Fluorescence-guided resection of breast tumors using a topically-applied molecular probe

乳腺癌是女性中最常见的癌症，估计有246，660 2015年，美国有40，450例病例（和40，450例死亡）。由于更好的筛查技术， 75%的患者是乳房保留手术（BCS）的候选人，以消除癌症。BCS是 乳腺切除术优于替代方案（乳房切除术），长期生存率相当[1]。的 术后通过病理学评估BCS的成功。切除的显微镜边缘的状态 肿瘤切除术标本仍然是局部复发最重要的预后和风险因素[2，3]。一 阳性边缘表明浸润性癌或导管原位癌接触到组织边缘， 肿瘤切除标本在接受BCS和放射治疗的患者中，切缘阳性与 与阴性边缘相比，局部复发风险增加2倍[4]。的裁断 据估计，8%至86%的时间发生阳性边缘，需要患者返回进一步检查。 治疗通常与较差的美容效果和局部和远处复发的增加有关。 疾病目前的病理学方法仅评估取出的标本的整个体积的1%的约1/10。 边缘采样不足的结果是，5-16%的病理学上有肿瘤的患者发生局部复发。 边缘干净，表明在病理分析期间未对一个或多个肿瘤区域进行采样 导致肿瘤残留在患者体内。此外，乳腺癌患者之间仍然没有普遍的共识， 对于接受BCS的患者，外科医生对什么构成足够的阴性边界[5]。综合这些 数据表明，对快速和全球性地识别癌症组织的技术的临床需求尚未得到满足， 手术腔，并可用于在手术过程中引导他们的手术切除。分子成像 目前正在开发手术期间的肿瘤引导切除术。然而，大多数方法采用IV 施用光学成像剂，这需要数小时或数天来突出肿瘤组织。此外，委员会认为， 主要肿块周围组织中的浸润癌细胞可能没有形成血管系统， 不会被注射的药剂识别出来最后，照亮整个癌症肿块可能会产生高的 来自肿瘤的背景信号不是肿块切除术的“边缘”。利用增加的蛋白酶 为了在乳腺癌边缘表达，我们引入了体内局部施用的新概念， 淬灭的荧光分子成像探针，以识别手术后可能残留在手术腔中的癌症。 标准治疗切除术这建立在多年的临床前研究基础上，旨在表征、执行 毒理学，最后是1A和B期临床试验，以证明这种新方法的实用性。它有 有可能减少再切除以及病理学采样不足的假阴性率， 从而节省医疗保健成本并提高患者的生活质量。

Project Summary/Abstract: Breast cancer is the most common cancer in women, with an estimated 246,660 cases (and 40,450 deaths) in the US during 2015. Due to better screening techniques cancers are caught earlier and 75% of patients are candidates for breast conserving surgery (BCS) to remove the cancer. BCS is cosmetically preferable to the alternative (mastectomy) and long-term survival rates are equivalent [1]. The success of BCS is assessed post-operatively by pathology. The status of the microscopic margins of excision of the lumpectomy specimen is still the most important prognostic and risk factor for local recurrence [2,3]. A positive margin indicates that invasive carcinoma or ductal carcinoma in situ is touching a tissue edge of a lumpectomy specimen. Among patients treated by BCS and radiation therapy, positive margins are associated with a 2-fold increase in the risk of local recurrence when compared with negative margins [4]. A finding of positive margins is estimated to occur between 8% to 86% of the time, requiring patients to return for further treatment often associated with poorer cosmetic results and increases in local and distant recurrence of the disease. Current pathology methods only assess about 1/10 of 1% of the entire volume of the removed specimen. A consequence of margin undersampling is that local recurrence occurs in 5-16% of patients with pathologically clean margins, suggesting that one or more regions of tumor had not been sampled during pathological analysis resulting in tumor remaining in the patient. In addition, there is still no universal agreement among breast surgeons on what constitutes an adequate negative margin for patients undergoing BCS [5]. Together these data demonstrate the unmet clinical need for technologies that rapidly and globally identify cancerous tissues in the surgical cavity and can be used to guide their surgical resections during the procedure. Molecular imaging guided resections of tumors during surgeries are now being developed. However, most approaches employ IV administration of optical imaging agents, which require hours or days to highlight tumor tissues. Moreover, infiltrating cancer cells in tissues surrounding the main mass may not have developed a vasculature and likely would not be identified using injected agents. Finally, illuminating the entire cancer mass may create a high background signal from tumor that is not “at the margin” of the lumpectomy. Exploiting increased protease expression at the edge of breast cancers we introduce the novel concept of in vivo topical administration of quenched fluorescent molecular imaging probes to identify cancer that may remain in the surgical cavity after standard-of-care resection. This builds on years of preclinical studies and seeks to characterize, perform toxicology, and finally a Phase 1A & B clinical trial to demonstrate the utility of this novel approach. It has the potential to reduce re-excisions as well as the false negative rate from pathology undersampling, with a consequent savings in healthcare costs and, enhancement in patient life quality.