Genetic polymorphism at Val80 (rs700518) of the CYP19A1 gene is associated with aromatase inhibitor associated bone loss in women with ER (+) breast cancer

Napoli, Nicola; Rastelli, Antonella; Ma, Cynthia; Yarramaneni, Jayasree; Vattikutti, Swapna; Moskowitz, Gerard W.; Giri, Tusar; Mueller, Casey A.; Kulkarny, Vibhati; Qualls, Clifford; Ellis, Matthew J.; Armamento-Villareal, Reina

doi:10.1016/j.bone.2013.04.021

Cited by 51 publications

(52 citation statements)

References 43 publications

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“…Napoli et al (2013) found the SNP rs700518 (G/A at Val(80)) in the CYP19A1 gene associated with AIBL at the LS and the total hip at 12 months. Hence, we cannot rule out that genetic variants in these genes, which act downstream of CYP11A1, could also intervene in the bone metabolism regulation.…”

Section: Discussionmentioning

confidence: 94%

CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss

Rodríguez-Sanz

Garcia-Giralt

Prieto-Alhambra

et al. 2015

Journal of Molecular Endocrinology

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Aromatase inhibitors (AIs) used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer cause diverse musculoskeletal side effects that include bone loss and its associated fracture. About half of the 391 patients treated with AIs in the Barcelona-Aromatase induced bone loss in early breast cancer cohort suffered a significant bone loss at lumbar spine (LS) and/or femoral neck (FN) after 2 years on AI-treatment. In contrast, up to one-third (19.6% LS, 38.6% FN) showed no decline or even increased bone density. The present study aimed to determine the genetic basis for this variability. SNPs in candidate genes involved in vitamin D and estrogen hormone-response pathways (CYP11A1, CYP17A1, HSD3B2, HSD17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, DHCR7, GC, CYP2R1, CYP27B1, VDR and CYP24A1) were genotyped for association analysis with AI-related bone loss (AIBL). After multiple testing correction, 3 tag-SNPs (rs4077581, s11632698 and rs900798) located in the CYP11A1 gene were significantly associated (P!0.005) with FN AIBL at 2 years of treatment. Next, CYP11A1 expression in human fresh bone tissue and primary osteoblasts was demonstrated by RT-PCR. Both common isoforms of human cholesterol side-chain cleavage enzyme (encoded by CYP11A1 gene) were detected in osteoblasts by western blot. In conclusion, the genetic association of CYP11A1 gene with AIBL and its expression in bone tissue reveals a potential local function of this enzyme in bone metabolism regulation, offering a new vision of the steroidogenic ability of this tissue and new understanding of AI-induced bone loss. Journal of Molecular EndocrinologyResearch M RODRI´GUEZ-SANZ and others CYP11A1 is associated with AI-related bone loss 55:1 69-79http://jme.endocrinology-journals.org Ñ 2015 Society for Endocrinology DOI: 10.1530/JME-15-0079Printed in Great BritainPublished by Bioscientifica Ltd. IntroductionAromatase inhibitors (AIs) are commonly used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer. Although AIs are generally well tolerated with few serious adverse events, a number of musculoskeletal side effects affecting quality of life have been noted and often lead to discontinuation of therapy (Eastell et al. 2006, Henry et al. 2008.The most common side effects reported with AIs are exacerbation of menopausal symptoms as a result of low estrogen levels; these include pain syndromes, bone loss and associated fracture , Laroche et al. 2014. Several prospective studies and clinical trials have noted the need for assessment and treatment of these musculoskeletal adverse events (Reid et al. 2008, Brufsky et al. 2009, Servitja et al. 2012. In particular, bone mineral density (BMD) reduction and fracture incidence associated with AI therapy can be significantly reduced by oral bisphosphonates (BP) treatment (Bouvard et al. 2014).We are currently conducting a prospective, nonselected, observational, clinical cohort study (BarcelonaAromatase induced bone loss in early breast cancer (B-ABLE...

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Section: Discussionmentioning

confidence: 94%

CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss

Rodríguez-Sanz

Garcia-Giralt

Prieto-Alhambra

et al. 2015

Journal of Molecular Endocrinology

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“…For instance, fracture risk has been reported to increase by 55-115 % with anastrozole in the ATAC [68] and Austrian Breast & Colorectal Cancer Study Group (ABCSG) [69] trials, by 15-50 % with letrozole in the BIG-198 [70] and MA17 [71] trials, and by 41 % with exemestane in the IES trial [72], as compared to tamoxifen or placebo. However, recent data show that bone loss associated to treatment with aromatase inhibitors in breast cancer patients is influenced by CYP19 polymorphisms [73].…”

Section: Aromatase Inhibitorsmentioning

confidence: 99%

Cancer-associated bone disease

Rizzoli

Body²,

Brandi³

et al. 2013

Osteoporos Int

128

103

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Bone is commonly affected in cancer. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition, causing bone fragility. Bone-modifying agents, such as bisphosphonates and denosumab, are efficacious in preventing and delaying cancer-related bone disease. With evidence-based care pathways, guidelines assist physicians in clinical decision-making. Of the 57 million deaths in 2008 worldwide, almost two thirds were due to non-communicable diseases, led by cardiovascular diseases and cancers. Bone is a commonly affected organ in cancer, and although the incidence of metastatic bone disease is not well defined, it is estimated that around half of patients who die from cancer in the USA each year have bone involvement. Furthermore, cancer-induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer, or from therapies administered to treat the primary condition thus causing bone loss and fractures. Treatment-induced osteoporosis may occur in the setting of glucocorticoid therapy or oestrogen deprivation therapy, chemotherapy-induced ovarian failure and androgen deprivation therapy. Tumour skeletal-related events include pathologic fractures, spinal cord compression, surgery and radiotherapy to bone and may or may not include hypercalcaemia of malignancy while skeletal complication refers to pain and other symptoms. Some evidence demonstrates the efficacy of various interventions including bone-modifying agents, such as bisphosphonates and denosumab, in preventing or delaying cancer-related bone disease. The latter includes treatment of patients with metastatic skeletal lesions in general, adjuvant treatment of breast and prostate cancer in particular, and the prevention of cancerassociated bone disease. This has led to the development of guidelines by several societies and working groups to assist physicians in clinical decision making, providing them with evidencebased care pathways to prevent skeletal-related events and bone loss. The goal of this paper is to put forth an IOF position paper addressing bone diseases and cancer and summarizing the position papers of other organizations. Epidemiology of cancer-associated bone disease Bone metastasisCancer affects nearly 12.7 million people and is associated with over 7 million deaths in 2008 [1]. Cancer is a rising global health burden and it is estimated that in 2030, cancer deaths will be tallied at over 13 million (World Health Organization (WHO) 2010 Global Status Report [2]). Addressing the morbidity and mortality of cancer is an important public health concern. On purpose, we are limiting our analysis to cancer bone involvement in adults and do not discuss cancer in children.Metastases from cancer are associated with 90 % of cancer deaths [3]. It was estimated that one half of people who die from cancer in the USA have bone involvement [4][5][6]. Different tumou...

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“…Common polymorphisms of the CYP19A1 gene are associated with BMD and fractures in late postmenopausal women [67][68][69][70] . Interestingly, some studies suggest that those polymorphisms, as well as some SNPs in estrogen receptors, might also be associated with the beneficial effect of aromatase inhibitors in women with breast cancer, as well as with their adverse effect on bone mass [71][72][73] .…”

Section: Genetic Factors Influencing Drug Responsementioning

confidence: 99%

Genetic and acquired factors influencing the effectiveness and toxicity of drug therapy in osteoporosis

López-Delgado¹,

Riancho‐Zarrabeitia²,

Riancho³

2016

Expert Opinion on Drug Metabolism & Toxicology

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Genetic polymorphism at Val80 (rs700518) of the CYP19A1 gene is associated with aromatase inhibitor associated bone loss in women with ER (+) breast cancer

Cited by 51 publications

References 43 publications

CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss

CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss

Cancer-associated bone disease

Genetic and acquired factors influencing the effectiveness and toxicity of drug therapy in osteoporosis

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