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: 9250612
• 负责人: Stefan Alexandru Carp
• 金额: $ 52.47万
• 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/9250612
• 关键词: Area Under Curve; Behavior; Biological Markers; Biomechanics; Biopsy; Blood Vessels; Blood flow; Breast; Breast Cancer Patient; Breast-Conserving Surgery; Cancer Patient; Cicatrix; Clinical Research; Contrast Media; Coupling; Custom; Data; Data Quality; Development; Diagnosis; Diffuse; Digital Breast Tomosynthesis; Digital X-Ray; Disease; Drug Delivery Systems; Drug Kinetics; ERBB2 gene; Early treatment; Enrollment; Exhibits; Functional Imaging; Gadolinium DTPA; Goals; Hemoglobin; Image; In complete remission; Individual; Intercellular Fluid; Lead; Lesion; Magnetic Resonance Imaging; Malignant - descriptor; Mammary Gland Parenchyma; Mammography; 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; Prediction of Response to Therapy; Premenopause; Primary Neoplasm; Procedures; Property; Protocols documentation; ROC Curve; Relaxation; Reperfusion Therapy; Research; Roentgen Rays; Scanning; Spectrum Analysis; Staging; Stimulus; Stress; Survival Rate; System; Techniques; Testing; TimeLine; Tissues; Treatment outcome; Tumor Markers; Tumor Tissue; Validation; Variant; Work; base; cancer therapy; chemotherapy; clinical translation; contrast enhanced; cost; diffuse optical tomography; drug development; effective therapy; elastography; experience; healing; hemodynamics; imaging biomarker; imaging modality; improved; improved outcome; in vivo; individualized medicine; ineffective therapies; instrumentation; malignant breast neoplasm; mechanical properties; metabolic rate; molecular imaging; optical imaging; pressure; public health relevance; radiologist; response; response biomarker; targeted agent; therapy development; tool; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; viscoelasticity; 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（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结果。然而，NACT 会带来不同的结果。虽然 70-80% 的患者表现出一定程度的缓解，但只有大约 25% 的患者达到病理完全缓解，这是唯一与改善生存相关的结果。这种变异性推动了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反应引导的 NACT 可能会导致生存率增加。随着靶向药物的使用越来越多，监测对于三阴性乳腺癌尤其重要。 功能成像方法提供了对早期反应的最佳敏感性，因为肿瘤生理学的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）正在成为一种有前途的非侵入性工具，用于探测肿瘤微环境。我们的团队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，我们最近发现，在治疗之前，乳腺癌肿瘤在点阵乳房 X 线摄影样压缩后的粘弹性松弛阶段表现出再灌注延迟和血红蛋白氧饱和度 (SO2) 相对于周围健康组织持续降低。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 30 天后几乎消失，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应力是癌症治疗发展的有希望的新途径。动态光学成像作为一种多功能非侵入性工具可以帮助实现这一目标，它可以探测血管（通过总血红蛋白浓度 (HbT) 和 SO2）和肿瘤生物力学特性（通过监测对压迫的血流动力学响应）。 该项目的目标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式光学+X 射线乳房X 线摄影扫描仪，以便于临床转化，但我们还将采用磁共振成像和MR 弹性成像来研究压迫反应的生理基础。