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Previous issue date: 2016-12-02 / Despite the advances resulting from the molecular characterization of breast cancer
that allowed the use of more selective therapeutic targets, the disease still causes
different clinical outcomes with high rates of recurrence and mortality. In this context
of complexity and heterogeneity of breast cancer, are important the investigations
of new biomolecular markers related to breast oncogenesis that may contribute to
know the prognosis and improve the clinical management of patients. The sirtuin-1
(SIRT-1) is a histone deacetylase implicated in various epigenetic critical functions
into cells, among these, the maintenance of genomic stability, proliferation and cell
aging. The aim of this study was to investigate the grade of expression of the sirtuin-
1 (SIRT-1) in a cohort of 457 women with breast cancer and verify the effect,
independent or in combination with other variables in the prognosis of these patients.
It is a survival analysis study based on hospital medical records of women with breast
cancer undergoing treatment in Erechim-RS from 2003 to 2013 and followed until 31
July 2015. The analysis of the grade of SIRT-1 expression was performed by
immunohistochemistry in 123 patients (26.9%) of the total cohort. Overall survival
specific disease (OS) was estimated by the Kaplan-Meier method and the risk of
death from breast cancer by the method of Cox proportional hazards. The research
was approved by the Research Ethics Committee of PUC-RS as reported number
465.362. The median age was 57.4 years and the median estimate of breast cancer
survival was 79.6% at 5 years and 69.1% at 10 years, with median follow-up time of
61.9 months. Risk factors associated with worse prognosis were: age between 60
and 69 years (HR = 1.88; 95% CI 1.02 - 3.44; p = 0.042); older than 70 years (HR =
2.92; CI 95% 1.70 - 5.01; p = 0.000); tumor size greater than 2 cm (HR = 1.86; CI
95% 1.04 -3.36; p = 0.038); metastasis in 4 or more axillary lymph nodes (HR = 2.37;
CI 95% 1.38 - 4.08; p = 0.002); located clinical staging (CS II, TNM) (HR = 3.39; CI
95% 1.35 - 8.51; p = 0.009); advanced clinical staging (CS III, TNM) (HR = 6.32; CI
95% 2.49-16.08; p = 0.000); high histologic grade (HR = 6.32; CI 95% 1.63 - 29.99; p
= 0.008); triple negative molecular profile (HR = 2.33; CI 95% 1.19 - 4.58; p = 0.014)
and radical surgery (HR = 2.10; CI 95% 1.31 - 3.36; p = 0.002). The positive
expression of progesterone receptor (HR = 0.52, CI 95% 0.34 - 0.79; p = 0.002) was
a better prognostic factor for patients. The grade of overexpression of SIRT-1, defined as nuclear expression of SIRT-1 greater than 80% was observed in 6.5% of
cases. The SIRT-1 overexpression characterized a subgroup of women who had a
worse prognosis with shorter survival and increased risk of death from breast cancer
(HR = 2.66; CI 95% 1.03 - 6.86; p = 0.043). Multivariate regressive models (Cox)
were constructed and the overexpression of SIRT-1 remained significant statistic
demonstrating independent factor associated with worse prognostic in breast cancer.
Therefore, the evaluation of the grade of expression of the SIRT-1, in the cohort of
Erechim-RS, proved to be an independent prognostic marker for analysis of the risk
of death from breast cancer. / Apesar dos avan?os decorrentes da caracteriza??o molecular do c?ncer de mama que permitiram o emprego de alvos terap?uticos mais seletivos, a doen?a ainda ocasiona diferentes desfechos cl?nicos, com elevadas taxas de recidiva e mortalidade. Neste contexto de complexidade e heterogeneidade do c?ncer de mama, s?o importantes as investiga??es de novos marcadores biomoleculares relacionados ? oncog?nese mam?ria que possam contribuir para conhecer o progn?stico e aprimorar o manejo cl?nico das pacientes. A Sirtu?na-1 (SIRT-1) ? uma histona desacetilase implicada em diversas fun??es epigen?ticas cr?ticas para as c?lulas, dentre estas, a manuten??o da estabilidade gen?mica, a prolifera??o e o envelhecimento celular. O objetivo deste estudo foi investigar o grau de express?o da Sirtu?na-1 (SIRT-1) em uma coorte de 457 mulheres portadoras de c?ncer de mama e verificar o seu efeito, independente ou em associa??o a outras vari?veis, no progn?stico destas pacientes. Trata-se de um estudo de an?lise de sobrevida com base em registros de mulheres portadoras de c?ncer de mama submetidas a tratamento em Erechim-RS no per?odo de 2003 a 2013 com seguimento at? 31 de julho de 2015. A an?lise do grau de express?o de SIRT-1 foi realizada por t?cnica de imuno-histoqu?mica em 123 pacientes (26,9%) do total da coorte. A sobrevida global doen?a espec?fica foi estimada pelo m?todo de Kaplan-Meier e, o risco de morte, por c?ncer de mama, pelo m?todo de riscos proporcionais de Cox. A pesquisa foi aprovada no Comit? de ?tica e Pesquisa da PUC-RS, sob n? 465.362. A idade mediana foi de 57,4 anos e a estimativa mediana de sobrevida por c?ncer de mama foi de 79,6% em 5 anos e 69,1% em 10 anos, com tempo mediano de seguimento de 61,9 meses. Os fatores de risco associados a pior progn?stico foram: faixa et?ria entre 60 e 69 anos (HR=1,88; IC95% 1,02-3,44; p=0,042); faixa et?ria maior que 70 anos (HR=2,92; IC95% 1,70-5,01; p=0,000); tamanho tumoral acima de 2 cm (HR=1,86; IC95% 1,04-3,36; p=0,038); presen?a de met?stase em 4 linfonodos axilares ou mais (HR=2,37; IC95% 1,38-4,08; p=0,002); estadiamento cl?nico localizado (EC II,TNM) (HR=3,39; IC95% 1,35-8,51; p=0,009); estadiamento cl?nico avan?ado (EC III,TNM) (HR=6,32; IC95% 2,49-16,08; p=0,000); grau histol?gico alto (HR=6,32; IC95% 1,63-29,99; p=0,008); perfil molecular triplo negativo (HR=2,33; IC95% 1,19-4,58; p=0,014) e a cirurgia radical (HR=2,10; IC95% 1,31-3,36; p=0,002). A express?o positiva do receptor de progesterona (HR=0,52; IC95% 0,34- 0,79; p=0,002) foi um fator de melhor progn?stico para as pacientes. O grau de hiperexpress?o da SIRT-1, definida como express?o nuclear da SIRT-1 maior que 80%, foi verificada em 6,5% dos casos. A hiperexpress?o da SIRT-1 caracterizou um subgrupo de mulheres que apresentaram pior progn?stico, com menor sobrevida e maior risco de morte por c?ncer de mama (HR=2,66; IC95% 1,03-6,86; p=0,043). Foram elaborados modelos regressivos multivariados (Cox) e a hiperexpress?o de SIRT-1 manteve signific?ncia estat?stica demonstrando fator independente associado a pior progn?stico no c?ncer de mama. Portanto, a avalia??o do grau de express?o da SIRT-1, na coorte de Erechim-RS, demonstrou ser um marcador independente para determinar o progn?stico no c?ncer de mama.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/7150 |
| Date | 02 December 2016 |
| Creators | Sartori, Juliano |
| Contributors | Schneider, Rodolfo Herberto |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Gerontologia Biom?dica, PUCRS, Brasil, Instituto de Geriatria e Gerontologia |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 4438661476953179033, 600, 600, 600, 2296420844541114010, -969369452308786627 |
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