ottles of aspirin and ibuprofen won’t soon be carrying labels saying they reduce the risk of breast cancer recurrence after surgery, but that kind of cheap drugstore remedy stemmed metastasis in a startling new study in mice.
Although lumpectomy is often curative, in some cases it can activate tiny, distant tumors that had been held in check, sometimes for years, by the immune system. Plain old penny-a-pill NSAIDs (nonsteroidal anti-inflammatory drugs) like aspirin, however, can prevent the immune system from letting down its anti-cancer guard, according to a study on lab mice published on Wednesday in Science Translational Medicine.
Recent studies have found that even the most beneficial mainstream therapies have a dark side. Chemotherapy before breast cancer surgery, for instance, might fuel metastasis in some patients; chemo can also make malignant cells that survive treatment more aggressive.
And while the immune system can keep micrometastases — those too small to show up on imaging — in check, surgery can disrupt that. It even has a name: “surgery-driven interruption of dormancy in breast cancer.”
It has not been clear, however, exactly how that happens or whether it can be stopped. It would be unethical to do a definitive study by giving half of breast cancer patients recommended surgery and half not, and then comparing what happens to dormant micrometastases. So scientists led by Robert Weinberg of the Whitehead Institute tried to see what they could learn from mice.
They injected lab mice with aggressive breast cancer cells. When the cells had characteristics that made the mice’s immune system attack them, almost all the animals — up to 90 percent — rejected the cancers as vigorously as they would a mismatched organ transplant. That suggested that when the immune system is fired up, it can keep tiny malignancies in check, by unleashing cell-killing white blood cells called CD8+ T cells.
That finding may explain one big puzzle: About 35 percent of women diagnosed with breast cancer already have thousands of micrometastases, Weinberg said, but only half of them eventually develop metastatic, life-threatening cancer. In the lucky half, the immune system might be controlling the dangerous cells. “There are tumors that are doomed to be rejected by the immune system,” Weinberg said. “We wanted to ask, what mechanisms awaken previously dormant micrometastases?”
The scientists, therefore, tested what would happen if the mice underwent surgery. To make the animals’ experience as consistent as possible, the researchers didn’t remove tumors (since some mice might have a large one and others a small one) but, instead, tiny sterile sponges that had previously been implanted.
That’s an unnatural enough situation to raise questions, scientists not involved in the study said. “Weinberg gets some pushback because he works on artificial systems,” said biologist Sui Huang, of the Institute for Systems Biology, who was not involved in the new study. “But this is often the only way to expose fundamental principles of biology,” he added, calling the study “careful and convincing.”
After doing the surgery, the scientists examined breast cancer cells that had been injected in the mice. In mice that underwent surgery, 60 percent of the cells kept growing and formed tumors. In mice that did not have surgery, only 10 percent did. Based on results from 273 mice, the scientists concluded, “surgical wounding” can promote the growth of metastasized breast cancer cells previously held in check by the immune system.
“In every individual experiment that we undertook with hundreds of mice,” they wrote, “tumor outgrowth was, without exception, observed in a larger proportion of mice” that had surgery than in those that didn’t. They got similar results when mice were injected with melanoma cells: Tumors burst their immune-system bounds after a mouse’s surgery.
Co-author Jordan Krall of the Whitehead Institute, called it “the first causative evidence of surgery having this kind of systemic response.”
Now for the good news. Giving the mice an NSAID (the scientists used the anti-arthritis drug meloxicam, sold as Mobic) two hours before surgery and then twice a day for three days after kept the wound from awakening the quiescent cancer cells. Intriguingly, breast cancer patients taking an NSAID for pain following lumpectomy had fivefold lower rates of cancer recurrence than patients taking opioids, according to a 2012 study.
More research is needed to see if the mouse results happen in people, too, Weinberg said, but studies of breast cancer patients have shown that if metastasis is going to happen, it does so six to 18 months after surgery. That fits with the timeline in mice, where surgery unleashes a flood of inflammatory cells from the bone marrow and those cells turn into a kind that dismantles the immune system’s check on micrometastases.
These inflammatory “monocytes” are also mobilized in breast cancer patients after surgery, a 2010 study found.
Weinberg said he and his colleagues are definitely not suggesting cancer patients decline recommended lumpectomy or mastectomy or other surgery. Rather, they hope this research leads to human studies that rigorously test adding NSAIDs to post-op protocols.
Breast cancer surgeons cautioned that results in mice don’t necessarily apply to people, and that the sponge-removing surgery might not be a good simulation of lumpectomy.
“I do not know if this mimics the potential effect of a lumpectomy or mastectomy, but the inflammatory response to an implanted foreign body would be expected to be quite robust,” said UCLA’s Dr. Deanna Attai, a past president of the American Society of Breast Surgeons. That inflammation, not surgery, might be awakening dormant cancer cells. Nevertheless, she said, “this study and the handful of others like it certainly are interesting and warrant further study.”