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）：由于乳腺癌（BC），每年有40,000名妇女在美国死亡。尽管可以早期检测到BC，但是直到以后才检测到大量数量，并且使用疗法治疗这些患者以控制原发性肿瘤和微转移性疾病。使用成像和临床评估对治疗反应进行监测。未能检测到早期进展是一种错过的机会，可以在最大化疾病的影响时采用合适的疗法。鉴定和验证替代标志物用于鉴定疾病进展，将为临床医生提供及时的BC治疗管理信息。该应用的目的是研究新型88KDA自分泌生长因子GP88的性能特征，作为乳腺癌患者疾病进展的替代标记。 GP88是增殖，生存和侵入性的关键生物驱动力，在侵入性导管癌中过度表达，而在良性病变和正常乳腺组织中阴性。开发了两项测试以测量癌症标本中的GP88表达。肿瘤活检和EIA的IHC测试，用于测量在临床试验中已验证的生物流体中循环GP88的测试。组织GP88的表达是BC复发的预测标志物，而血清GP88在卑诗省患有进行性疾病的患者中升高，但在没有疾病迹象的卑诗省患者中却没有。这项修订后的SBIR I期的具体目的是研究GP88作为I-SPY试验入学的BC患者疾病进展的替代标记。 I-SPY试验是一项全国研究，旨在确定在新辅助环境中为3期乳腺癌女性在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例在特定时间点和治疗后的特定时间点收集的组织和血清样品患者，并在治疗后三年接受了受试者。 122例（55％）的患者受益于新辅助治疗，40名（18％）患者获得了一定的好处（肿瘤降低了10％-40％），59例（27％）患者没有受益（疾病进展）。目的是：1：确定血清/组织GP88水平是否是替代标志物，以鉴定乳腺癌患者无法受益于持续的新辅助化疗。我们将确定在接受新辅助化疗的化学疗法患者中，GP88水平与肿瘤体积降低/增加之间的相关性。 2：确定血清GP88是否可以用于鉴定乳腺癌患者，最有可能在新辅助治疗的初始好处后重复出现。我们将确定在开始新辅助治疗之前，那些高血清和低血清或组织GP88水平的患者之间复发的风险是否存在可量化差异。完成这些特定目标后，该研究将评估GP88作为替代化学疗法的疾病进展，并在开始治疗之前初始血清GP88水平与复发风险相关，并将为临床医生提供其他工具，以监测治疗和治疗过程中的治疗反应和疾病进展。 公共卫生相关性：（LAI）乳腺癌（BC）在美国妇女中的发生率仅次于肺癌，并且是癌症相关死亡的主要原因之一；每年有40,000名妇女死亡。在潜在的手术前，检测到卑诗省的患者被放射线，化学疗法和/或激素治疗治疗。在治疗期间，使用X射线和临床评估对肿瘤反应进行监测，不精确的方法检测可能表明治疗衰竭的肿瘤大小的细微变化。 X射线成像的使用相对不频繁，主观，需要先前的研究。没有直接或替代的特定特定诊断标记，用于监测卑诗省的疾病活动。我们已经将GP88确定为一种生物标志物，可以用作检测接受治疗的BC患者肿瘤变化的替代物。一项小型研究中的初步数据表明，在卑诗省患者的血清中可以鉴定出GP88，并且在治疗后的进行性疾病患者中升高，但在患有“没有疾病证据”的患者中升高，因此表明它可以作为评估化学疗法反应的替代标记物。该项目将调查使用GP88作为检测化学疗法无反应的替代标记物的使用，并提供信息，使临床医生在可能最有效的情况下可以采用第二或第三线治疗，并可以节省患者不必要的毒性和与无效的第一线治疗相关的不必要的毒性和成本。