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Journal of Clinical Oncology, Vol 26, No 10 (April 1), 2008: pp. 1764-1765 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.5432
Modification of Tamoxifen Response: What Have We Learned?Department of Epidemiology, Boston University School of Public Health, Boston, MA
Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
Department of Surgery, Aalborg Hospital, Aalborg, Denmark
Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark
Department of Oncology, Aalborg Hospital, Aalborg, Denmark
Department of Medicine, Boston University School of Medicine, Boston, MA
Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark To the Editor: In a recent Journal of Clinical Oncology editorial, Desta and Flockhart1 asked a yes-no question about the germline pharmacogenetics of tamoxifen response: "Have we learned enough?" They ultimately answer by writing that recommendations regarding genetic testing for CYP2D6 variants must await further data, but the list of open questions preceding this answer did not include the question of whether there is a main effect. We therefore raise this question about the main effect: "Has it been established that tamoxifen is a less effective adjuvant therapy for estrogen receptor–positive breast cancer patients with functionally variant CYP2D6 allele(s) than for those without functionally variant alleles?" Figure 1 depicts the results of the five epidemiologic studies of this question.2-6 To examine the departure of the distribution of these results from the null (ie, relative risk of 1.0), we first ranked the five relative risks of recurrence from lowest to highest (citations 2 to 6 in ascending order). We then plotted each study's relative risk and its 95% CI against the inverse normal of its rank percentile.7 The stippled line shows the regression of inverse-variance weighted log-relative risk against the inverse normal of rank percentile. If the accumulated evidence is a random sample from a log normal distribution of relative risks centered on the null, then the relative risks should fall along this line and the line should intersect the x-axis at zero. The results of the accumulated studies fit just such a pattern. Indeed, the inverse-variance weighted geometric mean of the relative risks equals 1.04 (95% CI, 0.77, 1.41). Each study has certain strengths and limitations, some of which were pointed out by Desta and Flockhart, and consideration of them against one another is of value. Nonetheless, the simplest explanation for the results to date is that they are sampled from an underlying null association.
The integer above each interval in Fig 1 shows the number of women in the study (as best we can determine) with a recurrence and with the variant allele(s). Because both recurrence and the variant allele are rare, this number is the primary determinant of the study's precision. Summed over all of the studies, there are only approximately sixty women with both a recurrence and the variant allele(s), about half from studies reporting a protective association and half from studies reporting a causal association. In our view, sixty women, evenly distributed about the null, is too small a number to consider the association between CYP2D6-variant alleles and tamoxifen effectiveness to be precisely established. Whether tamoxifen's effectiveness in the adjuvant setting is modified by gene variants and other medications is an important question. Based on the underlying pharmacology, ably reviewed by Desta and Flockhart in their editorial and elsewhere, it is reasonable to hypothesize that tamoxifen's effectiveness would be reduced by genetic variants or other medications that interfere with the metabolism of tamoxifen to its pharmacologically most active forms. However, the epidemiologic evidence accumulated to date does not support that conclusion. We therefore answer the question we posed at the outset with an unequivocal "no, it has not been established that tamoxifen is a less effective adjuvant therapy for estrogen receptor–positive breast cancer patients with functionally variant CYP2D6 allele(s) than for those without functionally variant alleles." We encourage researchers to continue to generate and publish evidence that informs the answer regardless of whether the result comports with the compelling hypothesis suggested by the pharmacology. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS Supported by grants from the US National Cancer Institute (R01 CA118708), Danish Cancer Society (DP06117), and the Karen Elise Jensen Foundation. REFERENCES
1. Desta Z, Flockhart DA: Germline pharmacogenetics of tamoxifen response: Have we learned enough? J Clin Oncol 25:5147-5148, 2007 2. Wegman P, Vainikka L, Stal O, et al: Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res 7:R282-R290, 2005 3. Nowell SA, Ahn J, Rae JM, et al: Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat 91:249-258, 2005[CrossRef][Medline] 4. Wegman P, Elingarami S, Carstensen J, et al: Genetic variants of CYP2A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res 9:R7, 2007[CrossRef][Medline] 5. Goetz MP, Knox SK, Suman VJ, et al: The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 101:113-121, 2007[CrossRef][Medline] 6. Schroth W, Antoniadou L, Fritz P, et al: Breast cancer treatment outcome with adjuvant tamoxifen in relation to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25:5187-5193, 2007 7. Cunnane C: Unbiased plotting positions: A review. J Hydrology 37:205-222, 1978[CrossRef] Related Reply
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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