Serum GP88 biomarker as a surrogate marker for disease progression in breast canc

血清 GP88 生物标志物作为乳腺癌疾病进展的替代标志物

• 批准号: 8058236
• 负责人: Ginette Serrero
• 金额: $ 11.33万
• 依托单位: A AND G PHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-27 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058236
• 关键词: Adjuvant; Adjuvant Chemotherapy; Adjuvant Therapy; Adopted; Aftercare; American College of Radiology Imaging Network; Archives; Benign; Biological; Biological Assay; Biological Markers; Biological Markers; Biopsy; Breast; Cancer Etiology; Cancer Patient; Cancer and Leukemia Group B; Cessation of life; Characteristics; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic radiologic examination; Disease; Disease Progression; Ductal; Enrollment; Epithelium; Evaluation; Face; Failure; Growth Factor; Human; Image; Image Analysis; Imaging technology; Incidence; Investigation; Laboratories; Lesion; Liquid substance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Mammary Gland Parenchyma; Measurable; Measurement; Measures; Medical; Methods; Molecular Analysis; Monitor; Neoadjuvant Therapy; No Evidence of Disease; Operative Surgical Procedures; PC cell-derived growth factor; Patients; Performance; Phase; Play; Primary Neoplasm; Progressive Disease; Radiation; Recurrence; Research; Research Personnel; Risk; Role; Sampling; Serum; Small Business Innovation Research Grant; Specialized Program of Research Excellence; Specimen; Staging; Surrogate Markers; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment Failure; Tumor Volume; Validation; Woman; autocrine; base; cancer recurrence; cancer therapy; chemotherapy; cost; hormone therapy; lymph nodes; malignant breast neoplasm; molecular marker; novel; overexpression; research clinical testing; response; standard of care; success; therapy outcome; therapy resistant; tool; treatment strategy; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): 40,000 women die annually in the US as a result of breast cancer (BC). Although BC can be controlled if detected early, a significant number is not detected until later and these patients are treated using therapies to control both primary tumor and micro-metastatic disease. Therapy response is monitored using imaging and clinical assessment. Failure to detect early progression is a missed opportunity to adopt suitable therapies at a time when their impact on the disease can be maximized. Identification and validation of surrogate markers for identification of disease progression would provide clinicians with timely information in the management of BC therapy. The purpose of this application is to investigate the performance characteristics of the novel 88kDa autocrine growth factor GP88 as a surrogate marker for disease progression in breast cancer patients. GP88 is a critical biological driver for proliferation, survival, and invasiveness and is over expressed in invasive ductal cancers while negative in benign lesions and normal breast tissue. Two tests were developed to measure GP88 expression in cancer specimens; an IHC test for tumor biopsies and an EIA to measure circulating GP88 in biological fluids that have been validated in clinical trials. Tissue GP88 expression was predictive marker of BC recurrence while serum GP88 was elevated in BC patients with progressive disease, but not in BC patients with no evidence of disease. The specific aims of this revised SBIR Phase I are to investigate GP88 as a surrogate marker for disease progression in BC patients enrolled in the I-SPY Trial. The I-SPY trial is a national study to identify biomarkers predictive of response to therapy throughout the treatment cycle for women with Stage 3 breast cancer in neoadjuvant setting. This trial enrolled 221 patients with tissue and serum samples collected at specific time points pre and post-treatment and subjects followed for three years post-therapy. 122 (55%) patients benefited from neo-adjuvant treatment, 40 (18%) patients received some benefit (tumors reduced by 10% - 40%) and 59 (27%) patients showed no benefit (disease progressed). Aims are: 1: Determine if serum/tissue GP88 levels are a surrogate marker to identify breast cancer patients not benefiting from on-going neo-adjuvant chemotherapy. We will determine if there is a correlation between GP88 level and decreased/increased tumor volume in chemo-naive patients undergoing neo-adjuvant chemotherapy. 2: Determine if serum GP88 can be used to identify breast cancer patients most likely to have recurrence following an initial benefit from neo-adjuvant therapy. We will determine if there is a quantifiable difference in the risk of recurrence between those patients with high and low serum or tissue GP88 levels, prior to commencing neo-adjuvant therapy. Upon completion of these specific aims, this investigation will evaluate GP88 as a surrogate to identify disease progression in patients undergoing chemotherapy and additionally if initial serum GP88 level prior to commencing therapy is correlated to risk of recurrence and will provide additional tools to clinicians to monitor therapy response and disease progression during and after treatment. PUBLIC HEALTH RELEVANCE: (Lay) Breast cancer (BC) incidence in US women is second only to lung cancer and is one of the leading causes of cancer related death; 40,000 women die annually. Patients in whom BC is detected as having spread beyond the breast are treated with radiation, chemotherapy and/or hormonal therapy prior to potential surgery. During and post treatment, tumor response is monitored using x-ray and clinical evaluation, imprecise methods for detection of subtle changes in tumor size that may indicate treatment failure. Use of X-ray imaging is relatively infrequent, subjective and requires availability of prior studies. There are no easily available specific diagnostic markers, direct or surrogate, for monitoring disease activity in BC. We have identified GP88 as a biomarker that may be used as a surrogate for detection of tumor changes in BC patients undergoing therapy. Preliminary data in a small study demonstrated that GP88 can be identified in serum of BC patients and is elevated in patients with progressive disease but not in patients with "no evidence of disease" following therapy, thus indicating that it may be useful as a surrogate marker for assessing response to chemotherapy. This project will investigate the use of GP88 as a surrogate marker for detection of non-response to chemotherapy and will provide information that may enable clinicians to adopt 2nd or 3rd line therapies when they may be most effective and may save patients un-necessary toxicity and costs associated with ineffective 1st line therapy.

描述（由申请人提供）：美国每年有40,000名妇女死于乳腺癌（BC）。虽然早期发现可以控制BC，但大量患者直到后来才被发现，这些患者使用治疗方法来控制原发肿瘤和微转移性疾病。使用影像学和临床评估来监测治疗反应。如果不能发现早期进展，就错过了在适当治疗对疾病影响可以最大化的时候采取适当治疗的机会。识别和验证替代标记物以识别疾病进展将为临床医生提供及时的BC治疗管理信息。本应用程序的目的是研究新型88kDa自分泌生长因子GP88作为乳腺癌患者疾病进展的替代标志物的性能特征。GP88是增殖、存活和侵袭性的关键生物学驱动因子，在浸润性导管癌中过表达，而在良性病变和正常乳腺组织中为阴性。开发了两种检测方法来测量GP88在癌症标本中的表达；一种用于肿瘤活检的免疫组化测试，以及一种用于测量生物体液中循环GP88的环评，这些都已在临床试验中得到验证。组织GP88的表达是BC复发的预测指标，而血清GP88在进展性BC患者中升高，但在无疾病证据的BC患者中没有升高。这项修订后的SBIR I期临床试验的具体目的是研究GP88作为I- spy试验中BC患者疾病进展的替代标志物。I-SPY试验是一项国家研究，旨在确定在新辅助治疗下3期乳腺癌妇女整个治疗周期中预测治疗反应的生物标志物。该试验招募了221名患者，在治疗前和治疗后的特定时间点收集组织和血清样本，并在治疗后随访三年。122例（55%）患者受益于新辅助治疗，40例（18%）患者获得一些益处（肿瘤缩小10% - 40%），59例（27%）患者没有获益（疾病进展）。目的是：1：确定血清/组织GP88水平是否可以作为鉴别乳腺癌患者是否受益于持续的新辅助化疗的替代标志物。我们将确定GP88水平与接受新辅助化疗的初次化疗患者肿瘤体积减小/增大之间是否存在相关性。2：确定血清GP88是否可用于鉴别最初接受新辅助治疗后最有可能复发的乳腺癌患者。在开始新辅助治疗之前，我们将确定血清或组织GP88水平高与低的患者在复发风险方面是否存在可量化的差异。在完成这些特定目标后，本研究将评估GP88作为替代物，以确定接受化疗的患者的疾病进展，以及开始治疗前的初始血清GP88水平是否与复发风险相关，并将为临床医生提供额外的工具，以监测治疗期间和治疗后的治疗反应和疾病进展。