Journal of Personalized Medicine Review Generating a Precision Endoxifen Prediction Algorithm to Advance Personalized Tamoxifen Treatment in Patients with Breast Cancer Thomas Helland 1,2,3,* , Sarah Alsomairy 1, Chenchia Lin 1, Håvard Søiland 3, Gunnar Mellgren 2,3 and Daniel Louis Hertz 1 1 Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USA; [email protected] (S.A.); [email protected] (C.L.); [email protected] (D.L.H.) 2 Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, 5021 Bergen, Norway; [email protected] 3 Department of Clinical Science, University of Bergen, 5007 Bergen, Norway; [email protected] * Correspondence: [email protected]; Tel.: +47-92847793 Abstract: Tamoxifen is an endocrine treatment for hormone receptor positive breast cancer. The effectiveness of tamoxifen may be compromised in patients with metabolic resistance, who have insufficient metabolic generation of the active metabolites endoxifen and 4-hydroxy-tamoxifen. This has been challenging to validate due to the lack of measured metabolite concentrations in tamoxifen clinical trials. CYP2D6 activity is the primary determinant of endoxifen concentration. Inconclusive results from studies investigating whether CYP2D6 genotype is associated with tamoxifen efficacy may be due to the imprecision in using CYP2D6 genotype as a surrogate of endoxifen concentration Citation: Helland, T.; Alsomairy, S.; without incorporating the influence of other genetic and clinical variables. This review summarizes Lin, C.; Søiland, H.; Mellgren, G.; the evidence that active metabolite concentrations determine tamoxifen efficacy. We then introduce a Hertz, D.L. Generating a Precision novel approach to validate this relationship by generating a precision endoxifen prediction algorithm Endoxifen Prediction Algorithm to and comprehensively review the factors that must be incorporated into the algorithm, including Advance Personalized Tamoxifen genetics of CYP2D6 and other pharmacogenes. A precision endoxifen algorithm could be used to Treatment in Patients with Breast validate metabolic resistance in existing tamoxifen clinical trial cohorts and could then be used to Cancer. J. Pers. Med. 2021, 11, 201. select personalized tamoxifen doses to ensure all patients achieve adequate endoxifen concentrations https://doi.org/10.3390/ and maximum benefit from tamoxifen treatment. jpm11030201 Keywords: endoxifen; 4OHtam; tamoxifen metabolism; CYP2D6; pharmacogenetics; SULT; UGT; Academic Editor: Alan L. Myers CYP3A; CYP2C; personalized treatment Received: 18 February 2021 Accepted: 9 March 2021 Published: 13 March 2021 1. Introduction and Objective Publisher’s Note: MDPI stays neutral Tamoxifen is an endocrine drug that has significantly improved outcomes in hormone with regard to jurisdictional claims in receptor positive breast cancer [1]. However, the 10-year recurrence rate in patients using published maps and institutional affil- tamoxifen is ~30% [1]. Tamoxifen is a weak anti-estrogen that requires metabolic conversion iations. to active metabolites that have higher affinity to the estrogen receptor (ER). This conversion is mediated by several cytochrome P450 (CYP) enzymes in which CYP2D6 plays a central role in the generation of the main active metabolite endoxifen [2]. Diminished CYP2D6 phenotypic activity is associated with lower levels of endoxifen [2,3] that may reduce Copyright: © 2021 by the authors. treatment response [4], which we refer to as metabolic resistance [4–6]. However, few Licensee MDPI, Basel, Switzerland. large clinical trials have measured endoxifen concentration, preventing confirmation of This article is an open access article metabolic resistance or identification of an endoxifen threshold below which efficacy is distributed under the terms and compromised. Many studies have investigated the association of tamoxifen treatment conditions of the Creative Commons outcomes with CYP2D6 genotype, as a surrogate of endoxifen concentration (Figure1). The Attribution (CC BY) license (https:// inconclusive findings [7] from these analyses may be due to the imprecision in predicting creativecommons.org/licenses/by/ endoxifen from only CYP2D6 genotype [8]. 4.0/). J. Pers. Med. 2021, 11, 201. https://doi.org/10.3390/jpm11030201 https://www.mdpi.com/journal/jpm J. Pers. Med. 2021, 11, 201 2 of 23 J. Pers. Med. 2021, 11, x FOR PEER REVIEW 2 of 24 This reviewifen comprehensively treatment outcomes with reviews CYP2D6 the genotype, factors as a thatsurrogate contribute of endoxifen to concentra- imprecision in endoxifen predictiontion (Figure by CYP2D6 1). The inconclusiveand describes findings [7] from the these contribution analyses mayof be otherdue to the non- im- CYP2D6 precision in predicting endoxifen from only CYP2D6 genotype [8]. genetic and clinical factorsThis review to comprehensively endoxifen concentrations. reviews the factors that The contribute objective to imprecision of this review in is to provide a better understandingendoxifen prediction ofby CYP2D6 these factorsand describes to movethe contribution this field of other away non-CYP2D6 from thege- use of a netic and clinical factors to endoxifen concentrations. The objective of this review is to single genotype (CYP2D6provide a better) and understanding toward building of these factors a precision to move this endoxifen field away from prediction the use of modela that integrates geneticsingle and genotype clinical (CYP2D6 variables.) and toward This building algorithm a precis couldion endoxifen enable prediction definitive model analyses of the associationthat of integrates endoxifen genetic concentration and clinical variables. with This tamoxifen algorithm could treatment enable definitive effectiveness anal- and yses of the association of endoxifen concentration with tamoxifen treatment effectiveness could then be usedand for could personalized then be used for tamoxifen personalized dosingtamoxifen todosing ensure to ensure that that all all patients patients achieve target endoxifen concentrationsachieve target endoxifen and concentrations receive maximum and receive benefitmaximum from benefit tamoxifen from tamoxifen treatment. treatment. Figure 1. Approaches for investigating metabolic resistance in breast cancer patients. The CYP2D6-endoxifen relationship isFigure well established. 1. Approaches The endoxifen-efficacy for investigating relationship has metabolic been reported resistance but not sufficientl in breasty validated cancer due patients.to a lack of The CYP2D6- availableendoxifen data. The relationship CYP2D6-efficacy is relationship well established. has not been conclusively The endoxifen-efficacy demonstrated due to relationshipthe imprecision in hasusing been reported CYP2D6 as a surrogate of endoxifen concentration. Box plot and survival curves are for illustration purposes only. EM = Extensivebut not Metabolizer, sufficiently IM = Intermediate validated Metabolizer, due to aPM lack = Poor of Metabolizer. available data. The CYP2D6-efficacy relationship has not been conclusively demonstrated due to the imprecision in using CYP2D6 as a surro- 2. Tamoxifen Clinical Use, Metabolism and Metabolic Resistance gate of endoxifen concentration.2.1. Tamoxifen Treatment Box and plot Mechanism and survival of Action curves are for illustration purposes only. EM = Extensive Metabolizer,Tamoxifen IM is= a Intermediateselective estrogen Metabolizer, receptor modulator PM used = Poor in the Metabolizer. treatment and pre- vention of hormone receptor positive breast cancer. In the adjuvant setting, tamoxifen (20 2. Tamoxifen Clinicalmg/day) Use, is mainly Metabolism indicated for premenopau and Metabolicsal patients Resistance with a recommended treatment 2.1. Tamoxifen Treatmenttime of 5 years and that Mechanism may also beof extended Action to 10 years [1,9]. Although the overall reduction in mortality from tamoxifen treatment is substantial, the recurrence rate reduction re- Tamoxifen ismains a selective about 50% estrogen during treatment receptor and one-third modulator in the subsequent used in five the years treatment [1], with and pre- some patients experiencing treatment failure. Tamoxifen may also be used to reduce the vention of hormonerisk of receptor developingpositive breast cancer breast in high-ris cancer.k women In with the or adjuvantwithout neoplastic setting, events tamoxifen (20 mg/day) is mainly[10,11]. indicated for premenopausal patients with a recommended treat- ment time of 5 yearsThe that rationale may for also tamoxifen be extended treatment of tohorm 10one years receptor [1 positive,9]. Although breast cancer theis overall to prevent transcription of ER-regulated genes involved in breast cancer differentiation, reduction in mortalityproliferation, from and tamoxifen migration [12]. treatment Tamoxifen’s is mechanism substantial, of action the involves recurrence binding the rate reduc- tion remains aboutligand 50% binding during pocket treatment of the ER that and promot one-thirdes a conformational in the subsequentchange preventing five re- years [1], cruitment of coactivators and instead cause association with corepressors thus repressing with some patients experiencing treatment failure. Tamoxifen may also be used to re- duce the risk of developing breast cancer in high-risk women with or without neoplastic events [10,11]. The rationale for tamoxifen treatment of hormone receptor positive breast cancer is to prevent transcription of ER-regulated