Journal of the National Cancer Institute Advance Access originally published online on September 9, 2008
JNCI Journal of the National Cancer Institute 2008 100(18):1332-1333; doi:10.1093/jnci/djn270
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© The Author 2008. Published by Oxford University Press.
CORRESPONDENCE |
Response: Re: Pharmacogenomic Variation of CYP2D6 and the Choice of Optimal Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A Modeling Analysis
Affiliations of authors: Departments of Radiation Oncology (RSP) and Medical Oncology (HJB, EPW, JCW), Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Correspondence to: Rinaa S. Punglia, MD, MPH, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, 44 Binney Street, Boston, MA 02115 (e-mail: rpunglia{at}partners.org).
We thank Gurwitz and Newman for their interest in our findings. The authors make important points about the variation in CYP2D6 genotype distribution across ethnic populations. That very heterogeneity, as well as uncertainty about the effect of CYP2D6 genotype on outcomes of sequential treatment with tamoxifen and an aromatase inhibitor, prompted us to conclude that definitive recommendations regarding genetic testing are premature. However, we agree with Gurwitz and Newman that our model does raise the possibility that CYP2D6 genetic testing could inform clinical decision making regarding optimal adjuvant endocrine treatment, and we await ongoing studies to clarify the role of such testing in treatment selection.
Chlebowski and Col indicate that the severe side-effect profile of tamoxifen is more worrisome than that seen with aromatase inhibitors. They suggest that our model would have little applicability in postmenopausal women because of the difference in toxicity between the aromatase inhibitors and tamoxifen. Although we recognize that the toxicity profiles of the two drugs differ, the 100-month data from the double-blind Arimidex, Tamoxifen, Alone, or in Combination (ATAC) trial actually demonstrated an excess of non–breast cancer deaths for women who took the aromatase inhibitor (1). We agree that a consideration of side effects is critical when selecting agents for an individual, particularly agents that require long-term administration. However, we intentionally did not incorporate toxicity because the goal of our analysis was to model the variation in breast cancer outcomes according to CYP2D6 genotype directly by using recurrence information from clinical trials. Our model was designed to provide an estimate of recurrence based on CYP2D6 genotype rather than on quality-of-life or toxicity predictions for subsets of patients. Clinicians and their patients have to consider these disease recurrence outcomes together with the relatively common toxicities that affect quality of life and rare life-threatening complications.
Chlebowski and Col also raise the interesting possibility that the switching or crossover trials may be enriched with women who do not metabolize tamoxifen because these women are more likely to adhere to tamoxifen regimens. However, patients in switching or crossover trials were not required to be compliant with tamoxifen, only disease-free at the time of randomization, which was 2–3 years after initiation of tamoxifen. Our analysis did not model the sequential endocrine therapy strategies used in the crossover trials because we had no data to inform variation in outcomes by CYP2D6 genotype in this setting. However, as Chlebowski and Col note, some data do suggest that women who are poor metabolizers of tamoxifen may be more compliant with tamoxifen treatment (2). If this finding is confirmed in the upfront tamoxifen versus aromatase inhibitor trials, our model, which used estimates from these trials, would then underestimate the benefit of tamoxifen in women who do not carry a CYP2D6 mutation and are compliant with treatment.
REFERENCES
1. Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol (2008) 9:45–53.[CrossRef][Web of Science][Medline]
2. Rae JM, S Rae JM, Sikora MJ, et al. Cytochrome P450 2D6 activity predicts adherence to tamoxifen therapy. Breast Cancer Res Treat (2007) 106(suppl_1):521.
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J Natl Cancer Inst 2008 100: 1331.
J Natl Cancer Inst 2008 100: 1331-1332.
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