While tamoxifen – an anti-hormone therapy – is effective at preventing recurrence of hormone-sensitive breast cancer in approximately 50 percent of women, the drug is inexplicably ineffective in some women. While researchers are unsure as to how to explain this phenomenon, some evidence points to tumor genetics as a possible source of incompatibility with tamoxifen.
According to Dr. Daniel L. Hertz, an assistant professor in the University of Michigan College of Pharmacy and member of the University of Michigan Comprehensive Cancer Center, “We do know that some tumors are inherently resistant to tamoxifen because of tumor genetic changes. These tumor have found pathways to overcome anti-estrogen treatment. But we also believe some patients may be less likely to benefit from tamoxifen or endocrine therapy because of their genetics.” Some researchers believe that tamoxifen is not converted to an extra-potent estrogen inhibitor – called endoxifen – in some patients, which may explain the poorer outcomes for patients with low endoxifen who are also taking tamoxifen.
Yet another theory is that genetic variation in patients with certain changes on the gene CYP2D6, may be responsible for the ineffectiveness and lower survival rates of some patients on tamoxifen. Researchers at the International Tamoxifen Pharmacogenetics Consortium came to this conclusion after performing a meta-analysis on a number of clinical trials involving the drug, however further study of the prospective trials did not substantiate the link.
Hertz and his colleagues further investigated the trials to determine if genotyping-related errors could explain the inconsistency of the findings. While the original investigators had attributed statistical differences to errors in genotyping patients, the new meta-analysis suggests these statistical deviations could be attributed to patients enrolled from multiple institutions.
Using advances statistical modelling, Hertz and his team discovered that errors in genotyping patients would only introduce an inconsequential bias to the prospective trail analysis. Unfortunately, the results of the meta-analysis has done little to clarify the aberrations in effectiveness of tamoxifen among patients.
“Genotyping from the tumor in these prospective clinical trials is not the reason these analyses are negative,” said Hertz. “Either there is some other reason that the later studies were negative or the initial study suggesting CYP2D6 as a marker was falsely positive.”
In yet another study performed by Hertz and his colleagues, the researchers found that gene variants in CYP2D6 as well as an additional gene – CYP2C9 – are involved in levels of endoxifen in the system. According to Hertz, multiple genetic markers may influence the effectiveness of tamoxifen.
“At this point we still have a hypothetical association between genotype and efficacy that has not been validated,” said Hertz. “For now, there is no clinical benefit to using CYP2D6 to inform tamoxifen treatment decisions. We need to validate these hypotheses.”
- Why does tamoxifen work better in some women? – http://www.sciencedaily.com/releases/2015/12/151210181625.htm