Quantitative Analyses of HER2 Upregulation in Luminal Breast Cancer in Response to Neoadjuvant Endocrine Therapy

项目描述 内分泌治疗可显著改善雌激素受体阴性患者的长期预后， 阳性（ER+）乳腺癌（BC），也称为管腔BC。然而，耐药转移性疾病 在20-25%的患者中发生。HER 2生长因子受体的上调代表了一种常见的逃避 这是癌细胞以ER非依赖性方式存活并继续增殖所使用的策略。 为了降低BC的死亡率，需要更准确的诊断工具来指导量身定制的补充剂 对进展风险升高的患者进行线治疗。临床医生需要准确的肿瘤检测来指导 选择性地向可能的应答者施用补充剂，并避免在无应答者中的毒性。 该项目将探索创新的自动化组织细胞计数技术， 新辅助内分泌治疗前后肿瘤中的治疗耐药相关蛋白HER 2。 该策略的重点是开发ER+/HER 2- BC中HER 2蛋白表达的最敏感指标 鉴定对内分泌治疗有反应而经历HER 2上调的肿瘤，以及鉴定HER 2- 相关的增殖性“热点”。我们将使用多重免疫荧光标记组织学肿瘤 检测和分析HER 2蛋白单独或联合表达的细胞水平和模式 Ki 67在肿瘤组织中的表达。探索的指标将包括细胞的边缘和空间分布， HER 2信号捕获表达的异质性。新辅助治疗前后的肿瘤活检和手术 我们最近完成的新辅助内分泌治疗临床试验的切除将支持所提出的 组织细胞计数分析。 我们进一步寻求通过确定以下指标来确定BC中肿瘤选择性HER 2驱动的内分泌耐药性： 未经治疗的肿瘤活检组织中的HER 2信号，最能预测随后的HER 2或HER 3上调 HER 2相关增殖热点对内分泌治疗的反应。 拟议的研究预计将产生新的诊断指标，用于合理招募患者进入 针对侵袭性乳腺癌患者的定制补充HER 2靶向治疗的计划随访随机临床试验 ER+ BC。这项工作有可能直接对不列颠哥伦比亚死亡率产生积极影响。

Project Description Endocrine therapy provides significant improvement in long-term outcomes for patients with estrogen receptor- positive (ER+) breast cancer (BC), also known as luminal BC. However, therapy-resistant metastatic disease develops in 20-25% of patients. Upregulation of the HER2 growth factor receptor represents a common escape strategy used by cancer cells to survive and continue to proliferate in an ER-independent manner. To reduce mortality from BC, more accurate diagnostic tools are needed to guide tailored supplementary first line therapy for patients at elevated risk of progression. Clinicians need accurate tumor tests to guide administration of supplementary agents selectively to likely responders and avoid toxicity in non-responders. This project will explore innovative automated histo-cytometric techniques to analyze expression of targetable, therapy resistance-relevant protein HER2 in tumors pre- and post-neoadjuvant endocrine therapy. The strategy is centered on developing the most sensitive metric of HER2 protein expression in ER+/HER2- BC to identify tumors that undergo HER2 upregulation in response to endocrine therapy, as well as identify HER2- associated proliferative ‘hotspots’. We will use multiplex immunofluorescence labeling of histological tumor sections to detect and analyze cellular levels and patterns of HER2 protein expression alone or in conjunction with Ki67 within the tumor tissue. The metrics explored will include marginal and spatial distributions of cellular HER2 signals to capture heterogeneity of expression. Pre- and post-neoadjuvant tumor biopsies and surgical resections from our recently completed neoadjuvant endocrine therapy clinical trial will support the proposed histo-cytometric analyses. We further seek to identify tumor-selective HER2-driven endocrine resistance in BC by identifying the metric of HER2 signal in therapy-naïve tumor biopsies that is most predictive of subsequent upregulation of HER2 or HER2-associated proliferative hot-spots in response to endocrine therapy. The proposed research is expected to yield new diagnostic metrics for rational recruitment of patients into a planned follow-on randomized clinical trial of tailored supplementary HER2-targeted treatment for aggressive ER+ BC. The work has direct potential to positively impact BC mortality.