TAMOXIFEN FOR TNBC?

Triple-negative breast cancer (TNBC) tumors with estrogen receptor-beta and a mutated p53 tumor suppressor might be responsive to tamoxifen, a series of preclinical studies suggests.

"About 70%-80% of TNBC comes under this category," Dr. Gokul Das of Roswell Park Comprehensive Cancer Center in Buffalo, New York, told Reuters Health by email. "On the other hand, TNBC with ER-beta and wild type (normal) p53 would not benefit from tamoxifen therapy, and tamoxifen may even affect this group adversely."

The team's previous work, he said, involved "testing the hypothesis that ER-beta may bind to mutant p53 and wild type p53, but with opposite functional outcomes. Our experiments over the years have proved that hypothesis to be true, and (in the current study), we validated this phenomenon and its potential impact on patient outcomes by analyzing a large breast cancer patient database."

In a series of experiments using various assays, Dr. Das and colleagues determined that estrogen receptor-beta's interaction with wild-type and mutant p52 caused pro-proliferative and anti-proliferative (i.e., anti-cancer) effects, respectively, in breast cancer cells.

Further, the addition of tamoxifen increased the interaction between ER-beta and mutant p53, leading to apoptosis, according to their report April 16 online in the Journal of the National Cancer Institute.

They validated the findings in an analysis of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) TNBC database. In patients with mutant TP53-expressing basal-like tumors, those with high ER-beta levels had better survival. By contrast, those with wild type p53-expressing tumors and high ER-beta levels trended toward worse survival.

Patient data from the Roswell cohort, they noted, "are consistent with that obtained from the much larger METABRIC cohort."

"Our study suggests that (ER-beta)-mutant TP53 combination prognosticates survival in TNBC revealing a novel strategy to stratify TNBC for therapeutic intervention potentially by repurposing tamoxifen," the authors conclude.

"We will continue with further preclinical studies and expect to proceed toward a clinical trial at Roswell Park in the near future," Dr. Das said. "While tamoxifen and the chemotherapeutic agents have been well studied and used for decades, and tamoxifen is one of the best-tolerated drugs currently used to treat cancer, we will have to complete additional preclinical studies and a clinical trial before we can draw firm conclusions about the efficacy and safety of this approach."

"We hope to report results from these additional studies within three years' time," he said.

Dr. Carol Lange and Dr. Douglas Yee, both of the University of Minnesota Masonic Cancer Center in Minneapolis, told Reuters Health in a joint email, "If...clinical trials support this ER-beta-dependent action discovered in vitro, tamoxifen, and drugs like it, will be an important new targeted therapy for women with mutant-p53+ TNBC, perhaps in combination with existing widely used treatments for TNBC, such as doxorubicin."

They added, "Since tamoxifen is already routinely used to treat women with ER-alpha-positive breast cancer, the studies may have high clinical impact in the near future, with appropriately designed trials to measure both ER-alpha and ER-beta."

"While it is unknown if the ER-beta/mutant p53 interaction induces apoptosis in other cancer types that harbor mutant p53+ proteins, the Das studies have opened the way for a better understanding of how to manipulate and leverage ER-beta-driven events in deadly TNBC cancers that harbor mutant p53 proteins," Drs, Lange and Yee concluded.

SOURCE: http://bit.ly/2vdC0j5 and http://bit.ly/2vfUIXd

J Natl Cancer Inst 2019.