Expression of aldehyde dehydrogenase after neoadjuvant chemotherapy is associated with expression of hypoxia-inducible factors 1 and 2 alpha and predicts prognosis in locally advanced breast cancer

OBJECTIVE: To analyze the expression of hypoxia-inducible factors (hypoxia-inducible factor 1A and hypoxia-inducible factor 2A) and aldehyde dehydrogenase proteins in patients with locally advanced breast carcinoma who were subjected to neoadjuvant chemotherapy. METHODS: We included 90 patients with histologically confirmed stage II and III breast carcinoma who were treated with neoadjuvant chemotherapy between 2000 and 2005. Immunohistochemistry for aldehyde dehydrogenase, hypoxia-inducible factor 1A, and hypoxia-inducible factor 2A was performed before and after neoadjuvant chemotherapy. We analyzed the influence of clinical and pathological features on clinical and pathological response, disease-free survival, and overall survival. RESULTS: An objective clinical response to neoadjuvant chemotherapy was observed in 80% of patients, with 12% showing a complete pathological response. Among all clinical and pathological parameters, only the expression of hypoxia-inducible factor 1A was associated with a pathological response. A positive association was found between expression of aldehyde dehydrogenase and that of hypoxia-inducible factor 1A before and after chemotherapy. Aldehyde dehydrogenase expression was associated with expression of hypoxia inducible-factor 2A in tumors after neoadjuvant treatment. In a univariate analysis, prognosis was influenced by age, pathological response, metastasis to axillary lymph nodes after neoadjuvant chemotherapy, overexpression of hypoxia-inducible factor 2, and the presence of aldehyde dehydrogenase-positive cells within the primary tumor after neoadjuvant chemotherapy. In a multivariate analysis, only age and the presence of aldehyde dehydrogenase-positive cells after chemotherapy were associated with reduced overall survival. CONCLUSION: The presence of aldehyde dehydrogenase-positive cells within the residual tumor after neoadjuvant chemotherapy is associated with an increase in the expression of hypoxia-inducible factor 2A and with poor prognosis in patients with locally advanced breast cancer

Expression of Hypoxia-inducible factor 1-α and Vascular endothelial growth factor-C in locally advanced breast cancer patients

BACKGROUND: Locally advanced breast cancers are more prevalent in underdeveloped countries. Targeted therapy has been improved to identify hallmarks that are specific to these subtypes of tumors. OBJECTIVES: We aimed to prospectively assess the expression of Hypoxia inducible factor-1 α and vascular endothelial growth factor-C in locally advanced breast cancer patients. METHODS: Thirty women underwent incisional biopsies for the histopathological diagnosis of breast carcinoma and participated in neoadjuvant chemotherapy. The association of Hypoxia inducible factor-1 α and vascular endothelial growth factor-C with age, tumor size, histological grade, clinical staging, hormonal and axillary status, clinical and pathological response after neoadjuvant chemotherapy, expression of estrogen and progesterone receptors, and the presence of c-erbB-2 antigen was studied. RESULTS: Hypoxia inducible factor-1 α expression and Vascular endothelial growth factor-C expression were observed in 66.7% and 63.3% of all patients, respectively, and were marginally associated with each other (p = 0.06). Among the studied variables, only positive axillary status was associated with the presence of HIF-1α (p = 0.02). Complete pathological response was significantly associated (p = 0.04) with the expression of vascular endothelial growth factor-C prior to neoadjuvant chemotherapy. CONCLUSION: We concluded that Hypoxia inducible factor-1 α was associated with a poor prognosis and that vascular endothelial growth factor-C could be used as a predictive factor in locally advanced breast cancer patients with complete pathological response after neoadjuvant chemotherapy

Expression of Hypoxia-inducible factor 1-α and Vascular endothelial growth factor–C in locally advanced breast cancer patients

BACKGROUND: Locally advanced breast cancers are more prevalent in underdeveloped countries. Targeted therapy has been improved to identify hallmarks that are specific to these subtypes of tumors. OBJECTIVES: We aimed to prospectively assess the expression of Hypoxia inducible factor-1 α and vascular endothelial growth factor-C in locally advanced breast cancer patients. METHODS: Thirty women underwent incisional biopsies for the histopathological diagnosis of breast carcinoma and participated in neoadjuvant chemotherapy. The association of Hypoxia inducible factor-1 α and vascular endothelial growth factor-C with age, tumor size, histological grade, clinical staging, hormonal and axillary status, clinical and pathological response after neoadjuvant chemotherapy, expression of estrogen and progesterone receptors, and the presence of c-erbB-2 antigen was studied. RESULTS: Hypoxia inducible factor-1 α expression and Vascular endothelial growth factor-C expression were observed in 66.7% and 63.3% of all patients, respectively, and were marginally associated with each other (p = 0.06). Among the studied variables, only positive axillary status was associated with the presence of HIF-1α (p = 0.02). Complete pathological response was significantly associated (p = 0.04) with the expression of vascular endothelial growth factor-C prior to neoadjuvant chemotherapy. CONCLUSION: We concluded that Hypoxia inducible factor-1 α was associated with a poor prognosis and that vascular endothelial growth factor-C could be used as a predictive factor in locally advanced breast cancer patients with complete pathological response after neoadjuvant chemotherapy

The prognostic impact of local recurrence on early breast cancer patients treated with breast conserving therapy

OBJETIVO: investigar o impacto da recorrência local no prognóstico de pacientes com câncer de mama em estágio inicial tratado com cirurgia conservadora. MÉTODO: foi realizado estudo de coorte retrospectivo incluindo 192 pacientes com câncer de mama em estágio inicial submetidas a tratamento conservador. Utilizando critérios clínicos e patológicos (tempo para recorrência, local da recorrência e tipo histológico) classificamos as pacientes em três grupos. O grupo de recorrência local verdadeira (RLV), o grupo de novo tumor primário (NP) e o grupo livre de recorrência local (LRL). Foi comparada a evolução entre os diferentes grupos. RESULTADOS: menor idade e uma maior proporção de pacientes na pré-menopausa foram observas no grupo NP. A presença de RLV foi o mais importante fator prognóstico sendo que 40% das pacientes deste grupo desenvolveram doença metastática sincrônica à recorrência local. Doença metastática ocorreu em 28,5% e 4,7% nos grupos NP e LRL, respectivamente (p< 0,0001). A taxa de sobrevida global em cinco anos foi de 75% no grupo RLV, 100% no grupo NP e 98,2% no grupo LRL (p< 0,0001). Tipo histológico, margens cirúrgicas, metástase em linfonodos axilares e expressão de receptores hormonais não foram preditores de recorrência local. Pacientes que não foram submetidas a hormonioterapia adjuvante e a idade foram os mais importantes fatores preditores de recorrência local. CONCLUSÃO: recorrência local verdadeira é um fator prognóstico em pacientes com câncer de mama inicial tratado com cirurgia conservadora. A idade é o mais importante fator na recorrência local neste grupo de pacientes. O alto risco recorrência local nestas pacientes é um fator limitante da cirurgia conservadora.BACKGROUND: In order to investigate the impact of local recurrence on breast cancer patient prognosis, we developed this study. METHOD: A retrospective cohort study including 192 patients with early stage breast cancer subjected to breast conserving surgery (BCT) was performed to evaluate the local recurrence pattern and its role on disease progression. Using clinical and pathological criteria (time for recurrence, site of local recurrence and histological type) we classified patients as true local recurrence (TR group), new primary tumor (NP group), and patients free of local recurrence (FLR group). We compared the clinical course among these groups. RESULTS: Patients classified as NP are associated with young age and pre-menopausal status. The presence of TR is the most important predictive factor of prognosis and 40% of patients presented synchronic metastatic disease. The metastatic disease occurred in 28.5% and 4.7% of patients in the NP and FLR groups, respectively (p< 0.0001). Five-year overall survival rate was 75% in the TR group, 100% in the NP group and 98.2% in the FLR group (p< 0.0001). The Histological type and grade, margins status, lymph node metastasis and hormonal receptors were not predictive factors of local recurrence. Patients who were not submitted to hormonal therapy and young age are the most important predictive factors of local recurrence. CONCLUSION: True local recurrence had an influence on overall survival in patients with early breast cancer and the main risk factor for local recurrence was young age. The high-risk incidence for recurrence after BCT in such patients is a limiting factor of therapy

Age as an independent prognostic factor in breast cancer

OBJETIVO: comparar as características epidemiológicas e clínicas e a evolução pós-tratamento de mulheres com câncer de mama diagnosticadas antes ou após os 40 anos de idade. MÉTODOS: foi realizado um estudo retrospectivo, tipo caso-controle, com análise de informações obtidas dos prontuários de pacientes atendidas entre janeiro de 1994 e junho de 2004. Excluímos os casos com carcinomas intraductais e no estádio IV. Foram formados três grupos: pacientes com menos de 40 anos no diagnóstico (n=72), pacientes entre 40 e 50 anos (n=68) e pacientes com mais de 50 anos (n=75). Foram coletadas e analisadas informações sobre a idade no momento do diagnóstico, maior diâmetro das lesões, estadiamento clínico, tipo, grau histológico, presença de receptores hormonais e o estado dos linfonodos. O teste do chi2 foi empregado para variáveis qualitativas. Para as variáveis quantitativas que não apresentam distribuição normal (como número de gânglios axilares acometidos por metástases e tempo de seguimento), foi utilizado o teste de Kruskal-Wallis. Para a construção das curvas de sobrevida livre de doença e sobrevida global, foi utilizado o teste log-rank. RESULTADOS: não houve diferença na distribuição por estádios, no grau de diferenciação tumoral ou na distribuição dos tipos histológicos, na expressão de receptores de estrogênio ou c-erb-B2 entre os grupos. Encontramos diferença na expressão de receptores de estrogênio, que foi menos freqüente no grupo com menos de 40 anos em relação ao grupo com mais de 50 anos (36,2 versus 58,4%). Não houve diferença nos diâmetros tumorais, que foram em média de 5,1, 4,7 e 5 cm. Não encontramos diferença nas taxas de acometimento de linfonodos axilares, que foram de 63,9, 46,9 e 50%, respectivamente nas pacientes com menos de 40 anos, pacientes entre 40 e 50 anos e pacientes com mais de 50 anos. A média de seguimento foi de 54 meses nos três grupos. Houve recidiva da doença em 22,6% das pacientes com menos de 40 anos, 60% das pacientes entre 40 e 50 anos e 22,6% das pacientes com mais de 50 anos, com diferença significante (p<0,0001). Encontramos taxa de óbito pela doença de 46,9% nas pacientes com menos de 40 anos, mais elevada que nas pacientes entre 40 e 50 anos (26,9%) e pacientes com mais de 50 anos (22,6%), p=0,0019. A análise logística mostrou que somente a idade inferior a 40 anos e a presença de mais de um gânglio axilar acometido por metástase foram fatores independentes para risco de morte pela doença. CONCLUSÕES: A IDADe menor que 40 anos é um fator de risco independente no câncer de mama. Os indicadores de prognóstico tradicionais como estádio, diâmetro tumoral, comprometimento axilar e receptores hormonais não mostraram associação com a evolução das pacientes.PURPOSE: to compare the epidemiologic and clinical characteristics, and the follow-up of breast cancer in women diagnosed under and over 40 years of age. METHODS: a retrospective study, case-control type, with analysis of information obtained from medical records of patients attended from January 1994 to June 2004. Cases of intraductal carcinoma and at stage IV were excluded. Three groups were formed: patients under 40 years old at the diagnosis (n=72); patients between 40 and 50 (n=68) and patients over 50 (n=75). Data about age at the moment of diagnosis, lesion largest diameter, clinical stage, type, histological grade, presence of hormonal receptors and state of the lymph nodes were collected and analyzed. The chi2 test was used for qualitative variables. For quantitative variables without normal distribution (such as number of axillary nodes with metastasis and follow-up duration), the Kruskal-Wallis' test was used. For delineating the curves of free-of-disease and global survival, the log-rank test was used. RESULTS: there was no difference among the groups in the stage distribution, concerning the tumoral differentiation grade or in the distribution of histological types, and in the estrogen receptor and c-erb-B2 expression. Difference was found in the RP expression, which was less frequent in the group of patients under 40, than in the group of patients over 50 (36.2% versus 58.4%) respectively. There was no difference among the groups in the mean tumoral diameter (5.1, 4.7 and 5 cm, respectively). There was also no difference among the groups, concerning the rate of axillary lymph node metastasis (63.9, 46.9 and 50%, respectively). The average follow-up was 54 months for all the groups. Disease recurrence occurred in 22.6% of patients under 40 years old, in 60% of patients between 40 and 50, and in 22.6% of patients over 50, with a significant difference among groups (p<0.0001). Death caused by the disease was higher among patients under 40 (46.9%) than among patients between 40 and 50 (26.9%) and over 50 (22.6%), p=0.0019. The logistic analysis showed that "age under 40" and the "presence of more than one metastatic axillary node" were independent death risk factors. CONCLUSIONS: age under 40 is an independent risk factor for breast cancer. The traditional prognostic indicators, such as stage, tumoral diameter, axillary involvement and presence of hormonal receptors are not associated with the disease evolution