A few weeks ago, I was paging through an issue of Journal of Clinical Oncology (ugh,I know I should have something better to do with my time) when I came across a correspondence from Bhattacharya, Abderrahman and Jordon at M. D. Anderson. The title was “Tamoxifen Decreases Mortality, but How?” (http://ascopubs.org/doi/full/10.1200/JCO.2016.69.1618)
They reminded us that tamoxifen was never considered cytotoxic, at least not at first. It was believed that if tamoxifen were discontinued, the patient’s endogenous estrogen would reactivate micrometastases leading to recurrence. But as the use of tamoxifen moved from the metastatic to the adjuvant setting, a strange thing happened. Survival improved. Why?
According to authors, the question was answered in the lab. As it turns out, after 5 years of tamoxifen (yes, 5 years, how convenient!) a cell population forms that is vulnerable to estrogen-induced apoptosis. Not being a scientist, over even one particularly prone to scientific thought, that is where my understanding ends. So in summary it seems that in some way, tamoxifen primes cancer cells over a 5 year period for estrogen-induced apoptosis.
A bit of historic perspective may be in order. High dose estrogen therapy using diethylstilbestrol (DES) was the standard of care for treating metastatic breast cancer from the 1950s to the late 1970s. It was initially used in pregnant females with threatened abortion. The side effects eventually led to its demise; birth defects and a rare form of vaginal cancer in DES babies just to mention a few. Nonsteroidal antiestrogens were then developed where the initial interest focused on their use as antifertility agents. They eventually evolved into selective ER modulators (SERMS). In head to head combat, DES and tamoxifen seemed to have similar anti-cancer benefit but because of side effects tamoxifen was declared winner and DES was removed from the market.
There is clinical data to support the use of estrogen following several years of priming by antiestrogens. Lønning et al from Norway and the UK published data on 32 heavily antiestrogen pretreated patients (http://Breast Cancer Research and Treatment 67:111-16, 2001). In general, there were high response rates and several complete responses. To me, this looks like a promising area of research, particularly in the era of tumor genomics and attempts to measure downstream ER signaling. Maybe it’s time to pull a new treatment out of an old bag of tricks?