Matthew P Deek1, Kim Van der Eecken2, Ryan Phillips1, Neil R Parikh3, Pedro Isaacsson Velho4, Tamara L Lotan5, Amar U Kishan3, Tobias Maurer6, Paul C Boutros7, Christopher Hovens8, Matthew Abramowtiz9, Alan Pollack9, Neil Desai10, Bradley Stish11, Felix Y Feng12, Mario Eisenberger4, Michael Carducci4, Kenneth J Pienta13, Mark Markowski4, Channing J Paller4, Emmanuel S Antonarakis4, Alejandro Berlin14, Piet Ost2, Phuoc T Tran15. 1. Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 2. Department of Radiation Oncology, Ghent University, Ghent, Belgium. 3. Department of Radiation Oncology, UCLA, Los Angeles, CA, USA. 4. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 5. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 6. Department of Urology, Martini-Klinik, Hamburg, Germany. 7. Department of Human Genetics, UCLA, Los Angeles, CA, USA. 8. Department of Surgery, Royal Melbourne Hospital, Melbourne, Australia. 9. Department of Radiation Oncology, University of Miami, Miami, FL, USA. 10. Department of Radiation Oncology, UT Southwestern, Dallas, TX, USA. 11. Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA. 12. Departments of Medicine, Urology, and Radiation Oncology, UCSF, San Francisco, CA, USA. 13. 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. 14. Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Canada. 15. 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. Electronic address: tranp@jhmi.edu.
Abstract
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, micrometastatic), 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.
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, micrometastatic), 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.
Authors: Rohan R Katipally; Sean P Pitroda; Aditya Juloori; Steven J Chmura; Ralph R Weichselbaum Journal: Nat Rev Clin Oncol Date: 2022-07-12 Impact factor: 65.011
Authors: Igor Tsaur; Roman A Blaheta; Robert Dotzauer; Cristian Mirvald; Jonathan Olivier; Cristian Surcel; Maximilian P Brandt; Giorgio Gandaglia; Ioanel Sinescu Journal: World J Urol Date: 2022-10-02 Impact factor: 3.661
Authors: Philip Sutera; Matthew P Deek; Kim Van der Eecken; Alexander W Wyatt; Amar U Kishan; Jason K Molitoris; Matthew J Ferris; M Minhaj Siddiqui; Zaker Rana; Mark V Mishra; Young Kwok; Elai Davicioni; Daniel E Spratt; Piet Ost; Felix Y Feng; Phuoc T Tran Journal: Prostate Date: 2022-08 Impact factor: 4.012
Authors: 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; Matthew P Deek Journal: Prostate Cancer Prostatic Dis Date: 2022-01-11 Impact factor: 5.455
Authors: Mike Wenzel; Felix Preisser; Benedikt Hoeh; Maria Schroeder; Christoph Würnschimmel; Thomas Steuber; Hans Heinzer; Severine Banek; Marit Ahrens; Andreas Becker; Pierre I Karakiewicz; Felix K H Chun; Luis A Kluth; Philipp Mandel Journal: Front Oncol Date: 2021-04-23 Impact factor: 6.244