In Situ Clonal Heterogeneity in Prostatic Diagnostic Biopsies

Prostate Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04873427
• Other study ID #: CLM_RAD_001
• Status: Terminated
• Start date: April 15, 2021
• Est. completion date: January 15, 2023

Study information

• Verified date: February 2023
• Source: Clinica Luganese Moncucco
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 40
• Est. completion date: January 15, 2023
• Est. primary completion date: January 15, 2023
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A and older

Eligibility

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;

Related Conditions & MeSH terms

• Disease Susceptibility
• Genetic Predisposition
• Genetic Predisposition to Disease
• Prostate Cancer
• Prostatic Neoplasms

Intervention

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

Locations

Country	Name	City	State
Switzerland	Alessandra Franzetti Pellanda	Lugano	Ticino

Sponsors (1)

Lead Sponsor	Collaborator
Clinica Luganese Moncucco

Country where clinical trial is conducted

Switzerland, 

References & Publications (23)

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* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	reconstruction of local PCa heterogeneity	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	relationships between pathological differentiation (Gleason score) and genomics-measured heterogeneity	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