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The study by Okishiro et al1 concludes that the cytochrome P450 (CYP) genotype CYP2D6*10/*10 is unlikely to have a clinically significant impact on prognosis in women with breast cancer who receive adjuvant tamoxifen.

However, several aspects of the study by Okishiro et al call their conclusions into question and raise serious doubts whether a statistical review was performed as part of the peer-review process.

First, questions exist regarding the makeup of the authors' cohort, including the number of patients who either refused consent or did not undergo blood collection. Furthermore, because the timing of blood collection is not specified, there would be great opportunity for bias if patients were identified and blood collection was initiated months or years after surgery, in that the patients who developed recurrent disease and/or died would not have been included. The authors did not provide the rationale for including patients who had estrogen receptor-negative disease (for which tamoxifen is not effective) or patients who also received chemotherapy (which reduces the likelihood of a breast event and, thus, the statistical power). The consistency of the surveillance schedule and the documentation needed to verify disease progression were not addressed. Finally, the number of patients who could not be located, the number of disease progressions, and the number deaths without progression were not provided.

Despite these issues, the most disconcerting aspect of this report is that the authors were not required to provide the smallest detectable hazard ratio given their study characteristics. Compared with CYP2D6 extensive metabolizers, poor metabolizers exhibit a 3-fold higher risk of recurrence,2, 3 whereas CYP2D6 intermediate metabolizers (those with “intermediate” reductions in endoxifen concentrations) exhibit a lower risk of recurrence.2-5 Given the characteristics of the study by Okishiro et al (median follow-up, 56 months among 173 patients, with 25% with the *10/*10 genotype; enrollment period, 6 years; follow-up, 4 years; and 5-year recurrence-free survival rate, 90% in the *10/*10 genotype subgroup), a 2-sided α = .05 log-rank test has a power of 26% to detect a 2-fold increase in the hazard of disease recurrence in the *10/*10 carriers relative to *10/wild type (wt) or wt/wt carriers.

The relation between the CYP2D6*10 genotype and recurrence in tamoxifen-treated patients is an important question that the study by Okishiro et al is neither designed nor statistically powered to answer.

REFERENCES

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  • 1
    Okishiro M, Taguchi T, Jin Kim S, Shimazu K, Tamaki Y, Noguchi S. Genetic polymorphisms of CYP2D6*10 and CYP2C18*2,*3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen. Cancer. 2009; 115: 952-961.
  • 2
    Goetz MP, Knox SK, Suman VJ, et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat. 2007; 101: 113-121.
  • 3
    Schroth W, Antoniadou L, Fritz P, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CIP2C19 genotypes. J Clin Oncol. 2007; 25: 5187-5193.
  • 4
    Kiyotani K, Mushiroda T, Sasa M, et al. Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci. 2008; 99: 995-999.
  • 5
    Xu Y, Sun Y, Yao L, et al. Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol. 2008; 19: 1423-1429.

Matthew Goetz MD*, Vera Suman PhD†, * Department of Oncology, Mayo Clinic, Rochester, Minnesota, † Department of Biostatistics, Mayo Clinic, Rochester, Minnesota.