University of Toronto, Toronto, ON, Canada
Bhandari Vinayak , Lydia Liu , Shadrielle Espirritu , Emilie Lalonde , Takafumi Yamaguchi , Lawrence Heisler , Julie Livingstone , Vincent Huang , Yu-Jia Shiah , Veronica Sabelnykova , Fouad Yousif , Michael Fraser , Melvin Chua , Theodorus Van Der Kwast , Stanley K. Liu , Paul Christopher Boutros , Robert G. Bristow
Background: Localised prostate cancers are classified into risk-groups using clinical measurements like grade and stage to inform treatment decisions. However, these groupings are imprecise: ~30% of intermediate-risk patients suffer relapse of their disease despite precision image-guided radiotherapy or radical prostatectomy. One reason for this variability in response to treatment is the underlying cellular and molecular heterogeneity of tumours. Prostate tumour cells exist within a microenvironment characterized by gradients of oxygen levels and prostate tumours with low levels of oxygen (hypoxia) have poor clinical outcomes. Methods: Hypoxia was measured using multiple mRNA-based signatures. We examined 548 patients with localised prostate cancer and statistically assessed the association of hypoxia with copy-number alterations (CNAs), single-nucleotide variants (SNVs), genomic rearrangements, focal genomic events (i.e. kataegis, chromothripsis), telomere length, clinical indices (i.e. grade, stage) and subclonal architecture. Results: Elevated hypoxia was associated with allelic loss of PTEN, higher rates of chromothripsis and intraductal and cribriform carcinoma (IDC-CA). To translate these findings into a biomarker for prostate cancer precision medicine, we integrated tumour microenvironmental data with genomic and pathological information to stratify patients into distinct prognostic groups. Patients with localized prostate cancer that have polyclonal tumours with elevated hypoxia, allelic loss of PTEN and IDC-CA were at the highest risk of rapid biochemical failure (P = 3.48 x10-3, Logrank test) and metastasis (P = 4.61 x 10-3, Logrank test), even after controlling for T-category, Gleason score and pre-treatment PSA. Conclusions: These data suggest that the aggressiveness of prostate cancers is driven by the interplay of the tumour microenvironment, tumour evolutionary trajectories and its genomic mutational profile.
Disclaimer
This material on this page is ©2024 American Society of Clinical Oncology, all rights reserved. Licensing available upon request. For more information, please contact licensing@asco.org
Abstract Disclosures
2023 ASCO Genitourinary Cancers Symposium
First Author: Sophia C. Kamran
2024 ASCO Genitourinary Cancers Symposium
First Author: Sagar A. Patel
2023 ASCO Annual Meeting
First Author: Praful Ravi
2022 ASCO Genitourinary Cancers Symposium
First Author: Jones T. Nauseef