28 A new study published in Nature has mapped how metastatic bladder cancer evolves and spreads, identifying differences between tumour subtypes that could inform earlier intervention, monitoring and future treatment strategies. Bladder cancer is the 11th most common cancer in the UK, with around 10,900 new cases diagnosed each year. While nearly 80% of patients survive, metastatic disease remains a major challenge. Its natural history is not fully understood, particularly for rare subtypes, making it difficult for clinicians to predict disease progression and determine the most appropriate treatment. Researchers from Fred Hutch Cancer Center and the University of Washington reconstructed the evolutionary histories of 104 tumours from 20 patients. The analysis found that metastasis to metastasis seeding was the dominant pattern of cancer spread, suggesting that an early metastatic tumour can become a source for further metastases. “The major driver of death from bladder cancer is metastasis, and in order to understand and target it we needed better data to learn about how the tumours migrate and spread,” said study co-senior author Gavin Ha, PhD, an associate professor in the Public Health Sciences Division at Fred Hutch and holder of the Shintaffer Family Endowed Chair in Bioinformatics. “We want to find earlier opportunities for intervention, so understanding the order of metastatic spread is important.” The researchers used a first of its kind rapid autopsy programme developed by Fred Hutch and the University of Washington to collect multiple tumour samples from patients with advanced bladder cancer, including rare subtypes that have previously been understudied. The programme was conducted in collaboration with co-senior authors Ming Lam, PhD, a research associate professor in the Department of Urology at the , and Omar Mian, MD, an associate professor in the divisions of Human Biology and Radiation Oncology at Fred Hutch. The samples allowed researchers to examine genomic differences within and between tumours from the same individuals, providing information about genomic architecture, including genes, DNA sequences and genetic variations that shape biological functions and disease. Researchers found that metastatic tumours could seed new metastases, contributing to the spread of more aggressive bladder cancer subtypes from one metastatic site to another. “What we found is that perhaps metastases are the staging point for disease to spread to other places,” said co-senior author Andrew Hsieh, MD, an expert in prostate and bladder cancer and a professor and associate director of the Human Biology Division at Fred Hutch. The study also identified substantial differences between histological subtypes in the burden, timing and heterogeneity of genomic alterations. The Nature study found that plasmacytoid and neuroendocrine variants developed early driver alterations associated with shorter survival. Researchers found that differences between tumour subtypes could also be detected using circulating DNA from the blood, potentially providing a non invasive way to monitor tumour evolution and the development of more aggressive characteristics. “We hope that these findings help us further examine whether a single metastases or residual metastasis could respond to more tailored therapies,” added Hsieh, who holds the Larry and Virginia Gordon Endowed Chair in Prostate and Bladder Cancer Research at Fred Hutch. The findings also have implications for treatment timing. The researchers reported that earlier intervention in oligometastatic disease could potentially suppress metastasis to metastasis spread and limit polyclonal tumour evolution, although further research is needed. Building on this work, the REINFORCE phase I/II clinical trial, led by Dr Martin Ma, is investigating whether consolidative treatment can safely arrest metastatic progression and delay disease progression. The approach combines radiation therapy to the bladder or surgical removal of the bladder, known as radical cystectomy, with ablation of selected metastatic sites using Stereotactic Body Radiation Therapy (SBRT). The trial is evaluating consolidative radiation therapy or cystectomy in patients with advanced bladder cancer who respond favourably to enfortumab vedotin plus pembrolizumab. It also includes metastasis directed SBRT for selected metastatic sites. “We are grateful to all the patients and their families who have contributed to this study and entrusted us with an opportunity to help others,” said Hsieh. “We are learning from their experiences with metastatic bladder cancer and are hopeful that their contributions will make the disease easier to bear for future patients.” The researchers said the study provides a detailed view of how different histological subtypes of metastatic bladder cancer evolve and spread. The findings could support further research into earlier intervention, non invasive monitoring through circulating DNA and treatment strategies tailored to individual tumour subtypes.