Tamoxifen dose reduction may be possible for women experiencing severe hot flash toxicity that threatens their compliance with the drug, an Australian pilot study suggests.

According to NSW research comprising a cohort of 20 women with a history of breast cancer, halving the tamoxifen dose from 20mg to 10mg reduced the women’s Loprinzi Hot Flash Scores from a median of 131 at baseline to 47.

While the change was not statistically significant, 85% of women also reported a subjective improvement in their symptoms.

Levels of the tamoxifen metabolite endoxifen dropped from a median of 25.6 nM at baseline to 14.1 nM after the dose reduction.

The study investigators noted there was a wide variability in endoxifen levels but the proportion of women below the recommended threshold of 15 nM increased from 20% to 50% with dose reduction.

Dr Clara Lee, a medical oncologist at Westmead and Bankstown Hospitals, told the limbic that the metabolism of tamoxifen was incredibly complex.

And there was also discordance in the literature about the importance of endoxifen thresholds.

“Just recently we have had two studies, one in the neoadjuvant and metastatic setting and one in the adjuvant setting, that have demonstrated that there isn’t a correlation between endoxifen levels and clinical and breast cancer outcomes.

“But that is only in the last year or so. Prior to that the literature looked at 15 nM levels to be threshold.”

She said given the uncertainty about therapeutic thresholds, there was value in considering dose reduction for the small number of women who were severely affected by symptoms.

“In our cohort of women, and I think in clinical practice as well, we would only apply this sort of strategy if they had such terrible hot flashes that it threatened compliance.”

“This is almost a salvage manoeuvre to see if they could continue to take their tablets.”

She said the study was limited by its small size and should be replicated in a larger cohort.

“I think our pilot study demonstrates that dose reduction of tamoxifen can be useful in these women who are really unable to take tamoxifen and although the effectiveness of that was not statistically significant when we tested it, I think that is probably because we had such a small cohort and if we had a larger cohort I imagine we might have a more robust finding.”

Therapeutic drug monitoring would add value

Dr Lee said therapeutic drug monitoring, which was not routinely available outside the research setting, would also be of value.

“I think it should be used more often and should be adopted outside the research setting where it currently sits. That would be a really good measure of tamoxifen effect although those two recent papers have suggested that endoxifen levels is a bit less important than we originally thought.”

She added that some clinicians used CYP2D6 genotyping for their patients as an estimate for endoxifen levels but it was not necessarily accurate.

“We would recommend checking active metabolites particularly endoxifen because that will give you the most information about your patients and how they are metabolising tamoxifen and what benefit they are getting.”

“It is not as simple as just looking at CYP2D6. There are multiple factors involved and I think this study and other looking at tamoxifen and active metabolites, and the discordance in the literature, just highlight how complicated things are and how we should try to further our understanding of that.”

“So it’s tricky when there is discordant data but I certainly would be nervous reducing doses without knowing what the endoxifen levels were.”