Genetic signatures to predict prostate cancer metastasis and identify tumor aggressiveness
Inventors
Davicioni, Elai • Erho, Nicholas • Ashab, Hussam Al-Deen • Alshalalfa, Mohammed
Assignees
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Publication Number
US-11078542-B2
Publication Date
2021-08-03
Expiration Date
Abstract
The present invention relates to methods, systems and kits for the diagnosis, prognosis and the determination of cancer progression of prostate cancer in a subject. The invention also provides clinically useful genomic classifiers for predicting prostate cancer metastasis and identifying tumor aggressiveness. The methods, systems and kits can provide expression-based analysis of biomarkers for purposes of predicting metastatic disease and lethal prostate cancer in a subject. Further disclosed herein, in certain instances, are probe sets for use in predicting prostate cancer metastasis in a subject. Classifiers for predicting prostate cancer metastasis are provided. Methods of treating cancer based on tumor aggressiveness are also provided. The methods and classifiers of the present invention are also useful for predicting early prostate cancer metastasis.
Core Innovation
The invention provides prostate-cancer expression-signature systems and classifiers (DV1 and DV2) that use expression-based biomarker analysis. The systems include probe sets and related target panels defined by target sequences to support diagnosing, prognosing, and monitoring progression.
The approach measures expression levels for a plurality of targets, including SMC4, PABPC1, TRIQK, TIPARP, and AZGP1, and other coding and non-coding targets across DNA and RNA. Assay modalities described include microarray, sequencing, PCR/qPCR, in situ hybridization, and immunoassays, followed by classifier scoring and interpretation using classifier approaches such as GLMNET (elastic net) and machine learning classification algorithms.
The classifiers subtype prostate cancer as metastatic based at least on the expression level of the plurality of targets and are used to predict metastasis and tumor aggressiveness, including clinical associations with metastasis-related outcomes and risk features such as grade groups and NCCN risk categories. The document also describes correlational clinical validation using retrospective and prospective cohorts and re-review or upgrade of biopsy grade, and it relates classifier results to specific clinical parameters such as lymph node involvement, extra-prostatic extension, seminal vesicle invasion, biochemical recurrence, prostate cancer death, distant metastasis-free survival, and postoperative metastasis and prostate cancer-specific mortality (PCSM).
Claims Coverage
The independent claims cover an expression-based method that measures expression levels for a specific plurality of targets, subtypes prostate cancer as metastatic based on the expression levels, and administers a treatment only when the subtype indicates metastatic disease. One inventive concept includes three core inventive features.
Expression-level measurement for a defined target plurality
Obtaining or having obtained an expression level in a sample from a subject with prostate cancer for a plurality of targets comprising SMC4, PABPC1, TRIQK, TIPARP, and AZGP1.
Metastatic subtyping based on expression levels
Subtyping the prostate cancer as metastatic based at least on the expression level of the plurality of targets.
Treatment selection triggered by metastatic subtyping
Administering a treatment selected from adjuvant chemotherapy, systemic radiation therapy, and/or anti-androgen therapy to the subject when the subtyping indicates that the prostate cancer is metastatic.
DNA and/or RNA targets
The plurality of targets comprises DNA and/or RNA.
Permitted biological sample sources
The biological sample is a urine sample, a blood sample, or a prostate tumor sample.
Overall, the claims center on measuring expression levels for a defined set of targets, subtyping prostate cancer as metastatic from those expression levels, and administering adjuvant chemotherapy, systemic radiation therapy, and/or anti-androgen therapy when metastatic disease is indicated; dependent claims further restrict the targets to DNA and/or RNA and limit the sample types to urine, blood, or prostate tumor sample.
Stated Advantages
Enables prediction of aggressive prostate cancer outcomes, including postoperative metastasis and prostate cancer-specific mortality (PCSM).
Provides treatment guidance by linking classifier risk groups to adjuvant versus salvage radiotherapy (RT) outcomes.
States that classifier-based subtyping can be used to determine treatment and predict higher-grade disease and metastasis/progression.
States that classifier-based subtyping can predict therapy benefit.
Documented Applications
Diagnosing, prognosing, and monitoring progression of prostate cancer using expression-signature systems/classifiers (DV1/DV2).
Predicting metastasis and tumor aggressiveness using classifier subtyping based on expression levels.
Supporting clinical correlation and validation of classifier results with features such as grade groups and NCCN risk categories, and with outcomes including lymph node involvement, extra-prostatic extension, seminal vesicle invasion, biochemical recurrence, prostate cancer death, distant metastasis-free survival, postoperative metastasis, and prostate cancer-specific mortality (PCSM).
Selecting a treatment regimen based on a genomic classifier score and metastatic subtyping, including use of adjuvant chemotherapy, systemic radiation therapy, and/or anti-androgen therapy.
Validation and outcome prediction for genomic classifiers DV1 and DV2 for aggressive prostate cancer, including cumulative incidence and multivariable analysis hazard ratios for 5- and 10-year postoperative metastasis and PCSM.
Treatment guidance for connecting classifier risk groups (Low/Int/High) to adjuvant versus salvage radiotherapy (RT) outcomes.
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