# US 12,000,002 B2 · Pre-surgical risk stratification based on PDE4D7 expression and pre-surgical clinical variables

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- Number: US 12,000,002 B2
- Document ID: US12000002B2
- Status: Granted
- Kind: B2
- Application number: 16/771,558
- Filed: 2018-12-19
- Published: 2020-10-01
- Granted: 2024-06-04
- Earliest claimed: 2017-12-21
- Assignees: Koninklijke Philips N.V.
- Applicants: Koninklijke Philips N.V.
- Inventors: Ralf Dieter Hoffmann
- Web page: https://patentgrep.com/patent/US12000002B2

## CPC

- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- G16B 25/10: Gene or protein expression profiling; Expression-ratio estimation or normalisation
- G16B 40/00: ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
- G16H 50/30: for calculating health indices; for individual health risk assessment
- C12Q 2600/112: Disease subtyping, staging or classification
- C12Q 2600/118: Prognosis of disease development
- C12Q 2600/158: Expression markers
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16H: HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA

## Abstract

The invention relates to a method of pre-surgical risk stratification of a prostate cancer subject, comprising determining a gene expression profile for phosphodiesterase 4D variant 7 (PDE4D7) in a biological sample obtained from the subject, determining gene expression profile, and determining a pre-surgical prognostic risk score for the subject based on the expression based risk score and pre-surgical clinical variables of the subject. This may allow for an improved stratification of the subject in a pre-surgical setting that may result in better primary treatment decisions. For instance, the pre-surgical prognostic risk score may allow to make better recommendation on whether to select active surveillance vs. active intervention, e.g., radical prostatectomy, for certain sub-populations of prostate cancer patients.

## Claims

### Claim 1

A method of risk stratification of a prostate cancer subject, comprising:
obtaining a biological sample from the prostate cancer subject, wherein the prostate cancer subject has not undergone prostate cancer surgery;
determining a gene expression profile for phosphodiesterase 4D variant 7 (PDE4D7) in the biological sample obtained from the subject;
determining an expression based risk score for the subject based on the gene expression profile;
determining a prognostic risk score for the subject based on the expression based risk score and clinical variables of the subject; and
administering a primary treatment for the subject based on the prognostic risk score, wherein the primary treatment is selected from the group consisting of: (i) at least a partial prostatectomy; and (ii) an active therapy selected from radiation treatment, hormone therapy, chemotherapy, and a combination thereof.

### Claim 2 (depends on 1)

The method as defined in claim 1, wherein the clinical variables comprise one or more of: (i) an age of the subject; (ii) a prostate-specific antigen (PSA) level; (iii) a primary and secondary biopsy Gleason score; (iv) a clinical stage; and (v) a percentage of tumor positive biopsies.

### Claim 3 (depends on 1)

The method as defined in claim 1, further comprising:
determining a Cancer of the Prostate Risk Assessment (CAPRA) score for the subject;
wherein the prognostic risk score is determined by combining the expression based risk score and the CAPRA score.

### Claim 4 (depends on 3)

The method as defined in claim 3, wherein the expression based risk score and the CAPRA score are combined with a regression function derived from a population of prostate cancer subjects.

### Claim 5 (depends on 1)

The method as defined in claim 1, wherein the prognostic risk score is determined as a modified Cancer of the Prostate Risk Assessment (CAPRA) score for the subject, in which a primary and secondary biopsy Gleason score is replaced by the expression based risk score.

### Claim 6 (depends on 5)

The method as defined in claim 5, wherein the expression based risk score is a value in a predefined range, wherein depending on the value a number of points in the range from 0 to 3 are added in the modified CAPRA score.

### Claim 7 (depends on 1)

The method as defined in claim 1, further comprising:
proposing a primary treatment for the subject based on the prognostic risk score;
wherein the primary treatment is selected from the group consisting of: (i) at least a partial prostatectomy; (ii) an active therapy selected from radiation treatment, hormone therapy, chemotherapy, and a combination thereof; and (iii) active surveillance.

### Claim 8 (depends on 1)

The method as defined in claim 1, further comprising:
normalizing the gene expression profile with respect to one or more reference genes selected from the group consisting of: Homo sapiens hypoxanthine phosphoribosyltransferase 1 (HPRT1), Tubulin-Alpha-1b (TUBA1B), Homo sapiens pumilio RNA-Binding Family Member (PUM1), and Homo sapiens TATA box binding protein (TBP),
wherein the expression based risk score is determined based on the normalized gene expression profile.

### Claim 9 (depends on 8)

The method as defined in claim 8, wherein the one or more reference genes comprise at least two, or at least three, or all of HPRT1, TUBAIB, PUM1, and TBP.

### Claim 10 (depends on 1)

The method as defined in claim 1, wherein the expression based risk score is determined with a scoring function, based on the gene expression profile, the scoring function having been derived from gene expression profiles for biological samples of prostate cancer subjects.

### Claim 11 (depends on 8)

The method as defined in claim 8, wherein the determining of the gene expression profile comprises performing RT-qPCR on RNA extracted from the biological sample, wherein a Cq value is determined for PDE4D7 and for each of the one or more reference genes, and wherein the determining of the expression based risk score includes normalizing the Cq value for PDE4D7 using the Cq value for each of the one or more reference genes and computing the expression based risk score as a linear function of the normalized Cq value.

### Claim 12 (depends on 1)

The method as defined in claim 1, wherein the gene expression profile further includes expression information from phosphodiesterase 4D variant 5 (PDE4D5) and/or from phosphodiesterase 4D variant 9 (PDE4D9), wherein an expression based risk score is determined for the subject for each of the phosphodiesterase 4D variants based on the gene expression profile, and wherein the prognostic risk score for the subject is determined based on the expression based risk scores and the clinical variables of the subject.

### Claim 13

Use of a gene expression profile for phosphodiesterase 4D variant 7 (PDE4D7) in risk stratification of a prostate cancer subject, comprising:
obtaining a biological sample from the prostate cancer subject, wherein the prostate cancer subject has not undergone prostate cancer surgery;
determining the gene expression profile in the biological sample obtained from the subject;
determining an expression based risk score for the subject based on the gene expression profile
determining a prognostic risk score for the subject based on the expression based risk score and clinical variables of the subject;
administering a primary treatment for the subject based on the prognostic risk score, wherein the primary treatment is selected from the group consisting of: (i) at least a partial prostatectomy; and (ii) an active therapy selected from radiation treatment, hormone therapy, chemotherapy, and a combination thereof.