Search

US-20260125761-A1 - PREDICTION OF AN OUTCOME OF NEOADJUVANT ANDROGEN DEPRIVATION THERAPY IN A PROSTATE CANCER SUBJECT

US20260125761A1US 20260125761 A1US20260125761 A1US 20260125761A1US-20260125761-A1

Abstract

The invention relates to a method of predicting a response of a prostate cancer subject to neoadjuvant androgen deprivation therapy. The method is based on predicting an outcome based on the expression levels of genes identified herein. The invention provides a method to establish whether neoadjuvant androgen deprivation therapy is useful for a subject and thus should be administered or not. Further provided are the use of a kit for determining expression levels for predicting a response of a prostate cancer subject to neoadjuvant androgen deprivation therapy.

Inventors

  • Ralf Dieter Hoffmann

Assignees

  • KONINKLIJKE PHILIPS N.V.

Dates

Publication Date
20260507
Application Date
20231011
Priority Date
20221018

Claims (19)

  1. 1 . A method of treating a subject suffering from prostate cancer based on a predicted response to said treatment, the method comprising: determining or receiving the result of a determination of a gene expression profile comprising: the gene expression level of PDE4D, preferably the gene expression of a specific isoform PDE4D5, PDE4D7 and/or PDE4D9, and/or three or more gene expression levels, wherein the three or more gene expression levels are selected from: PDE4D7 correlated genes selected from the group consisting of: ABCC5, CUX2, KIAA1549, PDE4D, RAP1GAP2, SLC39A11, TDRD1, and VWA2, said gene expression profile being determined in a biological sample obtained from the subject, determining the prediction of the outcome based on the gene expression profile, wherein said prediction is a favourable or a non-favourable response to neoadjuvant androgen deprivation therapy, and providing neoadjuvant treatment to the subject when a favorable response is predicted.
  2. 2 . The method of claim 1 , wherein the prediction is based on the expression level of PDE4D and wherein the prediction is chance of Biochemical Recurrence (BCR).
  3. 3 . The method of claim 1 , wherein the prediction is further based on at least one of the following parameters: tumor size or volume; TMPRSS2-ERG fusion status; ERG and/or PTEN expression level(s); and/or presence of metastases.
  4. 4 . The method of claim 1 , wherein the neoadjuvant androgen deprivation therapy comprises treatment with an antiandrogen.
  5. 5 . The method of claim 1 , wherein the outcome is at least one of: predicted residual tumor burden; predicted tumor size; predicted chance of tumor metastasis; or predicted chance of biochemical recurrence.
  6. 6 . The method of claim 1 , wherein said favourable or non-favourable response is tumor size, tumor burden, number of tumor positive lymph nodes, probability of survival, overall survival, cancer free survival, overall death, or cancer specific death.
  7. 7 . The method of claim 1 , wherein said favourable outcome or non-favourable outcome is improved chance of survival in response to a treatment.
  8. 8 . The method claim 1 , wherein the three or more genes comprise one or more immune defence response gene, one or more T-Cell receptor signalling gene and three or more PDE4D7 correlated genes.
  9. 9 . The method of claim 8 , wherein: the one or more immune defense response genes comprise three or more, preferably, six or more, more preferably, nine or more, most preferably, all of the immune defense genes, and/or the one or more T-Cell receptor signalling genes comprise three or more, preferably, six or more, more preferably, nine or more, most preferably, all of the T-Cell receptor signalling genes, and/or the three or more PDE4D7 correlated genes comprise four or more, preferably, six or more, most preferably, all of the PDE4D7 correlated genes.
  10. 10 . The method of claim 1 , wherein the determining of the prediction of the outcome comprises combining the three or more gene expression levels with a regression function that has been derived from a population of prostate cancer subjects.
  11. 11 . The method of claim 1 , wherein the determining of the prediction of the outcome is further based on one or more clinical parameters obtained from the subject.
  12. 12 . The method of claim 1 , wherein the determining of the outcome comprises combining the gene expression profile and one or more clinical parameters obtained from the subject with a regression function that has been derived from a population of prostate cancer subjects.
  13. 13 . The method of claim 1 , wherein the biological sample is obtained from the subject before the start of the therapy, preferably wherein the biological sample is a prostate sample or a prostate cancer sample.
  14. 14 . (canceled)
  15. 15 . The method of claim 1 , wherein the steps of predicting an outcome is performed using a diagnostic kit, the kit comprising: at least one of: a polymerase chain reaction primer or probes, for determining a gene expression profile in a biological sample obtained from a prostate cancer subject and/or in a sample, the gene expression profile comprising: the gene expression level of PDE4D, preferably the gene expression of a specific isoform PDE4D5, PDE4D7 and/or PDE4D9, and/or three or more expression levels, wherein the three or more gene expression levels are selected from: PDE4D7 correlated genes selected from the group consisting of: ABCC5, CUX2, KIAA1549, PDE4D, RAP1GAP2, SLC39A11, TDRD1, and VWA2.
  16. 16 . The method of claim 2 , wherein the prediction is based on the gene expression of a specific isoform PDE4D5, PDE4D7 and/or PDE4D9.
  17. 17 . The method of claim 2 , wherein the expression level of PDE4D is combined with one or more expression levels selected from ABCC5, CUX2, KIAA1549, RAP1GAP2, SLC39A11, TDRD1, and VWA2.
  18. 18 . The method of claim 17 , wherein the gene expression of a specific isoform of PDE4D selected from PDE4D5, PDE4D7 and/or PDE4D9 is combined with one or more expression levels selected from ABCC5, CUX2, KIAA1549, RAP1GAP2, SLC39A11, TDRD1, and VWA2.
  19. 19 . The method of claim 4 , wherein said antiandrogen is selected from cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, abiraterone, abiraterone acetate, seviteronel, apalutamide, darolutamide, Leuprorelin and galeterone.

Description

FIELD OF THE INVENTION The invention relates to a method of predicting a response of a prostate cancer subject to neoadjuvant androgen deprivation therapy, and to a computer program product for predicting a response of a prostate cancer subject to radiotherapy. Moreover, the invention relates to a diagnostic kit, to a use of the kit, to a use of the kit in a method of predicting a response of a prostate cancer subject to neoadjuvant androgen deprivation therapy, to a use of a gene expression profile for each of one or more PDE4D7 correlated genes in a method of predicting a response of a prostate cancer subject to radiotherapy, and to a corresponding computer program product. INTRODUCTION Cancer is a class of diseases in which a group of cells displays uncontrolled growth, invasion and sometimes metastasis. These three malignant properties of cancers differentiate them from benign tumours, which are self-limited and do not invade or metastasize. Prostate Cancer (PCa) is the second most commonly-occurring non-skin malignancy in men, with an estimated 1.3 million new cases diagnosed and 360,000 deaths world-wide in 2018 (see Bray F. et al., “Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries”, CA Cancer J Clin, Vol. 68, No. 6, pages 394-424, 2018). In the US, about 90% of the new cases concern localized cancer, meaning that metastases have not yet been formed (see ACS (American Cancer Society), “Cancer Facts & FIGS. 2010”, 2010). For the treatment of primary localized prostate cancer, several radical therapies are available, of which surgery (radical prostatectomy, RP) and radiation therapy (RT) are most commonly used. RT is administered via an external beam or via the implantation of radioactive seeds into the prostate (brachytherapy) or a combination of both. It is especially preferable for patients who are not eligible for surgery or have been diagnosed with a tumour in an advanced localized or regional stage. Radical RT is provided to up to 50% of patients diagnosed with localized prostate cancer in the US (see ACS, 2010, ibid). After treatment, prostate cancer antigen (PSA) levels in the blood are measured for disease monitoring. An increase of the blood PSA level provides a biochemical surrogate measure for cancer recurrence or progression. Androgen deprivation therapy (ADT), also called androgen suppression therapy, is an antihormone therapy whose main use is in treating prostate cancer. Prostate cancer cells usually require androgen hormones, such as testosterone, to grow. ADT reduces the levels of androgen hormones, with drugs or surgery, to prevent the prostate cancer cells from growing. Neoadjuvant androgen deprivation therapy (NADT) is systemic therapy administered after the diagnosis of prostate cancer but before locoregional therapy such as radical prostatectomy (RP) or radiation. With NADT prior to RP, the intent is to eradicate malignant androgen-dependent cells, in the hope that sufficient tumor regression will permit complete resection of residual prostate cancer, improving pathologic outcome and survival. The role of preoperative androgen deprivation remains controversial, however. WO 2022/043299A1 discloses a gene signature which can be used in predicting a response to Salvage androgen deprivation therapy (SADT). However analysis for prediction of SADT response is based of patients that are significantly pre-treated. These men all had surgery first to remove their prostate, then they experienced biochemical recurrence, then they were subjected to salvage radiation of the pelvic bed, and then they were treated with ADT. This means that the recurrent tumors treated with RT are by far not the same tumors anymore from a molecular and phenotypic point of view compared to the tumor the same men had when they were treatment-naïve (i.e., before surgery). Therefore gene signatures that are predictive for SADT do not necessarily predict NADT treatment response. Pechlivanis et al. (Cancers, vol. 14, no. 1, 29 Dec. 2021 (2021 Dec. 29), page 166) and Tewari et al. (Cell Reports, vol. 36, no. 10, 1 Sep. 2021 (2021 Sep. 1), pages 109665-109665) disclose describe correlations or associations of certain genes to the pathological minimal residual disease response of neoadjuvant deprivation therapy. Wilkinson et al. (EUROPEAN UROLOGY, vol. 80, no. 6, 27 Mar. 2021 (2021 Mar. 27), pages 746-757) discloses that poor neoadjuvant androgen deprivation therapy is associated with loss of the q10 genomic region (PTEN), TP53 mutations and ERG expression. Patients diagnosed with high risk localized prostate cancer have variable outcomes following surgery. Trials of intense NADT have shown lower rates of recurrence among patients with minimal residual disease after treatment. The molecular features that distinguish exceptional responders from poor responders are not known. Therefore there is an ongoing need for new and improved methods for predicting ne