SBIR-STTR Award

Direct to Phase II

The objective of this Phase II project is to improve outcomes and survival for patients with melanoma byreducing the number of false negative sentinel lymph node biopsies wherein metastatic disease is missedthrough conventional tissue processing and histological characterization. It is estimated that 4,200 patients aremisdiagnosed in this manner in the US per year which results in more conservative treatment regimens forthese patients than is required to effectively treat their disease. The outcome of patients not receiving theproper treatment regimen is that they experience a three-year reduction in ten-year survival which on a qualityadjusted life year basis translates into a $1.2 billion economic loss. To address this problem, we havedeveloped a three-dimensional tissue imaging and digital analysis approach which allows for the completecharacterization of sentinel lymph node biopsy tissues and the identification of isolated tumor cells and micro-metastases that are commonly missed with traditional histopathology. We have demonstrated through ourpreliminary studies that using this approach we can identify these cancer cells in tissues that were previouslycharacterized as node negative and that we can differentiate true negative from false negative samples.The focus of this project is to take this approach and transform it into a CLIA diagnostic assay that can beoffered as a laboratory developed test to patients with negative sentinel lymph node biopsies at the conclusionof this Phase II work. Initially, the test will be offered following traditional tissue evaluation but eventually couldbe used as a primary diagnostic approach for all melanoma sentinel lymph node biopsy tissues. Thedevelopment of this assay will be completed through conducting a retrospective clinical study in partnershipwith Cedars-Sinai with archived negative sentinel lymph node biopsy tissue blocks where the approach will beused to characterize these samples in their entirety. Through this study, we will demonstrate the accuracy,specificity and sensitivity of the test and will be able to quantify the extent to which it reduces the incidence offalse negatives in the characterization of sentinel lymph node biopsies. Through the execution of this clinicalstudy, we will build a statistical model that will threshold samples based upon their underlying three-dimensional features (e.g. total number of cancer cells, cancer cell aggregate volume, density of cancer cells)and classify them as "˜no metastases present' (i.e. true negative) or "˜metastases present' (i.e. true positive).Furthermore, the software we develop will for positive samples describe where a section should be taken fromthe sample for confirmation by a Visikol pathologist using traditional histopathology such that the report fromthe assay fits into the traditional classification paradigm. Lastly, we will transform our digital pathology softwareanalysis approach into a 21 CFR part 11 compliant application which will be required at the conclusion of theproject to start offering the assay as a CLIA test. To support this approach and to allow for the launch of alaboratory developed test, we will also build the validation documentation package and associated testsrequired to demonstrate the range, specificity, reproducibility, accuracy and precision of the assay. Therefore,at the conclusion of this project we will have built and validated an assay which can start to be offered topatients following the build-out of a CLIA lab and staffing with clinical personnel.

Public Health Relevance Statement:
Narrative The objective of this Phase II project is to improve the diagnosis of metastatic melanoma by reducing the number of patients who are incorrectly diagnosed with non-metastatic disease when their primary tumor has spread to their lymph nodes and they do have metastatic disease. It is estimated that 4,200 patients are misdiagnosed in this manner in the US per year which results in these patients not receiving the proper treatment regimen and experiencing three-year reductions in ten-year survival. Through this project, a diagnostic platform for sentinel lymph node 3D imaging will be developed that will dramatically reduce misdiagnosis, thus resulting in improved outcomes for patients and over $1.2 billion in economic value per year on a quality adjusted life year basis.

Project Terms:
Archives ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; malignant breast neoplasm ; Breast Cancer ; malignant breast tumor ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Skin Cancer ; Malignant Skin Neoplasm ; malignant skin tumor ; Classification ; Systematics ; Clinical Research ; Clinical Study ; Cessation of life ; Death ; Diagnosis ; Diagnostic Imaging ; Disease ; Disorder ; Economics ; Incidence ; Laboratories ; lymph nodes ; Lymph Node Reticuloendothelial System ; Lymph node proper ; Lymphatic nodes ; lymph gland ; lymphnodes ; melanocyte ; melanoma ; Malignant Melanoma ; Statistical Models ; Probabilistic Models ; Probability Models ; statistical linear mixed models ; statistical linear models ; Neoplasm Metastasis ; Metastasis ; Metastasize ; Metastatic Lesion ; Metastatic Mass ; Metastatic Neoplasm ; Metastatic Tumor ; Secondary Neoplasm ; Secondary Tumor ; cancer metastasis ; tumor cell metastasis ; Pathology ; Patients ; Pilot Projects ; pilot study ; Probability ; Recurrence ; Recurrent ; Sensitivity and Specificity ; Computer software ; Software ; Specificity ; Surveys ; Survey Instrument ; Testing ; Tissues ; Body Tissues ; Translating ; Treatment Protocols ; Treatment Regimen ; Treatment Schedule ; Work ; Quality-Adjusted Life Years ; QALY ; Quality-Adjusted Life Expectancy ; Caring ; Guidelines ; base ; density ; Label ; improved ; Procedures ; Clinical ; Phase ; Histologic ; Histologically ; Evaluation ; Metastatic Melanoma ; Malignant Cell ; cancer cell ; Pathologist ; tool ; Diagnostic ; Research Specimen ; Specimen ; Protocol ; Protocols documentation ; Distant ; In Situ ; 3-D ; 3D ; three dimensional ; 3-Dimensional ; Operative Procedures ; Surgical ; Surgical Interventions ; Surgical Procedure ; surgery ; Operative Surgical Procedures ; interest ; experience ; Tumor Cell ; neoplastic cell ; Histopathology ; Adjuvant Therapy ; Biopsy Sample ; Biopsy Specimen ; Primary Tumor ; Primary Neoplasm ; Manpower ; personnel ; Human Resources ; Reporting ; Abscission ; Extirpation ; Removal ; Surgical Removal ; resection ; Excision ; Axillary Lymph Node ; Axillary Node ; Axillary lymph node group ; Sentinel Node Biopsy ; Sentinel Lymph Node Biopsy ; Sampling ; assay development ; develop software ; developing computer software ; software development ; 3-D Imaging ; 3D imaging ; Three-Dimensional Imaging ; Documentation ; tissue processing ; Address ; Detection ; NCCN ; National Comprehensive Cancer Network ; Proliferating ; Reproducibility ; American Joint Committee on Cancer ; AJCC ; Clinical Treatment ; trial regimen ; trial treatment ; Nonmetastatic ; Non-metastatic ; Patient-Focused Outcomes ; Patient outcome ; Patient-Centered Outcomes ; Validation ; Monitor ; Process ; Sentinel Lymph Node ; Sentinel Node ; follow-up ; Active Follow-up ; active followup ; follow up ; followed up ; followup ; Adjuvant ; Development ; developmental ; Image ; imaging ; economic value ; monetary value ; digital ; Outcome ; Population ; clinical effect ; chemotherapy ; diagnostic assay ; improved outcome ; Tissue imaging ; imaging approach ; imaging based approach ; imager ; digital pathology ; Nivolumab ; Opdivo ; Clinical Laboratory Improvement Amendments ; diagnostic platform ; diagnostic system ;