Secondary analysis data presented this week at the 2015 San Antonio Breast Cancer Symposium (8–12 December, TX, USA) has raised questions regarding whether variations in the CYP2D6 gene could be responsible for varying response levels to tamoxifen.
Treatment with tamoxifen has been demonstrated to reduce the risk of breast cancer recurrence by approximately 50 %. However, the efficacy of this hormone therapy varies from patient to patient – a disparity for which investigators do not currently have an explanation.
“We do know that some tumors are inherently resistant to tamoxifen because of tumor genetic changes,” commented Daniel L Hertz of the University of Michigan Comprehensive Cancer Center (MI, USA), who presented the data from this analysis at the conference yesterday. “These tumor have found pathways to overcome antiestrogen treatment. But we also believe some patients may be less likely to benefit from tamoxifen or endocrine therapy because of their genetics.”
An established theory for these differing responses is that in some patients, tamoxifen is not activated to the more potent inhibitor termed endoxifen. Patients with low levels of endoxifen may have worse outcomes when receiving tamoxifen.
A prior meta-analysis study carried out by the International Tamoxifen Pharmacogenetics Consortium demonstrated that patients with certain variants of the CYP2D6 gene were associated with a worse survival; however, this association was not found in later analyses of prospective clinical trials.
Hertz et al. revisited these previous studies to assess whether errors in genotyping could have brought about these varying results. Statistical deviations seen in the original meta-analysis had been attributed to genotyping error; however, this secondary analysis revealed that statistical deviations were linked to enrolling patients from multiple institutions, not genotyping error.
Furthermore, advanced statistical modeling carried out by Hertz and colleagues confirmed that genotyping error would introduce negligible bias to the analyses of the prospective trials.
“Genotyping from the tumor in these prospective clinical trials is not the reason these analyses are negative,” Hertz continued. “Either there is some other reason that the later studies were negative or the initial study suggesting CYP2D6 as a marker was falsely positive.”
A further study carried out by Hertz and colleagues, and also presented at San Antonio, determined that variants in CYP2D6 and another gene CYP2C9 contribute to endoxifen exposure, suggesting that it may not be one single marker that predicts tamoxifen response.
“At this point we still have a hypothetical association between genotype and efficacy that has not been validated,” Hertz concluded. “For now, there is no clinical benefit to using CYP2D6 to inform tamoxifen treatment decisions. We need to validate these hypotheses.”