Multigene Assay for Breast Fibroepithelial Tumour Classification
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Solution Overview
Problem
Current methods for diagnosing fibroepithelial tumours of the breast, particularly distinguishing between benign fibroadenomas and malignant phyllodes tumours, are inadequate due to overlapping morphology and limited diagnostic markers, leading to unpredictable clinical outcomes.
Innovation Solution
A multigene assay that analyzes the expression profiles of specific genes such as PRAME, ADH1B, CTHRC1, NPTX2, NEFL, ABCA8, and others in biological samples to determine a p-score, which differentiates between fibroadenomas and phyllodes tumours, guiding clinical management.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If morphologic predictors (mitotic activity, infiltrative borders, tumour necrosis, positive margins, tumour size) are used for diagnosis, then diagnostic information can be obtained from routine pathology, but the diagnosis is not definitive due to overlapping morphology between fibroadenomas and phyllodes tumours
Solution Approach 1:
The patent transitions from morphological parameters (visual assessment of mitotic activity, borders, necrosis) to molecular parameters (gene expression profiles). By measuring expression levels of specific genes (e.g., ADH1B, CTHRC1, NPTX2, NEFL, ABCA8, DAPL1, TP63, COL17A1, GCNT2, CCL19, MMP3, FN1, TRERF1, TRIM29, TESC, KIF20A, UHRF1, HEPACAM2, APOD, SERHL2, KIF15, HOXD13, GAGE2B, CALML5, C2orf40, ADH1C, CYP1B1, SPAG11B, GRB7, UBE2C, SYNGAP1, LAMB1, OR5P3, SPC25, SHISA2, SCARA5, LHX2, RORC, DPYSL4, CH25H, CHST1) and calculating a p-score, the assay provides definitive diagnostic classification that resolves the ambiguity of overlapping morphology.
2Ease of operation
If biopsy or excision material is used for diagnosis, then non-invasive sampling is achieved, but the material is limited and may not provide sufficient diagnostic information
Solution Approach 1:
The patent extracts and measures molecular parameters (gene expression levels) from limited biopsy material, transforming insufficient morphological information into comprehensive molecular diagnostic data. The multigene assay amplifies the diagnostic value of small samples by quantifying expression profiles of multiple genes and computing a p-score, thereby recovering diagnostic information that would be unavailable from routine morphology alone.
3Device complexity
If a single gene marker is used for differentiation, then the assay is simple and quick, but the differentiation accuracy is insufficient due to the heterogeneous nature of fibroepithelial tumours
Solution Approach 1:
The patent divides the diagnostic task into multiple independent gene measurements rather than relying on a single marker. The multigene panel segments the complex diagnostic problem into quantifiable expression levels of individual genes (ADH1B, CTHRC1, NPTX2, NEFL, ABCA8, DAPL1, TP63, COL17A1, GCNT2, CCL19, MMP3, FN1, TRERF1, TRIM29, TESC, KIF20A, UHRF1, HEPACAM2, APOD, SERHL2, KIF15, HOXD13, GAGE2B, CALML5, C2orf40, ADH1C, CYP1B1, SPAG11B, GRB7, UBE2C, SYNGAP1, LAMB1, OR5P3, SPC25, SHISA2, SCARA5, LHX2, RORC, DPYSL4, CH25H, CHST1), which are then integrated through a p-score calculation to achieve high differentiation accuracy.
Solution Approach 2:
The diagnostic approach combines multiple gene expression signals into a composite diagnostic indicator (p-score). Rather than relying on a single molecular marker, the patent synthesizes information from multiple genes into an integrated diagnostic metric that captures the heterogeneous nature of fibroepithelial tumours and provides robust classification between fibroadenomas and phyllodes tumours.
Data Source
AI summary
An in vitro method of determining the type of a fibroepithelial tumour of the breast in a biological sample is provided. The method comprises the steps of obtaining an expression profile of one or more genes selected from the group consisting of PRAME, ADH1 B, CTHRC1, NPTX2, NEFL, ABCA8, DAPL1, TP63_v2, COL17A1, GCNT2, CCL19, MMP3, FN1, TRERF1, TRIM29, TESC, KIF20A, UHRF1, HEPACAM2, APOD, SERHL2. KIF15, HOXD13, GAGE2B, CALML5, C2orf40, ADH1C, CYP1B1, SPAG11B, GRB7, UBE2C, SYNGAP1, TP63_v1, LAMB1, OR5P3, SPC25, SHISA2, SCARA5, LHX2, RORC, DPYSL4, CH25H, and CHST1 in a sample and determining the differential activity of the one or more genes relative to a control; correlating the differential activity of the one or more genes relative to the control to obtain a p-score; and determining the type of fibroepithelial tumour based on the p-score, wherein a p-score of less than 0.5 is indicative of a fibroadenoma and a p-score of 0.5 and above is indicative of phyllodes tumour. Particularly, the said method is exemplified using an expression profile of five genes comprising of PRAME, FN1, CCL19, ABCA8 and APOD. A method for managing the treatment of a subject with a fibroepithelial tumour of the breast is also provided as well as a kit when used in the methods of the present invention.