Evaluation of prognostic factors in stage IIA breast tumors and their correlation with mortality risk

Breast tumors exhibit extensive molecular and clinical heterogeneity. One of the most utilized breast carcinoma classifications is based on its molecular aspects and subdivides breast cancer into five major groups based on the expression of certain genes. In this study, we evaluated which factors are important in determining a prognosis after 5 years of follow-up for patients with clinical stage IIA breast tumors. We took into consideration the different phenotypes (luminal A luminal B HER-2 overexpression, basal and triple-negative), various epithelial-mesenchymal (EMT) molecular markers and adhesion molecules (E-cadherin, P-cadherin, N-cadherin, vimentin, twist snail and slug) and NOS-2, in addition to clinical and demographic data, tumor characteristics and treatment types. METHODS: The study population consisted of 82 patients with breast cancer. We analyzed eight molecular markers by immunohistochemistry on tissue microarrays containing breast tumor specimens from patients with ten years of follow-up, and we classified each tumor according to its estrogen receptor, progesterone receptor and HER-2 expression. We then placed the tumor into one of the above categories. RESULTS: The presence of several clinical and demographic factors, various histopathologies, treatment forms and several immunohistochemical markers were not associated with a worse prognosis for group IIA patients. The factors that were associated with a mortality risk were the triple-negative (odds ratio (OR) = 11.8, 95 percent confident interval (CI) = 2.0-70.3, P = 0.007) and basal (OR =18.4, 95 percent CI = 1.8-184.7, P= 0.013) phenotypic patterns. CONCLUSIONS: The EMT markers and NOS-2 were not mortality risk factors. Basal and triple-negative phenotypic patterns were related to a higher mortality risk in patients with stage IIA tumors.

Carcinomas mamários de tipo basal: perfil clínico-patológico e evolutivo / Basal-like breast cancers: clinicopathological features and outcome

OBJETIVO: Investigar a frequência de carcinomas mamários de fenótipo basal em uma série de tumores triplo-negativos (TTN), definidos pela negatividade para receptores de estrógeno (RE), de progesterona (RP) e HER2. MÉTODOS: Selecionamos 140 TTN, obtendo-se características clínico-patológicas e sobrevida. Microarranjo de tecido (2 cilindros de cada tumor) foi construído e submetido à imunoistoquímica para RE, RP, HER2, citoqueratinas (Cks) 5 e 14, EGFR, p63 e p53. Consideramos carcinomas de fenótipo basal os tumores negativos para RE, RP e HER2, e positivos para CK5. RESULTADOS: Encontramos 105 carcinomas de fenótipo basal entre 140 TTN (frequência=75 por cento). A idade média das pacientes foi de 54,8 anos, sendo que 34,3 por cento estavam na pré-menopausa. A maioria dos tumores foi classificada como carcinoma ductal invasor de alto grau. Os TTN exibiram positividade para CK5 (75,0 por cento), CK14 (29 por cento), EGFR (36,4 por cento), p63 (28,6 por cento) e p53 (67,1 por cento). Estadiamento avançado da doença foi observado em 52 pacientes (50 por cento), com diâmetro tumoral maior que 5 cm em 41 casos (39 por cento) e metástases axilares em 61 casos (59,2 por cento). Seguimento clínico foi obtido em 89 pacientes (média=51 meses). Destas, 45 pacientes (50,5 por cento) evoluíram sem doença; 6 (6,7 por cento) estavam vivas com doença e 38 (42,6 por cento) morreram pelo câncer. Recidiva sistêmica ocorreu em 42 pacientes (47,1 por cento), sendo pulmões, cérebro e ossos os principais sítios de metástases. As médias das sobrevidas global e livre de doença foram de 36 e 28 meses, respectivamente. CONCLUSÕES: Nosso estudo confirma comportamento clínico agressivo e elevada frequência dos carcinomas de fenótipo basal entre os TTN, semelhante ao descrito em casuísticas norte-americanas e europeias.

OBJECTIVE: The aim of our study was to investigate basal phenotype in a series of triple-negative (estrogen and progesterone receptors-negative and HER2-negative) invasive mammary carcinomas. METHODS: We selected 140 previously tested triple-negative tumors. Clinical, histopathological and survival data were obtained. A tissue microarray containing 2 cylinders from each tumor was constructed and immunohistochemistry for estrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratins (CK) 5 and 14, EGFR, p63, and p53 was performed. We considered basal like-cancers (BLC) those tumors that were ER/PR/HER2-negative and CK5-positive. RESULTS: We found 105 cases of BLC from 140 triple-negative tumors (frequency=75.0 percent). The mean age at diagnosis was 54.8 years-old and 34.3 percent were premenopausal women. The majority of tumors were high grade (83.7 percent) and of ductal/no-special-type (80.8 percent). Triple-negative tumors showed immunoreactivity for CK5 (75.0 percent), CK14 (29.0 percent), EGFR (28.6 percent), p63 (28.6 percent), and p53 (67.1 percent). Tumor size larger than 5cm was observed in 41 cases (39.0 percent) and axillary metastases were detected in 61 patients (59.2 percent). Follow-up was recorded for 89 patients (mean=51 months): 45 patients (50.5 percent) with no evidence of disease; 6 patients (6.7 percent) were alive with disease; and 38 patients (42.6 percent) died of the disease. Relapse was detected in 42 women (47.1 percent), lungs, brain, and bones being the most common sites of metastasis. The mean overall survival was 36 months and the mean disease-free interval was 28 months. CONCLUSION: Our findings confirmed that BLC are poor prognosis and highly-frequent carcinomas among triple-negative tumors, similar to data previously reported in North American and European patients.

Perfil de citoceratinas e sua relação com diferenciação, e fatores clínico-morfológicos em carcinomas ductais SOE de mama estudados em “array de tecido” (tissue microarray – TMA) / Cytokeratin profile: relation with differentiation, clinical and morphological features in invasive ductal carcinomas of the breast using tissue microarrays

Com o desenvolvimento de novas técnicas de avaliação dos perfis de expressão gênica (PEG) foram identificados subgrupos de risco diferenciado de carcinomas mamários. No entanto, as diferenças nos PEG não se traduzem em características morfológicas que possam ser prontamente identificadas no exame anatomopatológico rotineiro. ... A maioria dos estudos da literatura tem avaliado o perfil de expressão das CKs em grupos heterogêneos de tumores mamários diluindo, assim, o significado mais preciso dos resultados. Por este motivo, o objetivo principal do presente trabalho foi verificar numa amostra exclusiva de 1.167 casos de carcinomas ductais invasivos (CDI), com acompanhamento clínico médio de 62 meses, a associação da revisão padronizada das características clínico-morfológicas e dos perfis de expressão IIQ de 15 marcadores prognósticos e preditivos, otimizando as reações através da técnica de TMA. ... RESULTADOS: No total destes 1.167 casos de CDI, observamos significância estatística (P < 0,05) de diversas variáveis clínicas e morfológicas para a sobrevida global em 5 anos nas análises univariadas dos casos de ambos os grupos (índice mitótico, graus histológico, nuclear e extensão da necrose). No grupo de doença avançada, houve significância da presença de componente in situ associado ao invasivo, do status nodal e da intensidade do infiltrado inflamatório peritumoral. ... CONCLUSÃO: A revisão padronizada das variáveis clínico-morfológicas fornece importantes subsídios para a decisão da melhor conduta terapêutica nos casos de CDI. Verificamos que o subgrupo IIQ basalóide apresenta a pior evolução clínica nos grupos da amostra total e doença avançada, com relevância prognóstica (P < 0,05). A análise IIQ com as CKs basais complementa os critérios de decisão de conduta terapêutica e a associação de novos marcadores poderá adicionar informações relevantes aos fatores preditivos e prognósticos já estabelecidos na prática oncológica.

Through development of new techniques of gene expression profiling (GEp) diverse risk subgroups of breast carcinomas were identified. However, the differences within GEP do not convert into readily identiflable morphological characteristics in routine histological examination. ln cases with the same clinical stage and similar histological graduation it may be difficult to reach optimal therapeutic decisions. Even in case of early diagnosis, many cases have unfavorable clinical outcome. lmmunohistochemical stains (lHC) with biomarkers based on GEP findings showed that the most relevant groups are the hormone receptor (HR) expressing, the HER2 overexpressing and the basal-like carcinomas. This later group is typically HR - and HER2 - (ie not amplified) and shows expression of one or more basal cytokeratins (CKs) of the mammary ductal epithelium (CKs 5,6; 14 and 17). Most studies have been analyzing the CK profile in heterogeneous groups of mammary tumors, thus, diluting a more precise significance of the results. Before this background, the main objective of this study was to verify in a group of 1.167 cases of ductal invasive carcinomas (lDC) exclusively, with medium clinical follow up of 62 months, the association of standardized revision of the clinical and morphological characteristics and the IHC profile of 15 prognostic and predictive markers, optimizing the technical reactions applying the tissue microarray technique. The markers utilized were CK 5,6; 8; 13; 14; 17; 18; HR (estrogen and progesterone), HER2, EGFR; p53; p63; Ki-67; psoriasin and ezrin. The patients were divided in two groups, according to the clinical staging (CS): localized disease (CS I and ll) and advanced disease (CS lll and lV). RESULTS: The five year overall survival analyses of these 1.167 IDC cases showed statistical signiflcant results (P < 0,05) of some clinical and morphological variables for both groups of patients (mitotic index, histological and nuclear grades, necrosis extension). Within the advanced disease group significance of the rn srtu associated with the invasive component, the nodal status and the intensity of the inflammatory peritumoral infiltrate was observed. Regarding the IHC profiles, the HR expressing, the HER2 overexpressing and the basal-like were significant. Ezrin showed signiflcance on the univadable analysis for the advanced disease group (p = 0,023). coNCLUSIoN: The standardized revision of the clinical and morphological variables provides important information for the clinical decision making in IDC patients. We verified that the IHC basal-like subgroup shows the worst clinical outcome in the whole group (clinical stages I - lV) of cases and in the group of advanced disease (clinical stages lll and lV) of this study (P < 0,05). ln the group of localized disease, the subgroup HER2-positive had the worst prognosis. The IHC analysis with the basal cKs provides important aditional inputs for the clinical decision making. The association of new markers may add relevant information to the established predictive and prognostic factors of the clinical oncology practice (AU)