Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer

Borrie, Adrienne E; Rose, Rhiannon V.; Choi, Yunhee; Perera, Francisco; Read, Nancy; Sexton, Tracy; Lock, Michael; Vandenberg, Theodore A.; Hahn, Karin; Dinniwell, Robert; Younus, Jawaid; Logan, Diane; Potvin, Kylea; Yaremko, Brian; Yu, Edward; Lenehan, John; Welch, Stephen; Tyndale, Rachel F.; Teft, Wendy A.; Kim, Richard B.

doi:10.1007/s10549-018-4910-z

Cited by 12 publications

(9 citation statements)

References 19 publications

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“…In postmenopausal women treated for breast cancer with a standard Lz dose of 2.5 mg per day, the variation in plasma concentrations of Lz is largely explained by BMI, age and CYP2A6 genotype, and the therapeutic range of Lz is considered wide. Serum Lz level or CYP2A6 genotype have not been associated with arthralgia, a commonly reported adverse effect of Lz (Desta et al, 2011;Tanii et al, 2011;Borrie et al, 2018), and in the current study, Lz was well-tolerated and high Lz levels were not associated with the patient-reported side effects.…”

Section: Discussionsupporting

confidence: 61%

Anti-Müllerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone

Kohva

Varimo

Huopio

et al. 2020

ESPE

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STUDY QUESTION: Does treatment of constitutional delay of growth and puberty (CDGP) in boys with aromatase inhibitor letrozole (Lz) or conventional low-dose testosterone (T) have differing effects on developing seminiferous epithelium? SUMMARY ANSWER: Anti-Müllerian hormone (AMH) declined similarly in both treatment groups, and the two Sertoli cell-derived markers (AMH and inhibin B (iB)) exhibited differing responses to changes in gonadotrophin milieu. WHAT IS KNOWN ALREADY: Boys with CDGP may benefit from puberty-inducing medication. Peroral Lz activates gonadotrophin secretion, whereas intramuscular low-dose T may transiently suppress gonadotrophins and iB. Kohva et al.

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Section: Discussionsupporting

confidence: 61%

Anti-Müllerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone

Kohva

Varimo

Huopio

et al. 2020

ESPE

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“…Although osteoporosis or decreases in bone mineral have not been found in letrozole‐treated boys in previous studies, it is worth noting that in rodents, letrozole causes sustained reductions in bone strength and alterations in periosteal, endosteal, and skeletal geometry, resulting in vulnerable bones 11,31,32 . Arthralgia has been widely reported in postmenopausal women but not in boys; its presence was confirmed in this study 6,12,34 . The adverse bone effects described above could not be attributed to GH; instead, the mechanism likely involves cyclooxygenase‐2 (COX‐2), which plays an essential role in bone formation and is indirectly inhibited by AIs 35,36 .…”

Section: Discussionmentioning

confidence: 51%

“…The optimal measures of sensitivity (66.7%) and specificity (68.7%) were defined at a letrozole concentration threshold of 101.0 ng/mL, with an area under the curve of 0.76 widely reported in postmenopausal women but not in boys; its presence was confirmed in this study. 6,12,34 The adverse bone effects described above could not be attributed to GH; instead, the mechanism likely involves cyclooxygenase-2 (COX-2), which plays an essential role in bone formation and is indirectly inhibited by AIs. 35,36 Skin diseases have been broadly described in postmenopausal women and correlate with letrozole-induced changes in sex hormone levels.…”

Section: Discussionmentioning

confidence: 99%

Off‐label use of letrozole in Chinese short pubertal boys: Effectiveness, safety, and exposure–response analysis

Zhang

et al. 2021

Brit J Clinical Pharma

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Aims: Recently, letrozole has been used off-label to treat short pubertal boys. The experience on letrozole effectiveness and safety has been obtained primarily from Caucasian children. A simple extrapolation of the data to Chinese paediatric populations is questionable because of the substantial ethnic differences between the two populations. Therefore, the present study aimed to determine the effectiveness and safety of letrozole use in Chinese short pubertal boys as well as to establish an exposure-response relationship.Methods: Forty-one Chinese boys were included in the study. Patients were given letrozole tablets (2.5 mg) once daily in combination with growth hormone, and follow-up visits were made after 1, 3, 6 and 12 months of treatment. Plasma samples were taken from clinical examinations and analysed using high performance liquid chromatography with fluorescence detection.Results: After 1 year of treatment, 35 (88%) boys showed increased predicted adult heights. However, possible adverse drug reactions were seen in nine boys (22%).Predicted adult heights increased significantly from 168.4 ± 3.7 to 173.0 ± 4.2 cm, while oestrogen levels dropped from 33.2 ± 7.4 to 21.6 ± 7.3 pg/mL. Increments in predicted adult height were significantly correlated with trough letrozole concentrations (r = 0.39, P = .01). Conclusion:Letrozole treatment in Chinese pubertal populations should be further optimized, and more personalized therapies should be developed.

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“…Figure 1 displays the detailed screening and selection processes. A total of 18 articles, featuring 17 genes, met inclusion criteria (Borrie et al, 2018;Desta et al, 2011;Fontein et al, 2014;Garcia-Giralt et al, 2013;Gervasini et al, 2017;Gregory, Chen, Murphy, Atchley, & Kamdem, 2017;Henry et al, 2013;Ingle et al, 2010;Jeong, Woo, Flockhart, & Desta 2009;Kamdem, David, & Zeruesenay, 2014;Lintermans et al, 2016;Liu et al, 2012;Mao et al, 2011;Park et al, 2011;Rumiato et al, 2016;Sun, Chen, Dellinger, Sharma, & Lazarus, 2010;Wang et al, 2013, Wang et al, 2015.…”

Section: Candidate-gene Identificationmentioning

confidence: 99%

“…Jeong et al (2009) provided in vitro evidence that letrozole was a strong inhibitor of CYP2A6. Desta et al (2011) and Borrie et al (2018) found that plasma letrozole concentration was highly variable (>10-fold) and significantly associated with CYP2A6 genotype (CYP2A6*2, CYP2A6*4, CYP2A6*9, CYP2A6*12). However, Borrie et al also found no significant association between CYP2A6 variation and arthralgias.…”

Section: Metabolism Of and Response To Aismentioning

confidence: 99%

Genetic Underpinnings of Musculoskeletal Pain During Treatment With Aromatase Inhibitors for Breast Cancer: A Biological Pathway Analysis

Zhu

Koleck

Bender

et al. 2019

Biological Research For Nursing

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Background: Musculoskeletal pain (MSKP) is the most reported symptom during treatment with aromatase inhibitors (AIs) for breast cancer. The mechanisms underlying MSKP are multidimensional and not well understood. The goals of this biological pathway analysis were to (1) gain an understanding of the genetic variation and biological mechanisms underlying MSKP with AI therapy and (2) identify plausible biological pathways and candidate genes for future investigation. Method: Genes associated with MSKP during AI therapy or genes involved in drug metabolism of and response to AIs were identified from the literature. Studies published through February 2019 were queried in PubMed®. The genes identified from the literature were entered into QIAGEN’s Ingenuity® Pathway Analysis (IPA) software to generate canonical pathways, upstream regulators, and networks through a core analysis. Results: The 17 genes identified were ABCB1, ABCG1, CYP17A1, CYP19A1, CYP27B1, CYP2A6, CYP3A4, CYP3A5, ESR1, OATP1B1, OPG, RANKL, SLCO3A1, TCL1A, UGT2A1, UGT2B17, and VDR. These genes are involved in encoding bone-remodeling regulators, drug-metabolizing enzymes (cytochrome P450 family, UDP-glucuronosyltransferases family), or drug transporters (ATP-binding cassette transporters, organic anion transporters). Multiple plausible biological pathways (e.g., nicotine degradation, melatonin degradation) and candidate genes (e.g., NFKB, HSP90, AKT, ERK1/2, FOXA2) are proposed for future investigation based on the IPA results. Conclusion: Multiple genes and molecular-level etiologies may contribute to MSKP with AI therapy in women with breast cancer. Our innovative combination of gene identification from the literature plus biological pathway analysis allowed for the emergence of novel candidate genes and biological pathways for future investigations.

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Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer

Abstract: CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.

Cited by 12 publications

References 19 publications

Anti-Müllerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone

Anti-Müllerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone

Off‐label use of letrozole in Chinese short pubertal boys: Effectiveness, safety, and exposure–response analysis

Genetic Underpinnings of Musculoskeletal Pain During Treatment With Aromatase Inhibitors for Breast Cancer: A Biological Pathway Analysis

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