American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer

Burstein, Harold J.; Prestrud, Ann Alexis; Seidenfeld, Jerome; Anderson, Holly; Buchholz, Thomas A.; Davidson, Nancy E.; Gelmon, Karen; Giordano, Sharon H.; Hudis, Clifford A.; Malin, Jennifer L.; Mamounas, Eleftherios P.; Rowden, Diana; Solky, Alexander J.; Sowers, Mary Fran; Stearns, Vered; Winer, Eric P.; Somerfield, Mark R.; Griggs, Jennifer J.

doi:10.1200/jco.2009.26.3756

Cited by 667 publications

(460 citation statements)

References 83 publications

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“…These risk factors for BC on the other hand were associated with a decreased risk for cancer treatment-induced bone loss (CTIBL) and fracture incidence 8 . Hereby, circulating sex hormones represent the mediator for the increased risk of BC and preventative factor for CTIBL.…”

Section: Bone Physiology and Pathophysiologymentioning

confidence: 99%

“…7 Current guidelines recommend aromatase inhibitors (AIs) for postmenopausal women with hormone receptorpositive BC at some point during adjuvant treatment, either as up-front therapy or as sequential treatment after tamoxifen. 8,9 In postmenopausal women, the aromatase enzyme is located in the muscle and adipose tissue converting androgen precursors into estrogen. 10 AIs (anastrozole, exemestane and letrozole) block the aromatase enzyme leading to a decrease in circulating serum estrogens and thereby improving disease-free survival as well as overall survival compared with tamoxifen in the adjuvant, as well as in the metastatic setting.…”

Section: Introductionmentioning

confidence: 99%

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Cancer Treatment-Induced Bone Loss in women with breast cancer

Hadji

2015

BoneKEy Reports

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Osteoporosis is one of the most frequent diseases in postmenopausal women, leading to an increased fracture risk due to the physiologic loss of the bone protective effects of estrogen. Hereby, several risk factors for fracture such as prevalent fracture, low bone mineral density (BMD), age, low body mass index, family history, tendency to falls, smoking, use of SSRIs, glucocorticoid use etc. have been identified. In addition, the further reduction in endogenous estrogens with chemotherapy (CHT), GnRH analoga or aromatase inhibitors (AIs) continuously increases fracture risk. Breast cancer (BC) on the other hand is the most frequent cancer type in women. Recent reports indicate a continuous increased incidence, whereas mortality, due to early diagnosis and treatment improvements, is decreasing. Dependent on specific tumor characteristics, radiation, CHT, antibody treatment as well as endocrine treatment have been included into the adjuvant clinical treatment setting. Some but not all of these cancer-specific treatments interfere with bone turnover, leading to an accelerated bone loss referred to as cancer treatment-induced bone loss (CTIBL). Whereas CHT leads to an unspecific increase in bone resorption, AI reduces residual serum endogenous estrogen level and is associated with a decrease in BMD and increased fracture risk. Independent of the type of AI administered, bone loss is 2-3-fold increased compared with healthy, age-matched postmenopausal controls. Therefore, several guidelines have emerged to help managing CTIBL in women with BC including strategies to identify and treat those at highest risk for fractures. This review summarizes the current knowledge on CTIBL and fracturing risk and indicates preventative strategies.

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Section: Bone Physiology and Pathophysiologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cancer Treatment-Induced Bone Loss in women with breast cancer

Hadji

2015

BoneKEy Reports

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“…There is a wide degree of interindividual and interethnic differences in the steady-state plasma concentrations of tamoxifen and its metabolites which have been shown to influence therapeutic outcome [6,7]. This area of research has generated intense clinical interest because of its potential to select women with postmenopausal hormone receptor positive early stage breast cancer who are poor metabolizers of tamoxifen to receive alternative adjuvant endocrine therapy with aromatase inhibitors [8]. The deviations in plasma concentrations of tamoxifen and its metabolites can be due to drug-drug interactions or genetic variants present in the genes responsible for encoding the various proteins involved in regulating its disposition [3].…”

Section: Introductionmentioning

confidence: 99%

Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients

Lim

Chen

Singh

et al. 2011

Brit J Clinical Pharma

112

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Tamoxifen is metabolized to active metabolites, 4‐hydroxytamoxifen and endoxifen, by multiple cytochrome P450 (CYP) enzymes including CYP2D6, CYP3A4/5, CYP2C9/19, CYP1A2 and CYP2B6.• The steady‐state plasma concentrations of tamoxifen and its metabolites can be affected by variations in the activity of these enzymes.• Although CYP2D6*4 and *10 have been shown to influence the plasma concentration of endoxifen in Caucasian and Korean patients respectively, there is still a paucity of data on CYP2D6 pharmacogenetics in other Orientals such as Chinese, Malays and Indians.WHAT THIS STUDY ADDS• Pharmacogenetic analyses of a comprehensive panel of CYP2D6 polymorphisms (*2, *2A, *3, *4, *5, *6, *7, *8, *9, *10, *12, *14, *17, *29, *41 and *xN) were performed in three distinct Asian ethnic groups and breast cancer patients with CYP2D6*5 and *10 found to be highly prevalent.• Both CYP2D6*5 and *10 were significantly associated with lower endoxifen and higher N‐desmethyltamoxifen concentrations as well as a lower rate of metabolic conversion of N‐desmethyltamoxifen to endoxifen.• Polymorphisms present in CYP3A5, CYP2C9 and CYP2C19 were not found to be significantly associated with plasma concentrations of analytes suggesting that these enzymes may be playing minor roles in the metabolic pathway of tamoxifen compared with CYP2D6.AIM To investigate the impact of genetic polymorphisms in CYP2D6, CYP3A5, CYP2C9 and CYP2C19 on the pharmacokinetics of tamoxifen and its metabolites in Asian breast cancer patients.METHODS A total of 165 Asian breast cancer patients receiving 20 mg tamoxifen daily and 228 healthy Asian subjects (Chinese, Malay and Indian; n= 76 each) were recruited. The steady‐state plasma concentrations of tamoxifen and its metabolites were quantified using high‐performance liquid chromatography. The CYP2D6 polymorphisms were genotyped using the INFINITI™ CYP450 2D6I assay, while the polymorphisms in CYP3A5, CYP2C9 and CYP2C19 were determined via direct sequencing.RESULTS The polymorphisms, CYP2D6*5 and *10, were significantly associated with lower endoxifen and higher N‐desmethyltamoxifen (NDM) concentrations. Patients who were *1/*1 carriers exhibited 2.4‐ to 2.6‐fold higher endoxifen concentrations and 1.9‐ to 2.1‐fold lower NDM concentrations than either *10/*10 or *5/*10 carriers (P < 0.001). Similarly, the endoxifen concentrations were found to be 1.8‐ to 2.6‐times higher in *1/*5 or *1/*10 carriers compared with *10/*10 and *5/*10 carriers (P≤ 0.001). Similar relationships were observed between the CYP2D6 polymorphisms and metabolic ratios of tamoxifen and its metabolites. No significant associations were observed with regards to the polymorphisms in CYP3A5, CYP2C9 and CYP2C19.CONCLUSIONS The present study in Asian breast cancer patients showed that CYP2D6*5/*10 and *10/*10 genotypes are associated with significantly lower concentrations of the active metabolite of tamoxifen, endoxifen. Identifying such patients before the start of treatment may be useful in optimizing therapy with tamoxifen. The role of CYP3A5, CYP2C9 and CYP2C19 seem to be minor.

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“…Contrary to this statement and due to lack of strong evidence, the American Society of Clinical Oncology (ASCO) [28] and the St. Gallen's expert consensus (2011) do not recommend the routine use of CYP2D6 genotyping in the setting of decision making about administration of tamoxifen. The analysis of existing literature regarding the clinical importance of CYP2D6 polymorphism in the outcome of breast cancer actually leads to conflicting results.…”

Section: Discussionmentioning

confidence: 98%

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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American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer

Cited by 667 publications

References 83 publications

Cancer Treatment-Induced Bone Loss in women with breast cancer

Cancer Treatment-Induced Bone Loss in women with breast cancer

Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients

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

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