Dynamic Optical Imaging Biomarkers of Tumor Response to Therapy

 描述（由申请人提供）：新辅助化疗（NACT）通常用于治疗局部晚期乳腺癌患者。它可以通过早期治疗微转移、降低疾病分期和提高保乳手术率来改善预后。然而，NACT的结果各不相同。虽然70- 80%的患者表现出一定程度的反应，但只有约25%的患者达到病理完全反应，这是唯一与生存率提高相关的结果。这种可变性促使治疗监测技术的发展，以识别无效的治疗，特别是考虑到最近的数据显示响应引导的NACT可能导致生存率增加。监测可能对三阴性乳腺癌特别重要，并且随着靶向药物的使用越来越多。 对早期反应的最佳敏感性由功能成像方法提供，因为肿瘤生理学的变化发生在实际肿瘤缩小之前。近红外漫反射光谱和成像（NIR-DOSI）是一种很有前途的非侵入性工具，用于探测肿瘤微环境。我们的团队一直是动态光学成像的先驱之一，除了量化基线血红蛋白浓度和氧合之外，还能够探测乳腺组织对外部刺激的反应。特别是，我们最近已经表明，在治疗前，乳腺癌肿瘤表现出延迟再灌注和持续降低血红蛋白氧饱和度（SO2）与周围的健康组织在粘弹性松弛阶段后，部分乳房摄影样压缩。这种反应可能是由僵硬度和间质液压力增加以及恶性病变的较高代谢率的相互作用决定的。初步数据表明，对于有反应的肿瘤，这些差异在NACT后30天几乎消失，而对于无反应的肿瘤则持续存在，这表明动态光学成像可用于探测肿瘤的生物力学特性。肿瘤硬度和IFP增加已被证明会导致药物递送不良，并与转移的可能性增加相关。通过血管正常化改善血流，以及使用抗纤维化剂减少内应力是癌症治疗发展的有希望的新途径。动态光学成像可以帮助这一奋进，作为一种多功能的非侵入性工具，探测血管（通过总血红蛋白浓度（HbT）和SO2）和生物力学肿瘤特性（通过监测血液动力学响应压缩）。 本项目的目的是验证由于乳房压迫引起的组织HbT和SO2的变化作为指导乳腺癌新辅助化疗的生物标志物。我们的主要方法是开发一种组合光学+X射线乳腺摄影扫描仪，以便于临床翻译，但我们也将采用磁共振成像和MR弹性成像来研究压缩反应的生理基础。

 DESCRIPTION (provided by applicant): Neoadjuvant chemotherapy (NACT) is often used in the management of patients with locally advanced breast cancer. It can improve outcomes by early treatment of micro-metastases, downstaging the disease, and increasing breast conserving surgery rates. However, NACT is met with heterogeneous outcomes. While 70- 80% of the patients demonstrate some degree of response, only approximately 25% achieve a pathologic complete response, the only outcome shown to correlate with improved survival. Such variability has motivated the development of therapy monitoring techniques to identify ineffective treatments, especially given recent data showing response guided NACT may lead to increased survival. Monitoring may be particularly important for triple negative breast cancer, and with the increasing use of targeted agents. The best sensitivity to early response is provided by functional imaging methods, because changes in tumor physiology occur before actual tumor shrinkage. Near infrared diffuse optical spectroscopy and imaging (NIR-DOSI) is emerging as a promising non-invasive tool for probing the tumor microenvironment. Our group has been one of the pioneers of dynamic optical imaging, which is able to probe the response of breast tissue to external stimuli, in addition to quantifying baseline hemoglobin concentration and oxygenation. In particular, we have recently shown that, prior to treatment, breast cancer tumors exhibit delayed reperfusion and a persistent reduction in hemoglobin oxygen saturation (SO2) vs. the surrounding healthy tissue during the viscoelastic relaxation phase following fractional mammographic like compression. This response is likely determined by the interplay of the increased stiffness and interstitial fluid pressure, and the higher metabolic rate of malignant lesions. Preliminary data indicates these differences nearly disappear by 30 days into NACT for responding tumors, while persisting for non-responding ones, suggesting dynamic optical imaging could be used to probe the tumor biomechanical properties. Tumor stiffness and increased IFP have been shown to cause poor drug delivery and correlate with an increased likelihood of metastasis. Improved blood flow through vascular normalization, and reduction of internal stresses using anti-fibrotic agents are promising new avenues of cancer therapy development. Dynamic optical imaging can help this endeavor as a versatile non-invasive tool that probes both the vascular (through total hemoglobin concentration (HbT) and SO2) and biomechanical tumor properties (through monitoring the hemodynamic response to compression). The goal of this project is to validate the variation of tissue HbT and SO2 due to breast compression as biomarkers for guiding breast cancer neoadjuvant chemotherapy. Our main approach is to develop a combined optical+x-ray mammography scanner for ease of clinical translation, but we will also employ Magnetic Resonance Imaging and MR Elastography to investigate the physiological basis of the compression response.