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OBJECTIVE: Tumor-infiltrating lymphocytes are detectable in up to 75% of triple-negative breast cancer. The composition of these infiltrates may influence prognosis and is not known regarding regulatory or effector lymphocytes. The objectives of this study were to describe and quantify the composition of the tumor-infiltrating lymphocytes before and after chemotherapy (neoadjuvant chemotherapy) and to evaluate their association with complete pathological response and overall survival. METHODS: This was a retrospective observational study. Clinical and pathological data from 38 triple-negative breast cancer patients treated with neoadjuvant chemotherapy at the University Hospital (HUCFF/UFRJ), between November 2004 and November 2018, were analyzed. The Stromal tumor-infiltrating lymphocytes (Stromal tumor-infiltrating lymphocytes) have been identified on hematoxylin and eosin-stained sections according to the guidelines of the "International tumor-infiltrating lymphocytes Working Group." Immunohistochemistry studies were performed to identify T-cell subsets (i.e., CD3, CD4, CD8, and FOXP3) and T-cell exhaustion (i.e., programmed cell death protein 1). RESULTS: Statistically significant changes in stromal tumor-infiltrating lymphocyte categories were observed before and post-neoadjuvant chemotherapy, with 32% of intermediate cases becoming high. The correlation between pre-neoadjuvant chemotherapy stromal tumor-infiltrating lymphocytes and pathological response, pre-neoadjuvant chemotherapy and post-neoadjuvant chemotherapy, and stromal tumor-infiltrating lymphocytes and overall survival was not statistically significant. However, we noticed an increase of cells that favor the antitumor activity (i.e., CD3, CD8, and CD8/FOXP3 ratio) and decreased levels of cells inhibiting tumor activities (i.e., FOXP3 and programmed cell death protein 1) post-neoadjuvant chemotherapy. Importantly, programmed cell death protein 1 expression pre-neoadjuvant chemotherapy showed an association with pathological response. CONCLUSION: In this study, we observed that chemotherapy significantly increases stromal tumor-infiltrating lymphocytes, CD8 T cells, as well as CD8/FoxP3 ratio. Most importantly, programmed cell death protein 1 expression before neoadjuvant chemotherapy positively correlates with pathological response suggesting the use of programmed cell death protein 1 as a prognostic marker before neoadjuvant chemotherapy.
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Receptor de Morte Celular Programada 1 , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Terapia Neoadjuvante , Linfócitos T CD8-Positivos , Fatores de Transcrição ForkheadRESUMO
SUMMARY OBJECTIVE: Tumor-infiltrating lymphocytes are detectable in up to 75% of triple-negative breast cancer. The composition of these infiltrates may influence prognosis and is not known regarding regulatory or effector lymphocytes. The objectives of this study were to describe and quantify the composition of the tumor-infiltrating lymphocytes before and after chemotherapy (neoadjuvant chemotherapy) and to evaluate their association with complete pathological response and overall survival. METHODS: This was a retrospective observational study. Clinical and pathological data from 38 triple-negative breast cancer patients treated with neoadjuvant chemotherapy at the University Hospital (HUCFF/UFRJ), between November 2004 and November 2018, were analyzed. The Stromal tumor-infiltrating lymphocytes (Stromal tumor-infiltrating lymphocytes) have been identified on hematoxylin and eosin-stained sections according to the guidelines of the "International tumor-infiltrating lymphocytes Working Group." Immunohistochemistry studies were performed to identify T-cell subsets (i.e., CD3, CD4, CD8, and FOXP3) and T-cell exhaustion (i.e., programmed cell death protein 1). RESULTS: Statistically significant changes in stromal tumor-infiltrating lymphocyte categories were observed before and post-neoadjuvant chemotherapy, with 32% of intermediate cases becoming high. The correlation between pre-neoadjuvant chemotherapy stromal tumor-infiltrating lymphocytes and pathological response, pre-neoadjuvant chemotherapy and post-neoadjuvant chemotherapy, and stromal tumor-infiltrating lymphocytes and overall survival was not statistically significant. However, we noticed an increase of cells that favor the antitumor activity (i.e., CD3, CD8, and CD8/FOXP3 ratio) and decreased levels of cells inhibiting tumor activities (i.e., FOXP3 and programmed cell death protein 1) post-neoadjuvant chemotherapy. Importantly, programmed cell death protein 1 expression pre-neoadjuvant chemotherapy showed an association with pathological response. CONCLUSION: In this study, we observed that chemotherapy significantly increases stromal tumor-infiltrating lymphocytes, CD8 T cells, as well as CD8/FoxP3 ratio. Most importantly, programmed cell death protein 1 expression before neoadjuvant chemotherapy positively correlates with pathological response suggesting the use of programmed cell death protein 1 as a prognostic marker before neoadjuvant chemotherapy.
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The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.
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Introduction: The objective of this study is to describe the profile of patients from a public institution, submitted to neoadjuvant chemotherapy (NACT), comparing the verified pathological response with literature data. Methods: Observational retrospective cohort study on breast cancer patients diagnosed between September 2001 and October 2018 and treated with NACT at Hospital Universitário Clementino Fraga Filho (HUCFF/UFRJ), located in Rio de Janeiro, Brazil. The adopted neoadjuvant chemotherapy regimen was based on anthracycline and docetaxel. Results: A total of 133 patients were evaluated. The average age in this group was 54 years (28-86), 49 women (37%) were under 50 years old. The following distribution by molecular subtype was observed: overexpression or amplification of the human epidermal growth factor receptor 2 (HER2+) (13 women, 26.6%), Luminal (19 women, 38.8%), and Triple-negative (TN) (17 women, 34.6%). The HER2+ and TN subtypes had a higher incidence of cases between 40-49 years and 50-59 years. As for the initial staging, 34% were IIIA; 26%, IIB; and 19%, IIIB. Only one patient did not undergo surgery after NACT, 33 (24.8%) underwent conservative surgery, and 99 patients (74.4%) underwent mastectomy. Regarding the axillary approach, 41 (31%) underwent sentinel lymph node biopsy and 88 (66%) had an indication for lymphadenectomy. In the anatomopathological evaluation of the surgery, 12 (9.1%) patients obtained a pathologic complete response (pCR) and 113 (84.9%), partial or no response to chemotherapy. Conclusion: This research enabled the identification of clinicopathologic characteristics and outcome of patients who received neoadjuvant chemotherapy in a public university service. The predominance of advanced tumors was observed, stressing the need for public health policies for the screening of breast cancer as well as the guarantee of timely treatment for diagnosed cases. The data somewhat reflect the difficulty that the public sector encounters to carry out the most appropriate treatment. The authors expect that this article, by analyzing the profile and the adopted treatment in real-life cases and in a public university institution, can contribute to the improvement of breast cancer treatment in Brazil.
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Breast cancer is the leading cause of cancer related deaths in women. Most breast cancers stem from mammary ductal cells that secrete nipple aspirate fluid (NAF), a biological sample that contains proteins associated with the tumor microenvironment. In this study, NAF samples from both breasts of 7 Brazilian patients with unilateral breast cancer were analyzed. These samples were systematically compared using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and two-dimensional fluorescence difference gel electrophoresis (2D-DIGE); substantial qualitative individual differences were observed. In general, when NAF samples were compared from both breasts within the same patient their electrophoretic patterns were very similar, regardless of their cancer status. A comparison of all patients identified 2 main NAF protein profiles. The HomEP, homogeneous expression profile, was characterized by typical SDS-PAGE and 2D-DIGE protein patterns that were observed in patients with a good breast cancer prognosis and were similar to previous Type I NAF classifications that used one-dimensional electrophoresis. The HetEP, heterogeneous expression profile, was characterized by distinct protein patterns that have not been reported in previous studies and have been primarily observed in breast cancer patients with a poor prognosis. The NAF samples were rich in metal-dependent proteolytic enzymes, as visualized by SDS-PAGE zymography. They varied qualitatively with respect to their gelatinolytic band distribution. However, there were no correlations between these characteristics and the pathologic features of these tumors. A comparative analysis of NAF samples taken from each breast in a single patient showed conserved zymographic patterns. In conclusion, the present study highlights important distinctions in the protein content of individual NAF samples and provides insight into the composition of the tumor microenvironment. These data reinforce breast cancer as a heterogeneous disease with a diverse natural history, which is becoming increasingly evident through other recent studies.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Eletroforese em Gel de Poliacrilamida , Proteínas de Neoplasias/biossíntese , Fluido do Aspirado de Mamilo/metabolismo , Proteômica/métodos , Eletroforese em Gel Bidimensional , Feminino , Humanos , Proteínas de Neoplasias/análiseRESUMO
A descarga papilar está presente em 5% das mulheres e ocorre em razão de causas fisiológicas, doenças benignas da mama e câncer de mama. Algumas das lesões benignas da mama estão relacionadas a um maior risco de desenvolvimento de patologia maligna mamária. A papilar para a avaliação desse sintoma mamário e sua relação com as lesões benignas importância da descarga papilar está na possibilidade de essa condição associar-se a câncer de mama. Uma avaliação clínica detalhada é fundamental para a determinação da abordagem terapêutica da paciente com descarga papilar. Foram avaliadas 23 pacientes do Serviço de Mastologia do Instituto Fernandes Figueira/Fiocruz submetidas à exérese de árvore ductal em virtude de descarga e com o câncer de mama. Das 23 pacientes analisadas, o resultado histopatológico foi de lesão benigna não proliferativa em 26,1%, lesão proliferativa sem atipias em 60,8%, hiperplasia ductal com atipias em 8,7% e câncer em 4,4%. Os resultados demonstraram que em 69,5% dos casos a histopatologia foi de lesão proliferativa de mama, que, apesar de benigna, apresenta maior risco de desenvolvimento do câncer de mama. Apesar de a descarga papilar estar na maioria dos casos relacionada à doença mamária benigna, em alguns casos esta se associa a um risco aumentado de câncer de mama. É fundamental ressaltar que pode haver uma relação entre a descarga papilar e o câncer de mama, embora este não seja a correspondência histopatológica mais freqüente da descarga papilar.
Nipple discharge is present in 5% of women and occurs due to physiological causes, benign breast disease and breast cancer. Some of benign breast lesions are associated with a higher risk of malignant breast diseases development. The importance of nipple discharge is the possibility of this condition to be associate with breast cancer. A detailed clinical evaluation is fundamental to determinate the therapeutic approach of a patient with nipple discharge. Twenthy-three patients from the Mastology Department of Fernandes Figueira Institute/Fiocruz were submitted to removal of central mammary ducts due to nipple discharge for evaluation of this symptom and its relationship with benign breast lesions and breast cancer. The histopathological results from 23 patients that have been analysed were not proliferative benign breast lesions in 26.1%, proliferative lesions without atypias in 60.8%, atypical ductal hyperplasia in 8.7% and 4 cancer in 4,4%. The results proved 69.5% of proliferative breast lesions thats presents a higher risk of breast cancer development. Although nipple discharge is associated in most of the cases with benign breast diseases sometime it is related to a higher risk of breast cancer. It is important to emphasize that it could be a relation between nipple discharge and breast cancer even if it is not the most frequent, histopathological correspondence of nipple discharge.
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Humanos , Feminino , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/etiologia , Doenças Mamárias/etiologia , Doenças Mamárias/fisiopatologia , Neoplasias da Mama/diagnóstico , Mama/anatomia & histologia , Mama/lesões , Ultrassonografia MamáriaRESUMO
Aproximadamente 20 % dos casos de câncer de mama familiar estão associados a um dos genes de susceptibilidade hereditária para câncer de mama e ovário, BRCA1 e BRCA2. Recentes trabalhos têm demonstrado o mecanismo de ação destes genes com funções estabelecidas na manutenção da integridade do genoma e no controle da recombinação homóloga. A história familiar, a bilateralidade, o acometimento precoce e achados histopatológicos específicos são fatores sugestivos da presença de mutações nestes genes. Esta revisão sumariza alguns destes conhecimentos, na tentativa de colocá-los no contexto atual das funções destes genes.
Approximately 20% of the cases related to familiar breast cancer are associated to one gene of hereditary susceptibilityfor breast and ovarian cancer, BRCA1 and BRCA2. Recent works have demonstrated the mechanism of action of these genes, with functions well established for maintaining the genome integrity and for controlling homologatesrecombination. Familiar history, bilaterality, precocious diseases, as well as specific histopathologic results areindicative factors of the presence of mutation in these genes. This literature review summarizes some of thisknowledge, trying to understand them in the current functional context of these genes.