Methods for determining prognosis of colorectal cancer
Inventors
O'Shannessy, Daniel John • Nicolaides, Nicholas C. • SOMERS, Elizabeth B.
Assignees
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Publication Number
US-10539565-B2
Publication Date
2020-01-21
Expiration Date
Abstract
Provided herein are methods for determining the risk that a subject diagnosed with colorectal cancer will develop a recurrence of colorectal cancer and methods of predicting clinical outcome for a subject diagnosed with colorectal cancer by a) determining the level of expression for each marker of a panel of markers in a panel of tumor compartments in a tumor tissue sample from the subject, wherein the panel of markers comprises at least two of TEM1, HIF2α, CAIX, PDGFRβ, fibronectin, collagen I, collagen IV, and CD31 and wherein the panel of tumor compartments comprises at least three tumor compartments of pure stroma, tumor, stromal vessel, and tumor vessel; b) determining the TAPPS score for said subject; and c) comparing the TAPPS score of the subject to the TAPPS score of a population of subjects diagnosed with colorectal cancer. Also provided are related computer-implemented methods and systems, kits, and tumor microarrays.
Core Innovation
The patent describes methods for colorectal cancer clinical outcome prediction and recurrence risk assessment based on expression levels of a multi-marker panel. The panel includes TEM1 (endosialin), HIF2α, CAIX, PDGFRβ, fibronectin, collagen I, collagen IV, and CD31, quantified in tumor compartments including pure stroma, tumor, stromal vessel, and tumor vessel. The measured expression levels are used to compute a TEM1-associated pathway prognostic signature (TAPPS) score and to stratify clinical outcomes into low, intermediate, and high risk categories.
The prognostic computation uses coefficients from multivariate Cox proportional hazards models, and the resulting TAPPS score is compared to a population to determine risk stratification. The patent reports clinical performance including Kaplan-Meier survival analysis and that the TAPPS score provides independent prognostic value. The document further describes refined models including R-TAPPS and mTAPPS that use fewer compartment-specific biomarkers while maintaining prognostic assessment.
The patent additionally outlines compartment-focused biomarker detection and localization using a tissue microarray and quantitative immunofluorescence approaches, including AQUA® and related methods. The assessment is connected to a compartment-masking/imaging approach for quantifying markers within specific compartments, and the described labeling workflows include use of antibody binding targets such as vimentin, cytokeratin, CD31, TEM-1, HIF2α, collagen IV, and fibronectin-1 followed by assessment of degree of labeling.
Claims Coverage
The partial content includes two independent claims, both directed to methods of labeling a tissue sample array followed by assessing the degree of labeling. Across the independent claims, the inventive coverage focuses on conditional co-labeling of tissue samples with named biomarker antibodies, including TEM-1, HIF2α, collagen IV, and fibronectin-1, tied to the initial vimentin/cytokeratin/CD31 antibody-contact configurations.
Conditional multi-antibody labeling with vimentin/cytokeratin/CD31 configurations
Obtaining a tissue sample array from a subject; contacting tissue samples with antibodies that specifically bind vimentin and with an antibody that specifically binds cytokeratin and a second antibody that specifically binds CD31, including vimentin with CD31 and cytokeratin with CD31 formats; contacting at least one tissue sample contacted with vimentin with an antibody that specifically binds TEM-1; contacting at least one tissue sample contacted with cytokeratin and CD31 with an antibody that specifically binds TEM-1; contacting at least one tissue sample contacted with vimentin and CD31 with an antibody that specifically binds HIF2α; contacting at least one tissue sample contacted with cytokeratin with an antibody that specifically binds collagen IV; contacting at least one tissue sample contacted with vimentin with an antibody that specifically binds fibronectin-1; and then assessing the tissue array for degree of labeling.
Conditional co-labeling with TEM-1, collagen IV, and fibronectin-1 based on vimentin/cytokeratin labeling
Obtaining a tissue sample array having a plurality of tissue samples from a subject; contacting a plurality of the tissue samples with an antibody that specifically binds vimentin and contacting a plurality of the tissue samples with an antibody that specifically binds cytokeratin; wherein at least one tissue sample contacted with vimentin is also contacted with an antibody that specifically binds TEM-1; at least one tissue sample contacted with cytokeratin is also contacted with an antibody that specifically binds collagen IV; at least one tissue sample contacted with vimentin is also contacted with an antibody that specifically binds fibronectin-1; and wherein the tissue sample array is then assessed for degree of labeling.
Both independent claims cover tissue sample array labeling methods that conditionally add specific named antibody targets, including TEM-1, HIF2α, collagen IV, and fibronectin-1, depending on whether tissue samples were first contacted with vimentin and/or cytokeratin and optionally CD31, followed by assessing the degree of labeling.
Stated Advantages
The TAPPS score provides independent prognostic value.
Refined models R-TAPPS and mTAPPS use fewer compartment-specific biomarkers while maintaining prognostic assessment.
Documented Applications
Clinical outcome prediction and recurrence risk assessment in colorectal cancer using compartment-quantified, multi-marker expression panels to compute a TAPPS score with risk stratification.
Labeling and quantitative immunofluorescence-based compartment-focused biomarker detection and localization on tissue microarrays, including use of AQUA®-type approaches and degree-of-labeling assessment.
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