SAN ANTONIOAdding the epidermal growth factor receptor (EGFR) inhibitor
gefitinib mesylate (Iressa, also known as ZD1839) to tamoxifen (Nol-vadex) has
improved initial antitumor response and delayed the development of acquired
tamoxifen resistance in a xenograft model of human breast cancer, according to
Rachel Schiff, PhD, of Baylor College of Medicine’s Breast Center. Dr. Schiff
reported her group’s results at the 25th Annual San Antonio Breast Cancer
Symposium (abstract 18).
Dr. Schiff said that resistance to selective estrogen-receptor modulators (SERMs)
arises from an imbalance in their agonist and antagonist properties. Their
studies support the concept that activation of the EGFR pathway en-hances
tamoxifen’s agonist effect, which contributes to acquired resistance, and show
that EGFR inhibition can eliminate this agonist effect.
In preclinical models of MCF-7 breast cancer tumors overexpressing HER-2,
the researchers found that tamoxifen stimulated tumor growth, thereby promoting
the development of de novo resistance. By blocking the EGFR/HER-2 pathway with
gefitinib, however, they were able to restore tamoxifen sensitivity in this
breast cancer model.
They then examined tamoxifen in MCF-7 tumors that did not overexpress HER-2,
observing that tamoxifen resistance developed within 2 to 4 months. "This
acquired resistance was caused by tamoxifen-stimulated growth," Dr. Schiff
said. "Tamoxifen, over time, had become more of an agonist, as it is in the
HER-2 tumors. So then the question becomes: Can targeting the EGFR/HER-2
pathway delay the development of acquired resistance to tamoxifen in tumors
with normal levels of EGFR/HER-2?"
To answer that question, the researchers established
non-HER-2-overexpress-ing MCF-7 tumors in nude mice that were receiving
estrogen supplementation. The ovariectomized mice were then randomized to
continued estrogen stimulation, with or without gefitinib; estrogen
deprivation, with or without gefitinib; or tamoxifen, with or without gefitinib.
"As you might expect, ZD1839 had no effect in the estrogen-stimulated tumor
host," Dr. Schiff said. "This suggests that the estrogen stimulation is not
dependent on the EGFR/HER-2 pathway." Gefitinib also had little benefit in mice
that were estrogen deprived.
Among tamoxifen-treated mice, however, Dr. Schiff reported that gefitinib
appreciably improved tamoxifen response and markedly delayed the onset of
tamoxifen resistance from 2 to 3 months to more than 6 months (see
researchers also found that gefitinib had only a modest positive effect when it
was added later in the treatment course, suggesting that combining the two
drugs from the outset would be the most effective treatment approach.