A polymorphism at the 3'-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole

García-Casado, Zaida; Guerrero-Zotano, Ángel; Llombart-Cussac, Antonio; Calatrava, Ana; Fernández-Serra, Antonio; Ruiz-Simon, Amparo; Gavilá, Joaquín; Climent, Miguel Ángel; Almenar, S.; Cervera-Deval, José; Campos, Josefina; Albaladejo, Carlos Vázquez; Llombart‐Bosch, Antonio; Guillém, Vicente; Löpez‐Guerrero, José Antonio

doi:10.1186/1471-2407-10-36

Cited by 68 publications

(59 citation statements)

References 45 publications

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“…41 Several breast cancer studies report on genetic influences at this locus with regard to hormone levels 41 and treatment effects. 40,43 A allele carriers had significantly lower CSF E2/T ratios, yet they tended to have better GOS-6 scores. The rs4646 A allele also tended to be linked to lower serum E2/T ratios.…”

Section: Garringer Et Almentioning

confidence: 99%

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Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

Garringer

Niyonkuru

McCullough

et al. 2013

Journal of Neurotrauma

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Although experimental traumatic brain injury (TBI) studies support estradiol as a neuroprotectant and potent stimulator of neuroplasticity, clinical studies suggest a negative association between endogenous estradiol profiles and mortality/poor outcomes. However, no studies have evaluated associations with cerebral spinal fluid (CSF) hormone profiles and aromatase gene (cytochrome P450 [CYP]19A1) variability on clinical TBI outcomes. We evaluated 110 adults with severe TBI. Average and daily estradiol, testosterone, and estradiol/testosterone ratios (E2:T) were measured using CSF and serum samples and compared to healthy controls. Eighteen tagging and four functional single-nucleotide polymorphisms (SNPs) for CYP19A1 were genotyped and compared to hormones, acute mortality, and Glasgow Outcome Scale (GOS) scores 6 months post-TBI. TBI subjects had lower CSF estradiol over time versus controls. CSF testosterone was initially high, but declined over time. E2/T ratios were initially low, compared to controls, but rose over time. Higher mean E2/T ratio in bivariate analysis was associated with lower mortality ( p = 0.019) and better GOS-6 scores ( p = 0.030). rs2470152 influenced CSF E2/T ratio and also serum and CSF testosterone ( p £ 0.05 all comparisons). Multiple-risk SNPs rs2470152, rs4646, and rs2470144 were associated with worse GOS-6 scores ( p £ 0.05, all comparisons), and those with > 1 risk SNP variant had a higher risk for poor outcome, compared with those with £ 1 risk variant. TBI results in low CSF estradiol and dynamic CSF testosterone and E2/T ratio. In contrast to clinical serum hormone studies, higher CSF E2/T ratio was associated with better outcome. Further, genetic variation in CYP19A1 influences both hormone dynamics and outcome post-TBI.

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Section: Garringer Et Almentioning

confidence: 99%

“…rs4646 is a tSNP located on the 3¢ untranslated region of the gene 40 and is in close proximity to the functional SNP, rs700519, a nonsyonymous coding SNP. The nucleotide exchange results in an amino acid change from arginine to cysteine.…”

Section: Garringer Et Almentioning

confidence: 99%

Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

Garringer

Niyonkuru

McCullough

et al. 2013

Journal of Neurotrauma

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“…For instance, two tightly linked SNPs in CYP19 were significantly associated with improved efficacy of letrozole (Wang et al 2010). In contrast, a polymorphism at the 3 0 -UTR region of the aromatase gene defines a subgroup of patients refractory to neoadjuvant letrozole associated with poor prognosis (Garcia-Casado et al 2010). Another possible explanation is the in vivo androgen agonistic effects of 17-hydro-exemestane, a metabolite of exemestane.…”

Section: Perspectivesmentioning

confidence: 95%

Aromatase inhibitors in the breast cancer clinic: focus on exemestane

Asten¹,

Neven²,

Lintermans³

et al. 2014

Endocrine-Related Cancer

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Breast cancer is the most prevalent type of cancer in women and responsible for significant female cancer-related mortality worldwide. In the Western world, over 80% of breast cancers are hormone-receptor positive for which endocrine therapy is administered. The main anti-estrogen treatments in use consist of selective estrogen-receptor modulators, such as tamoxifen, and third-generation aromatase inhibitors (AIs), such as exemestane, letrozole, and anastrozole. In this review, the focus will lie on exemestane, its clinical use, and its side-effect profile. Exemestane is the only third-generation steroidal AI. Its efficacy as a first-line treatment in metastatic breast cancer has been demonstrated. Therefore, exemestane could be considered a valid first-line therapeutic option, but it also can be used in second-line or further situations. Exemestane is mostly used as part of sequential adjuvant treatment following tamoxifen, but in this setting it is also active in monotherapy. Furthermore, this AI has been studied in the neoadjuvant setting as presurgical treatment, and even as chemoprevention in high-risk healthy postmenopausal women. It may reverse side effects of tamoxifen, such as endometrial changes and thromboembolic disease but may also cause some inconvenient side effects itself. Additionally, there is a lack of total crossresistance between exemestane and nonsteroidal AIs as far as their anti-tumoral efficacy is concerned; moreover the two classes of AIs display a nontotal overlapping toxicity profile. Taking together, exemestane can be considered as a useful treatment option at all stages of breast cancer.

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“…In postmenopausal women treated with letrozole for metastatic breast cancer, time to progression (TTP) was significantly prolonged in those with the rare T allele of rs4646 compared with homozygotes for the wildtype variant (GG) [5]. The same variants (GT and TT) were also associated with a poorer benefit from letrozole (shorter progression-free survival) compared to GG, evaluated in a neoadjuvant setting [6].…”

Section: Introductionmentioning

confidence: 94%

CYP19A1 Genetic Polymorphisms rs4646 and Osteoporosis in Patients Treated with Aromatase Inhibitor-Based Adjuvant Therapy

Mazzuca¹,

Botticelli²,

Mazzotti

et al. 2016

Eurasian J Med

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Objective: Third-generation aromatase inhibitors (AI) are potent suppressors of aromatase activity. The aim of this study was to measure the incidence of adverse effects in breast cancer patients treated with AI-based adjuvant therapy and the relationship with the CYP19A1 genotypes. Materials and Methods:Forty-five postmenopausal breast cancer patients (46-85 yrs) in AI adjuvant treatment were genotyped for the rs4646 polymorphisms of CYP19A1 gene and three variations were identified. Toxicities were registered at each follow-up medical examination, and classified in accord with the Common Terminology Criteria for Adverse Events.Results: Twenty-four (53.3%) patients presented the GG genotype; 19 (42.2%) the GT, and 2 (4.4%) the TT. The AI treatment was Anastrazole for 35 patients (77.8%) and Letrozole for the others (n=10; 22.2%). Osteoporosis was significantly associated with the GG genotype (p=0.001). Treatment discontinuation (TD) was observed in 6 cases (13.3%). The only parameter able to predict TD was the appearance of severe arthralgia/myalgia (Odds Ratio, OR=23.75; p=0.009), when adjusted for age and AI treatment. Conclusion:Our results suggest that CYP19A1 polymorphic variants may influence susceptibility to develop AI-related side effects. Further prospective studies are needed to confirm the role of the aromatase gene (CYP19A1) polymorphisms in predicting adverse effects to AI-based therapy. Sonuç: Bulgularımız CYP19A1 polimorfik varyantların Aİ ile ilişki-li yan etkiler geliştirme duyarlılığını etkileyebileceğini düşündür-mektedir. Aİ bazlı terapilerin advers etkilerini öngörmede aromataz gen (CYP19A1) polimorfizminin rolünü doğrulamak için ileri prospektif çalışmalara ihtiyaç vardır.Anahtar Kelimeler: Adjuvan hormonal terapi, rs4646, aromataz inhibitörü, meme kanseri, CYP19A1, tek nükleotid polimorfizmleri

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A polymorphism at the 3'-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole

Cited by 68 publications

References 45 publications

Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

Aromatase inhibitors in the breast cancer clinic: focus on exemestane

CYP19A1 Genetic Polymorphisms rs4646 and Osteoporosis in Patients Treated with Aromatase Inhibitor-Based Adjuvant Therapy

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