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(12) Patent Application Publication (10) Pub. No.: US 2017/0191133 A1 Davicioni (43) Pub US 2017.0191133A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0191133 A1 Davicioni (43) Pub. Date: Jul. 6, 2017 (54) SYSTEMIS AND METHODS FOR Publication Classification EXPRESSION-BASED DISCRIMINATION OF (51) Int. C. DISTINCT CLINICAL DISEASE STATES IN CI2O I/68 (2006.01) PROSTATE CANCER (52) U.S. C. CPC ...... CI2O 1/6886 (2013.01); C12O 2600/112 (71) Applicant: GENOMEDX BIOSCIENCES, INC., (2013.01); C12O 2600/118 (2013.01); C12O Vancouver (CA) 2600/158 (2013.01) (72) Inventor: Elai Davicioni, La Jolla, CA (US) (57) ABSTRACT A system for expression-based discrimination of distinct clinical disease states in prostate cancer is provided that is (21) Appl. No.: 15/092,468 based on the identification of sets of gene transcripts, which are characterized in that changes in expression of each gene (22) Filed: Apr. 6, 2016 transcript within a set of gene transcripts can be correlated with recurrent or non-recurrent prostate cancer. The Prostate Cancer Prognostic system provides for sets of “prostate Related U.S. Application Data cancer prognostic' target sequences and further provides for combinations of polynucleotide probes and primers derived (63) Continuation of application No. 12/994.408, filed on there from. These combinations of polynucleotide probes Feb. 17, 2011, now abandoned, filed as application can be provided in solution or as an array. The combination No. PCT/CA2009/000694 on May 28, 2009. of probes and the arrays can be used for diagnosis. The (60) Provisional application No. 61/056,827, filed on May invention further provides further methods of classifying 28, 2008. prostate cancer tissue. Patent Application Publication Jul. 6, 2017. Sheet 1 of 9 US 2017/O191133 A1 FG. A Patent Application Publication Jul. 6, 2017. Sheet 2 of 9 US 2017/O191133 A1 & Patent Application Publication Jul. 6, 2017. Sheet 3 of 9 US 2017/O191133 A1 Patent Application Publication Jul. 6, 2017. Sheet 4 of 9 US 2017/O191133 A1 ¿?*8). ?0000'0×d 8% ågå Patent Application Publication Jul. 6, 2017. Sheet 5 of 9 US 2017/O191133 A1 : i. 3. SYS F.G. 3 Patent Application Publication Jul. 6, 2017. Sheet 6 of 9 US 2017/O191133 A1 & & wer x : s . 8 SE x 8. Yes 83888 x 8.3: Patent Application Publication Jul. 6, 2017. Sheet 7 of 9 US 2017/O191133 A1 ---------------------- : i s x & x x : x : 838 kix: Patent Application Publication Jul. 6, 2017. Sheet 8 of 9 US 2017/O191133 A1 : i s Patent Application Publication Jul. 6, 2017. Sheet 9 of 9 US 2017/O191133 A1 : : s ''''''''''''''''''''''''''''''''''''''''''''''''''''1'''''''''''''''''''''''''''''''''''''''''''''''''''''''' 838 :x: US 2017/O 191133 A1 Jul. 6, 2017 SYSTEMIS AND METHODS FOR cancer and this has resulted in an increased number of EXPRESSION-BASED DISCRIMINATION OF patients being treated but not significantly decreased the DISTINCT CLINICAL DISEASE STATES IN mortality rate. PROSTATE CANCER 0007. Despite the controversies surrounding PSA testing as a screening tool, most physicians confidently rely on PSA CROSS-REFERENCE TO RELATED testing to assess pre-treatment prognosis and to monitor APPLICATIONS disease progression after initial therapy. Successive increases in PSA levels above a defined threshold value or 0001. This application is a continuation of U.S. applica variations thereof (i.e. Rising-PSA), also known as bio tion Ser. No. 12/994,408 filed Feb. 17, 2011, now aban chemical recurrence has been shown to be correlated to doned, which claimed the benefit of 5 USC S371 National disease progression after first-line therapy (e.g., prostatec Stage application of International Application No. PCT/ tomy, radiation and brachytherapy). However, less than a /3 CA2009/000694 filed May 28, 2009, which claims priority of patients with rising-PSA will eventually be diagnosed benefit of U.S. 61/056,827 filed May 28, 2008, now expired. with systemic or metastatic disease and several studies have The disclosure of each of the prior applications is considered shown that after long-term follow up, the majority will never part of and is incorporated by reference in the disclosure of show any symptoms of disease progression aside from this application. increases in PSA measurement. The limitations of using the PSA biomarker and the absence of additional biomarkers for INCORPORATION OF SEQUENCE LISTING predicting disease recurrence have led to the development of 0002 The material in the accompanying sequence listing statistical models combining several clinical and pathologi is hereby incorporated by reference into this application. The cal features including PSA results. Several of these nomo accompanying sequence listing text file, name GBX1140 2 grams have been shown to improve the predictive power for Sequence Listing..txt, was created on Jun. 22, 2016, and is disease recurrence in individual patients over any single independent variable. These models (see Citation #14) are 744 kb. The file can be assessed using Microsoft Word on a used routinely in the clinic and are currently the best computer that uses Windows OS. available tools for prediction of outcomes, although they do not provide high levels of accuracy for groups of patients FIELD OF THE INVENTION with highly similar histological/pathological features or 0003. This invention relates to the field of diagnostics and those at intermediate risk of disease recurrence after pros in particular to systems and methods for classifying prostate tatectomy. cancer into distinct clinical disease states. 0008. The use of quantitative molecular analyses has the potential to increase the sensitivity, specificity and/or overall BACKGROUND accuracy of disease prognosis and provide a more objective basis for determination of risk stratification as compared to 0004 Prostate cancer is the most common malignancy conventional clinical-pathological risk models (see Citation affecting U.S. men, with approximately 240,000 new cases #13). The PSA test demonstrates the deficiencies of relying diagnosed each year. The incidence of prostate cancer is on the measurement of any single biomarker in clinically increasing, in part due to increased Surveillance efforts from heterogeneous and complex prostate cancer genomes. the application of routine molecular testing Such as prostate Therefore, genomic-based approaches measuring combina specific antigen (PSA). For most men, prostate cancer is a tions of biomarkers or a signature of disease recurrence are slow-growing, organ-confined or localized malignancy that currently being investigated as better Surrogates for predict poses little risk of death. The most common treatments for ing disease outcome (see Citations # 1-13). For prostate prostate cancer in the U.S. are Surgical procedures such as cancer patients these efforts are aimed at reducing the radical prostatectomy, where the entire prostate is removed number of unnecessary Surgeries for patients without pro from the patient. This procedure on its own is highly curative gressive disease and avoid inadvertent under-treatment for for most but not all men. higher risk patients. To date, genomic profiling efforts to 0005. The vast majority of deaths from prostate cancer identify DNA-based (e.g., copy-number alterations, meth occur in patients with metastasis, believed to be present ylation changes), RNA-based (e.g., gene or non-coding already at the time of diagnosis in the form of clinically RNA expression) or protein-based (e.g., protein expression undetectable micro-metastases. In these patients, it is clear or modification) signatures, useful for disease prognosis that prostatectomy alone is not curative and additional have not however resulted in widespread clinical use. therapies such as anti-androgen or radiation therapy are 0009. There are several key reasons explaining why prior required to control the spread of disease and extend the life genomic profiling methods for prostate cancer have not yet of the patient. been incorporated in the clinic. These include the small 0006 Most prostatectomy patients however face uncer sample sizes typical of individual studies, coupled with tainty with respect to their prognosis after Surgery: whether variations due to differences in study protocols, clinical or not the initial surgery will be curative several years from heterogeneity of patients and lack of external validation the initial treatment because the current methods for assess data, which combined have made identifying a robust and ment of the clinical risk Such as the various pathological reproducible disease signature elusive. Specifically for gene (e.g., tumor stage), histological (e.g., Gleasons), clinical or RNA expression based prognostic models; the mitigating (e.g., Kattan nomogram) and molecular biomarkers (e.g., technological limitations include the quality and quantity of PSA) are not reliable predictors of prognosis, specifically RNA that can be isolated from routine clinical samples. disease progression. Routine PSA testing has certainly Routine clinical samples of prostate cancer include needle increased Surveillance and early-detection rates of prostate biopsies and Surgical resections that have been fixed in US 2017/O 191133 A1 Jul. 6, 2017 formalin and embedded in paraffin wax (FFPE). FFPE expression level of said one or more nucleic acid sequences derived RNA is typically degraded and fragmented to with the disease state of prostate cancer tissue. between 100-300 by in size and without poly-A tails making 0016. In accordance with another aspect of the present it of little use for traditional 3'-biased gene expression
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