Scientists from The Scripps Research Institute (TSRI) have found that two estrogen-mimicking compounds found in many foods appear to potently reverse the effects of palbociclib/letrozole, a popular drug combination for treating breast cancer. The study, published by Warth et al in Cell Chemical Biology, suggests that exposure to chemical compounds called xenoestrogens may significantly reduce the effectiveness of anti-estrogen treatments for cancer.
“Breast cancer patients taking palbociclib (Ibrance)/letrozole should consider limiting their exposure to foods that contain xenoestrogens,” said Gary Siuzdak, PhD, the study’s senior author and Senior Director of TSRI’s Scripps Center for Metabolomics.
Palbociclib/letrozole combination therapy was approved by the U.S. Food and Drug Administration in 2015, after trial findings showed it doubled the progression-free survival time in postmenopausal women with estrogen receptor (ER)–positive, metastatic breast cancer. Letrozole blocks the production of estrogen, thus reducing the growth-promoting stimulation of ERs on breast cancer cells. Palbociclib blocks a different signaling pathway to impede cell division. The combination is now one of the standard therapies for ER-positive breast cancers.
Dr. Siuzdak and colleagues, including lead author Benedikt Warth, PhD, then a visiting Erwin-Schrödinger Fellow in the Siuzdak Lab, used advanced metabolomics technology to analyze the effects of palbociclib/letrozole on breast cancer cells. Metabolomics studies detail cells’ metabolomes—populations of metabolites.
“By profiling cell metabolomes with and without drug treatment, we can get very useful information … for example, about the biologic pathways perturbed by the drug,” said Dr. Siuzdak, Professor of Chemistry, Molecular, and Computational Biology.
Cancer researchers are increasingly concerned that xenoestrogens in food and water may enhance the growth of estrogen-fueled cancers, and may also hamper the effectiveness of antiestrogen drugs such as letrozole. TSRI scientists therefore examined breast cancer cells treated with palbociclib/letrozole to see how their metabolite populations changed when they were also exposed to two common dietary xenoestrogens: zearalenone and genistein.
Zearalenone is produced by fungi that colonize maize, barley, wheat, and other grains. It has been linked to birth defects and abnormal sexual development in pigs and other livestock, and is suspected of having caused an outbreak of early breast development among girls in Puerto Rico in the 1970s. Genistein is produced in certain plants including soybeans and is often highly concentrated in phytoestrogen-rich food supplements.
Their analysis revealed that neither palbociclib nor letrozole alone had a strong effect on metabolites in an ER-positive breast cancer cell line. However, the combination had a strikingly large impact.
“The combination had a much more pronounced effect on cell growth–related metabolites, which is consistent with the clinical trial results,” Dr. Warth said.
Even using very low doses, similar to typical dietary exposures, the researchers found that both model xenoestrogens largely reversed the metabolomic impact of the cancer drug combination. “This included many key metabolites,” said Dr. Siuzdak.
Under the influence of either xenoestrogen, the breast cancer cells also resumed proliferating at a rate comparable to that seen in the absence of drug treatment. “It’s intriguing that even a low, background-level exposure to these xenoestrogens was enough to impact the effect of the therapy to this degree,” said Dr. Warth.
The results indicate that these dietary xenoestrogens do have the potential to affect cancer therapy outcomes—and genistein and zearalenone are just two of the many xenoestrogens commonly found in the human diet. “There’s a high likelihood that other xenoestrogens would counteract the therapy in a similar way,” explained Dr. Siuzdak.
The impact of xenoestrogens on health and on hormonally targeted therapies is nevertheless an understudied, underfunded area of research, the researchers emphasized.
“We generally know very little about the interactions of bioactive compounds we are exposed to through our food or the environment with drug treatments,” Dr. Warth said. “So, in this field there are probably a lot of clinically relevant discoveries yet to be made.”
“What I find intriguing is that metabolomics can be used to identify active metabolites that are therapeutically beneficial or, as in this case, exogenous fungal and plant metabolites that are detrimental,” Dr. Siuzdak stated. “Clearly, metabolites can have a significant impact in modulating therapeutics.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.