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）。虽然如果早期检测到BC可以控制，但直到后来才检测到大量患者，并且这些患者使用控制原发性肿瘤和微转移性疾病的疗法进行治疗。使用成像和临床评估监测治疗反应。未能检测到早期进展是错失了在可以最大限度地发挥其对疾病影响的时候采用合适疗法的机会。识别和验证用于识别疾病进展的替代标志物将为临床医生提供BC治疗管理中的及时信息。本申请的目的是研究新型88 kDa自分泌生长因子GP 88作为乳腺癌患者疾病进展的替代标志物的性能特征。GP 88是增殖、存活和侵袭性的关键生物驱动因素，并且在侵袭性导管癌中过表达，而在良性病变和正常乳腺组织中为阴性。开发了两种测试来测量癌症标本中的GP 88表达;用于肿瘤活检的IHC测试和用于测量已在临床试验中验证的生物液体中的循环GP 88的EIA。组织GP 88表达是BC复发的预测标志物，而血清GP 88在疾病进展的BC患者中升高，但在没有疾病证据的BC患者中不升高。本修订版SBIR I期的具体目的是研究GP 88作为入组I-SPY试验的BC患者疾病进展的替代标志物。I-SPY试验是一项全国性研究，旨在确定在新辅助治疗条件下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。该试验入组了221例患者，在治疗前和治疗后的特定时间点采集了组织和血清样本，并对受试者进行了治疗后3年的随访。122例（55%）患者从新辅助治疗中获益，40例（18%）患者获得了一些获益（肿瘤缩小10% - 40%），59例（27%）患者未显示获益（疾病进展）。目标是：一曰：确定血清/组织GP 88水平是否是识别未从正在进行的新辅助化疗中获益的乳腺癌患者的替代标志物。我们将确定在接受新辅助化疗的化疗初治患者中GP 88水平与肿瘤体积减少/增加之间是否存在相关性。第二章：确定血清GP 88是否可用于识别新辅助治疗后最有可能复发的乳腺癌患者。我们将确定在开始新辅助治疗之前，血清或组织GP 88水平高和低的患者之间复发风险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GP 88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GP 88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。 公共卫生关系：乳腺癌（BC）在美国女性中的发病率仅次于肺癌，是癌症相关死亡的主要原因之一;每年有40，000名女性死亡。检测到BC扩散到乳房以外的患者在可能的手术之前接受放射治疗，化疗和/或激素治疗。在治疗期间和治疗后，使用X射线和临床评估来监测肿瘤反应，这些方法不精确，用于检测可能表明治疗失败的肿瘤大小的细微变化。X线成像的使用相对较少，主观性较强，需要既往研究。没有容易获得的直接或替代的特异性诊断标志物用于监测BC中的疾病活动。我们已经确定GP 88作为生物标志物，可以用作检测接受治疗的BC患者的肿瘤变化的替代物。一项小型研究的初步数据表明，GP 88可以在BC患者的血清中鉴定，并且在疾病进展的患者中升高，但在治疗后“没有疾病证据”的患者中不升高，因此表明它可能用作评估对化疗反应的替代标记物。本项目将研究GP 88作为检测化疗无应答的替代标志物的用途，并将提供信息，使临床医生能够在最有效时采用二线或三线治疗，并可为患者节省与无效一线治疗相关的不必要的毒性和费用。