A potential way to reduce the risk of postpartum breast cancers

Breast cancers that emerge in young women within a few years after pregnancy are strikingly more dangerous. A new study suggests that the common pain reliever ibuprofen might work as a preventive treatment to reduce the risk.

Postpartum breast cancers are about three times more likely to spread and give rise to life-threatening metastatic tumors than those in women the same age who have not given birth. The new findings, based on a mouse model of breast cancer, represent an important step in considering ibuprofen as a cancer prevention agent in young women after pregnancy, according to researchers at OHSU in Portland, Oregon.

Figure: A graphical summary from Pennock et al. J ImmunoTherapy Cancer (2018)The research also shows how ibuprofen or other non-steroidal anti-inflammatory drugs might make breast cancers more vulnerable to immunotherapy drugs that restore the ability of immune T cells to attack tumors.

“For many tumors there’s not enough T-cells around, so even if you have a drug that helps T-cells function, it doesn’t do any good,” says Pepper Schedin, Ph.D., the study’s senior author. She is a professor in the Department of Cell, Developmental & Cancer Biology in the OHSU School of Medicine.

“What’s so amazing about ibuprofen here is that it seems to be pulling in T cells,” she says. “We think that this work is going to have implications beyond this study in terms of combination immunotherapy.”

Why postpartum breast cancers are more dangerous

Previous research in Schedin’s lab has helped reveal how changes in the mammary gland after pregnancy create a tumor-promoting environment. At the end of lactation, 80 to 90 percent of milk-secreting cells undergo programmed cell death, in a process called mammary gland involution. The early phase of gland involution resembles an acute inflammatory response that subsides and is followed by an immune response similar to what happens during wound healing.

“Experiencing the involution environment really causes the tumor cells to take off,” says Nathan Pennock, Ph.D., a post-doctoral fellow in Schedin’s lab and first author of the new paper.

Schedin Lab members Sonali Jindal, Jay Narasimhan and Pepper Schedin in front, left to right, and behind them Alex Quackenbush, Andrea Calhoun, Elizabeth Mitchell, Alex Klug, and Nathan Pennock.

Given the known activity of ibuprofen on inflammatory responses and cancer promotion, Pennock, Schedin and colleagues wanted to deeply understand the effects of ibuprofen during mammary gland involution and early development of breast cancer. Theirs is the first study using a fully immune competent rodent model to explore how a physiologically normal yet “inflammatory” process is altered by ibuprofen to support anti-tumor immune responses.

In one line of experiments, they implanted breast tumor cells in postpartum mice one day after weaning, and in matching animals that had not given birth. Tumor cells in the postpartum mice grew more rapidly, and the growth advantage persisted long after the process of involution completed and breast tissue returned to its baseline state.

Tumors in the postpartum mice also showed a different immune system response: T cell numbers fell, while immature monocytes increased compared with tumors in the mice that hadn’t given birth, factors known to be associated with poorer outcomes.

“What’s key and unique about this paper is that we’re looking at immune cells we know to be altered during the normal involution process, and find that these same immune cells cause the resulting tumors to be more aggressive,” Pennock says.

Enhancing anti-tumor immunity

To test the impact of ibuprofen, the researchers fed chow with various doses of the drug to postpartum mice starting at the time of weaning and to mice that had not given birth. A day later they injected breast cancer cells into the mammary glands of mice and monitored tumor growth.

Moderate dose ibuprofen – the equivalent of about 300 mg per day in women – was associated with significant reductions in tumor size in postpartum mice at the two higher doses compared with postpartum mice fed chow with no ibuprofen. But ibuprofen made no difference in tumor growth in the mice that never gave birth – supporting the idea that ibuprofen acts largely by changing the normal involution process, rather than by inhibiting tumor cells directly.

And in further experiments the researchers found that ibuprofen, in fact, enhances anti-tumor immune system activity. For example, ibuprofen treatment resulted in an increase in T cells and a decrease in immature monocytes – reversing the changes seen in postpartum mice not treated with ibuprofen. Ibuprofen treatment, they found, also enriched for cytokines known to facilitate cytotoxic T cell function.

Preliminary safety testing in mice showed no obvious downsides to using ibuprofen for cancer prevention after pregnancy. The data from mice suggest that human-equivalent doses would be no more than one or two tablets a day for something like three to six months surrounding weaning. The authors emphasize, however, that their animal study is only a preliminary step in assessing the safety and effectiveness for chemopreventive use in women who are weaning their children.

Meanwhile, the work adds to the evidence that ibuprofen and related non-steroidal anti-inflammatory drugs, or NSAIDs, could present a simple and affordable drug to improve cancer patients’ response to immunotherapy agents such as checkpoint inhibitors, which have been remarkably effective but only in small subsets of patients and cancer types.

Further reading:

Ibuprofen supports macrophage differentiation, T cell recruitment, and tumor suppression in a model of postpartum breast cancer by Nathan David Pennock, Holly A. Martinson, Qiuchen Guo, Courtney B. Betts, Sonali Jindal, Takahiro Tsujikawa, Lisa M. Coussens, Virginia F. Borges, and Pepper J. Schedin. Journal for ImmunoTherapy of Cancer (October 2018)

Why breast cancer is more dangerous for new moms by Joe Rojas-Burke. Cancer Translated (February 20, 2017)

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