In a follow-up to their late-2003 study showing that the selective serotonin uptake inhibitor (SSRI) paroxetine can decrease the metabolism and efficacy of tamoxifen, researchers have now pinpointed genotypes that are linked with this effect, as well as other SSRIs that cause the same result.

Their findings, published in the January 5 Journal of the National Cancer Institute (JNCI), come from 80 women newly diagnosed with breast cancer and starting tamoxifen treatment. Twenty-four in this group were also taking SSRIs—including paroxetine, fluoxetine, sertraline, citalopram, and venlafaxine.

Previous studies have shown that when tamoxifen is broken down, the resulting molecules are as much as 100 times more powerful at blocking estrogen receptors and thereby exerting a cancer-inhibitive effect. The keys to breaking it down, however, are enzymes in the cytochrome P (CYP) group, including CYP2D6, which can be blocked by some SSRIs.

After genotyping the women in this study, monitoring their medication history, and testing their blood for plasma levels of tamoxifen and its metabolites, the team found that nonfunctional polymorphisms in either one or both copies of CYP2D6 are associated with SSRI use and low tamoxifen activity. Compared with women with two functional copies of the gene, those with one nonfunctional copy showed a 45 percent lower plasma level of tamoxifen metabolites, and those with two nonfunctional copies had levels that were significantly lower.

The research team also found that the stronger the SSRI’s inhibitive effect on CYP2D6, the lower the plasma level of tamoxifen metabolites, with paroxetine having the strongest effect in this regard.

“We’ve withheld clinical recommendations, because at this point we don’t have outcome data,” said lead author Dr. David A. Flockhart of Indiana University School of Medicine. In the article, however, he and the other authors state that “knowledge of a drug’s ability to inhibit CYP2D6 enzyme activity may help clinicians to anticipate important drug interactions” and that genetic testing “may help identify a group of women who may experience greater benefit from tamoxifen and/or who might benefit more from one SSRI over another.”

After 25 years on the market, tamoxifen is one of the most widely prescribed treatments for hormone receptor-positive breast cancer at all stages. According to the drug’s manufacturer, the duration and penetration of its use equals more than 10 million patient years.

But tamoxifen doesn’t work for everyone; just over one-third of women who have advanced tumors do not respond to it, and tumors eventually develop a resistance to it.

One of the side effects of tamoxifen is hot flashes, which occur two to three times more often among women who are taking the drug than among those who do not. SSRIs, which are most often prescribed as antidepressants, are also prescribed to help prevent these hot flashes, a trend that Dr. Flockhart says appears to be increasing.

“In this trial, the number of women taking SSRI antidepressants completely surprised us,” he said. “We thought it would be closer to a tenth, but instead it was 28 percent of the group. The SSRIs are important to a lot of women who find the hot flashes really debilitating.”

This research, which was funded in part by the National Institute of General Medical Sciences Pharmacogenetics Research Network, does not include outcomes of the genotype and SSRI use. However, the authors presented early data from another study at the 27th Annual San Antonio Breast Cancer Symposium, in December 2004, that show an effect of the genotype on disease-free survival. A paper on this study is currently in review by JNCI, said Dr. Flockhart.

He also noted that the 80 women in the current study are part of a larger group of 300 expected to complete enrollment in the summer of 2005, and said that once the data are collected from the larger group, “we would be prepared to make clinical recommendations at that point.”

By Brittany Moya del Pino