VisR Ultrasound for Noninvasively Interrogating Stromal Collagen Organization in Women as a Breast Cancer Biomarker

项目摘要 乳腺癌现在是最普遍的癌症，有230万妇女被诊断，68.5万人死亡 在全球虽然，在过去十年中，死亡率每年下降约1%，这在很大程度上是由于 通过筛查进行早期检测，目前的筛查标准，数字乳腺X射线摄影，缺乏灵敏度， 在放射学上致密的乳房中受到挑战。磁性增强剂可提高致密乳房的敏感性 磁共振成像（MRI）是一种有效的方法，但需要对比度增强和大量额外的成本是缺点。一 无对比、低成本替代的超声应变弹性成像（SE）已被证明可以实现高超声弹性成像。 乳腺癌诊断的敏感性和特异性。然而，虽然SE诊断可疑乳房肿块， 通过询问组织硬度，不能辨别硬化的根本原因。在众多可能的 原因，基质胶原组织是新的一个焦点，由于其最近被证明的关联 与乳腺癌分期、预后、治疗反应等临床特征相关。因此，划定 体内基质胶原组织化不仅可以改善乳腺癌诊断和治疗， 管理，但也有助于阐明复杂和了解甚少的病理生理学乳腺癌 发展、进步和侵略性。一种无创评估基质胶原的方法 超声剪切波弹性成像（SWE）是乳房中的组织，但剪切波传播是 63%的恶性乳腺肿块受到抑制，导致测量质量低下。缺乏一个强大的 询问基质胶原组织的超声方法代表了开发 快速出现的和非常有前途的乳腺癌生物标志物。为了填补这一空白，我们的团队开发了 粘弹性响应（VisR）超声，一种通过超声检查询问胶原纤维组织的轴上方法。 乳房肿块和周围基质的硬度各向异性，而不观察剪切波传播。我们 在30名BIRADS-4或-5肿块的妇女中获得的初步体内数据表明， 肿块与周围组织硬度各向异性（RMSA）的比值区分活检证实的恶性 乳腺良性肿块9例，敏感性95%，特异性89%。此外，在我们的试点中， 可行性研究4名妇女进行连续监测，同时接受新辅助化疗（NAC），VisR RMSA从恶性趋向于良性适应症，对治疗有反应。的成功 研究激励VisR RMSA测量技术的进一步发展，其扩展到 揭示了VisR RMSA结果与基质胶原组织之间的关系， 应用于癌症检测和治疗监测。我们假设：晚期VisR RMSA与 间质胶原纤维组织与乳腺肿块良恶性鉴别 以及预测女性体内对NAC的病理完全应答（pCR）。

PROJECT SUMMARY Breast cancer is now the most prevalent cancer, with 2.3 million women diagnosed and 685,000 deaths globally. Although, the death rate has declined by about 1% per year over the last decade due in large part to earlier detection through screening, the current screening standard, digital mammography, lacks sensitivity and is challenged in radiographically dense breasts. Sensitivity in dense breasts is improved by magnetic resonance imaging (MRI), but required contrast enhancement and substantial additional cost are drawbacks. A non-contrast, low-cost alternative, ultrasound strain elastography (SE) has been shown to achieve high sensitivity and specificity for breast cancer diagnosis. However, while SE diagnoses suspicious breast massed by interrogating tissue stiffness, the underlying cause of stiffening is not discerned. Among the many possible causes, stromal collagen organization is newly a focus of intense interest due to its recently proven association with breast cancer stage, prognosis, treatment response, and other clinical features. Therefore, delineating stromal collagen organization in vivo would not only improve breast cancer diagnosis and treatment management but also help to elucidate the complex and poorly understood pathophysiology of breast cancer development, progression, and aggressiveness. One approach to noninvasively evaluating stromal collagen organization in the breast is ultrasound shear wave elastography (SWE), but shear wave propagation is inhibited in 63% of malignant breast masses, leading to low-quality measurements. The lack of a robust ultrasound approach to interrogating stromal collagen organization represents a major gap in exploiting a rapidly emerging and highly promising biomarker for breast cancer. To fill this gap, our group has developed Viscoelastic Response (VisR) ultrasound, an on-axis approach to interrogating collagen fiber organization via stiffness anisotropy in breast masses and surrounding stroma without observing shear wave propagation. Our preliminary in vivo data, acquired in 30 women with BIRADS-4 or -5 masses, demonstrate that VisR-derived ratio of mass-to-surrounding tissue stiffness anisotropy (RMSA) differentiated biopsy-confirmed malignant (n=9) from benign (n=21) breast masses with a sensitivity of 95% and a specificity of 89%. Further, in our pilot feasibility study of four women monitored serially while undergoing neoadjuvant chemotherapy (NAC), VisR RMSA trended from malignant to benign indication with response to treatment. The success of our investigations motivates further advancement of VisR RMSA measurement technology, its extension to revealing the relationship between VisR RMSA outcomes and stromal collagen organization, and broader application to cancer detection and treatment monitoring. We hypothesize: Advanced VisR RMSA correlates to stromal collagen fiber organization, which is relevant to differentiating malignant from benign breast masses and predicting pathologic complete response (pCR) to NAC in women, in vivo.