Analysis of Androgene Receptors Axis and DNA Damage Repair Genes in Patients With Prostate Cancer

NCT ID: NCT03677414

Last Updated: 2018-09-19

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 59 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2018-09-10
• Study Completion Date: 2021-08-31

Brief Summary

In this project, we would like to focus on castration-sensitive prostate cancer (CRPC). This is a highly variable clinical picture with differentiated and burdening symptoms. The clinical parameters used to estimate the prognosis have so far only shown a very limited valence; genetic markers have so far only rarely been investigated.

In the course of our preliminary investigations, we were already able to isolate 189 plasma samples from 59 patients with metastatic prostate cancer. These samples are prepared by highly innovative techniques, e.g. "whole genome sequencing", in order to gain comprehensive insights into the spectrum of genetic changes under therapy and the associated tumor evolution. These results should be compared with the genetic material of the respective prostate tumors, which originate from previous operations. This highly comprehensive data, which will yield results on copy number changes, mutations, and gene expression, will allow analysis of signaling pathways of unprecedented resolution to increase the efficacy of targeted therapies in patients and minimize the burden of non-effective therapy side effects.

Detailed Description

The investigators collected 189 plasma samples from 59 patients with metastasized CRPC treated with abiraterone/enzalutamide. In order to stratify plasma DNA samples based on the presence of low (i.e. z-score ≤5; corresponds to <10% ctDNA) versus high (z-score >5; corresponds to ≥10% ctDNA) genomic complexity in ctDNA the investigators employed the modified Fast Aneuploidy Screening Test-Sequencing System (mFAST-SeqS), which provides a plasma based marker of aneuploidy (z-score). Altogether 106 plasma samples with a low z-score will be evaluated only with the AVENIO ctDNA Expanded Kit, which is capable of detecting mutations with VAFs as low as 0.1% . From the 83 plasma samples with increased z-score will be sequenced with high coverage (70x) so that both mutations and nucleosome positions can be extracted from the obtained sequences. With the other 32 high z-score samples plasma-Seq will be conducted to establish genome-wide copy number profiles and 31 prostate cancer genes will be enriched to screen for mutations in these genes.

At present, there is no evidence what parameters should be used to decide which treatment options are best for metastatic prostate cancer patients. The suggested innovative technologies, i.e. nucleosome position mapping and gene expression analyses will provide systematic maps of nucleosome positions. The sequencing of plasma samples with 70x will provide in addition a comprehensive view on the mutation spectrum in metastatic prostate cancer. By inclusion of primary tumor analyses, an unprecedented view on prostate cancer genome Evolution will be obtained. Overall, the comprehensive data set (copy number changes, mutations, gene expression) will allow pathway analyses with unprecedented resolution.

Conditions

Prostatic Neoplasms

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: CROSS_SECTIONAL

Eligibility Criteria

Inclusion Criteria

• subject has proven histological diagnosis of prostate cancer
• subject was treated with abiraterone and/or enzalutamide.

Exclusion Criteria

• patient rejects the participation

• Minimum Eligible Age: 18 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Medical University of Graz

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jochen B Geigl, Prof, MD

Role: PRINCIPAL_INVESTIGATOR

Institute of Human Genetics

Locations

Institute of Human Genetics, Medical University of Graz

Graz, , Austria

Countries

Austria

References

Ulz P, Belic J, Graf R, Auer M, Lafer I, Fischereder K, Webersinke G, Pummer K, Augustin H, Pichler M, Hoefler G, Bauernhofer T, Geigl JB, Heitzer E, Speicher MR. Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer. Nat Commun. 2016 Jun 22;7:12008. doi: 10.1038/ncomms12008.

Reference Type: BACKGROUND

PMID: 27328849 (View on PubMed)

Ulz P, Heitzer E, Speicher MR. Co-occurrence of MYC amplification and TP53 mutations in human cancer. Nat Genet. 2016 Feb;48(2):104-6. doi: 10.1038/ng.3468. No abstract available.

Reference Type: BACKGROUND

PMID: 26813759 (View on PubMed)

Ulz P, Thallinger GG, Auer M, Graf R, Kashofer K, Jahn SW, Abete L, Pristauz G, Petru E, Geigl JB, Heitzer E, Speicher MR. Inferring expressed genes by whole-genome sequencing of plasma DNA. Nat Genet. 2016 Oct;48(10):1273-8. doi: 10.1038/ng.3648. Epub 2016 Aug 29.

Reference Type: BACKGROUND

PMID: 27571261 (View on PubMed)

Maia MC, Salgia M, Pal SK. Harnessing cell-free DNA: plasma circulating tumour DNA for liquid biopsy in genitourinary cancers. Nat Rev Urol. 2020 May;17(5):271-291. doi: 10.1038/s41585-020-0297-9. Epub 2020 Mar 17.

Reference Type: DERIVED

PMID: 32203306 (View on PubMed)

Other Identifiers

21-228 ex 09/10

Identifier Type: OTHER

Identifier Source: secondary_id

FWF Project KLI 710-B26

Identifier Type: -

Identifier Source: org_study_id