The Annual San Antonio Breast Cancer Symposium has been going on since 1977! From a one-day regional conference, the Symposium has grown to a five-day international meeting attended by advocates, clinicians, basic scientists and pharmaceutical companies from over 90 countries. It is a great opportunity to catch up on what is happening in research and treatment as well as to see old friends and meet new ones. I was particularly impressed this year with the number and variety (geographic, age, specialties) of women presenters.
As a surgeon, I was struck by the fact that the role of surgery and the value of mastectomy in breast cancer treatment has significantly diminished. There are several drivers of this shift but the key is the change in our understanding of the disease and its progression. When I started as a breast surgeon, we believed that after a cancer started growing in the breast, it slowly moved from one lymph node to another and then, after invading all the nodes, went into the blood stream, where it traveled to other parts of the body. We thought if we got there soon enough, and did a big enough surgery, we could slam the door before the migration to the nodes and blood stream began.
Now we understand that most, if not all, breast cancers have sent cells out into the blood stream way before we are able to diagnose the disease. Up to 40 percent of breast cancer patients have detectable disseminated tumor cells already in their bone marrow at the time of diagnosis. The fact that we can find these circulating tumor cells (CTCs) in the blood or disseminated tumor cells (DTCs) in the bone marrow at the time a person is first diagnosed with an early-stage breast cancer shows that what we have termed early detection is not really very early.
Unfortunately, being able to find those cells doesn’t mean we fully understand what their presence means. Some of the circulating cells may die in the blood stream, while others may find their way to a new organ—such as the lung, liver, bones or brain—where they will hide, and never be heard from again. And in still others, those cells may be hidden for decades, and then, for some reason, get woken up.
During her talk at the Symposium, Zena Werb, a professor at the University of California, San Francisco, and a leader in research on the breast microenvironment, demonstrated that there are sites throughout the body—termed premetastatic niches—that are distant from the developing breast tumor and that change as early as the hyperplasia stage (the first step in a cell becoming abnormal) in anticipation that a cancer will spread. The cancer cells that get to these areas where they can lay low (or become dormant) have been able to deceive the immune system and are usually resistant to the chemotherapy, hormone therapy or targeted therapy that has been aimed at them. In some cases, the treatment may even create these resistant cells.
Cancer cells that are in a dormant state can remain dormant in their hiding places for months or years, until conditions change and something wakes them up leading to late recurrences many years after an initial diagnosis. What puts them to sleep and what wakes them up? We don’t really know, but it is thought to have something to do with both the microenvironment that surrounds the dormant cells as well as the larger environment of the whole body.
So much for our old thinking that a diagnosis of breast cancer was an emergency necessitating a rush to the operating room to remove the offending tissue. In fact, our current thinking is that there may be a benefit to using chemotherapy or hormone therapy or a targeted therapy before surgery—which is called neoadjuvant treatment. This allows the doctor to see whether your cancer is responding to the therapy. It also focuses the initial treatment on where the tumor cells have the potential to do the most damage—the vital organs in the body—and less on the where it started, the breast.
Thinking about cancer this way suggests that rushing to have a mastectomy at the time of diagnosis may not be the best option. In fact, if we use neoadjuvant therapy to treat the tumor, and it disappears completely, it’s possible surgery may not be necessary at all. As a surgeon, that’s not something I’d ever thought we’d see happen! Does this approach insure that people will be cured? It is really too soon to tell. If you have breast cancer cells that get out of the breast but stay asleep or dormant in other organs, you will be fine. This means the real question needs to be, what puts the cells to sleep and what wakes them up? Maybe all we need to do is figure out how to keep them asleep.
On the other hand, if the goal is to kill them, might it be possible to utilize the cell’s own quality control system to get the cells to self-destruct? There are some older drugs such as chloroquine, an antimalarial drug, that studies have shown can kill dormant mammary tumor cells. The drug has no effect on the primary tumor or on recurrent cancer growth—just on those dormant cells. The research here is just getting started.
It’s exciting to see that because of the research advances we are making, the days of slash, burn and poison are waning. All that we have learned about the biology of cancer and how it spreads has given us new ways to think about how to approach both early stage and metastatic breast cancer. It also makes me think that we need to focus even more research on metastatic breast cancer. I really think the clues to the cure are in those cells that escape.