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1.
Pharmacogenet Genomics ; 31(1): 1-9, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32649577

RESUMO

OBJECTIVES: Based on our previous findings that postmenopausal women with estrone (E1) and estradiol (E2) concentrations at or above 1.3 pg/ml and 0.5 pg/ml, respectively, after 6 months of adjuvant anastrozole therapy had a three-fold risk of recurrence, we aimed to identify a single-nucleotide polymorphism (SNP)-based model that would predict elevated E1 and E2 and then validate it in an independent dataset. PATIENTS AND METHODS: The test set consisted of 322 women from the M3 study and the validation set consisted of 152 patients from MA.27. All patients were treated with adjuvant anastrozole, had on-anastrozole E1 and E2 concentrations and genome-wide genotyping. RESULTS: SNPs were identified from the M3 genome-wide association study. The best model to predict the E1-E2 phenotype with high balanced accuracy was a support vector machine model using clinical factors plus 46 SNPs. We did not have an independent cohort that is similar to the M3 study with clinical, E1-E2 phenotypes and genotype data to test our model. Hence, we chose a nested matched case-control cohort (MA.27 study) for testing. Our E1-E2 model was not validated but we found the MA.27 validation cohort was both clinically and genomically different. CONCLUSIONS: We identified a SNP-based model that had excellent performance characteristics for predicting the phenotype of elevated E1 and E2 in women treated with anastrozole. This model was not validated in an independent dataset but that dataset was clinically and genomically substantially different. The model will need validation in a prospective study.


Assuntos
Anastrozol/efeitos adversos , Neoplasias da Mama/genética , Predisposição Genética para Doença , Recidiva Local de Neoplasia/genética , Adulto , Anastrozol/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/sangue , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/patologia , Estradiol/sangue , Estrona/sangue , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Polimorfismo de Nucleotídeo Único/genética
2.
Clin Cancer Res ; 30(15): 3147-3156, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38752717

RESUMO

PURPOSE: We previously reported that postmenopausal women with estrogen receptor-α-positive breast cancer receiving adjuvant anastrozole 1 mg/day (ANA1) with estrone (E1) ≥1.3 pg/mL and estradiol (E2) ≥0.5 pg/mL [inadequate estrogen suppression (IES)] had a threefold increased risk of a breast cancer event. The objective of this study was to determine if increasing anastrozole to 10 mg/day (ANA10) could result in adequate estrogen suppression (AES: E1 <1.3 pg/mL and/or E2 <0.5 pg/mL) among those with IES on ANA1. PATIENTS AND METHODS: Postmenopausal women with estrogen receptor-α-positive breast cancer planning to receive adjuvant ANA1 were eligible. E1 and E2 were assessed pre- and post-8 to 10 weeks of ANA1. Those with IES were switched to 8- to 10-week cycles of ANA10 followed by letrozole 2.5 mg/day. E1 and E2 were assessed after each cycle. Anastrozole concentrations were measured post-ANA1 and post-ANA10. Primary analyses included patients who documented taking at least 80% of the planned treatment (adherent cohort). RESULTS: In total, 132 (84.6%) of 156 eligible patients were ANA1 adherent. IES occurred in 40 (30.3%) adherent patients. Twenty-five (78.1%) of 32 patients who began ANA10 were adherent, and AES was achieved in 19 (76.0%; 90% confidence interval, 58.1%-89.0%) patients. Anastrozole concentrations post-ANA1 and post-ANA10 did not differ by estrogen suppression status among adherent patients. AES was maintained/attained in 21 (91.3%) of 23 letrozole-adherent patients. CONCLUSIONS: Approximately 30% of ANA1-adherent patients had IES. Among those who switched to ANA10 and were adherent, 76% had AES. Further studies are required to validate emerging data that ANA1 results in IES for some patients and to determine the clinical benefit of switching to ANA10 or an alternative aromatase inhibitor.


Assuntos
Anastrozol , Neoplasias da Mama , Nitrilas , Pós-Menopausa , Triazóis , Humanos , Anastrozol/administração & dosagem , Anastrozol/uso terapêutico , Anastrozol/efeitos adversos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pessoa de Meia-Idade , Idoso , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Estrogênios/administração & dosagem , Estadiamento de Neoplasias , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Estudos Prospectivos , Estradiol/administração & dosagem , Estrona/sangue , Estrona/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos
3.
Clin Pharmacol Ther ; 110(4): 1038-1049, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34048027

RESUMO

Aromatase inhibitors (AIs) are the treatment of choice for hormone receptor-positive early breast cancer in postmenopausal women. None of the third-generation AIs are superior to the others in terms of efficacy. We attempted to identify genetic factors that could differentiate between the effectiveness of adjuvant anastrozole and exemestane by examining single-nucleotide polymorphism (SNP)-treatment interaction in 4,465 patients. A group of SNPs were found to be differentially associated between anastrozole and exemestane regarding outcomes. However, they showed no association with outcome in the combined analysis. We followed up common SNPs near LY75 and GPR160 that could differentiate anastrozole from exemestane efficacy. LY75 and GPR160 participate in epithelial-to-mesenchymal transition and growth pathways, in both cases with SNP-dependent variation in regulation. Collectively, these studies identified SNPs that differentiate the efficacy of anastrozole and exemestane and they suggest additional genetic biomarkers for possible use in selecting an AI for a given patient.


Assuntos
Anastrozol/uso terapêutico , Androstadienos/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Antígenos CD/genética , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Lectinas Tipo C/genética , Antígenos de Histocompatibilidade Menor/genética , Estadiamento de Neoplasias , Seleção de Pacientes , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Receptores Acoplados a Proteínas G/genética , Resultado do Tratamento
4.
JCI Insight ; 5(16)2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32701512

RESUMO

Aromatase inhibitors (AIs) reduce breast cancer recurrence and prolong survival, but up to 30% of patients exhibit recurrence. Using a genome-wide association study of patients entered on MA.27, a phase III randomized trial of anastrozole versus exemestane, we identified a single nucleotide polymorphism (SNP) in CUB And Sushi multiple domains 1 (CSMD1) associated with breast cancer-free interval, with the variant allele associated with fewer distant recurrences. Mechanistically, CSMD1 regulates CYP19 expression in an SNP- and drug-dependent fashion, and this regulation is different among 3 AIs: anastrozole, exemestane, and letrozole. Overexpression of CSMD1 sensitized AI-resistant cells to anastrozole but not to the other 2 AIs. The SNP in CSMD1 that was associated with increased CSMD1 and CYP19 expression levels increased anastrozole sensitivity, but not letrozole or exemestane sensitivity. Anastrozole degrades estrogen receptor α (ERα), especially in the presence of estradiol (E2). ER+ breast cancer organoids and AI- or fulvestrant-resistant breast cancer cells were more sensitive to anastrozole plus E2 than to AI alone. Our findings suggest that the CSMD1 SNP might help to predict AI response, and anastrozole plus E2 serves as a potential new therapeutic strategy for patients with AI- or fulvestrant-resistant breast cancers.


Assuntos
Anastrozol/farmacologia , Inibidores da Aromatase/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Proteínas Supressoras de Tumor/genética , Anastrozol/administração & dosagem , Anastrozol/farmacocinética , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Aromatase/genética , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Estradiol/administração & dosagem , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Farmacogenética , Pós-Menopausa
5.
Clin Cancer Res ; 26(12): 2986-2996, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32098767

RESUMO

PURPOSE: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. EXPERIMENTAL DESIGN: Matched case-control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. RESULTS: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1-/- T47D breast cancer cell line. CONCLUSIONS: This matched case-control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.


Assuntos
Anastrozol/uso terapêutico , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Fase IV como Assunto , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Prognóstico , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
AJNR Am J Neuroradiol ; 26(10): 2652-7, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16286418

RESUMO

BACKGROUND AND PURPOSE: Vertebroplasty is rapidly disseminating as a treatment for vertebral compression fractures, but its efficacy has not been assessed with a well-validated, back pain-specific instrument. We report the use of the Roland-Morris Disability Questionnaire (RDQ) in patients undergoing vertebroplasty for painful osteoporotic compression fractures. METHODS: Retrospective review of patients treated with vertebroplasty who completed the RDQ and 2 verbal pain scales (0-10) for pain at rest and pain with activity at baseline, 1 week, 1 month, 6 months, and 1 year post-vertebroplasty. Changes in outcome measures were analyzed by using a paired t test and correlations were assessed with Spearman rho. Multiple linear regression was used to analyze the relationship between baseline scores and independent variables. RESULTS: One hundred thirteen patients were treated at 164 vertebral levels. At baseline, RDQ scores were associated with rest and activity pain (P < .001 and P = .002, respectively) but were not associated with other independent variables. All 3 outcome scores decreased by 1 week and remained improved through maximal follow-up (P < .001). RDQ scores improved by a mean of 7.0 points at 1 week and remained improved at 1 year (P = .02). RDQ scores correlated with both rest and activity pain, but the absolute correlation was slightly better (+0.15 on average) with activity pain. CONCLUSIONS: Patients who underwent vertebroplasty experienced relief of back pain and symptoms, as shown by improvement in verbal pain and RDQ scores. The RDQ correlates well with measures of pain, shows clinically significant improvement and is responsive to changes across time. More important, the RDQ provides an easily administered, well-validated, back pain-specific outcome measure that could be adopted to assess vertebroplasty outcomes.


Assuntos
Vértebras Lombares/cirurgia , Avaliação de Resultados em Cuidados de Saúde , Vértebras Torácicas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Avaliação da Deficiência , Feminino , Seguimentos , Fraturas por Compressão/fisiopatologia , Fraturas por Compressão/cirurgia , Humanos , Dor Lombar/etiologia , Dor Lombar/fisiopatologia , Vértebras Lombares/lesões , Vértebras Lombares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Osteoporose/fisiopatologia , Osteoporose/cirurgia , Medição da Dor , Ossos Pélvicos/lesões , Ossos Pélvicos/fisiopatologia , Ossos Pélvicos/cirurgia , Estudos Retrospectivos , Fraturas da Coluna Vertebral/fisiopatologia , Fraturas da Coluna Vertebral/cirurgia , Inquéritos e Questionários , Vértebras Torácicas/lesões , Vértebras Torácicas/fisiopatologia
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