‘Heretical’ Idea for Treating Triple-Negative Breast Cancer Moves Forward

By Deborah Borfitz 

October 15, 2024 | The clinical utility of treating cancer by modulating the estrogen receptor could radically and quickly expand, initially for patients with triple-negative breast cancer (TNBC) but potentially thereafter to those with melanoma and cancers found in the colon, lung, head, and neck. Hope springs from findings emerging from the lab of Professor Donald McDonnell, Ph.D., at Duke University School of Medicine, where the field of oral selective estrogen down-regulators (SERDs) was pioneered nearly two decades ago. 

Up to now, only estrogen receptor-positive (ER+) breast cancers were considered treatable with endocrine (hormone) therapy. But anecdotal evidence collected over the last 30 to 40 years suggests that the biology of TNBC could also be affected by hormonal status, as McDonnell and his team successfully demonstrated in a study that was published recently in Science Advances (DOI: 10.1126/sciadv.adp2442). 

It was, nonetheless, surprising to have his “heretical” suspicion so soundly confirmed, says McDonnell, who has been developing drugs for metastatic breast cancer for decades. His focus has mainly been on patients who have ER+ breast cancer, the most common and often the most treatable variety. 

McDonnell’s teams “biggest boast” to date is the repurposing of elacestrant, a game-changing SERD drug approved early last year by the U.S. Food and Drug Administration (FDA) for use in patients whose tumors are resistant to standard endocrine therapy. It targets tumors which express a mutated form of ER that is associated with resistance to standard-of-care endocrine therapies—present in up to 40% of metastatic breast cancers that are ER+ and negative for human epidermal growth factor receptor 2 (HER2). His group also demonstrated the utility of the ER modulator lasofoxifene for use in the same patient population and this drug is in late-stage clinical trials (ELAINE-3).   

He has since turned his attention to patients facing the more aggressive TNBC, meaning breast cancers that have no or low levels of ER, HER2, or the progesterone receptor (PR).  

It was of course viewed as highly unorthodox to suggest that TNBC, which does not express the estrogen receptor, might respond to estrogen-blocking therapy, McDonnell points out. But he and his team were asking a question that had never been posed before—what’s the impact on the cancer if, instead of targeting the cancer cell intrinsic estrogen receptor, they manipulated the estrogen receptors found in immune cells (e.g., T-cells, macrophages, and fibroblasts) inhabiting a tumor?  

TNBC was a perfect test case, since it allowed the researchers to disassociate the effects within cancer cells from those outside of them, continues McDonnell. In syngeneic cancer models (mice with a competent immune system), this is how they found that estrogen stimulated not just the growth of TNBC but multiple other cancer types. At that point, “the question became how quickly can we translate this finding to the clinic?” 

Remembering Eosinophils

Encouragingly, when it comes to the management of TNBC, the disease has an Achilles heel—namely, it’s vulnerable to treatment with immune checkpoint blockade (ICB), says McDonnell. It is now well established that outcomes in patients with TNBC are significantly improved when patients are given ICBs in addition to standard of care chemotherapies.  His team then asked whether they could manipulate immune cell function with ER-targeting drugs to increase the benefit of ICBs.  

This begged the question of whether any clinical data had emerged to suggest that estrogens regulate human immune function at all.  

To answer that question, postdoctoral fellow Sandeep Artham in the McDonnell lab conducted an extensive chart review of “hundreds of thousands” of premenopausal patients treated within the Duke University Health System to identify those who underwent medical or surgical oophorectomy to prevent the production of estrogens or were given a selective estrogen receptor modulator (SERM), like tamoxifen, as part of their breast cancer treatment. The research team then looked to see if over time any there were changes in their blood cell counts after the intervention. 

What they found was an association between decreased estrogen production and elevated blood levels of eosinophils, a type of white blood cell McDonnell says he hadn’t thought much about since graduate school. On a typical complete blood count test, eosinophils typically account for less than 2% of all white blood cells; their level is abnormally high only when a person has a parasitic infection, asthma, or certain kinds of esophagitis.  

While gathering the retrospective data, Artham found some emerging literature identifying a process known as TATE (tumor-associated tissue eosinophilia), he continues. “The crux of this is that patients who have high levels of eosinophils in their tumor did much better independent of any therapy and were substantially more responsive to immunotherapies.” But nearly every drug out there that was trying to improve the efficacy of immunotherapy was directed toward improving the T cell biology of cells. 

Five years ago, McDonnell says, his group decided to let others focus on T cells while they started looking at all the other immune cells that they imagined would be just as important. “Whereas existing ICBs that target T-cell function have been game-changing in the management of some cancers, additional approaches to target these specific immune cells have been less successful. We may have exhausted what we can do with the T cells,” he adds, referencing the work of others.   

To recapitulate what they observed in real-world human data, Artham and several of his colleagues led a study of “gargantuan proportions” wherein they inhibited estrogen signaling in immunocompetent mice by removing their ovaries and profiled the impact of this intervention on immune cell numbers and activity in several models of cancer. One of the most interesting findings was the increase in the number of eosinophils in tumors in animals where estrogen signaling was disrupted. 

Next, the researchers added contemporary estrogen receptor modulators used in the treatment of ER+ breast cancer in the mouse models of TNBC. In terms of increasing the amount of TATE, it worked equally well as taking out their ovaries, reports McDonnell.   

Inhibition vs. Degradation 

Given the “Pandora’s chest” of ligands that could be tested, McDonnell and his team first used AstraZeneca’s drug fulvestrant, a SERD that induces the degradation of ER in cells. This drug is approved for use in patients whose breast tumors express the estrogen receptor. 

While effective in mimicking the positive effects of removing the ovaries in ICB-treated animals they decided to explore other, more contemporary ER modulators. “Fulvestrant is an exceptionally hard drug to deliver to patients [painful, large injections] and additionally we have recently discovered that it might have secondary activities that likely limit its efficacy,” he says.  

Lasofoxifene—a SERM developed in a program led by McDonnell and his colleagues at Ligand Pharmaceuticals back in the early 1990s as a treatment for osteoporosis—emerged as a better option. The plan now is to add this drug to the standard chemotherapy and ICB cocktail in individuals with TNBC, and other cancers treated with ICBs, to increase TATE, McDonnell says, which “everything out there suggests that will increase the efficacy of [the immunotherapy drugs].” In the latest study, the data suggests lasofoxifene works better than fulvestrant because, being a SERM, “it doesn’t degrade the receptor; it just... inhibits it; a pharmacological distinction that we think is important.” 

The more immediate and novel use of lasofoxifene will be in a “window trial” where up to 50 patients with TNBC will be given the drug for a brief period prior to starting curative intent therapy, according to Alexandra Thomas, M.D., medical oncologist at the Duke Cancer Institute, who is designing the study. Participants would receive biopsies and blood work looking for biomarkers of effectiveness, one of the more important ones being eosinophils. 

The goal in future studies will be to increase the pathological complete response rate—meaning, no more invasive tumor in the breast or sampled lymph nodes—which even with contemporary therapy sits at around 65%, Thomas says. For the other 35%, “outcomes are not very good” with many of these patients ultimately developing metastatic disease.  

“We are in the early stages of developing a clinical trial,” Thomas reports. It is not yet funded or approved, but she says the team is confident it will happen in the very near future.  

One of McDonnell’s young trainees, Kaitlyn Andreano, “rediscovered” lasofoxifene by learning it could be used for late-stage metastatic breast cancer. Important to patients is the data from early trials of its use as a treatment for osteoporosis, finding it was easy to tolerate and had an excellent safety profile across 8,000 study participants, he says. The drug was never registered—purely for business reasons—and will now have a second life as an oncology medicine. 

Thomas says she is particularly excited by the “attractive side effect profile” of lasofoxifene because, longer term, it might provide a less toxic means of accentuating immune therapy—and thereby potentially enabling de-escalation of chemotherapy, which is notoriously toxic. “[McDonnell’s] lab has a track record of providing things that move the field forward.” 

As a future potential substitute for fulvestrant, lasofoxifene would also be a nice way forward for men with breast cancer. Surprisingly, most such cancers in men are the hormone receptor-positive variety.  

Happy ‘Accident’

Duke has licensed patents to Sermonix Pharmaceuticals (Cincinnati) that covers the use of lasofoxifene in ESR1-mutant breast cancers. The company now has phase 3 clinical trials underway for that indication and would welcome the opportunity to expand the drug’s labeling to multiple other cancers, says McDonnell. Many of the traditional steps in the drug development process are happening in parallel, which should significantly shorten the time to market.  

SERMs were developed for breast cancer “by accident,” being originally intended as drugs for osteoporosis by functioning as an estrogen to increase bone density. The last thing a woman in menopause needs when she is already short on estrogen is a drug that causes further bone loss, a list that includes aromatase inhibitors used to treat older women with ER+ breast cancer, McDonnell says. The “vicious joint pain” that accompanies treatment is one of the factors limiting compliance.    

Not only have SERMs been shown to preserve or improve bone density, but also to treat the vaginal atrophy in patients transitioning from their reproductive to non-reproductive years. They can therefore “minimize the impact of endocrine therapy on the overall patient experience” as well as greatly expand the clinical utility of modulating the estrogen receptor, McDonnell says. 

“How well you respond to immunotherapy really dictates your future in some respects,” he says. The popular immunotherapy drug pembrolizumab (Keytruda)—the only place where immunotherapy is given for curative intent to breast cancer patients—has improved overall survival by about 5% in early-stage TNBC, Thomas adds. A few years ago, it was shown to significantly improve the percentage of that population who achieved a pathological complete response when compared to patients being treated solely with chemotherapy.