Tumour-based Mutational Profiles Predict Visceral Metastasis Outcome and Early Death in Prostate Cancer Patients

Olivier Cussenot; Kirsten M Timms; Emmanuel Perrot; Pascal Blanchet; Laurent Brureau; Cara Solimeno; Gaelle Fromont; Eva Comperat; Geraldine Cancel-Tassin

doi:10.1016/j.euo.2023.12.003

Tumour-based Mutational Profiles Predict Visceral Metastasis Outcome and Early Death in Prostate Cancer Patients

Eur Urol Oncol. 2024 Jan 4:S2588-9311(23)00291-2. doi: 10.1016/j.euo.2023.12.003. Online ahead of print.

Authors

Olivier Cussenot¹, Kirsten M Timms², Emmanuel Perrot³, Pascal Blanchet³, Laurent Brureau³, Cara Solimeno², Gaelle Fromont⁴, Eva Comperat⁵, Geraldine Cancel-Tassin⁶

Affiliations

¹ CeRePP, Paris, France; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
² Myriad Genetics, Salt Lake City, UT, USA.
³ Department of Urology, CHU Pointe-a-Pitre/Abymes, Pointe-à-Pitre, Guadeloupe, France; Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Pointe-à-Pitre, Guadeloupe, France.
⁴ CeRePP, Paris, France; Faculté de Médecine, Inserm UMR1069 "Nutrition, Croissance et Cancer" Université François Rabelais, Tours, France; Departments of Pathology and Urology, CHRU Bretonneau, Tours, France.
⁵ CeRePP, Paris, France; Department of Pathology, Medical University of Vienna, Vienna, Austria.
⁶ CeRePP, Paris, France; GRC n°5 Predictive Onco-Urology, Sorbonne Université, Paris, France. Electronic address: g.cancel@cerepp.org.

PMID: 38182487
DOI: 10.1016/j.euo.2023.12.003

Abstract

Background: Visceral metastases are known to occur in advanced prostate cancer, usually when the tumour is resistant to androgen deprivation and, have worse outcomes regardless of therapies.

Objective: To analyse genomic alterations in tumour samples according to their lymphatic, bone, and visceral metastatic stages and overall survival.

Design, setting, and participants: We selected 200 patients with metastatic prostate cancer. Genomic profiling of 111 genes and molecular signatures (homologous recombination deficiency [HRD], microsatellite instability, and tumour burden mutation) was performed with the MyChoice test (Myriad Genetics, Inc, Salt Lake City, UT, USA).

Outcome measurements and statistical analysis: The association between genomic profiles and visceral metastatic evolution was evaluated using logistic regression. Kaplan-Meier and Cox proportional hazard analyses were used for analyses of early death.

Results and limitations: A total of 173 (87%) genomic profiles were obtained. Eighty-four (49%) patients died during the follow-up period (median duration = 76 mo). TP53 was the most frequently mutated gene, followed by FANC genes, including BRCA2, and those of the Wnt-pathway (APC/CTNNB1). TP53 gene mutations were more frequent in patients of European (42%) than in those of African (16%) ancestry. An HRD score of >25 was predictive of FANC gene mutations. The mutational status of TP53 (p < 0.001) and APC (p = 0.002) genes were significantly associated with the risk of visceral metastases. The mutational status of CTNNB1 (p = 0.001), TP53 (p = 0.015), BRCA2 (p = 0.027), and FANC (p = 0.005) genes were significantly associated with an earlier age at death. The limitations are the retrospective study design based on a selection of genes and the low frequency of certain molecular events.

Conclusions: Mutations in the TP53 gene and genes (APC/CTNNB1) related to the Wnt pathway are associated with metastatic visceral dissemination and early death. These genomic alterations could be considered as markers to identify prostate cancer patients at a high risk of life-threatening disease who might benefit from more intensified treatment or new targeted therapies.

Patient summary: In this report, we evaluated the relationships between genomic profiles (gene mutations and molecular signatures) of tumour samples from patients with metastatic prostate cancer and early death. We found that mutations of specific genes, notably TP53 and APC/CTNNB1 related to the Wnt pathway, are associated with visceral metastatic progression and an earlier age at death.

Keywords: DNA repair; Genes; Germline; Metastasis; Mutation; Prostate cancer; Somatic.