Association Between CYP2D6 Polymorphisms and Outcomes Among Women With Early Stage Breast Cancer Treated With Tamoxifen

Schroth, Werner; Goetz, Matthew P.; Hamann, Ute; Fasching, Peter A.; Schmidt, Marcus; Winter, Stefan; Fritz, Péter; Simon, Wolfgang; Suman, Vera J.; Ames, Matthew M.; Safgren, Stephanie L.; Kuffel, Mary J.; Ulmer, Hans Ulrich; Boländer, Julia; Strick, Reiner; Beckmann, Matthias W.; Koelbl, Heinz; Weinshilboum, Richard M.; Ingle, James N.; Eichelbaum, Michel; Schwab, Matthias; Brauch, Hiltrud

doi:10.1001/jama.2009.1420

Cited by 476 publications

(356 citation statements)

References 42 publications

(56 reference statements)

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“…Specifically, tamoxifen is metabolized predominantly by CYP2D6 to form two active metabolites, 4-hydroxytamoxifen (4-OH-TAM) and 4-hydroxy-Ndesmethyltamoxifen (endoxifen), which show much greater affinity for the estrogen receptor than tamoxifen (36,37); furthermore, 4-OH-TAM and endoxifen are metabolized by SULT1A1 to form highly reactive products, leading to DNA adducts (38,39). There is substantial evidence that functional polymorphisms (including SNPs and gene copy number variations) of CYP2D6 and SULT1A1 are associated with tamoxifen pharmacokinetics and clinical outcomes of efficacy and adverse effects (40)(41)(42)(43)(44). Of note, a recent study involving 1,325 breast cancer patients receiving tamoxifen suggests that the presence of two functional CYP2D6 alleles is associated with better clinical outcomes, and the presence of nonfunctional or reduced-function alleles with worse outcomes (44).…”

Section: Discussionmentioning

confidence: 99%

“…There is substantial evidence that functional polymorphisms (including SNPs and gene copy number variations) of CYP2D6 and SULT1A1 are associated with tamoxifen pharmacokinetics and clinical outcomes of efficacy and adverse effects (40)(41)(42)(43)(44). Of note, a recent study involving 1,325 breast cancer patients receiving tamoxifen suggests that the presence of two functional CYP2D6 alleles is associated with better clinical outcomes, and the presence of nonfunctional or reduced-function alleles with worse outcomes (44). In addition, the low-activity SULT1A1*2 allele has been associated with significantly poorer overall survival in breast cancer patients receiving tamoxifen (43).…”

Section: Discussionmentioning

confidence: 99%

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Association of Human Cytochrome P450 1A1 (CYP1A1) and Sulfotransferase 1A1 (SULT1A1) Polymorphisms with Differential Metabolism and Cytotoxicity of Aminoflavone

Zheng

Sha

Liu

et al. 2010

Molecular Cancer Therapeutics

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Aminoflavone (AF), a clinically investigational novel anticancer agent, requires sequential metabolic activation by CYP1A1 and SULT1A1 to exert its antitumor activities. The purpose of this study was to determine the functional significance of common polymorphisms of human CYP1A1 and SULT1A1 on the metabolism and cytotoxicity of AF. To this end, Chinese Hamster V79 cells were genetically engineered to stably express human CYP1A1*1 (wild-type), CYP1A1*2C (I462V), or CYP1A1*4 (T461N) and coexpress human CYP1A1*1 with human SULT1A1*1 (wild-type), SULT1A1*2 (R213H), or SULT1A1*3 (M223V). The metabolism and cytotoxicity of AF were evaluated in these cellular models. All common variants of CYP1A1 and SULT1A1 were actively involved in the metabolic activation of AF, but with a varying degree of activity. Whereas CYP1A1 I462V variant exhibited a superior activity (mainly caused by a significantly higher V max ) for hydroxylations of AF, expression of different CYP1A1 variants did not confer cell differential sensitivity to AF. The cells coexpressing CYP1A1*1 with SULT1A1

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association of Human Cytochrome P450 1A1 (CYP1A1) and Sulfotransferase 1A1 (SULT1A1) Polymorphisms with Differential Metabolism and Cytotoxicity of Aminoflavone

Zheng

Sha

Liu

et al. 2010

Molecular Cancer Therapeutics

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“…Importantly, this study also examined genotypes for an identical control group of women not treated with adjuvant tamoxifen, and genotype had no bearing on disease-related outcomes. A 1325-patient international consortium study confirmed these findings (Schroth et al, 2009). A smaller prior study (also including a control group) had failed to demonstrate the association of three loss-of-function CYP2D6 genotypes (CYP2D6*3, *4, and *6) with reduced tamoxifen-related survival benefit, but importantly, this study did not test for any of the other now known loss-of-function and reduced-function alleles (Nowell et al, 2005).…”

Section: Fcgriia Fcgriiiamentioning

confidence: 54%

Germline pharmacogenomics in oncology: Decoding the patient for targeting therapy

O’Donnell

Ratain

2012

Molecular Oncology

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A B S T R A C TPharmacogenomics is the study of genetic factors determining drug response or toxicity.The use of pharmacogenomics is especially desirable in oncology because the therapeutic index of oncology drugs is often narrow, the need for favorable drug response is often acute, and the consequences of drug toxicity can be life-threatening. In this review, we examine the state of pharmacogenomics in oncology, focusing only on germline pharmacogenomic variants. We consider several critical points when assessing the quality of pharmacogenomic findings and their relevance to clinical use, and discuss potential confounding factors limiting interpretation and implementation. Several of the most extensively studied drugegene pairs (irinotecan and UGT1A1; tamoxifen and CYP2D6; 5-fluorouracil and DPYD) are inspected in depth as illustrations of both the state of advancementdand the current limitations ofdpresent knowledge. We argue that there will likely soon be a critical mass of important germline pharmacogenomic biomarkers in oncology which deserve clinical implementation to provide optimal, personalized oncologic care.We conclude with a vision of how routine clinical testing of such germline markers could one day change the paradigm for cancer care.

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“…Although no difference in overall survival could be observed heterozygous EM/IM and PM had significant higher recurrence rates and worse eventfree and disease-free survival. CYP2D6*4 was present in 20% of study cases [10] . A small series of 84 patients under adjuvant treatment with tamoxifen from Spain focused exclusively in allele *4.…”

Section: Researchmentioning

confidence: 93%

“…August 10, 2014|Volume 5|Issue 3| WJCO|www.wjgnet.com Goetz et al [8] RFS DFS OS NS (P = 0.075) NS (P = 0.097) NS Worse (P = 0.005) Worse (P = 0.008) NS Scroth et al [9,10] RR MR [12] DFS 118 mo 114 mo 98 mo Bijl et al [13] RBCM NS Increased (P = 0.041) Newman et al [16] OS Worse Karle et al [17] PFS 14 mo 9 mo Abraham et al [20] BCSS NS Nowell [23] BCR, OS NS NS Rae et al [25] RR NS NS Regan et al [26] BCE prospective multicenter randomised trial (Austrian Breast and Colorectal Study 8 -ABCSG trial 8) have been newly published. In this cohort 3901 postmenopausal patients with resected ER+ early cancer were randomised to receive either five years tamoxifen or two years tamoxifen followed by anastrazole administration over three more years.…”

mentioning

confidence: 99%

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

Markopoulos

Kykalos

Mantas

2014

WJCO

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Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450 (CYP) enzymes, in particular the CYP2D6 isoform. CYP2D6*4 is one of the most frequent alleles associated with loss of enzymatic activity. The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning (null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The numerous existing studies investigating the association of CYP2D6 with treatment failure in breast cancer are inconsistent and give rather conflicting results. Currently, routine CYP2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: CYP2D6; Tamoxifen; Breast cancer; Adjuvant treatment Core tip: Currently, routine cytochrome P450 (CYP)2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome.Markopoulos C, Kykalos S, Mantas D. Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen.

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Association Between CYP2D6 Polymorphisms and Outcomes Among Women With Early Stage Breast Cancer Treated With Tamoxifen

Cited by 476 publications

References 42 publications

Association of Human Cytochrome P450 1A1 (CYP1A1) and Sulfotransferase 1A1 (SULT1A1) Polymorphisms with Differential Metabolism and Cytotoxicity of Aminoflavone

Association of Human Cytochrome P450 1A1 (CYP1A1) and Sulfotransferase 1A1 (SULT1A1) Polymorphisms with Differential Metabolism and Cytotoxicity of Aminoflavone

Germline pharmacogenomics in oncology: Decoding the patient for targeting therapy

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

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