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

新辅助内分泌治疗对管腔乳腺癌 HER2 上调的定量分析

• 批准号: 10200554
• 负责人: Lubna N. Chaudhary
• 金额: $ 8.88万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200554
• 关键词: Aftercare; Area; Biological Markers; Biopsy; Biopsy Specimen; Breast Cancer Treatment; Characteristics; Clinical; Clinical Management; Clinical Research; Clinical Trials; Cytometry; Detection; Diagnostic; Disease; Disease Resistance; ERBB2 gene; Endocrine; Estrogen receptor positive; Excision; Fluorescence; Goals; Growth Factor Receptors; Heterogeneity; Histological Labelings; Hot Spot; Image Analysis; Immunofluorescence Immunologic; Immunohistochemistry; Individual; Interdisciplinary Study; Intraobserver Variability; Lead; Malignant Neoplasms; Measurement; Measures; Mediating; Methodology; Methods; Neoadjuvant Therapy; Numerical value; Operative Surgical Procedures; Outcome; Pathologic; Pathologist; Pathology; Patient Recruitments; Patient-Focused Outcomes; Patients; Pattern; Process; Prognosis; Proliferating; Proteins; Randomized Clinical Trials; Recurrence; Research; Research Project Grants; Resistance; Resolution; Risk; Risk Reduction; Signal Transduction; Spatial Distribution; Stains; Techniques; Testing; Therapy Clinical Trials; Toxic effect; Translational Research; Tumor Tissue; Up-Regulation; Visual; Work; accurate diagnostics; base; cancer cell; cancer heterogeneity; clinical center; hormone therapy; image processing; imaging Segmentation; improved; innovation; insight; malignant breast neoplasm; mortality; novel diagnostics; personalized medicine; predictive marker; protein expression; response; response biomarker; segmentation algorithm; statistics; targeted agent; targeted treatment; therapy resistant; tool; tumor

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.

项目描述 内分泌疗法可为雌激素受体患者的长期结局显着改善 阳性（ER+）乳腺癌（BC），也称为Luminal BC。但是，耐治疗转移性疾病 20-25％的患者发展。 HER2生长因子受体的上调代表一个共同的逃生 癌细胞使用的策略生存并继续以ER独立的方式增殖。 为了降低卑诗省的死亡率，需要更准确的诊断工具来指导量身定制的补充性 升高风险升高的患者的线路治疗。临床医生需要准确的肿瘤测试来指导 选择性地施用补充剂来可能反应者，并避免在非反应者中的毒性。 该项目将探索创新的自动化组织 - 循环仪技术，以分析可目标的表达 肿瘤前后内分泌疗法中耐药性与抗性相关的蛋白HER2。 该策略集中于在ER+/HER2-BC中开发最敏感的HER2蛋白表达的度量 确定对内分泌疗法响应HER2上调的肿瘤，并确定HER2-- 相关的扩散剂“热点”。我们将使用组织学肿瘤的多重免疫荧光标记 单独或共同检测和分析HER2蛋白表达的细胞水平和模式的部分 在肿瘤组织中使用Ki67。探索的指标将包括细胞的边际和空间分布 HER2信号捕获表达的异质性。静脉前后肿瘤活检和手术 我们最近完成的新辅助内分泌疗法临床试验的切除术将支持提议的 组织仪分析。 我们进一步寻求通过识别的指标来识别卑诗省肿瘤选择性HER2驱动的内分泌耐药性 HER2信号在没有治疗的肿瘤活检中，最可预测随后上调的HER2或 HER2相关的增生剂热点响应内分泌疗法。 预计拟议的研究将产生新的诊断指标，以合理招募患者 计划的量身定制的补充Her2靶向治疗的随机随机临床试验 ER+ BC。这项工作具有直接影响BC死亡率的直接潜力。