Metastasis has classically been considered a binary state, which has heavily influenced treatment paradigms to favor systemic therapy. Recently, mounting evidence suggests metastasis is a spectrum of disease rather than a simple binary entity resulting in the notion of a potentially curable low-volume metastatic state with metastasis-directed local therapy. Significant efforts have been underway to categorize patients with metastatic castration-sensitive prostate cancer (mCSPC) by splitting disease into high- and low-volume states for treatment and risk stratification purposes. As investigators attempt to accurately categorize these patients, several definitions of disease volume have been proposed and applied in various clinical trials. Broadly, these can be separated into numeric/location-centric (ie CHAARTED and STAMPEDE) or enumeration only (i.e. Oligometastatic ≤3 or ≤5) definitions.
We have previously demonstrated that clinical data alone is insufficient to fully capture the heterogeneity exhibited by this patient population and that tumor genomics plays a key role across this spectrum of disease. We, therefore, aimed to evaluate this commonly used definition of disease burden in the context of patients with CSPC who underwent next-generation sequencing of their tumor.
Patients were classified into biochemically recurrent, “low-volume”, and “high-volume” metastatic disease utilizing four definitions. Patients classified as biochemical recurrence (BCR) had a rising PSA following definitive therapy to the primary tumor without any radiographic evidence of gross metastatic disease at last follow-up. The four definitions in our analysis included those from CHAARTED (high volume: visceral metastasis or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis), modified STAMPEDE (high volume: visceral metastasis or ≥4 bone lesions), oligometastatic ≤3 (high volume: greater than 3 metastases irrespective of location), and oligometastatic ≤5 (high volume: greater than 5 metastases irrespective of location).
We identified that all of these definitions were similarly effective at stratifying patients by clinical outcome (radiographic progression-free survival, time to castration resistance, and overall survival) (Figure). High volume disease was associated with significantly worse outcomes within all definitions. We also noted the underlying genetic makeup of tumors was similar across all definitions and increasing rates of driver mutations were identified across the spectrum of disease within all four definitions. Interestingly, patients with low-volume disease and TP53 mutations had clinical course more akin to patients with high-volume disease suggesting its ability to provide prognostic information. Finally, patients with discordant classifications (high volume by one definition but low by another) also appeared to have a more aggressive clinical course similar to those with high volume disease.
These findings demonstrate the similarities of four commonly utilized definitions of mCSPC in terms of patient classifications, clinical outcomes, and incidence of pathogenic driver mutations across the spectrum of disease. Future work is needed to further refine risk stratification by incorporating timing of disease (metachronous vs synchronous), and tumor genomics.
Written by: Matthew P Deek, Philip Sutera, Kim Van Der Eecken, Amar U Kishan, Anis Hamid, Emily Grist, Gerhardt Attard, Tamara Lotan, Adrianna A Mendes, Channing J Paller, Michael A Carducci, Ashley Ross, Hao Wang, Ken Pienta, Felix Y Feng, Emmanuel S Antonarakis, Piet Ost, Daniel Y Song, Stephen Greco, Curtiland Deville, Theodore DeWeese, Phuoc T Tran
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Departments of Pathology and human structure and repair, University of Ghent, Ghent, Belgium., Department of Radiation Oncology, UCLA, Los Angeles, CA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Department of Oncology, UCL Cancer Institute, London, UK., Division of Molecular Pathology, The Institute of Cancer Research, London, UK., Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Department of Urology, Northwestern University, Chicago, IL, USA., Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Departments of Radiation Oncology, Medicine and Urology, UCSF, San Francisco, CA, USA., Department of Radiation Oncology, Iridium Network, Antwerp, Belgium and Department of human structure and repair, Ghent University, Ghent, Belgium.
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