After cancer surgery — particularly for breast cancer — many patients experience an early tumor recurrence. It is not clear why, but new research suggests that common pain-reducing, anti-inflammatory drugs may prevent that from happening.
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The answer to early relapse after breast cancer surgery may be closer than we think.

In many cancer types — especially in the case of breast cancer — surgery is often preferred when it comes to removing primary tumors.

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However, the recurrence of cancer after surgery is not an uncommon occurrence.

Some who have gone through surgery are at an increased risk of early recurrence, although the precise reasons why are currently unclear.

In a new study whose results have been published in the journal Science Translational Medicine, first author Jordan Krall and colleagues — from the Whitehead Institute for Biomedical Research in Cambridge, MA, and other institutions — have begun to uncover some clues and investigate how these cases of early relapse might be avoided.

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“A partial explanation for these outcomes has become clear: in as many as one third of patients diagnosed with localized breast cancer, carcinoma cells have already disseminated to distant anatomical sites at the time of initial diagnosis,” the authors explain in their paper.

Until surgery, such tumor cells may remain in a state of limbo, with their harmful potential blocked by the body’s immune response.

“In a subset of patients, however,” the authors say, “a small fraction of such clinically inapparent cancer cells ultimately renew proliferation and spawn life-threatening metastases [or secondary tumors].”

However, Krall and team’s recent study on mice has revealed a ray of hope in the shape of a type of commonly available drug used to fight pain and reduce inflammation: nonsteroidal anti-inflammatory drugs (NSAIDs).

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NSAIDs seem to reduce the risk of early post-operatory relapse in the patients to whom they are administered during surgery.

“This represents the first causative evidence of surgery having this kind of systemic response,” says Krall. “Surgery is essential for treating a lot of tumors, especially breast cancer. But there are some side effects of surgery, just as there are side effects to any treatment.”

We’re starting to understand what appears to be one of those potential side effects, and this could lead to supportive treatment alongside […] surgery that could mitigate some of those effects.”

Jordan Krall

Could cancer surgery trigger metastases?

So far, it has been difficult for researchers and medical professionals to establish a clear causal relationship between cancer surgery and the triggering of these metastatic cells. Still, existing studies had noted that early relapses tend to peak at 12–18 months after surgery.

Moreover, a retrospective analysis conducted in 2010 looked at the medical data of 327 women who had undergone mastectomy and made an intriguing discovery.

Fewer participants who had received NSAIDs to manage post-surgical pain had early metastatic relapse compared with the women who had been prescribed opioids for the same reason.

Krall and colleagues wanted a better understanding of the mechanisms potentially underlying this association, as well as the causes for early relapse following cancer surgery.

In order to achieve this, they worked with mice models whose systems had been “engineered” to behave in a similar way to those of human patients who are predisposed to early metastatic relapse.

The researchers found that when the rodents underwent surgery, the cancer cells that had so far been kept in limbo by specialized immune cells known as T cells appeared to be “stimulated,” so that more and larger secondary tumors would develop.

In analyzing samples of blood and tumor, Krall and team found that the process of wound healing boosted the concentration of inflammatory moncytes, a type of adaptable cell that is activated in the case of tissue damage or inflammation.

Anti-inflammatory monocytes can differentiate into macrophages, a type of white blood cell that “eats up” cellular debris. But these macrophages also interfere with the action of the T cells responsible for keeping migrating cancer cells in a state of limbo.

‘An important first step’

The next step was to test whether NSAIDs would, in fact, be capable of preventing this dangerous cycle. So, Krall and team decided to give mice the drug meloxicam — often sold under the name Mobic — either during or after the surgery, to see what would happen.

Sure enough, the mice that had been medicated with meloxicam developed smaller metastatic tumors than their counterparts that did not receive NSAIDs. And, in many cases, these tumors even disappeared after a while.

Importantly, while meloxicam did offset the immunosuppressive response of the mice after surgery, it did not have a negative effect on the process of wound healing.

Despite these promising results, senior author Robert Weinberg warns that medical professionals should not rush to any conclusions just yet.

These experiments, he says, are only the start of a long journey toward fully understanding what happens in the bodies of people who undergo breast cancer surgery.

“This is an important first step in exploring the potential importance of this mechanism in oncology,” concludes Weinberg.