SBIR-STTR Award

Significance: Despite decreases in the overall number of new breast cancer (BC) cases reported in the US annually, there are still about 40,000 BC deaths annually, ~80% from metastatic breast cancer (MBC). Thus the ability to monitor MBC is important to determine disease status and therapy response. While the gold standard, imaging is expensive, time consuming and slow to detect disease response or progression, circulating biomarkers such as CA15-3, CA27.29 and CEA, also used to monitor MBC have limitations due to low specificity and sensitivity. Thus, providing better safe, inexpensive, non-invasive, specific and sensitive tests for new biomarkers to monitor disease is a key component in improving MBC patient care. Strategy: Measurement of critical biological drivers as biomarkers of the disease will provide a clearer understanding of current disease state and improve proactive clinical management. The PI has characterized a proprietary target biomarker, GP88 expressed in BC tissue, secreted in BC patients’ blood and playing a key role in BC tumorigenesis. GP88 IHC and EIA tests to measure GP88 tumor expression and circulating levels in BC patients were developed and clinically validated. Supporting Evidence: Pathological studies have established GP88 tumor expression as a predictive marker for recurrence. Clinical studies have shown BC patients with progressive disease have elevated GP88 serum levels compared to patients with no evidence of disease or healthy individuals. Patients with poor outcome had a significantly higher GP88 serum levels (56ng/ml, range 40-146ng/ml) than alive patients (36ng/ml, range 30-46ng/ml), p=0.016. These data indicate that if GP88 blood levels are maintained below a yet to be established cut-off level, then a patient can be expected to have a longer survival than patients with elevated GP88. Hypothesis: Measuring serum GP88 level could provide an ideal approach for monitoring disease status in MBC patients as adjunctive to imaging. This hypothesis will be investigated by measuring GP88 levels in sequential retrospective serum samples collected from 140 MBC patients enrolled in an IRB approved study at UMGCCC and correlate such levels with objective measures of clinical outcome determined using RECIST 1.1 criteria. Specific Aims: we will: 1a) establish by Kaplan-Meier survival graphs a GP88 threshold value that stratify BC patients for survival and clinical outcomes; 1b) determine if changes in GP88 serum level correlate with changes in RECIST1.1 criteria collected at the same time-points; 2) using receiver operating characteristics curves, identify GP88 cutoff values that effectively stratify patients by their clinical outcome; 3) using multivariate analysis and logistic regression evaluate if combining GP88 and CA15-3 results can improve upon, and enhance, the predictive performance of CA15-3. Overall Impact: Since GP88 is a driver of the disease, the use of the GP88 EIA test has the potential to provide real-time evaluation of the disease state, making GP88 a better biomarker to monitor MBC than those currently available. This will provide clinicians with a new assay to assess disease status to increase predictive values of existing techniques such as imaging.

Public Health Relevance Statement:
Of ~40,000 breast cancer (BC) related deaths, ~80% are where BC has spread outside the breast (MBC), even though at time of primary diagnosis there is often no evidence of tumor spread. Thus the ability to detect and monitor MBC is important in the management of BC. Provision of safe, inexpensive, non-invasive, specific and sensitive tests for monitoring of disease is key in disease management. The PI has characterized a biomarker called GP88. Biological and clinical studies have established the importance of GP88 in BC aggressiveness and as a predictive marker for recurrence. Published studies demonstrated GP88 is present in BC tissue but not in corresponding “normal” breast tissue, elevated levels of GP88 in BC tumor tissue are associated with poor outcome and compared to healthy individuals, elevated GP88 blood levels can be found in BC patients with progressive disease. Thus using blood tests to detect and quantify GP88 during treatment could provide an ideal target for monitoring disease progression in BC patients undergoing therapy. This SBIR Phase I study will measure GP88 levels in sequential blood samples collected from ~140 MBC patients enrolled in an IRB approved study and correlate such levels with objective measures of clinical outcome. This application will explore this relationship and determine the best cutoff level for GP88 when examining sequential data in comparison to disease status. If we can establish a relationship between the GP88 level in blood and the disease state the information will be useful for disease management of MBC patients.

Project Terms:
Address; Biological; Biological Assay; Biological Markers; Biological Process; Blood; Blood Circulation; Blood specimen; Blood Tests; Breast; Breast Cancer Patient; Caring; Case Study; Cessation of life; circulating biomarkers; Clinical; Clinical Management; Clinical Research; Comprehensive Cancer Center; cost effective; Current Procedural Terminology Codes; Data; Diagnosis; Disease; Disease Management; Disease Progression; Drug resistance; Early Diagnosis; Enrollment; Ensure; Equilibrium; Evaluation; Feasibility Studies; Goals; Gold; Graph; Hematological Disease; Image; Imaging technology; Immunoassay; improved; Individual; Institutional Review Boards; Left; Logistic Regressions; Longitudinal prospective study; malignant breast neoplasm; Mammary Gland Parenchyma; Mammary Neoplasms; Maryland; Measurement; Measures; Metastatic breast cancer; Monitor; Monitoring for Recurrence; Multivariate Analysis; Neoplasm Metastasis; No Evidence of Disease; Oncologist; Outcome; Patient Care; patient stratification; Patients; Performance; PGRN gene; Phase; phase 1 study; Play; predictive marker; Predictive Value; Progressive Disease; Protocols documentation; Publishing; Receiver Operating Characteristics; Recurrence; response; Risk; Role; Sampling; Sensitivity and Specificity; Serum; Small Business Innovation Research Grant; Stable Disease; Staging; standard of care; targeted biomarker; Techniques; Testing; Time; tissue biomarkers; Tissues; tumor; Tumor Tissue; tumorigenesis; Universities; Validation; Visit; Work

Cost-effective and minimally invasive monitoring of metastatic breast cancer (MBC) patients for disease progression or response to therapy is an unmet need in the clinical management of the disease. Imaging technologies are currently the gold standard of such monitoring. However, there is controversy regarding the type & frequency of imaging required. Imaging is expensive, time consuming, slow to detect disease changes and raises concern about repeated radiation exposure and costs are not always covered by insurance. Complementary approaches to imaging such as circulating tumor cells and biomarkers are used in the Standard of Care (SOC), although their application remains limited. A simple, cost-effective blood test to measure the level of biomarkers which are drivers of the disease aggressiveness should provide novel solutions for real-time monitoring of therapy response and reduce dependency on imaging in the MBC population. The PI has identified an 88kDa glycoprotein GP88 (progranulin), elucidated its biological activity as an autocrine growth & survival factor. GP88 is secreted from cancer cells and measurable in biological fluids at higher levels in breast cancer patients, compared to healthy individuals. Based on these characteristics, an innovative diagnostic test (Enzyme Immunoassay ? EIA) to measure GP88 in circulation was established. Our SBIR Phase 1 retrospective study demonstrated a statistical association between serum GP88 levels measured by the EIA test and objective measures of disease, i.e. RECIST 1.1 in 101 MBC patients. We established that a serum GP88 level of 56ng/mL was a stratification point below which patients have improved overall survival while patients with GP88>56 ng/ml have a poor outcome. We showed that serum GP88 levels were statistically correlated to response to therapy in addition to progression of disease unlike the SOC biomarker CA15-3 which is only associated to progression of disease. Based on these promising data, we are proposing an SBIR Phase 2 prospective longitudinal study over a 15-month period enrolling 120 MBC patients at two clinical sites by measuring serum GP88 level every month with imaging performed every 3 months. The objectives are to validate the findings of phase 1 and establish the predictive use of the GP88 test in monitoring MBC patients for disease progression/ response as an adjunct to imaging and aid in the clinical management of such patients. Specifically, we will (1) Validate that serum GP88 levels are correlated to disease response/ progression as defined by imaging results; (2) Examine the impact of successive high (>56ng/mL) and low (<56ng/mL) GP88 blood levels on future response/ progression and time to progression as defined by imaging results; (3) Validate that patients with consistent low (<56ng/mL) GP88 blood levels, have improved survival compared with patients with consistently high (>56ng/mL) GP88 blood levels. The outcomes of this phase 2 will be to establish clinical data to support commercialization of GP88 EIA as an integral part of clinical management of MBC patients that will contribute to improved care of MBC patients at reduced cost.

Thesaurus Terms:
Applications Grants; Autocrine; Base; Biological; Biological Markers; Biological Process; Blood; Blood Circulation; Blood Specimen; Blood Tests; Breast Cancer Patient; Cancer Cell; Caring; Cessation Of Life; Characteristics; Circulating Biomarkers; Clinical; Clinical Assessments; Clinical Data; Clinical Management; Clinical Research Site; Commercialization; Complement; Cost; Cost Effective; Data; Dependence; Diagnostic; Diagnostic Tests; Disease; Disease Management; Disease Progression; Disseminated Malignant Neoplasm; Drug Resistance; Enrollment; Enzyme Immunoassay; Experience; Exposure To; Follow-Up; Frequencies; Future; Glycoproteins; Gold; Growth; Health; Image; Imaging Technology; Improved; Individual; Innovation; Insurance; Laboratories; Liquid Substance; Longitudinal Prospective Study; Longitudinal Studies; Malignant Breast Neoplasm; Measurable; Measurement; Measures; Metastatic Breast Cancer; Minimally Invasive; Monitor; Neoplasm Circulating Cells; Novel; Oncologist; Outcome; Patient Monitoring; Patient Population; Patient Stratification; Patients; Pgrn Gene; Pharmaceutical Preparations; Phase; Population; Predicting Response; Process; Prospective; Quality Of Life; Radiation; Radiation Exposure; Real Time Monitoring; Recurrence; Response; Retrospective Cohort; Retrospective Studies; Risk; Sampling; Scanning; Schedule; Serum; Small Business Innovation Research Grant; Standard Of Care; Stratification; Testing; Therapeutic; Time; Toxic Effect; Tumor; Tumor Markers; Tumor Tissue; Tumorigenesis; Work;