Clinicians may be able to more accurately determine whether breast cancer will recur in patients taking tamoxifen by genotyping their cytochrome P450 2D6 gene, if research published in the Dec. 20 issue of The Journal of Clinical Oncology can be further verified and exploited by the molecular diagnostics field.
The data suggest that "women who inherit [a poor-metabolizer 2D6] genetic variant would be less likely to respond to tamoxifen," said James Rae, a researcher at the University of Michigan Comprehensive Cancer Center who co-led the study with Matthew Goetz, a Mayo Clinic oncologist.
The paper supports the notion that CYP450 testing could add to current pharmacogenomic factors to help clinicians guide treatment with the AstraZeneca drug tamoxifen, which is now generic. The finding also buttresses earlier research by the same group in the Jan. 5 issue of the Journal of the National Cancer Institute that found lower plasma levels of the drug and its metabolites in patients having certain CYP450 2D6 alleles.
The two together suggest that prescriptions of tamoxifen could eventually be modified by clinicians based on a patient's CYP450 2D6 genotype, but none of the researchers involved in either study would recommend altering prescriptions based on such information just yet.
"It's really up to the clinicians to decide the value" of testing, Goetz said.
The new study is a retrospective analysis of the tamoxifen-only arm of an unrelated Mayo Clinic study investigating fluoxymestrone treatment of breast cancer. "What we found in their patient set is that if the patients were 2D6 poor metabolizers, they [were] less likely to respond to tamoxifen, in that they were twice as likely to have disease relapse than patients who were wild-type for 2D6," said Rae.
"What we found in their patient set is that if the patients were 2D6 poor metabolizers, they [were] less likely to respond to tamoxifen, in that they were twice as likely to have disease relapse than patients who were wild-type for 2D6."
Rae is part of the Pharmacogenomics Research Network division headed by David Flockhart, chief of the Division of Clinical Pharmacology at the Indiana University School of Medicine, which aims to find genetic determinants of response to endocrine therapy, including tamoxifen.
The group surmises that 2D6 poor metabolizers of the drug have lower plasma levels of a metabolite called endoxifen that is 70 to 100 times as effective at blocking estrogen receptors than tamoxifen, said Rae. In poor metabolizers, tamoxifen is probably removed from the system through other mechanisms or broken down into less active metabolites by other enzymes.
Until the PGRN researchers had discovered the importance of endoxifen, they hypothesized that CYP450 2D6 activated tamoxifen by processing it into a more active form, 4-hydroxytamoxifen, said Rae. The metabolite 4-hydroxtamoxifen is also made by CYP450 enzymes 3A4 and 2C9, he said.
The current findings follow a study that Flockhart led last year that found that among 80 tamoxifen patients, women homozygous or heterozygous for particular 2D6 variant alleles had a statistically significant decrease in plasma levels of tamoxifen and its active metabolites after four months of treatment, as compared to women homozygous for 2D6 wild-type alleles.
To answer definitively whether patients having less active 2D6 variants are less likely to respond to tamoxifen, Rae and colleagues are negotiating with other researchers to "reproduce this [finding] in their datasets," Rae said. He and his colleagues also plan to investigate the role of different estrogen-receptor alleles in tamoxifen response, Rae added.
Neither endoxifen nor 4-hydroxtamoxifen is currently used as a standalone drug, Rae said. However, a pharmaceutical company Rae declined to name has been experimenting with the use of a 4-hydroxytamoxifen patch, and is now interested in exploring administration of endoxifen, he said.
Rae said he was not aware of whether diagnostics companies had shown interest in translating his group's research into a marketable test, although Flockhart's PGRN team had served as a beta-test site for the Roche AmpliChip P450, which tests for alleles of both the 2D6 and 2C19 genes. The 2C19 gene is not active in tamoxifen metabolism.
There appears to be a confluence of Rae and Goetz' research with diagnostic products made by other companies. Genomic Health's Oncotype Dx interrogates the expression patterns of 21 genes in order to estimate the risk of recurrence in patients on tamoxifen with node-negative, estrogen-receptor positive breast cancer. Also, A&G Pharmaceutical is developing a diagnostic to detect the protein GP88, which the company believes could prove to be a good test for identifying tumors unresponsive to tamoxifen. However, neither company could be contacted by press time to comment on the use of CYP450 genotyping in a fashion complementary to testing with their own products.
— Chris Womack ([email protected])