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):1331; doi:10.1093/jnci/djn269
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2008. Published by Oxford University Press.
CORRESPONDENCE |
Re: Pharmacogenomic Variation of CYP2D6 and the Choice of Optimal Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A Modeling Analysis
Affiliations of authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv Israel (DG); Department of Medical Genetics, University of Manchester, United Kingdom (WN)
Correspondence to: Dr David Gurwitz, PhD, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel (e-mail: gurwitz{at}post.tau.ac.il).
The modeling analysis of the Breast International Group 1–98 (BIG1-98) trial presented by Puglia et al. (1) provides an important impetus to further studies of tamoxifen pharmacogenetics. However, it is important to note that their analysis focused solely on the CYP2D6*4 allele. Although CYP2D6*4 is the allele most frequently associated with poor tamoxifen metabolizer status among whites, other alleles, including *3, *5, and *6, are also relatively common in this population (2). In addition, alleles associated with intermediate metabolizer status, including *41, are known to contribute to tamoxifen response (3) and should be considered in future analyses and, potentially, in diagnostic tests provided in the clinical setting. Breast cancer is also a clinically significant health problem in nonwhite populations (4). However, the major breast cancer adjuvant and chemoprevention trials are predominantly composed of white participants and so cannot address the relevance of CYP2D6 variation to tamoxifen response in other ethnic groups. Importantly, the major alleles associated with reduced CYP2D6 activity in Asians and Africans are CYP2D6*10 and CYP2D6*17, respectively. A recent study of 152 Chinese breast cancer patients who received tamoxifen (5) reported statistically significantly worse disease-free survival for CYP2D6*10 homozygous patients compared to individuals heterozygous or wild type for this allele (hazard ratio of recurrence = 4.7, 95% confidence interval = 1.1 to 20.0; P = .04). A smaller study from Japan (6) reported a 16-fold increased risk of cancer recurrence in CYP2D6*10 homozygotes (P = .006) compared with those homozygous for the wild-type allele during 10 years of follow up. Therefore, it is vital that the relevant alleles are considered and that appropriately powered studies are conducted across different ethnic groups to establish the value of CYP2D6 genotyping before initiating tamoxifen therapy.
We concur with the recent statement by the Consortium on Breast Cancer Pharmacogenomics (COBRA) concerning CYP2D6 genotype testing for breast cancer patients who are considering tamoxifen therapy (7) that such testing may not always be applicable and that "rigorous validation [of Punglia et al.’s results] is critical before widespread adoption." The alternative adjuvant drug class of choice, the aromatase inhibitors, carries risks and may not always be an appropriate alternative to tamoxifen, even for postmenopausal women with estrogen receptor (ER)–positive tumors. We also agree with COBRA that results of pharmacogenetic studies of archived samples from the large randomized trials of tamoxifen vs the aromatase inhibitors anastrozole (the Arimidex, Tamoxifen, Alone, or in Combination (ATAC) or letrozole (BIG1-98) trials will provide clear evidence regarding the role of CYP2D6 genotyping in the adjuvant tamoxifen setting (7). Likewise, retrospective analysis of breast cancer chemoprevention trials, such as the International Breast Cancer Intervention Study (IBIS) and the Study of Tamoxifen and Raloxifene (STAR), will establish the value of tamoxifen in the prophylactic setting.
Yet, we believe 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 when deciding between tamoxifen and aromatase inhibitors in the adjuvant setting. Patients have the inherent right to know about developments in medicine that may affect the clinical management of their cancer and allow them to take informed treatment decisions where alternative strategies are available.
REFERENCES
1. Punglia RS, Burstein HJ, Winer EP, Weeks JC. Pharmacogenomic variation of CYP2D6 and the choice of optimal adjuvant endocrine therapy for postmenopausal breast cancer: a modeling analysis. J Natl Cancer Inst (2008) 100(9):642–648.
2. Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics (2002) 3(2):229–243.[CrossRef][Web of Science][Medline]
3. Schroth W, Antoniadou L, Fritz P, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol (2007) 25(33):5187–5193.
4. Chlebowski RT, Chen Z, Anderson GL, et al. Ethnicity and breast cancer: factors influencing differences in incidence and outcome. J Natl Cancer Inst (2005) 97(6):439–448.
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(8):1423–1429.
6. 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(5):995–999.[CrossRef][Medline]
7. Hayes DF, Stearns V, Rae J, Flockhart D, on behalf of the Consortium on Breast Cancer Pharmacogenomics. A model citizen? Is tamoxifen more effective than aromatase inhibitors if we pick the right patients? J Natl Cancer Inst (2008) 100(9):610–613.
Response to this Correspondence
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2008 100: 1332-1333.
J Natl Cancer Inst 2008 100: 1333-1334.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||