Before anti-estrogens such as tamoxifen were developed to treat estrogen receptor
(ER)-positive breast cancer, high-dose estrogen therapies were used. This seems
counterintuitive since anti-estrogens block ER function, while estrogens increase ER
function, but these therapies are effective to similar extents for the treatment of
metastatic ER+ breast cancer. Estrogen therapies are most effective against cancers that
develop resistance to anti-estrogens, likely because such cancers have adapted to grow
without ER function, and restoring ER function (with estrogen) is damaging to the cancer
cells. In some patients with ER+ breast cancer that becomes resistant to anti-estrogens,
treatment with the estrogen 17B-estradiol induces tumor response. Furthermore, when
17B-estradiol-sensitive tumors eventually become resistant to 17B-estradiol, switching back
to anti-estrogen therapy is often effective. These observations suggest that cancers can
alternate between anti-estrogen-sensitive and 17B-estradiol-sensitive states. The
investigators hypothesize that treatment with alternating 17B-estradiol / anti-estrogen
therapies on a defined 8-week / 16-week schedule will more effectively prevent cancer growth
than continuous treatment with either type of therapy in patients with metastatic
anti-estrogen-resistant ER+ breast cancer.