To the Editor:
In a recent article in Journal of Clinical Oncology, Sanchez-Spitman et al1 report on their prospective clinical study to assess the impact of CYP2D6 genotype and endoxifen plasma concentrations on relapse-free survival (RFS). They did not observe an association between CYP2D6 genotype or endoxifen concentrations with RFS in women receiving an admixture of chemotherapy, trastuzumab, tamoxifen, and aromatase inhibitors (AIs), and they concluded that neither CYP2D6 genotyping nor endoxifen metabolite monitoring are justified for guiding tamoxifen treatment. However, we will articulate several major issues with their study that provide the basis for serious concern regarding their conclusions.
A major consideration when one does a pharmacogenomic study is that the proper population of patients is being studied.2 In the case of tamoxifen, this population is based on observations demonstrating an association between CYP2D6 genotype3,4 and/or endoxifen concentrations5 with disease-free survival in women receiving tamoxifen monotherapy for the adjuvant treatment of estrogen receptor–positive/human epidermal growth factor receptor 2–negative (ER-positive/HER2-negative) breast cancer. In contrast, CYP2D6 genotype, which is related to endoxifen concentrations,6 has not been found to be associated with clinical outcomes in women receiving chemotherapy before treatment with tamoxifen7 or in women switched to an AI after tamoxifen.8 A simple explanation is that these additional systemic therapies alter the hazard for both early and late breast cancer events. For example, adjuvant chemotherapy reduces events associated with de novo tamoxifen resistance9 and endocrine responsive events by suppressing ovarian function in premenopausal women.10
Sanchez-Spitman et al1 performed their power calculations by using data from clinical studies3,5 of women receiving tamoxifen monotherapy for 5 years for the adjuvant treatment of ER-positive breast cancer. However, instead of enrolling a similar population of women in the CYPTAM study, Sanchez-Spitman et al1 included women who received prior adjuvant chemotherapy (61%), who were treated with trastuzumab (9%), who were pretreated with tamoxifen (95%), and who then switched to an AI (66%) after a short duration (median, 2.6 years but as short as 3 months) of tamoxifen. Although the underlying assumptions and number of events needed for sufficient power to address the pharmacogenetic and endoxifen concentration questions were specifically lacking in their article, we attempted to perform a power calculation using the hazard ratio of 2.0 in the setting of a similar population of women receiving tamoxifen for 2.5 years.3 We assumed a 2-year RFS rate of 95% in the poor metabolizers, intermediate metabolizers, and heterozygous extensive metabolizers, an equal number of patients in each group, enrollment period of 3 years, and minimum follow-up of 3 years after close of enrollment. In this situation, a two-sided log-rank test with an overall sample size of 798 patients (399 in each group) achieves 80.0% power at a 0.050 significance level to detect a hazard ratio of 2.02 with an expected number of events of 66. Given that only 255 patients received tamoxifen monotherapy for a short duration, the study by Sanchez-Spitman et al1 was neither designed nor powered to identify an association between CYP2D6 genotype or endoxifen concentrations with RFS.
Additional concerns (acknowledged by Sanchez-Spitman et al1) are related to their study design that allowed women to enroll up to 12 months after tamoxifen initiation as well as the heavy use of censoring after patients were switched to an AI. Regarding their patient enrollment schema, the design introduced biases because women who recur within the first year of adjuvant tamoxifen treatment do not have the same chance at enrollment as those who recur after the first year of adjuvant tamoxifen treatment. Furthermore, women being considered for the Sanchez-Spitman et al1 study were enrolled on the basis of their pre-existing tolerance to tamoxifen and willingness to adhere to its administration. Other studies were not able to exclude such women because those studies enrolled patients at the time of planned tamoxifen initiation. Regarding the issue of censoring, approximately 66% of the patients were censored after 2 to 3 years of adjuvant tamoxifen (corresponding to approximately 1 to 2 years on study). The statistical methods used to analyze these data assume that censoring is at random and those who are censored have event prospects similar to those who continue on tamoxifen. With such heavily planned censoring for switching treatment, it is unclear what impact this had on the statistical results.
In summary, the following critical question surrounding the pharmacogenomics of tamoxifen remains: What is the impact of CYP2D6 genotype and/or endoxifen concentrations on the risk for recurrence in women receiving tamoxifen monotherapy for the adjuvant treatment of ER-positive/HER2-negative breast cancer? The study by Sanchez-Spitman et al1 was neither designed nor statistically powered to answer this question. Importantly, this question continues to remain globally relevant for hundreds of thousands of women being considered for tamoxifen each year.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Tamoxifen Metabolism and Breast Cancer Recurrence: A Question Unanswered by CYPTAM
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Matthew P. Goetz
Consulting or Advisory Role: Eli Lilly, Biotheranostics, Genomic Health, Novartis, Eisai, Sermonix Pharmaceuticals, Context Therapeutics, Pfizer
Research Funding: Eli Lilly, Pfizer
Patents, Royalties, Other Intellectual Property: Methods and Materials for Assessing Chemotherapy Responsiveness and Treating Cancer; Methods and Materials for Using Butyrylcholinesterases to Treat Cancer; Development of Human Tumor Xenografts from Women with Breast Cancer Treated with Neoadjuvant Chemotherapy (Inst)
Travel, Accommodations, Expenses: Eli Lilly
Yusuke Nakamura
Stock and Other Ownership Interests: OncoTherapy Science
Consulting or Advisory Role: OncoTherapy Science, FRONTEO Healthcare
Research Funding: OncoTherapy Science
Patents, Royalties, Other Intellectual Property: I have nearly 100 patents with University Tokyo and OncoTherapy Science.
Kazuma Kiyotani
Consulting or Advisory Role: Cancer Precision Medicine
No other potential conflicts of interest were reported.
REFERENCES
- 1.Sanchez-Spitman A, Dezentjé V, Swen J, et al. Tamoxifen pharmacogenetics and metabolism: Results from the prospective CYPTAM study. J Clin Oncol. 2019;37:636–646. doi: 10.1200/JCO.18.00307. [DOI] [PubMed] [Google Scholar]
- 2.Kiyotani K, Mushiroda T, Zembutsu H, et al. Important and critical scientific aspects in pharmacogenomics analysis: Lessons from controversial results of tamoxifen and CYP2D6 studies. J Hum Genet. 2013;58:327–333. doi: 10.1038/jhg.2013.39. [DOI] [PubMed] [Google Scholar]
- 3.Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005;23:9312–9318. doi: 10.1200/JCO.2005.03.3266. [DOI] [PubMed] [Google Scholar]
- 4.Province MA, Goetz MP, Brauch H, et al. CYP2D6 genotype and adjuvant tamoxifen: Meta-analysis of heterogeneous study populations. Clin Pharmacol Ther. 2014;95:216–227. doi: 10.1038/clpt.2013.186. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Saladores P, Mürdter T, Eccles D, et al. Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer. Pharmacogenomics J. 2015;15:84–94. doi: 10.1038/tpj.2014.34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Stearns V, Johnson MD, Rae JM, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 2003;95:1758–1764. doi: 10.1093/jnci/djg108. [DOI] [PubMed] [Google Scholar]
- 7.Kiyotani K, Mushiroda T, Hosono N, et al. Lessons for pharmacogenomics studies: Association study between CYP2D6 genotype and tamoxifen response. Pharmacogenet Genomics. 2010;20:565–568. doi: 10.1097/FPC.0b013e32833af231. [DOI] [PubMed] [Google Scholar]
- 8.Goetz MP, Suman VJ, Hoskin TL, et al. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin Cancer Res. 2013;19:500–507. doi: 10.1158/1078-0432.CCR-12-2153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726–3734. doi: 10.1200/JCO.2005.04.7985. [DOI] [PubMed] [Google Scholar]
- 10.International Breast Cancer Study Group. Colleoni M, Gelber S, et al. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol. 2006;24:1332–1341. doi: 10.1200/JCO.2005.03.0783. [DOI] [PubMed] [Google Scholar]