How Is Tamoxifen's Action Subverted?

Extract

Tamoxifen is the endocrine therapy of choice for all stages of breast cancer (1,2). Five years of adjuvant tamoxifen improves survival if the original tumor is classified as estrogen receptor (ER) positive, but there is virtually no benefit from tamoxifen if the tumor is ER negative (2). Tamoxifen is a nonsteroidal antiestrogen (3), so, based on the simple idea that the drug would block estrogen action at the level of the tumor (4,5), it would be hard to imagine that the concept would not rapidly translate from the laboratory to the clinic. Not so. Despite the finding by Kiang and Kennedy (6) in 1977 that ER-positive advanced disease was more likely to respond than ER-negative disease, it has taken more than 20 years and dozens of randomized clinical trials to prove the worth of the ER assay to predict the response to tamoxifen (2). Looked at another way, since Jensen's discovery and prediction that only tissues and tumors that contain ER (7,8) respond to estrogen (and can be blocked by antiestrogens), it has taken a huge clinical effort to convince oncologists on both sides of the Atlantic to select only ER-positive patients for treatment.