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FDA to Consider Relabeling Tamoxifen for 2D6 Response in Fall Meeting; Dx Shops May Benefit

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The US Food and Drug Administration will meet in October to discuss adding pharmacogenomic-based drug-metabolism information to the label of the widely used breast cancer drug tamoxifen, according to a person familiar with the agency's plans.

If the FDA decides to take the step, it will be the third time it has moved to update an approved drug's label with pharmacogenomic information and prescribing recommendations, and may therefore be a boon to molecular diagnostic shops dealing with metabolism-related gene variants, in this case CYP450 2D6. The agency relabeled Pfizer's Camptosar in June last year, and it decided to relabel warfarin in November.

With Camptosar, the first relabeling instance, the agency included information about the gene UGT1A1's influence on the risk of adverse events. A test based on interrogating CYP2D6 genes, on the other hand, would be the first time the FDA has looked at efficacy as the primary goal.

Tamoxifen has been the subject of pharmacogenomic studies for several years, but it took a large prospective clinical trial by the Pharmacogenomics Research Network before the FDA decided to hold a public advisory committee meeting to consider changing the drug's label, a person who will be involved in the October meeting told Pharmacogenomics Reporter this week on condition of anonymity. He asked to remain anonymous because he does not have authority to comment on the meeting.


"Half the clinicians [say], 'We should go with what we have already,' then you have other clinicians saying, 'Let's just hold off and not change our treatment based on preliminary data."

An FDA spokesperson said the agency does not discuss meetings before they have been publicly announced, and a spokesperson for AstraZeneca, the manufacturer of the original, non-generic tamoxifen, said the company had no information about relabeling. Manufacturers of generic versions of the drug did not return requests for comment before deadline.

When the FDA updated Camptosar's label last year, the result encouraged companies to develop and submit their own assays for interrogating a gene related to the drug's adverse events. The first FDA-cleared diagnostic for interrogating the UGT1A1 gene was an Invader test made by Third Wave Technologies. The newer Camptosar label recommends a lower starting dose of the drug in patients homozygous for the UGT1A1*28 allele.

The only large, prospective clinical trial linking CYP450 inhibitors and tamoxifen efficacy — which the FDA would most likely require before updating the label — is technically a retrospective analysis by the PGRN on the prospective North Central Cancer Treatment Group trial. That research, which looks only at the effects of the 2D6*4 polymorphism, was published in the December 2005 issue of the Journal of Clinical Oncology.

While that study showed an impact of CYP2D6 genotype on the risk of breast cancer relapse, the group presented an update of its research last week at the American Society of Clinical Oncologists meeting in Atlanta that added data about the effect of CYP2D6 inhibition on clinical outcome. That data was finally strong enough for the researchers to write in an ASCO abstract that 2D6 status can help identify patients who should receive tamoxifen therapy. Both iterations caused the PGRN scientists to conclude that patients taking the drug should not also take potent 2D6 inhibitors.

Specifically, the research showed that breast cancer patients who are CYP2D6-poor metabolizers have about three-fold higher risk of relapse than extensive metabolizers, despite tumor size, tumor grade, and Her2 status. Intermediate metabolizers have a risk of relapse about 1.7-fold higher than extensive metabolizers. Poor metabolizers who relapse do so earlier than extensive metabolizers, with a peak in relapses at about two years, versus four.

The trial's results were "completely consistent with our hypothesis that the activity of 2D6 in the liver is required for activation of tamoxifen response," James Rae, a study author and assistant professor of oncology at the University of Michigan Comprehensive Cancer Center, said this week.

"We're saying, 'If you're a poor metabolizer, you're going to get either very little or no benefit from tamoxifen, whereas if you're an extensive metabolizer, you're able to fully activate the drug and to get significant benefits,'" Rae told Pharmacogenomics Reporter.

Other research suggests that simply increasing the dose of tamoxifen will not help poor metabolizers, a factor that might mean that they are better suited to treatment with other drugs, said Matthew Goetz, a Mayo Clinic oncologist and an author of the study. True extensive metabolizers, on the other hand, may experience the same benefit from a lower dose than the clinical standard, he added.

As a next step in the process, Goetz and colleagues at the Mayo Clinic have "just proposed" a prospective clinical trial of tamoxifen and adjuvant hormonal therapies to the US National Cancer Institute that will involve between 5,000 and 6,000 breast cancer patients, he said. The trial will genotype all patients for CYP2D6, with CYP2D6 extensive metabolizers randomly assigned to two treatment arms: tamoxifen followed by an aromatase inhibitor or aromatase inhibitor alone. "What we're proposing is that if you're a poor metabolizer or an intermediate metabolizer, you would be treated off-study with an aromatase inhibitor," he said.

The trial has been approved "in part" by the Breast Cancer Inter-group of North America, said Goetz. It may be the first time a pharmacogenomic test will have been used in such a large prospective trial, he added.

The Dx Link

Gentris last week said it has licensed the CYP2D6*4 metabolism polymorphism from UK-based LGC for use in its genotyping service (see snippets, this issue). The polymorphism can affect metabolism of about 20 percent of commonly prescribed drugs, including analgesics, antidepressants, and cardiovascular drugs, the companies said.

In May, Gentris said it planned to launch a warfarin-related test next year in anticipation of the FDA's relabeling.

Tm Bioscience and Roche Molecular Diagnostics, which also have 2D6 genotyping programs, did not return calls seeking comment. LabCorp offers 2D6 testing, but a company spokesperson said the firm does not have information on the purposes for which customers order the diagnostic.

The important CYP2D6 polymorphisms related to poor metabolism in Caucasians are *3, *4, and *5. Reduced-function alleles often linked to intermediate metabolizers are *10, *17, and *41, and are most common in East Asians, Blacks, and Caucasians, respectively. Ultra-rapid metabolizers often carry *2A or a gene duplication of *2.

With the amount of data currently available concerning the usefulness of genomic information in tamoxifen dosing, it is possible clinicians may be doing a little off-label pharmacogenomics on their own.

"That's been a topic of a lot of conversation within our group," although the Cancer Center has not "taken a stance" on how to use genotyping with tamoxifen, said Rae. "Half the clinicians [say], 'We should go with what we have already,' then you have other clinicians saying, 'Let's just hold off and not change our treatment based on preliminary data.'"

The company Seryx produces reports for clinicians made up of relevant scientific literature, patient medical history, and genotype information to try to predict drug responses and interactions. Of the company's 487 total orders for reports involving about 45 drugs, four have involved tamoxifen, according to a company spokesperson. The number may not sound like much, but it is an indication that off-label genotyping is probably being done.

At the Mayo Clinic, clinicians are warning patients taking tamoxifen of the dangers of CYP-inhibiting agents, such as selective serotonin-reuptake inhibitors, but the clinic is not genotyping women before prescribing the breast cancer drug, Goetz said. One more prospective study with clinical outcome data will probably be enough for clinicians to feel confident about genotyping for off-label purposes, he said.

— Chris Womack ([email protected])

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