Journal
EUROPEAN UROLOGY
Volume 80, Issue 5, Pages 632-640Publisher
ELSEVIER
DOI: 10.1016/j.eururo.2020.12.040
Keywords
Oligometastatic prostate cancer; Next Generation Sequencing
Categories
Funding
- Ronald Rose and Joan Lazar, Nesbitt-McMaster Foundation
- Barbara's Fund
- National Capital Cancer Research Fund
- Prostate Cancer Foundation, Movember Foundation
- NIH/NCI [U01CA212007, U01CA231776, R21CA223403]
Ask authors/readers for more resources
Somatic mutational profiles across the spectrum of metastatic castration-sensitive prostate cancer reveal associations between TP53 mutations and clinical outcomes in patients with oligometastasis, indicating a potential biological definition of oligometastasis beyond numerical classifications. Mutation analysis in TP53 and DNA double-strand break repair genes may help predict the number of metastases and clinical outcomes in patients with mCSPC.
Background: Emerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical. Objective: To characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC. Design, setting, and participants: This was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometa-static), metachronous oligometastatic (<= 5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease. Outcome measurements and statistical analysis: We measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC). Results and limitations: The frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p < 0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio [HR] 1.59; p = 0.03) and the development of CRPC (HR 1.71; p = 0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined. Conclusions: Somatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration. Patient summary: Oligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available