Journal of the National Cancer Institute Advance Access originally published online on April 29, 2008
JNCI Journal of the National Cancer Institute 2008 100(9):642-648; doi:10.1093/jnci/djn100
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ARTICLES |
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 St, Boston, MA 02115 (e-mail: rpunglia{at}partners.org).
Background: Adjuvant endocrine treatment with aromatase inhibitors improves disease-free survival compared with tamoxifen in postmenopausal women with estrogen receptor–positive breast cancer. This difference could be due to differences in tamoxifen metabolism because levels of endoxifen, the active tamoxifen metabolite, vary with the number of mutant alleles, including the *4 allele, of the gene encoding cytochrome P450 2D6 (CYP2D6).
Methods: We created a Markov model to determine whether tamoxifen or aromatase inhibitor monotherapy maximized 5-year disease-free survival for patients with the wild-type CYP2D6 genotype (wt/wt). Annual risks of recurrence with aromatase inhibitors and tamoxifen in breast cancer patients who were not selected by CYP2D6 genotype were derived from the Breast International Group 1-98 trial. Genotype frequencies and the hazard ratio for cancer recurrence on tamoxifen among patients with the *4/*4 genotype relative to the wt/wt or wt/*4 genotypes (HR*4/*4 = 1.86) were based on data from an analysis of the North Central Cancer Treatment Group trial of adjuvant tamoxifen. We explored the impact of CYP2D6(*4) heterozygosity on disease-free suvival for wt/wt patients by studying a range of effect (ie, recurrence on tamoxifen) estimates, from no effect of the single mutation (Effwt/*4 = 0, recurrence rate in wt/*4 patients same as that in wt/wt patients) to complete effect (Effwt/*4 = 1 recurrence rate in wt/*4 patients same as that in *4/*4 patients).
Results: With HR*4/*4 = 1.86 and Effwt/*4 = 0.5, the 5-year disease-free survival of tamoxifen-treated patients with no mutations (wt/wt) was 83.9%, that is, essentially the same as that (84.0%) for genotypically unselected patients who were treated with aromatase inhibitors. With greater HR*4/*4 estimates, disease-free survival with tamoxifen exceed that with aromatase inhibitors in wt/wt patients, even at lower assumed Effwt/*4 ratios.
Conclusions: Modeling suggests that among patients who are wild type for CYP2D6, 5-year disease-free survival outcomes are similar to or perhaps even superior with tamoxifen than with aromatase inhibitors. Endocrine therapy tailored to CYP2D6 genotype could be considered for women who are newly diagnosed with breast cancer, particularly those who have with concerns about either the relative toxicity or the increased cost of aromatase inhibitors.
| CONTEXT AND CAVEATS Prior knowledge In two clinical trials, adjuvant endocrine treatment with aromatase inhibitors yielded improved disease-free survival compared with tamoxifen in postmenopausal women with estrogen receptor–positive breast cancer. Recent pharmacogenomic data suggest that the clinical benefit of tamoxifen may vary with the number of mutant alleles the patient carries in the gene that encodes CYP2D6, the cytochrome P450 isoform that is mainly responsible for catalyzing the conversion of tamoxifen to its functional metabolite endoxifen. Study design A decision-analytic model was constructed using data from CYP2D6 pharmacogenomic studies and used to evaluate whether an aromatase inhibitor or tamoxifen is the optimal initial treatment choice for postmenopausal women who do not carry a mutation that affects tamoxifen metabolism. Contribution Modeling suggests that among patients who are wild type for CYP2D6, adjuvant treatment with tamoxifen appears to provide 5-year disease-free survival outcomes that are similar or perhaps even superior to those achieved with aromatase inhibitors. Implications Endocrine therapy tailored to CYP2D6 genotype could be considered for women who are newly diagnosed with breast cancer. Limitations The model relies on the assumptions and estimates used. The model cannot be used to study the question of whether or how to sequence therapy. The findings apply to only postmenopausal women.
|
We would like to acknowledge Dr Richard Gelber (Dana-Farber Cancer Institute) and the BIG 1-98 Steering Committee; Drs Matthew Goetz and Vera Suman (Mayo Clinic College of Medicine); and Drs Werner Schroth, Michel Eichelbaum, and Hiltrud Brauch (Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University Tuebingen) for providing their data prior to publication to inform our modeling efforts.
The study sponsors had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.
Manuscript received October 4, 2007; revised February 15, 2008; accepted February 29, 2008.
Correspondence about this Article
Editorial about this Article
Related Article in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2008 100: 1331.
J Natl Cancer Inst 2008 100: 1331-1332.
J Natl Cancer Inst 2008 100: 610-613.
J Natl Cancer Inst 2008 100: 603.
This article has been cited by other articles:
|
|
 |
|
  D. Gurwitz and W. Newman Re: Pharmacogenomic Variation of CYP2D6 and the Choice of Optimal Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A Modeling Analysis J Natl Cancer Inst, September 17, 2008; 100(18): 1331 - 1331. [Full Text] [PDF]
|
|
|
|
|
|
R. T. Chlebowski and N. Col Re: Pharmacogenomic Variation of CYP2D6 and the Choice of Optimal Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A Modeling Analysis J Natl Cancer Inst, September 17, 2008; 100(18): 1331 - 1332. [Full Text] [PDF]
|
|
|
|
 |
|
 Pharmacogenomics, CYP2D6, and Adjuvant Endocrine Therapy Journal Watch Oncology and Hematology, May 13, 2008; 2008(513): 4 - 4. [Full Text]
|
|
|
|
|
|
D. F. Hayes, V. Stearns, J. Rae, D. Flockhart, and on behalf of the Consortium on Breast Cancer Pharm A Model Citizen? Is Tamoxifen More Effective Than Aromatase Inhibitors if We Pick the Right Patients? J Natl Cancer Inst, May 7, 2008; 100(9): 610 - 613. [Full Text] [PDF]
|
|