Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state in the progression of metastatic disease for which patients experience better outcomes in comparison to those with higher disease burden. Despite the generally more indolent nature, there is still much heterogeneity, with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Our aim was to investigate correlation of tumor genomics with the mode of progression (MOP) and pattern of failure (POF) following first treatment (metastasis-directed and/or systemic therapy) for omCSPC.
We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC who underwent tumor next-generation sequencing with at least 1 yr of follow-up after their first treatment. Descriptive MOP and POF results are reported with respect to the presence of genomic alterations in pathways of interest. MOP was defined as class I, long-term control (LTC; no radiographic progression at last follow-up), class II, oligoprogression (1-3 lesions), or class III, polyprogression (≥4 lesions). POF included the location of lesions at first failure. Genomic pathways of interest included TP53, ATM, RB1, BRCA1/2, SPOP, and WNT (APC, CTNNB1, RNF43). Genomic associations with MOP/POF were compared using χ2 tests. Exploratory analyses revealed that the COSMIC mutational signature and differential gene expression were also correlated with MOP/POF. Overall survival (OS) was calculated via the Kaplan-Meier method from the time of first failure.
We included 267 patients in our analysis; the majority had either one (47%) or two (30%) metastatic lesions at oligometastasis. The 3-yr OS rate was significantly associated with MOP (71% for polyprogression vs 91% for oligoprogression; p = 0.005). TP53 mutation was associated with a significantly lower LTC rate (27.6% vs 42.3%; p = 0.04) and RB1 mutation was associated with a high rate of polyprogression (50% vs 19.9%; p = 0.022). Regarding POF, bone failure was significantly more common with tumors harboring TP53 mutations (44.8% vs25.9%; p = 0.005) and less common with SPOP mutations (7.1% vs 31.4%; p = 0.007). Visceral failure was more common with tumors harboring either WNT pathway mutations (17.2% vs 6.8%, p = 0.05) or SPOP mutations (17.9% vs 6.3%; p = 0.04). Finally, visceral and bone failures were associated with distinct gene-expression profiles.
Tumor genomics provides novel insight into MOP and POF following treatment for metachronous omCSPC. Patients with TP53 and RB1 mutations have a higher likelihood of progression, and TP53, SPOP, and WNT pathway mutations may have a role in metastatic organotropism.
We evaluated cancer progression after a first treatment for metastatic prostate cancer with up to five metastases. We found that mutations in certain genes were associated with the location and extent of further metastasis in these patients.
European urology oncology. 2024 Jun 10 [Epub ahead of print]
Philip Sutera, Yang Song, Amol C Shetty, Keara English, Kim Van der Eecken, Ozan Cem Guler, Jarey Wang, Yufeng Cao, Soha Bazyar, Sofie Verbeke, Jo Van Dorpe, Valérie Fonteyne, Bram De Laere, Mark Mishra, Zaker Rana, Jason Molitoris, Matthew Ferris, Ana Kiess, Daniel Y Song, Theodore DeWeese, Kenneth J Pienta, Christopher Barbieri, Luigi Marchionni, Lei Ren, Amit Sawant, Nicole Simone, Alejandro Berlin, Cem Onal, Phuoc T Tran, Piet Ost, Matthew P Deek
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA., Department of Pathology and Human Structure and Repair, University of Ghent, Ghent, Belgium., Department of Radiation Oncology, Faculty of Medicine, Baskent University, Adana Dr. Turgut Noyan Research and Treatment Center, Adana, Turkey., Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA., Department of Pathology, Ghent University Hospital, Ghent, Belgium., Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium., Department of Pathology and Human Structure and Repair, University of Ghent, Ghent, Belgium; Department of Radiation Oncology, Iridium Network, Antwerp, Belgium., Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA., Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA., Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA., Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA., Princess Margaret Cancer Centre, University Health Network, Toronto, Canada., Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: ., Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium. Electronic address: ., Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA. Electronic address: .