Twenty-five years after tamoxifen was introduced for the treatment of breast cancer, David Flockhart and his team at Indiana University determined that the body coverts the drug into a different substance known as endoxifen, and the latter is actually the cancer-figher.
In fact 7% of the general population possess a wholly inactive enzyme and another 20-40% have a weakly active variation.
Flockhart told the New York Times that was “scary” because it meant tens of thousands of women had received a drug that did not protect them against recurrent breast cancer as they had thought.
It’s scary for Big Pharma too. Tamoxifen had fallen out of favor ever since clinical trials showed that aromatase inhibitor drugs performed better.
But the studies were done before we knew about 2D6 and as an aside, the aromatase inhibitors net up to 36 times more revenue per patient than the now-generic tamoxifen.
Suppose the trials had assessed only women with a fully active 2D6 enzyme. Could tamoxifen have performed as well or better than the aromatase inhibitors?
Matthew Goetz and colleagues from the Mayo clinic went back and checked tumor samples from a previous trial for 2D6 gene status and reported that 32% of women with the inactive variant had relapsed or died in 2 years. Only 2% percent of women with a fully active enzyme relapsed or died.
But other studies reached contradictory conclusions and it turns out there are dozens of 2D6 variants which can confound results in clinical labs.
Two years ago, an FDA advisory panel recommended that the 2D6 test be discussed on the label for tamoxifen. Just recently, the agency got around to accepting the recommendation.