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Medical News Today: Why does tamoxifen not work in some women with hormone-sensitive breast cancer?

Tamoxifen – a drug that blocks the action of the hormone estrogen – can halve the risk of breast cancer recurrence in women with hormone-sensitive breast cancer. However, it works better for some patients than others, and researchers trying to find out why are coming up with more questions than answers.
women in pink wearing breast cancer ribbon
While tamoxifen can halve the risk of breast cancer recurrence in women with hormone-sensitive breast cancer, it does not work for all of them.

Two new studies presented at the San Antonio Breast Cancer Symposium taking place in San Antonio, TX, this week attempt to shed more light on the matter.

Daniel L. Hertz, research assistant professor of pharmacy at the University of Michigan in Ann Arbor, was involved in both studies. He says one reason that tamoxifen does not work to prevent cancer recurrence is because the tumors find “pathways to overcome anti-estrogen treatment,” and adds:

“But we also believe some patients may be less likely to benefit from tamoxifen or endocrine therapy because of their genetics.”

For tamoxifen to work, it needs to be completely metabolized into its more potent form endoxifen. One theory about why tamoxifen does not work in some patients is that – for some reason – in those patients, the drug only produces low levels of endoxifen. Patients with low levels of endoxifen may have worse outcomes on tamoxifen.

One analysis of pooled data from tamoxifen studies – by the International Tamoxifen Pharmacogenetics Consortium – has suggested patients with certain variants of the gene CYP2D6 fared worse on tamoxifen. However, later analyses could not find this link.

More than one genetic marker involved

To attempt to resolve this mystery, Prof. Hertz and colleagues re-examined the evidence to find out whether errors in genotyping – the way genetic variants are identified – could have led to the disparate findings concerning the effect of CYP2D6 variants on tamoxifen effectiveness.

They concluded, however, that it was not genotyping errors but the way patients were enrolled from different participating centers that probably accounted for the statistical deviations seen in the original review.

Also, with the help of advanced statistical tools, Prof. Hertz and colleagues show that for the type of studies that were being analyzed – prospective trials – the bias from genotyping error would be negligible. Prof. Hertz explains:

“Genotyping from the tumor in these prospective clinical trials is not the reason these analyses are negative. Either there is some other reason that the later studies were negative or the initial study suggesting CYP2D6 as a marker was falsely positive.”

The result leaves more questions than answers about why tamoxifen works in some patients and not others. However, it seems to indicate that variants in patient genes is the right direction in which to search.

In the second study, Prof. Hertz and colleagues found that activation of tamoxifen to its more potent form endoxifen appears to be linked to variants not only in CYP2D6, but also in another gene called CYP2C9.

Prof. Hertz suggests the findings point to the effectiveness of tamoxifen being dependent on more than one genetic marker. He concludes:

“At this point we still have a hypothetical association between genotype and efficacy that has not been validated. For now, there is no clinical benefit to using CYP2D6 to inform tamoxifen treatment decisions. We need to validate these hypotheses.”

Meanwhile, Medical News Today recently reported on a study that suggests there may be underlying reasons why some breast cancer survivors succumb to the blood cancer leukemia after cancer therapy. After exploring some possible directions, the researchers said a long-term study of women with and without inherited breast cancer gene mutations who undergo similar therapies would provide better clues.

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