Is This a Stupid Idea?

In 2017, when McDonnell got back from Maine, he started thinking about estrogen’s effect on the eight or nine different immune system cells that live outside the cancer cell. “Most of them also express the estrogen receptor,” he says. So when a woman takes an anti-es­trogen pill, it’s not only inhibiting the action of the hormone in the cancer cell, but in all of those immune cells. “We know that beating the hell out of the estrogen receptor in the cancer cell is a good thing, but is it a good thing in the other cells?” McDonnell says. “And the answer is, I don't think so.”

As these ideas emerged, McDonnell had doubts. He didn’t know much about immunology. Plus, by changing course, it would be like saying he had been doing things wrong all this time. But he has never been one to keep to the status quo. As a college student at the National University of Ireland, Galway, with a scholarship to study marine biology, he switched his plans after meeting his future wife and getting to know her mother, who was battling breast cancer.

Decades later, thinking about changing paths again, he called his colleague, Nelson Chao, MD, for advice.

Chao, the Donald D. and Elizabeth G. Cooke Cancer Distinguished Research Professor at Duke, has extensive expertise in stem-cell transplant and in immunology. “I said, 'Listen Nelson, is this a stupid idea?’ And he said 'No, I think it’s worth looking at.'”

So McDonnell consulted his lab group, got their ideas, and wrote a grant application to the Department of Defense (DOD). Funded in 2018 with $7.3 million, the project involves McDonnell, his research team, and more than a dozen physicians, scientists, and staff from different departments at Duke, as well as researchers in genomics and drug discovery at UNC-Chapel Hill.

The work includes a clinical study led by Sarah Sammons, MD, assistant professor of medicine (medical oncology). The study has followed, for two years, 200 women with estrogen-receptor-positive breast cancer, beginning when they started endocrine therapy (following surgery, radiation, and chemotherapy).

The researchers assessed in the lab whether the anti-estrogen drugs had a positive, negative, or neutral effect on the patients’ immune systems. The answer, which isn’t published in the scientific literature yet, is that it depends on the type of breast cancer and its immune profile. “We have defined about three different facets of immune biology that we believe the estrogen receptor regulates in an important manner in breast cancer,” McDonnell says.

“We've been able to show that in some breast cancers, you want to inhibit estrogen receptors in the immune system, and in others, you don't.”

Breast cancer types vary so much that it could be considered several different diseases, McDonnell says. So figuring out how to use this information will require more work, though other findings from his lab about estrogen and the immune system are leading to a more immediate payoff for other cancers (see “A Detour into Melanoma.").