能对各种治疗的稳健性。我们的方法有望通过1)改进当前基于成像的评估标准和2)引入新的成像生物标记物，作为治疗反应和生存的早期预测指标，从而改变目前个性化新辅助治疗的范式。我们的工具将通过NIH/NCI工具登记和开放挑战活动作为开源软件共享。

 DESCRIPTION (provided by applicant): Imaging plays a critical role in evaluating tumor response to treatment; however the currently used methods remain significantly limited. For example, standards such as the RECIST are subjective and cannot be used to adequately characterize irregular lesions; tumor volume measures alone do not account for detailed structural changes; and features from selected tumor regions, such as "hot-spot" peak-enhancement, do not capture information from the entire tumor. As such, current approaches fall short of capturing the multi-faceted effects of treatment, including phenotypic tumor heterogeneity and its longitudinal change during treatment, which is increasingly recognized as an important predictive indicator. To date, few studies have explored using richer imaging descriptors, which could result in more powerful predictive markers. Moreover, fewer have attempted to combine multi-modal biomarkers, such as imaging with histopathologic and molecular markers, to develop enhanced predictive models for specific tumor sub-types and individual patients. We propose to develop advanced computational tools that will enable to i) extract novel multi-parametric imaging signatures and ii) accurately characterize their longitudinal patterns of change during neoadjuvant treatment via deformable image registration. Our approach is thus geared towards knowledge discovery, for determining which imaging parameters have the highest predictive value out of many possible ways to quantify information provided by imaging. In SA1 we will develop robust 4D deformable image registration methods, based on principles of mutual saliency, for estimating transformations that will enable us to robustly register serial imaging scans and obtain anatomically precise spatio-temporal parametric maps of longitudinal tissue effects induced by treatment. In SA2 we will analyze whole-tumor and normal tissue effects by performing multi- parametric feature extraction, including a rich set of morphologic, textural, kinetic and parenchymal tissue descriptors, which in conjunction to registration will allow us to comprehensively capture the dynamically evolving imaging phenotype during treatment. In SA3 we will test our method in a major breast imaging study, the I-SPY 1/ACRIN 6657 trial. We will apply machine learning tools to identify high-dimensional associations of imaging patterns, in conjunction to histopathologic tumor subtyping, that can best predict pathologic complete response (pCR) and 5-year disease free survival (DFS). In SA4 we will independently test our models with the I-SPY 2/ACRIN 6698 trial, where we will also evaluate the robustness of our features to a diverse range of treatments. Our methods hold the promise to shift the current paradigm in personalizing neoadjuvant treatment by 1) improving the current standards of imaging-based assessment and 2) introducing new imaging biomarkers that can be of higher value as early predictors of treatment response and survival. Our tools will be shared as open-source software via NIH/NCI tool registries and open-challenge activities.