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Research Worth Watching: Learning More About Metastases

Precision medicine is doing more than helping us to identify an exact mutation in a cancer cell and the drug that matches it. It is also allowing us to do new kinds of research on metastatic disease. We need this type of research because breast cancer deaths are rarely due to the cancer cells in the breast. Rather, breast cancer becomes deadly when cancer cells “get out” of the breast and spread to other organs you need to live, like the liver, lungs, or brain.

Scientists and doctors initially assumed metastasis was an orderly process that took place over time as the cancer cells spread from the tumor to nearby lymph nodes and then on to other areas of the body. This is why there has been such an emphasis on early detection: If we could find and remove the primary tumor before it spreads, the thinking went, then no one would die of breast cancer.

Since we assumed a tumor spread in an orderly fashion, we also assumed the metastases would have all the same mutations as the primary tumor—and respond to the same therapies. But when scientists performed genomic analyses on cells from the primary tumor and cells from metastatic sites, they discovered that they were, in fact, not always the same. Many metastases had mutations the primary tumor did not have. Suddenly, we had many new questions to ask—and answer.

The April issue of the journal Science contains a special section devoted to current hypotheses about metastases. The science is complicated—I admit that I don't understand all the details. But the high points are worth sharing because they shed light on ways new technologies are making possible innovative research that can uncover ways to treat metastatic disease more effectively—and maybe even to prevent it.

Here are the high points:

  • In a previous RWW I wrote about exosomes, or the messenger packets that cells can put into the blood stream to communicate with other cells or organs. I think I even compared them to tweets on Twitter. David Lyden is a cancer researcher who believes cancer cells send off exosomes through the blood to other organs, where they set up a local neighborhood (niche) to support cells that have left the tumor, should they show up. According to his hypothesis, the circulating tumor cells are basically “innocent bystanders” that get attracted to “pre-metastatic niches” established by the exosomes. This novel idea needs to be studied further—all of this research is in mice so far—but it opens up a whole new way to think about the spread of cancer. This work is not universally accepted, but if Lyden is right, then you could also envision sometime in the future a blood test for exosomes that would identify patients at high risk for developing metastatic disease.   
  • Other investigators are looking at how a certain type of immune cell—neutrophils—may aid and abet metastases in their migration. Neutrophils are a type of white blood cell that tends to be more common in cancer patients than in healthy people. These cells are the first responders to an infection or inflammation, so their presence in cancer patients has always been a puzzle. Recent research in mice has suggested that neutrophils, like exosomes, may play a role in the development of metastatic disease. Two other studies in mice found—surprisingly—an accumulation of neutrophils in the lung before the metastatic cancer cells arrived. And in both studies, signals from the primary tumor stimulated the neutrophils. Was the signal carried by the exosomes? These studies were conducted in a different lab, and they didn't look for exosomes. Even so, these researchers also referred to the pre-prepared metastatic spot, or pre-metastatic niche. There are many drugs that can block neutrophils, and scientists have found that they can prevent metastases in mice. Now, they are going to investigate whether these drugs improve outcomes when given with chemotherapy and/or radiation therapy. Stay tuned.
  • Scientists are also investigating whether metastases arise from a series of single cells that all have the same mutations when they leave the tumor or from clusters of cells with different mutations. In the first situation, you would expect the metastases to initially have the same mutations as the primary tumor and then later develop more mutations that differ. In the second scenario, the metastases would contain different mutations from the start. If it’s true that metastases travel in gangs or clusters, it would help explain why different metastatic sites can have different mutations and why they can all differ from the primary tumor.
  • New tools are also leading us to challenge the old dogma that the primary cancer had certain mutations in it driving its growth and that the metastases shared these as well. There may well be a dominant type of mutation, but there are also often other sub-groups of cells with other mutations. This is why women who have estrogen-receptor-positive tumors or HER2-positive tumors may later have triple negative metastases. Most tumors are not purely one type or another but a mixture with a dominant type driving at any one time.

A recent review described the different ways you can think about the composition of a tumor and its metastases. In a parallel progression model, the disease spreads to another site very early, and the cancers at both sites evolve independently, which means that the metastatic sites won’t necessarily match the primary tumor. Looking at tumors from this evolutionary standpoint suggests that precision medicine alone will not work because the metastases won’t necessarily be the same as the primary tumor. One study that modeled the metastatic process estimated an average of seven years between the birth of the cell that gave rise to the initial tumor and the seeding of the first metastasis. This suggests there is a window of opportunity to prevent metastatic disease and supports the push for early detection.

We still do not have a blueprint for how to prevent or cure metastatic disease. These studies give me a lot of hope that this blueprint is attainable. Only by understanding the basic biology of metastases as well as harnessing all of our tools—chemotherapy, targeted therapy, and immunotherapy—will we be able to identify the points where we can stop a tumor from spreading and end breast cancer once and for all.