By Turna Ray
Several studies presented at the San Antonio Breast Cancer Symposium last week investigated whether CYP2D6 testing can help doctors decide whether to treat breast cancer patients with tamoxifen, but the body of evidence did not resolve questions about the role of CYP2D6 genotypes or myriad other factors contributing to variability in tamoxifen metabolism.
Tamoxifen is a hormonal treatment that has been shown to reduce the risk of breast cancer recurrence. CYP2D6 enzymes convert tamoxifen to the metabolite endoxifen, which suppresses the development of cancer cells by blocking the estrogen receptors that drive tumor growth. Some studies have shown that patients with certain CYP2D6 mutations that make them “poor” or “intermediate” metabolizers of tamoxifen experience a higher breast cancer recurrence rate while on tamoxifen than “normal” metabolizers of the drug. Meanwhile, other published studies have shown no association between CYP2D6 genotypes and patient outcomes when treated with tamoxifen.
As far as the US Food and Drug Administration and payors are concerned, the clinical evidence supporting the utility of pharmacogenetic testing ahead of treating patients with tamoxifen is far from convincing. The FDA has been mulling whether to update tamoxifen’s label with information on CYP2D6 testing since 2006 (PGx Reporter 11/15/06).
Also, earlier this year, the Centers for Medicare Medicaid Services’ Medicare Coverage and Evidence Development Advisory Committee discussed whether there was sufficient evidence on CYP2D6 testing for tamoxifen to warrant coverage in the Medicare population. Based on an independent review of the published literature, MEDCAC found that 11 of 13 studies did not report an association between CYP2D6 status and disease recurrence. Furthermore, most of the reviewed studies were retrospective in design, while only two studies out of 13 were “repurposed randomized-controlled trials.” (PGx Reporter 02/03/10).
At the breast cancer conference held in San Antonio, Texas, last week, Matthew Goetz, assistant professor of oncology at the Mayo Clinic, reviewed several studies on tamoxifen metabolism and CYP2D6 testing. He pointed out that since 2003, 14 published studies have found that CYP2D6 genotyping to administer tamoxifen improves outcomes, while 15 studies have shown there is no association between genetic testing and improvement in a patient’s likelihood of breast cancer recurrence.
“There is marked heterogeneity with regard to the studies that are out there,” Goetz told PGx Reporter this week.
In Goetz’s view, the knowledge gaps regarding tamoxifen metabolism variability center around the specific interplay between endoxifen concentrations, differing features of tumor subtypes, and CYP2D6 and other genotypes. He noted that retrospective analysis in this case is unlikely to lead to conclusive answers since it wouldn’t account for patients who didn’t take the drug for the recommended five years, or those who simultaneously took other CYP2D6 inhibitors or over-the-counter drugs that might have interfered with tamoxifen’s efficacy.
“What we don’t know is how important is this reduction in CYP2D6 activity [and] what are the other factors that contribute to the variability in endoxifen concentrations,” Goetz said. “Probably the only way we’re going to sort this out is by doing prospective studies.”
SABCS Studies
The data presented at SABCS, while informative, still didn’t yield conclusive answers about the impact of CYP2D6 gene variations on the variability of tamoxifen response.
For example, one study, conducted by the International Breast Cancer Study Group and the Breast International Group 1-98 Collaborative Group, conducted CYP2D6 genotyping in tumors of patients who participated in the double-blind randomized trial BIG 1-98 from 1998 to 2000, to see if testing was predictive of disease outcome. The original BIG 1-98 trial enrolled more than 8,000 patients and compared patient outcomes when they were treated with the aromatase inhibitor letrozole, tamoxifen, and sequences of letrozole and tamoxifen as adjuvant endocrine therapy in post-menopausal women with endocrine-responsive breast cancer.
At SABCS, the researchers presented interim results after genotyping formalin-fixed, paraffin-embedded tumor samples from 2,000 patients. Going into the study, the authors hypothesized that certain CYP2D6 variants would be associated with shorter breast cancer-free intervals on tamoxifen monotherapy, and that a similar relationship would not be observed with letrozole monotherapy as a control. The researchers are also exploring whether there is a link between CYP2D6 genotypes and sequential therapies.
The preliminary results, as reviewed by Goetz in his presentation, show no association between CYP2D6 *4 genotypes or CYP2D6 haplotypes with breast cancer recurrence, either in the tamoxifen or the letrozole arm. The researchers plan to genotype another 2,000 patients before announcing the final results.
Another SABCS abstract, by researchers from Baylor College, Indiana University, and the University of Michigan, presented data from a large community-based cohort study that found evidence contrary to the hypothesis that low CYP2D6 confers worse outcomes when treated with tamoxifen.
The researchers in this study assessed whether there are associations between clinical outcomes and CYP2D6 variants and variants in UGT2B7. While CYP2D6 enzymes help convert tamoxifen to its active metabolite endoxifen, UGT2B7 is an enzyme that eliminates endoxifen. The study enrolled 500 patients with ER-positive, early breast cancer treated with adjuvant tamoxifen and another 500 who did not receive any adjuvant treatment. Study participants were genotyped and received a score between 0, for no CYP2D6 alleles, and 2, indicating high activity of CYP2D6 alleles. These patients were also grouped according to UGT2B7 status, based on the presence of the *2 allele.
