Evolution of structural rearrangements in prostate cancer intracranial metastases

www.nature.com/npjprecisiononcology ARTICLE OPEN Evolution of structural rearrangements in prostate cancer intracranial metastases 1234567890():,; Francesca Khani 1,2,11, William F. Hooper3,11, Xiaofei Wang 2, Timothy R. Chu3, Minita Shah3, Lara Winterkorn3, Michael Sigouros Vincenza Conteduca 2,4, David Pisapia1,2, Sara Wobker5, Sydney Walker6, Julie N. Graff6, Brian Robinson 1,2, Juan Miguel Mosquera 1,2, Andrea Sboner 1,2,7,8, Olivier Elemento 2,9, Nicolas Robine3,12 and Himisha Beltran 2,10,12 ✉ 2 , Intracranial metastases in prostate cancer are uncommon but clinically aggressive. A detailed molecular characterization of prostate cancer intracranial metastases would improve our understanding of their pathogenesis and the search for new treatment strategies. We evaluated the clinical and molecular characteristics of 36 patients with metastatic prostate cancer to either the dura or brain parenchyma. We performed whole genome sequencing (WGS) of 10 intracranial prostate cancer metastases, as well as WGS of primary prostate tumors from men who later developed metastatic disease (n = 6) and nonbrain prostate cancer metastases (n = 36). This first whole genome sequencing study of prostate intracranial metastases led to several new insights. First, there was a higher diversity of complex structural alterations in prostate cancer intracranial metastases compared to primary tumor tissues. Chromothripsis and chromoplexy events seemed to dominate, yet there were few enrichments of specific categories of structural variants compared with non-brain metastases. Second, aberrations involving the AR gene, including AR enhancer gain were observed in 7/10 (70%) of intracranial metastases, as well as recurrent loss of function aberrations involving TP53 in 8/10 (80%), RB1 in 2/10 (20%), BRCA2 in 2/10 (20%), and activation of the PI3K/AKT/PTEN pathway in 8/10 (80%). These alterations were frequently present in tumor tissues from other sites of disease obtained concurrently or sequentially from the same individuals. Third, clonality analysis points to genomic factors and evolutionary bottlenecks that contribute to metastatic spread in patients with prostate cancer. These results describe the aggressive molecular features underlying intracranial metastasis that may inform future diagnostic and treatment approaches. npj Precision Oncology (2023)7:91 ; https://doi.org/10.1038/s41698-023-00435-3 INTRODUCTION Systemic therapy for metastatic prostate cancer has improved significantly over the last decade, leading to improvements in overall survival1. Likely due to more effective disease control and patients living longer, patterns of metastases have also evolved. Prostate cancer typically spreads to lymph nodes and bone. In later stages, visceral metastasis to liver, lungs, or bone marrow may be observed. Intracranial brain metastases, once thought to be rare in prostate cancer, are increasingly described, which may be due to better systemic disease control with drugs that do not cross the blood-brain barrier2. The absolute incidence and associated clinical characteristics of intracranial metastases in prostate cancer in the current era is not well established, but it is a major cause of morbidity and mortality for affected patients. In other solid tumors, brain metastases have been associated with distinct and potentially actionable genomic alterations not observed in primary tumor tissues3–6. Understanding patterns of tumor evolution can provide insights into clinical strategies for detecting, preventing, or treating brain metastases. Prostate cancer is characterized by a relatively low mutational burden and a predominance of copy number alterations, complex rearrangements, and structural alterations that are not often appreciated through exome sequencing7. Here we performed whole genome sequencing (WGS) of a cohort of primary and metastatic prostate cancers, including intracranial prostate cancer metastases, to identify the spectrum of genomic alterations present in prostate cancer intracranial metastases and their concordance with other sites of disease. RESULTS Clinical Features We identified 36 patients with prostate cancer intracranial metastases (33 were from 2010 to 2018; 4 cases before 2010 (2003–2009)). These were further classified as parenchymal brain (n = 22, 61.1%), dural-based (n = 13, 36.1%) or both (n = 1, 2.8%). The median time from prostate cancer diagnosis to intracranial metastasis was 56.6 months. Prostate cancer grade at diagnosis was Grade Group 4 (GG4) or higher in 15 cases (41%), lower than GG4 in 11 cases (31%), with data on grade group unavailable from the remaining 10 cases (28%). The median number of lines of systemic therapy given for metastatic disease before intracranial metastasis was three (range 0–8). One patient presented with multiple de novo parenchymal brain metastases without any prior therapy for prostate cancer or other sites of metastasis. Median serum prostate specific antigen (PSA) level at the time of 1 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. 2Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. 3New York Genome Center, New York, NY, USA. 4Department of Medical and Surgical Sciences, Unit of Medical Oncology and Biomolecular Therapy, University of Foggia, Policlinico Riuniti, Foggia, Italy. 5Department of Pathology and Laboratory Medicine, UNC Chapel Hill, Chapel Hill, NC, USA. 6Department of Medical Oncology, Oregon Health Sciences University, Portland, OR, USA. 7The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA. 8Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. 9Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. 10Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 11These authors contributed equally: Francesca Khani, William F. Hooper. 12These authors jointly supervised this work: Nicolas Robine, Himisha Beltran. ✉email: Published in partnership with The Hormel Institute, University of Minnesota F Khani et al. 2 Table 1. Clinical features of prostate cancer patients with brain metastases. Characteristics of overall patients n (%) 36 (100%) Age at the time of brain metastases, years Median (range) 66 (50–86) Gleason score at diagnosis, n (%) <8 ≥8 Missing Histology, n (%) 11 (42.3) 15 (57.7) 10 Adenocarcinoma 28 (77.8) NEPC 8 (22.2) Prostatectomy, n (%) No 24 (66.7) Yes 12 (33.3) Radical radiotherapy, n (%) No Yes 14 (38.9) 22 (61.1) 1234567890():,; Site of brain metastasis, n (%) Parenchymal 22 (61.1) Dural 13 (36.1) Both 1 (2.8) Type of brain metastasis, n (%) Solitary Multiple Other sites of metastasis at the time of brain met diagnosis, n (%) Bone 22 (61.1) 14 (38.9) 32 (88.9) 12 (33.3) Nodal 11 (30.5) Lung 9 (25.0) Liver 6 (16.7) Other Number of prior (...truncated)