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Study Shows Wider Benefit for Anti-Androgen Receptor Therapy
“Triple-negative” breast cancers expressing very low levels of androgen receptor (AR) may benefit from therapies that inhibit that receptor, according to a University of Colorado Cancer Center study presented at the Endocrine Society Annual Meeting in Chicago.
Cancers that lack estrogen receptors and progesterone receptors and aren’t driven by the gene HER2 do not benefit from the targeted therapies that have greatly improved the survival of patients with other subtypes of breast cancer. But up to a third of these tumors express the AR, and clinical trials are under way to inhibit the AR in these tumors in much the same way that the drug tamoxifen inhibits estrogen receptor in estrogen-receptor-positive breast cancers.
“This line of work is starting to change our thinking about who and when — the timing and patient selection for anti-androgen receptor therapy in triple-negative breast cancer,” says Valerie Barton, the study’s first author and doctoral candidate in the lab of CU Cancer Center investigator Jennifer Richer, PhD.
Triple-negative breast cancers were recently divided into further subtypes, including a subtype with high AR expression. However, other subtypes also express the AR. How would these different subtypes respond to anti-AR therapy?
To find out, Barton and colleagues treated cell lines with the drug enzalutamide and with short hairpin RNAs designed to knock down AR levels. The drug enzalutamide is in wide use for prostate cancer, which tends to be driven by and dependent on AR.
Results showed that not only does anti-AR therapy reduce the ability of androgen-receptor-expressing triple-negative breast cancers to proliferate, migrate, and invade, but for these cells, AR seems essential to survival. When Barton and colleagues blocked AR in these cells, the cells died.
But it was not only the high androgen-receptor-expressing cells that were affected. “The study showed that androgen receptor has important roles in other subtypes of triple negative breast cancer as well,” Barton says.
Across multiple triple-negative breast cancer subtypes, inhibiting the AR greatly increased apoptosis, inhibited growth, and increased necrosis by 60% in animal models.
“We’re still early in the study of androgen receptor in breast cancer and already scientists are divvying up the disease to say, for example, that only the high androgen receptor-expressing subtype should be treated with anti-androgen receptor therapies,” Barton says. “But what we show is that even triple-negative breast cancers with lower androgen receptor expression critically depend on the androgen receptor and may benefit from anti-androgen receptor therapy. Our results suggest that anti-androgen receptor therapy may benefit a larger percentage of triple negative breast cancers than previously thought.”
Source: University of Colorado Cancer Center; June 23, 2014.