Dr. Isaacs said polyclonal seeding between different organ sites may be a common occurrence in mCRPC. Mutations selected from these clusters (181 to 429 mutations per patient in these 5 cases) were validated by deep sequencing of additional aliquots of DNA. In 7 out of 10 men, the metastatic tumors were genetically more similar to each other than to the primary tumor.

Alicia Morgans, MD, who is an assistant professor of medicine in the division of Hematology/Oncology at the Vanderbilt-Ingram Cancer Center in Nashville, TN, said this was a meticulously performed study that sheds new light on the complexity of the metastatic process in the most advanced form of prostate cancer.


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She said this study points to important new therapeutic approaches and not only demonstrates that clones in metastatic sites actually originate in other metastatic sites rather than the primary tumor, but that clonal populations appeared to cooperate with each other by sharing resistance mechanisms back and forth or inducing microenvironment remodeling that made it easier for other clonal populations to survive.

“This study describes clonal cancer colonies ‘manifesting destiny’ by spreading, evolving, and spreading again, tirelessly competing to be the dominant clone and control the system overall,” Dr. Morgans told Cancer Therapy Advisor.

“This study brings our understanding of metastatic disease in mCRPC into sharper focus. It beautifully maps monoclonal and polyclonal cancer cell spread, and demonstrates that metastasis-to-metastasis seeding of clonal populations may be more common than seeding from the primary tumor.”

The current study also dramatically illustrates that there is unlikely to be “one silver bullet” that will shut down the development of castration-resistance and the spread of disease, Dr. Morgans explained. In addition, this calls into question the predictive ability of some biopsy approaches.

“A single prostate cancer biopsy of a single metastatic site may provide less information about the mutations driving disease progression in an individual overall than we wish. Once again, things turn out to be more complicated than we once believed,” said Dr. Morgans.

An American Society of Clinical Oncology spokesman Sumanta Kumar Pal, MD, who is an assistant professor in the department of Medical Oncology and Therapeutics Research at the City of Hope Comprehensive Cancer Center in Los Angeles, CA, stated that these findings provide new clues on how it may be best to prevent mCRPC. He said it may be time to rethink how men with aggressive localized disease are diagnosed and managed.

RELATED: Role of Genetic Mutations in Metastatic Castrate-Resistant Prostate Cancer Treatment

“This has been shown in other studies, but only in theory. This adds an element of science to it and adds some validation because it is being shown in tissue specimens from these men,” Dr. Pal told Cancer Therapy Advisor

“This will test the premise if removing the prostate has impact. The removal of the prostate cancer might do little to affect metastasis. It may change how we approach treating patients and whether to remove the prostate.”

Dr. Isaacs said it may be possible to develop single oral agents that combine different targeted therapies. This type of precision medicine would involve a polypill containing compounds that target a variety of genetic pathways. “This could be an option,” said Dr. Isaacs.

Reference

  1. Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520(7547):353-357.