Clinical trial NCT04873427: In Situ Clonal Heterogeneity in Prostatic Diagnostic Biopsies
Official title: In Situ Clonal Heterogeneity in Prostatic Diagnostic Biopsies: Impact on Prostate Cancer Evolution and Clinical Outcome. A Retrospective, Proof of Concept Study
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Prostate Cancer
Genetic Predisposition
Keywords: Prostate Cancer
genetic heterogeneity
personalized medicine
Lead sponsor: Clinica Luganese Moncucco
Sponsor class: OTHER
First posted: 2021-05-05
Enrollment: 40
Sex: MALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: patients with prostate cancer

Brief 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.

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.

Eligibility criteria: 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;

Primary outcomes:
measure: reconstruction of local PCa heterogeneity
timeFrame: through study completion, an average of 2 years
Secondary outcomes:
measure: relationships between pathological differentiation (Gleason score) and genomics-measured heterogeneity
timeFrame: through study completion, an average of 2 years
Other outcomes:
Locations:
city: Lugano
country: Switzerland
facility: Alessandra Franzetti Pellanda
state: Ticino
Study officials:
affiliation: Clinica Luganese Moncucco
name: Alessandra Franzetti Pellanda, MD
role: PRINCIPAL_INVESTIGATOR
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