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):1333-1334; doi:10.1093/jnci/djn271
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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: The Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI (DFH, JR); Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD (VS); Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN (DF)
Correspondence to: Daniel F. Hayes, MD, The Breast Oncology Program, University of Michigan Comprehensive Cancer Center, 6312 Cancer Center, 1500 E. Medical Center Drive, Ann Arbor, MI (e-mail: hayesdf{at}umich.edu).
We appreciate the support from Gurwitz and Newman regarding our cautiously written statements recommending further validation of the role of CYP2D6 to select appropriate antiestrogen therapy for patients with estrogen receptor (ER)–rich early breast cancer. However, we disagree with their statement that "the current evidence—taking into consideration the new Asian studies—is already strong enough to warrant an ethical obligation for physicians to inform their postmenopausal ER-positive breast cancer patients about the availability and implications of CYP2D6 genetic testing."
New medical technologies and therapies always induce controversy and uncertainty. The medical community is frequently torn between the rapid acceptance of a new, exciting, and potentially helpful strategy and the possibility that after more extensive and careful investigation, the risks associated with its use might not outweigh the benefits. The available evidence to support the use of CYP2D6 genotype for selection of antiestrogen treatment of breast cancer patients would be considered level III evidence at best, using the levels of evidence scale published by the American Society of Clinical Oncology Tumor Marker Guidelines Panel (1). Indeed, two studies have reported the exact opposite of what we would have anticipated, that is, that CYP2D6 variants are associated with better response to tamoxifen (2,3). We cannot ignore or simply dismiss these results because they contradict our own theory.
Widespread testing for CYP2D6 genotype is appropriate only in the presence of an acceptable alternative to tamoxifen for poor metabolizers. For postmenopausal women, aromatase inhibitors are already widely used instead of tamoxifen, regardless of CYP2D6 genotype (4). However, if an aromatase inhibitor is not an appropriate alternative, for example, for a woman with advance osteoporosis, it is not clear that CYP2D6 genotype testing is appropriate given that no alternative to tamoxifen is available. In this case, treating a woman who is a poor metabolizer with an aromatase inhibitor would place her at greater jeopardy for osteoporotic fracture, which would be inappropriate if our hypothesis is incorrect.
The stakes are even higher for premenopausal women because the alternative to tamoxifen requires estrogen depletion by ovarian ablation and aromatase inhibitor therapy. Such an approach is fraught with considerable health and quality-of-life decrements, and perhaps even greater mortality over the long run (5). Complete estrogen depletion in premenopausal women should be considered investigational pending results from ongoing prospective randomized trials addressing its relative worth compared with tamoxifen alone (6).
Although we hope that the observation regarding CYP2D6 genotype and tamoxifen activity, to which we have contributed, is validated, we do not believe the data thus far are sufficiently robust to justify routine use of this test in clinical medicine at present. We appreciate that Gurwitz and Newman agree that retrospective review of completed trials that have analyzed outcomes in relation to CYP2D6 genotype in patients randomly assigned to tamoxifen or aromatase inhibitor therapy is essential. We urge investigators who have access to these samples to proceed with analyses of these genotypes using validated methods for formalin-fixed, paraffin-embedded tissues (7).
REFERENCES
1. Hayes DF, Bast RC, Desch CE. Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst (1996) 88(20):1456–1466.
2. Wegman P, Elingarami S, Carstensen J, Stal O, Nordenskjold B, Wingren S. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res. (2007) 9(1):R7.[CrossRef][Medline]
3. Wegman P, Vainikka L, Stal O. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res. (2005) 7(3):R284–R290.[CrossRef][Web of Science][Medline]
4. Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol (2005) 23(3):619–629.
5. Rocca WA, Grossardt BR, de Andrade M, Malkasian GD, Melton LJ. III. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol (2006) 7(10):821–828.[Web of Science][Medline]
6. Regan MM, Pagani O, Walley B. Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy? Ann Oncol (2008).
7. Rae JM, Cordero KE, Scheys JO, Lippman ME, Flockhart DA, Johnson MD. Genotyping for polymorphic drug metabolizing enzymes from paraffin-embedded and immunohistochemically stained tumor samples. Pharmacogenetics (2003) 13(8):501–507.[CrossRef][Web of Science][Medline]
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J Natl Cancer Inst 2008 100: 1331.
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