Much of the discussion and debate about breast cancer is currently over issues like screening guidelines, risk, and prophylactic bilateral mastectomies. This focus on risk reduction and early detection can lull us into a false sense of security, suggesting that if we just do this early stuff right we can prevent all breast cancer deaths. But women and men still die from breast cancer even after screening, bilateral mastectomies, “precision medicine,” and targeted therapy! Why? Because we don’t yet know enough about metastases.
Breast cancer cells can leave the breast and enter the blood stream and the rest of the body very early in their development, even before the tumor is evident on mammography or MRI. But how do those cancer cells get into the blood stream? We knew that tumors were able to grow the new blood vessels they needed to thrive, and we thought that in addition to nurturing the tumor these vessels gave the cancer cells a way to get into the blood stream. The growth of these new blood vessels, a process known as angiogenesis, has been the subject of much cancer research, and that effort led to the development of the drug Avastin (bevacizumab), which was designed to block angiogenesis.
But in clinical trials for breast cancer (and other types of cancers), the drug didn’t fulfill its promise, leading researchers to ask: So, where are those new blood vessels coming from?
An interesting study published online on April 8 in Nature gave us a hint that surprised everyone. Using lab mice, the research team found that breast cancer cells are able to impersonate blood vessels and then empty into a real blood vessel, a process called vascular mimicry. So, blocking the angiogenesis did not work because the new vessels are really not vessels at all!
Once the cancer cells that are impersonating blood vessels reach a “real” blood vessel they empty into it, which gives them a way out. At that point—and this is probably long before you notice a lump or have an abnormal mammogram—they head through the blood stream to another organ, where they find a comfortable niche to live in. They may live in these niches—some of which are in the bone marrow—forever without becoming life threatening. The how’s and why’s of this are not well understood but most likely, hormones help keep them in a dormancy state.
After months, years, or even decades, something—we don’t know what—causes some dormant cells to wake up. Could it be stress or an increase in inflammation caused by surgery or some other illness? Some researchers think so, and they are studying the possibility, but that’s far from clear. Others think it’s not so much that the cells “wake up” but that they develop a new power or skill that allows them to get out of the niche, spread to another organ, and thrive.
The ability to map mutations within the tumor is also adding to what we know about how metastases occurs, because it has allowed us to see that different parts of the same tumor can have different mutations. This is referred to as tumor heterogeneity. When pathologists test a breast biopsy or tumor tissue, they report information about the tumor’s subtype, such as ER-positive, HER2 positive, or triple negative. From that time on, you—and your tumor— typically carry that label. However, the report may not be 100% accurate.
A terrific recent paper suggests that a tumor is like a forest. It may have a predominant kind of tree but it may also have different types of trees. This means that when we give a cancer therapy to go after the predominant trees, it could allow a different kind of tree to become resistant to that treatment, and to thrive.
We’ve known that tumors can change from HER2+ to HER2- after they have metastasized, but to determine if this is true requires a biopsy of a new metastatic site, which is not always easy to do. And it’s not only HER2 that can change. New techniques such as “liquid biopsies” (a euphemism for blood tests) look for circulating cancer cells, with the aim of predicting these shifts. However, we still don’t know whether the cells in the blood stream are the ones that end up in the organs—which means it is not yet fully clear how useful these tests will be.
All of the advances I have discussed on how metastases happens, how to prevent it, and how to treat it are due in no small part to the work of activists. So, I’m pleased to be able to share that on April 16 at the American Association for Cancer Research annual meeting, METAvivor, an all-volunteer organization dedicated to changing the lives of patients with metastatic breast cancer, and The Metastasis Research Society, an international non-profit organization that promotes the exchange of information and research into metastasis, announced the establishment of the Strategic Alliance for Metastatic Cancer Research. Only through the combined forces of advocates and researchers will we find the answers we are all seeking.