In Situ Clonal Heterogeneity in Prostatic Diagnostic Biopsies

February 13, 2023 updated by: Marco Roncador, Clinica Luganese Moncucco

In Situ Clonal Heterogeneity in Prostatic Diagnostic Biopsies: Impact on Prostate Cancer Evolution and Clinical Outcome. A Retrospective, Proof of Concept Study

This is a retrospective, proof of concept study, which aims at reconstructing the cellular heterogeneity of the tumor in multi-needle diagnostic prostate biopsy as well as any biopsy containing potentially pre-malignant tissue, to study its implications in the clinical history of the disease. For each patient, 2 or more samples will be prepared starting from the FFPE diagnostic material. The biopsy used for assigning the Gleason score will be sequenced, together with two or more of the local peri-proximal biopsies with a higher level of differentiation. Samples will undergo Whole Exome Sequencing with an average coverage of 300x at the Wellcome Sanger Institute (WSI, Hinxton, UK). Sequencing data will be analysed for single nucleotide variants, copy number variants and structural variants by using state-of-the-art data analysis pipeline at WSI.

  1. Reconstruction of local PCa heterogeneity in multi-needle diagnostic biopsy with different Gleason scores (6-10) using high-coverage whole exome sequencing (WES) and DP-based clonal analysis;
  2. Characterization of the relationships between pathological differentiation (Gleason score) and genomics-measured heterogeneity and malignancy features;
  3. Assessment of clinical implications of clonal heterogeneity.

The study will include an average of 150 prostatic diagnostic biopsies from a cohort of 20 early metastatic PC patients and 20 non-relapsing/non-metastatic patients with indolent malignant disease.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Prostate cancer (PCa) is the leading malignancy of the male population. In current clinical practice, diagnostic confirmation of PCa is based on image-guided multi-needle biopsy, in order to capture the intrinsic biological heterogeneity of tumors and to provide a more accurate prediction of clinical outcomes. However, current morphology-based approaches (Gleason score) may not completely describe the complexity of a malignant gland. Not enough is currently known on the impact of genomic heterogeneity in a poorly-differentiated prostate, especially with regards to the development of an indolent versus metastatic prostate malignancy

This is a retrospective, proof of concept study, which aims at reconstructing the cellular heterogeneity of the tumor in multi-needle diagnostic prostate biopsy as well as any biopsy containing potentially pre-malignant tissue, to study its implications in the clinical history of the disease. For each patient, 2 or more samples will be prepared starting from the FFPE diagnostic material. The biopsy used for assigning the Gleason score will be sequenced, together with two or more of the local peri-proximal biopsies with a higher level of differentiation. Samples will undergo Whole Exome Sequencing with an average coverage of 300x at the Wellcome Sanger Institute (WSI, Hinxton, UK). Sequencing data will be analysed for single nucleotide variants, copy number variants and structural variants by using state-of-the-art data analysis pipeline at WSI.

  1. Reconstruction of local PCa heterogeneity in multi-needle diagnostic biopsy with different Gleason scores (6-10) using high-coverage whole exome sequencing (WES) and DP-based clonal analysis;
  2. Characterization of the relationships between pathological differentiation (Gleason score) and genomics-measured heterogeneity and malignancy features;
  3. Assessment of clinical implications of clonal heterogeneity.

The study will include an average of 150 prostatic diagnostic biopsies from a cohort of 20 early metastatic PC patients and 20 non-relapsing/non-metastatic patients with indolent malignant disease.

Descriptive statistics will be carried out and a Mann-Whitney test will be applied on a synthetic parameter for each patient biopsy heterogeneity result, grouped by indolent vs aggressive disease cohort.

The null hypotheses (no difference between the two cohort in heterogeneity) will be rejected if p < 0.05.

The proposed project will evaluate the impact of diagnostic intra-prostatic cell heterogeneity on the clinical course of PCa. The potential prognostic value of local disease clonality could indeed impact the clinical practice: patient with Gleason <7 and lower level of clonal heterogeneity may be moved from an active disease treatment to an active surveillance (AS) approach, avoiding overtreatment for the subjects. Conversely, patients with a similar Gleason score but a more heterogenous malignant population may be required to undergo more aggressive procedures.

Study Type

Observational

Enrollment (Actual)

40

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Switzerland
    • Ticino
      • Lugano, Ticino, Switzerland, 6900
        • Alessandra Franzetti Pellanda

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Sampling Method

Probability Sample

Study Population

patients with prostate cancer

Description

The inclusion criteria for the subjects in the indolent cohort will be:

  • a local disease with Gleason ≤ 7 (3+4, i.e. more differentiated tissue is found in diagnostic biopsies, better overall prognosis)
  • no metastasis whatsoever during the follow-up;

The inclusion criteria in the early-metastatic aggressive cohort will be:

  • an advanced prostatic neoplasia with Gleason score ≥ 7 (4+3, i.e. less differentiated tissue is found in diagnostic biopsies, worse overall prognosis)
  • multiple synchronous or metachronous metastasis.

Exclusion Criteria:

  • insufficient material on the tissue biopsy to be left in archives for further evaluations/analyses;
  • insufficient amount of tumor cells at baseline;

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only
  • Time Perspectives: Retrospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
early metastatic prostate cancer patients
Reconstruction of local PCa heterogeneity in multi-needle diagnostic biopsy with different Gleason scores (6-10) using high-coverage whole exome sequencing (WES) and DP-based clonal analysis
Genetic: clonal heterogeneity evaluation
Reconstruction of local PCa heterogeneity in multi-needle diagnostic biopsy with different Gleason scores (6-10) using high-coverage whole exome sequencing (WES) and DP-based clonal analysis
non-relapsing/non-metastatic patients with indolent malignant disease
Reconstruction of local PCa heterogeneity in multi-needle diagnostic biopsy with different Gleason scores (6-10) using high-coverage whole exome sequencing (WES) and DP-based clonal analysis
Genetic: clonal heterogeneity evaluation
Reconstruction of local PCa heterogeneity in multi-needle diagnostic biopsy with different Gleason scores (6-10) using high-coverage whole exome sequencing (WES) and DP-based clonal analysis

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
reconstruction of local PCa heterogeneity
Time Frame: through study completion, an average of 2 years
Primary endpoint is the reconstruction of local PCa heterogeneity in multi-needle diagnostic biopsy with different Gleason scores (6-10) using high-coverage whole exome sequencing (WES) and DP-based clonal analysis
through study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
relationships between pathological differentiation (Gleason score) and genomics-measured heterogeneity
Time Frame: through study completion, an average of 2 years
Secondary endpoints are characterization of the relationships between pathological differentiation (Gleason score) and genomics-measured heterogeneity and malignancy features; and assessment of clinical implications of clonal heterogeneity.
through study completion, an average of 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Clinica Luganese Moncucco

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 15, 2021

Primary Completion (Actual)

January 15, 2023

Study Completion (Actual)

January 15, 2023

Study Registration Dates

First Submitted

April 28, 2021

First Submitted That Met QC Criteria

May 4, 2021

First Posted (Actual)

May 5, 2021

Study Record Updates

Last Update Posted (Actual)

February 15, 2023

Last Update Submitted That Met QC Criteria

February 13, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CLM_RAD_001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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