A landmark study that traces the evolutionary history of genetic mutations in lethal prostate cancer has found that some metastases are actually seeded by cancer cells from other metastases, and not from the original primary tumor.
The findings will lead to a better understanding of prostate cancer metastases, said coauthor William Isaacs, PhD, professor of urology at the Johns Hopkins Brady Urological Institute and also professor of oncology at the Johns Hopkins University School of Medicine in Baltimore. "It gives us a better picture of what we are up against.... We need to understand this complexity so that we know how to act against it," he told Medscape Medical News.
This analysis also showed that there was a common genetic heritage in prostate cancer — unlike some other tumor types — which gives rise to hope for new therapies that could act at earlier stages of the disease.
In addition, it also confirmed the crucial importance of the androgen pathway for prostate cancer, and that developing further drugs that block this pathway remains "the right way to go," said another coauthor.
The findings were published online April 1 in Nature.
The study involved a detailed analysis of tumor samples taken from various anatomical sites (including bone, liver and lymph glands, as well as prostate) from 10 patients who had died from metastatic prostate cancer after having received treatment at Johns Hopkins Hospital.
Half of these patients had undergone a radical prostatectomy, some had radiation treatment, and all had been treated with hormonal therapy, Dr Isaacs noted.
Next, a team of international researchers performed whole-genome sequencing on each of the 51 tumor samples, and also on a sample of normal tissue taken from each individual.
This allowed the researchers to trace the evolutionary history of the genetic mutations involved, and "a very dynamic picture emerged," Dr Isaacs told Medscape Medical News.
"The disease becomes very heterogeneous as it spreads throughout the body over time, both between and among individuals," he said.
The analysis showed that metastases could be seeded by cells from the primary tumor or cells from other metastases. For instance, cells from the original primary tumor may spread to the lymph node but still retain the same genetic mutations that were found in the primary tumor, he explained. But from there, cancer cells may spread and establish a new metastasis in the liver and, at this site, they may undergo further genetic changes and become genetically distinct from the cells in the lymph nodes, forming a new clone; and now this new clone of cancer cells can in turn spread further and establish other metastases.
"The idea that metastatic tumors can seed and establish other metastatic tumors in patients is different from traditional theories that the primary tumor is solely responsible for disseminating cancer cells with metastatic potential," Dr Isaac commented in a statement.
Tracing Evolutionary History of Mutations
It was the whole-genome sequencing that allowed the researchers to identify where each tumor at each anatomical site came from. It allowed them to trace the evolutionary history of the genetic mutations and show that, for instance, a particular metastasis in the liver was made up of cells that had migrated from the bone metastasis.
It's a very complex and dynamic interaction," Dr Isaacs said. "We've known for a while that different types of cancer are very different from one another, but this shows that even within one individual, the cancer evolves and the different lesions in that individual are distinct from one another, with different biology, and so it's not surprising that when we use a single therapy, it affects only some of these lesions and not all of them."
"This has been seen previously in animal models, but this was the first time that it had been documented in such detail in a human setting," he added.
Hope for New Therapies
While the genetic heterogeneity may appear to spell gloom for the idea of precision medicine, with a single drug targeting a single mutation, there is hope for new treatment approaches from this research, Dr Isaacs commented. "An important finding was that there were genetic mutations that were found in all of the cancer cells, even though there were many others that were different," he noted.
The researchers drew evolutionary trees to trace these genetic mutations, and found that the "trunk" part of this tree (representing the initial evolution of the genetic mutations) was actually quite long, commented coauthor Ultan McDermott, MD, from the Wellcome Trust Sanger Institute in Hinxton, where he is a group leader in the Cancer Genome Project, and also a medical oncologist at Addenbrooke's Hospital in Cambridge, United Kingdom. "Most of the oncogenic mutations are shared clonally by all the tumor sites in each patient," he said, and "this common genetic heritage is a potential Achilles heel of the metastases."
It is this finding that gives hope for new therapies, he commented. "It takes a while before a tumor develops the ability to metastasize, but once it does, the patients' prognosis changes significantly," he explained, "so we have to zoom in on this crucial junction."
One difficulty is that many of the shared early genetic mutations are found in tumor suppressor genes, so the mutation leads to a loss of function, and it is difficult to develop a drug to restore that function, he told Medscape Medical News.
So far, the therapeutic successes from the precision medicine approach of targeting genetic mutations has been seen with drugs that act on oncogenes, where the drug turns off the activity of the oncogene. A good example is BRAF, and the successful treatment of melanoma with BRAF and MEK inhibitor drugs, Dr McDermott said.
There has been less research into drugs that target tumor suppressor genes, although there is an experimental agent, nutlin (an MDM2 inhibitor), that acts in this way, he said. This was a research area that was in vogue about 5 years ago, and then interest waned, but "one could argue that this new study in prostate cancer suggests we should revive this research approach."
One other finding from the study that has therapeutic implications is that the androgen-receptor pathway appears to be crucially important in prostate cancer. "Each metastasis is different...and they become resistant in different ways to prostate cancer treatment," Dr McDermott explained. All of the patients had androgen-deprivation therapy and all became resistant to this treatment, but the sequencing showed that each metastasis became resistant in a different way (e.g., by amplifying the androgen receptor, or the receptor is mutated so the drug no longer works). But while the mechanism of how they become resistant varied, all the mechanisms work towards the same goal of keeping the androgen pathway turned on.
"This is an important question in cancer: When the drugs stop working, is it because the cancer is now using a different pathway? Well, this is telling us that, no, the cancer cells are working hard to keep this androgen pathway turned on, because this pathway is so important to cancer survival," he said. This, in turn, suggests that working on drugs that block the androgen pathway is "the right way to go," and that second-generation androgen blockers may work even after initial androgen blockers stop working, he added.
Nature. Published online April 1, 2015. Abstract
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