Dynamic Optical Imaging Biomarkers of Tumor Response to Therapy

肿瘤治疗反应的动态光学成像生物标志物

• 批准号: 8888513
• 负责人: Stefan Alexandru Carp
• 金额: $ 52.14万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-03 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888513
• 关键词: Area Under Curve; Behavior; Biological Markers; Biomechanics; Biopsy; Blood Vessels; Blood flow; Breast; Breast Cancer Patient; Breast Cancer Treatment; Breast-Conserving Surgery; Cicatrix; Clinical; Clinical Research; Contrast Media; Coupling; Custom; Data; Data Quality; Development; Diagnosis; Diffuse; Digital Breast Tomosynthesis; Disease; Drug Delivery Systems; Drug Kinetics; ERBB2 gene; Early treatment; Enrollment; Exhibits; Functional Imaging; Gadolinium DTPA; Goals; Healed; Hemoglobin; Image; In complete remission; Individual; Intercellular Fluid; Lead; Lesion; Magnetic Resonance Imaging; Malignant - descriptor; Mammary Gland Parenchyma; Mammography; Mechanics; Methods; Monitor; Neoadjuvant Therapy; Neoplasm Metastasis; Optics; Outcome; Oxygen; PET/CT scan; Participant; Pathologic; Pathway interactions; Patient Schedules; Patients; Performance; Pharmaceutical Preparations; Phase; Physiological; Physiology; Positioning Attribute; Positron-Emission Tomography; Premenopause; Primary Neoplasm; Procedures; Property; Protocols documentation; ROC Curve; Relaxation; Reperfusion Therapy; Research; Roentgen Rays; Scanning; Staging; Stimulus; Stress; Survival Rate; System; Techniques; Testing; TimeLine; Tissues; Translations; Treatment outcome; Tumor Tissue; Validation; Variant; Work; base; cancer therapy; chemotherapy; contrast enhanced; cost; diffuse optical tomography; drug development; effective therapy; elastography; experience; healing; hemodynamics; imaging biomarker; imaging modality; improved; in vivo; individualized medicine; instrumentation; malignant breast neoplasm; meetings; metabolic rate; molecular imaging; optical imaging; pressure; public health relevance; radiologist; response; spectroscopic imaging; therapy development; tool; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; volunteer

 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.

 描述(申请人提供)：新辅助化疗(NACT)常用于局部晚期乳腺癌患者的治疗。它可以通过早期治疗微转移、降低疾病分期和增加保乳手术率来改善预后。然而，NACT遇到了不同的结果。虽然70%-80%的患者表现出一定程度的反应，但只有大约25%的患者达到病理完全反应，这是唯一与提高存活率相关的结果。这种变异性推动了治疗监测技术的发展，以确定无效的治疗方法，特别是考虑到最近的数据显示，反应引导的NACT可能会导致存活率增加。随着靶向药物的使用越来越多，对于三阴性乳腺癌来说，监测可能特别重要。功能成像方法对早期反应的敏感度最高，因为肿瘤生理变化发生在肿瘤实际缩小之前。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探测肿瘤微环境的工具。我们的团队一直是动态光学成像的先驱之一，它能够探测乳房组织对外部刺激的反应，以及量化基线血红蛋白浓度和氧合。特别是，我们最近已经证明，在治疗前，乳腺癌肿瘤在部分乳房X光照相加压后的粘弹性松弛阶段，与周围健康组织相比，表现出延迟的再灌注和持续的血红蛋白氧饱和度(SO2)降低。这种反应可能是由僵硬和间质液体压力增加以及恶性病变的较高代谢率相互作用所决定的。初步数据显示，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，这些差异仍然存在，这表明动态光学成像可以用于探索肿瘤的生物力学特性。肿瘤僵硬和IFP增加已被证明导致药物输送不良，并与转移可能性增加相关。通过血管正常化改善血流，以及使用抗纤维化药物减少内部应力是癌症治疗发展的新途径。作为一种多功能的非侵入性工具，动态光学成像可以帮助这一努力，它既可以探测血管(通过总血红蛋白浓度(HBT)和二氧化硫)，也可以探测肿瘤的生物力学属性(通过监测对压迫的血液动力学反应)。本项目的目的是验证乳腺压迫引起的组织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光学+X射线联合扫描仪，以便于临床转换，但我们也将使用磁共振成像和MR弹性成像来研究压迫反应的生理基础。