2 June 2019
Genetic profiling has provided insight into the evolution of cells that are shed from primary breast tumours and go on to cause metastases in other parts of the body. The work validates current approaches to primary treatment, and identifies opportunities to develop more effective treatment for metastatic disease.
Primary breast cancer can usually be treated with surgery and radiotherapy, but by the stage of diagnosis, the tumour might have shed cells that could cause metastases — new tumours in other parts of the body — which are usually fatal. Systemic treatment is needed to kill the shed cells and prevent metastases.
Treatment is chosen according to the subtype of cancer, determined by which cancer-causing mutations are present in the tumour. However, relatively little is known about the genetics of metastatic breast cancer. Work led by Per Eystein Lønning from the University of Bergen, Norway, and Peter Campbell from the Wellcome Trust Sanger Institute, UK, has provided new insight, with implications for therapy.
The researchers compared the mutations present in the cells of metastases with those in the original, or primary, breast tumours from the same patients. Almost all the mutations in the metastatic tumours were also present in the primary one, indicating that the metastatic cells were shed from the primary cancer late in the development of the tumour. Genetic profiling of the primary tumour is therefore likely to closely predict the genetic profile of any cells that have been recently shed, so systemic treatment chosen on the basis of mutations in the primary tumour is likely to be the most effective at preventing metastases.
Lønning, Campbell, and colleagues also investigated whether the main mutations that promote tumour growth—known as driver mutations—in metastatic tumour cells corresponded with those in the primary tumour cells. Metastases detected at the same time as the primary tumour mostly had the same driver mutations, supporting the selection of systemic treatment based on the profile of the primary tumour. However, metastases that were not detectable until later had accumulated additional driver mutations, meaning that therapy chosen on the basis of the primary tumour might be less effective.
The researchers say that the ability of cancer cells to continue accumulating mutations over time means that the genetic profiles of metastatic tumours are likely to exhibit greater variation between patients than those of primary tumours. They conclude that large studies of patients with metastatic breast cancer are needed to determine the extent of this complexity and identify new therapeutic targets.
Yates, L.R., Knappskog, S., Wedge, D., Farmery, J.H.R., Gonzalez, S. et al. Genomic evolution of breast cancer metastasis and relapse. Cancer Cell 32, 169–184 (2017). | article