Prevalencia de subtipos de cáncer de mama y su asociación con factores reproductivos / Prevalence of breast cancer subtypes and their association with reproductive factors

Introducción: Los factores reproductivos se asocian con cáncer de mama. Actualmente se estudia el comportamiento según subtipos moleculares. Objetivo: Establecer la prevalencia de estos subtipos y su asociación con factores reproductivos en mujeres atendidas en centros del nororiente colombiano. Método: Estudio observacional de corte transversal, en mujeres con cáncer de mama subtipos luminales y HER2 durante 2012-2021. Se indagaron variables sociodemográficas, factores reproductivos y estadio tumoral. Resultados: En total, 347 pacientes cumplieron criterios de elegibilidad, correspondiendo a luminal A el 49,8% (intervalo de confianza del 95% [IC95%]: 44,5-55,1), a luminal B el 29,1% (IC95%: 24,3-33,9) y a HER2 el 15,5% (IC95%: 11,7-19,4). Las mujeres con tumores de mama luminal B tenían más riesgo de tener estadios localmente avanzados (odds ratio [OR]: 1,83; IC95%: 1,11-3,01; p = 0,02). Agrupando los subtipos luminales frente a HER2 se encontró que el 40,72% de las pacientes con subtipos luminales no habían lactado, frente al 69,71% con HER2 (diferencia estadísticamente significativa a favor de luminal A; OR: 1,91; IC95%: 1,02-3,53; p = 0,041). Conclusiones: La prevalencia de tumores luminales es del 84,5%. Existe asociación diferencial entre el antecedente de lactancia materna y la aparición de subtipos luminales, es decir, las mujeres que no lactaron se corresponden con mayor frecuencia con HER2. No se estableció asociación con otros factores estudiados.

Introduction: Stimulus-estrogenic factors are associated with breast cancer. Currently, the behavior according to molecular subtypes is being studied. Objective: To establish the prevalence of these subtypes and their association with reproductive factors in women attended in centers in northeastern Colombia. Method: Observational cross-sectional study in women with breast cancer subtypes luminal and HER2 during 2012 -2021. Sociodemographic variables, stimulus-estrogenic factors and tumor stage were investigated. Results: In total, 347 patients met eligibility criteria, corresponding to luminal A 49.8% (95% confidence interval [95%CI]: 44.5-55.1), luminal B 29.1% (95%CI: 24.3-33.9) and HER2 15.5% (95%CI: 11.7-19.4). Women with luminal B breast tumors were at higher risk of having locally advanced stages (odds ratio [OR]: 1.83; 95%CI: 1.11-3.01; p = 0.02). Grouping the luminal subtypes versus HER2 showed that 40.72% of patients with luminal subtypes had not lactated, compared to 69.71% HER2 (statistically significant difference in favor of luminal A; OR: 1.91; 95%CI: 1.02-3.53; p = 0.041). Conclusions: The prevalence of luminal tumors is 84.5%. There is a differential association between the history of breastfeeding and the appearance of luminal subtypes, i.e., women who did not breastfeed are more likely to have HER2. No association was established with other factors studied.

Relevancia y prevalencia de los parámetros histopatológicos y subtipos moleculares del cáncer de mama en mujeres del área costera de Ecuador atendidas en una institución de Salud Pública / Prevalence and significance of breast cancer pathologycal subtypes in Ecuador

BACKGROUND: The success of breast cancer (BC) treatment depends largely on the clinical-histological characteristics of the patient. Immunohistochemical (IHC) Breast Cancer Subtypes are crucial for therapeutic purposes. AIM: To determine the relevance and prevalence of the histopathological parameters and molecular subtypes of BC among women attending public health services. MATERIAL AND METHODS: A retrospective cross-sectional study was carried out in 199 female patients with histopathological diagnosis of breast cancer, treated at a Guayaquil city hospital in Ecuador, from January 2014 to December 2017. RESULTS: Luminal A carcinoma was the most prevalent tumor in the studied women (54%). Thirty seven percent of patients did not have nodal involvement, 40% had one to three lymph nodes involved and 2% had 10 or more nodes involved. Most patients had a tumor size > 2 and ≤ 5 cm (72%) and moderately differentiated specifications (57%). CONCLUSIONS: The study allowed the characterization of breast cancer according to the prevalence of molecular subtypes and clinical and histological characteristics. These factors determine therapeutic behaviors that optimize the use of the limited resources of the Public Health System.

Análisis de la coexpresión de HER2/GRB7 y su asociación con variables clinicopatológicas en un grupo de mujeres colombianas con diagnóstico de cáncer de mama invasivo / Analysis of HER2/GRB7 co-expression and its association with clinicopathological variables in a group of Colombian women diagnosed with invasive breast cancer

Objetivo. Analizar las diferencias en la presentación de variables clínico-patológicas, de acuerdo con la expresión proteica de GRB7, en tumores HER2 positivos en mujeres colombianas con cáncer de mama invasivo, diagnosticado entre los años 2013 y 2015 en el Instituto Nacional de Cancerología E.S.E (INC). Métodos. Se incluyeron 158 pacientes con diagnóstico confirmado de cáncer de mama ductal invasivo. Se evaluó la expresión de los receptores hormonales (receptor de estrógeno (RE) y de progesterona (RP)), HER2, Ki67 y GRB7, mediante inmunohistoquímica (IHQ), y a partir de estos, se clasificaron los tumores en subtipos intrínsecos. Los análisis estadísticos incluyeron las pruebas de Chi-cuadrado/test exacto de Fisher para las variables categóricas, y la prueba U Mann Whitney/ Kruskal Wallis para las variables cuantitativas. Se evaluó la supervivencia global (SG) y libre de enfermedad (SLR) según la coexpresión de HER2/GRB7 usando el método de Kaplan-Meier y el test de log-rank. Resultados. La expresión de GRB7 se observó exclusivamente en tumores HER2-positivos (luminal B/HER2+ y HER2-enriquecidos: p<0,001). Los casos HER2+/GRB7+ mostraron una mayor expresión de Ki67 (40% vs. 27,5%, p=0,029), pero una tendencia a presentar un menor tamaño tumoral (30 mm vs. 51 mm, p=0,097), comparado con los tumores HER2+/GRB7-. No obstante, no se observaron diferencias en la supervivencia según la coexpresión de HER2/GRB7 (SG: p=0,6; SLR: p=0,07). Conclusiones. En nuestra muestra de estudio, la expresión de GRB7 en tumores HER2+ no se asoció con características clínico-patológicas de pronóstico desfavorable.

Objective: To analyze differences in the presentation of clinicopathological variables according to GRB7 protein expression in HER2-positive tumors in Colombian patients with invasive ductal breast carcinomas diagnosed between 2013 and 2015 at the Instituto Nacional de Cancerología (Bogotá, Colombia).Methods: A total of 158 breast cancer patients were included with a confirmed diagnosis of invasive ductal carcinoma. A single pathologist evaluated the protein expression of hormone receptors (estrogen (ER) and progesterone receptor (PR)), HER2, Ki67, and GRB7 by immunohistochemistry (IHC). The chi-square and Fisher's exact tests were used to assess differences between categorical variables, as well as the Mann-Whitney/Kruskal-Wallis U test for numerical variables. Overall (OS) and disease-free (DFS) survival were evaluated according to HER2/GRB7 co-expression using the Kaplan-Meier method and log-rank test.Results:GRB7 expression was observed exclusively in HER2-positive tumors (luminal B/HER2+ and HER2-enriched: p<0.001). HER2+/GRB7+ cases showed higher Ki67 expression (40% vs. 27.5%, p=0.029) and a tendency to present a smaller tumor (30 mm vs. 51 mm, p=0.097) compared to HER2+/GRB7- tumors. However, no differences in OS or DFS were observed by HER2/GRB7 co-expression (OS: p=0.6; DFS: p=0.07).Conclusions:Our results in Colombian patients indicate that GRB7 expression in HER2-positive breast tumors is not associated with unfavorable clinicopathological features.

Using the analytic hierarchy process to elicit patient preference in the evaluation of first-line treatment of HER2-overexpressing metastatic breast cancer / Uso do processo analítico hierárquico para eleger a preferência do paciente na avaliação da primeira linha de tratamento do câncer de mama metastático her2 hiperexpresso

Abstract Background The many combinations of chemotherapeutic agents and biologicals available in the Brazilian National Health System for the treatment of metastatic breast cancer require analysis that contribute to decision making. Objective The study's primary aim was to evaluate the first-line treatment of HER2- overexpressing metastatic breast cancer from the Brazilian Unified Health System perspective using multicriteria decision analysis (MCDA). Method The treatment options evaluated were (a) pertuzumab combined with trastuzumab and docetaxel, and (b) trastuzumab in combination with docetaxel. Using the hierarchical analytical method, medical oncologists compared the relevance of five predefined criteria: overall survival, response to treatment, adverse events, cost- effectiveness, and budget impact. Results The therapeutic scheme considered more appropriate by the model was pertuzumab combined with trastuzumab and docetaxel. The most sensitive criteria were adverse events, cost-effectiveness, and budget impact. The results suggest that the classification has a close relationship with the perspective of healthcare professionals participating in the questionnaire. Conclusion Defining the treatment of an incurable disease associated with a short survival time and high-cost treatment options necessitates complex decision-making. MCDA allows the weighting of criteria and considering criteria that would be difficult to measure in other methods, such as cost-effectiveness. These aspects differ from economic models and contribute to a broader evaluation of health decision-making.

Resumo Introdução As diversas combinações de agentes quimioterápicos e biológicos disponíveis no Sistema Único de Saúde brasileiro para o tratamento do câncer de mama metastático requerem análises que contribuam para a tomada de decisões. Objetivo O objetivo principal deste estudo foi avaliar o tratamento de primeira linha para câncer de mama metastático HER2 hiperexpresso sob a perspectiva do Sistema Único de Saúde, utilizando a análise de decisão multicritérios (MCDA). Método As opções de tratamento avaliadas foram: (a) pertuzumabe em combinação com trastuzumabe e docetaxel, e (b) trastuzumabe em combinação com docetaxel. Usando o método analítico hierárquico, médicos oncologistas compararam a relevância dos cinco critérios predefinidos: sobrevida global, resposta ao tratamento, eventos adversos, custo-efetividade e impacto orçamentário. Resultados O esquema terapêutico considerado mais apropriado pelo modelo foi pertuzumabe em combinação com trastuzumabe e docetaxel. Os critérios mais sensíveis foram eventos adversos, custo-efetividade e impacto orçamentário. Os resultados sugerem que a classificação está associada à perspectiva do profissional de saúde participante do questionário. Conclusão Definir o tratamento de uma doença incurável associada a um tempo de sobrevida curto e opções de tratamento de alto custo requer uma tomada de decisão complexa. O MCDA permite ponderar e considerar critérios que seriam difíceis de medir em outros modelos de decisão. Esses aspectos contribuem para uma avaliação mais ampla da tomada de decisões em saúde.

Use of artificial intelligence to predict response to neoadjuvant chemotherapy in breast cancer

:Breast cancer is the object of thousands of studies worldwide. Nevertheless, few tools are available to corroborate prediction of response to neoadjuvant chemotherapy. Artificial intelligence is being researched for its potential utility in several fields of knowledge, including oncology. The development of a standardized Artificial intelligence-based predictive model for patients with breast cancer may help make clinical management more personalized and effective. We aimed to apply Artificial intelligence models to predict the response to neoadjuvant chemotherapy based solely on clinical and pathological data. Methods: Medical records of 130 patients treated with neoadjuvant chemotherapy were reviewed and divided into two groups: 90 samples to train the network and 40 samples to perform prospective testingand validate the results obtained by the Artificial intelligence method. Results: Using clinicopathologic data alone, the artificial neural network was able to correctly predict pathologic complete response in 83.3% of the cases. It also correctly predicted 95.6% of locoregional recurrence, as well as correctly determined whether patients were alive or dead at a given time point in 90% of the time. To date, no published research has used clinicopathologic data to predict the response to neoadjuvant chemotherapy in patients with breast cancer, thus highlighting the importance of the present study. Conclusions: Artificial neural network may become an interesting tool for predicting response to neoadjuvant chemotherapy, locoregional recurrence, systemic disease progression, and survival in patients with breast cancer (AU)

Indicaciones para el uso de pertuzumab en cáncer de mama HER2 positivono metastásico en los escenarios neoadyuvante y adyuvante. Revisión de la evidencia y abordaje terapéutico en el Instituto Nacional de Cancerología - Colombia / Indications for the use of pertuzumab in non-metastatic HER2-positive breast cancer in the neoadjuvant and adjuvant. Review of the literature and therapeutic approach at the Instituto Nacional de Cancerología - Colombia

La adición de la terapia dirigida a la quimioterapia citotóxica en pacientes con cáncer de mama ha mejorado significativamente los desenlaces oncológicos en las pacientes con tumores HER2 positivo. El uso de pertuzumab durante el manejo neoadyuvante incrementa significativamente la respuesta patológica completa y en la actualidad permite emplear regímenes libres de antraciclinas con una eficacia similar y menores efectos cardiovasculares (en especial sobre la fracción de eyección). El beneficio en supervivencia libre de enfermedad invasiva, de adicionar pertuzumab en el escenario adyuvante en las pacientes sin tratamiento anti HER2 previo, está limitado a aquellas con ganglios positivos. La implementación de esquemas con bloqueo dual anti HER2, durante el tratamiento inicial del cáncer de mama HER2 positivo, mejora significativamente el pronóstico oncológico en este grupo de pacientes.

The addition of targeted therapy to cytotoxic chemotherapy in patients with breast cancer has significantly improved oncologic outcomes in patients with HER2-positive tumors. The use of pertuzumab during neoadjuvant management significantly increases the complete pathological response and currently allows the use of anthracycline-free regimens with similar efficacy and fewer cardiovascular effects (especially on ejection fraction). The benefit of pertuzumab in disease-free survival in the adjuvant setting for patients without prior anti-HER2 treatment is limited to those with positive nodes. The implementation of schemes with dual anti-HER2 blockade during the initial treatment of HER2-positive breast cancer significantly improves the oncological outcomes in this group of patients.

Predictores histopatológicos de respuesta a tratamiento en pacientes con cáncer de mama receptores hormonales positivos her2 negativo. Un estudio de centro único / Histopathological predictors of response to treat-ment in patients with hormone receptor positive her2 negative breast cancer. A single center study

In troducción: Una de cada 18 mujeres desarrolla a lo largo de su vida cáncer de mama, siendo esta la principal causa de muerte por cáncer en mujeres.El propósito del presente estudio fue establecer el valor predictivo de los factores histopatológicos presentes en tumores malignos de mama con recepto-res hormonales positivos Her2 negativo de un grupo de pacientes en un centro de referencia oncológico.Met odología: Este estudio longitudinal se realizó en el Instituto Oncológico Nacional "Dr Juan TancaMa-rengo", de Guayaquil -Ecuador. El período de inclusión del 2007 al 2009 con período de observación hasta diciembre del 2020. Con una muestra no probabilística, se incluyeron mujeres con cáncer de mama, hormonal positivo Her2Neu negativo, que hayan recibido tratamiento adyuvante durante un pe-riodo de seguimiento. Se midieron variables demográficas, clínicas, relacionadas al tumor, clasificación TNM y sobrevida.Se realiza un análisis univariado descriptivo de la muestra, un análisis bivariado, com-parando el grupo de pacientes fallecidas con el grupo de pacientes vivas; un análisis de correlación entre variables en escala; un análisis de supervivencia y finalmente se presenta una regresión COX para pre-decir la supervivencia en base a las variables.R esultados: Ingresaron al estudio 105 pacientes, de 54.1 ± 11.4 años. 58.1% de casos en etapa temprana y 41.9% en etapa localmente avanzada. La sobrevida global (SG) fue de 67.6%a 14 añosy la sobrevida librede progresión (SLP) del 59.05%. La terapia de bloqueo hormonal se asoció con la SLP (R=0.544, P<0.01) y con SG (R=0.399, P<0.05). El compromiso ganglionar en estadio N0 tuvo una SLP de 11.9 ± 0.4 años, en estadio N3 fue de 6.8 ± 1.6 años (P<0.01). El modelo de regresión de Cox para predecir el tiempo de vida libre de progresión o enfermedad fue estadísticamente significativo con la terapia de bloqueo hormonal (R2=0.607, P<0.001) Conclusión: Laterapia de bloqueo hormonal mantenida por más de 5 años tiene un impacto positivo en la supervivencia de las pacientes con cáncer de mama hormonal positivo Her2 Neu negativo

In troduction:One in 18 women develops breast cancer throughout her life, this being the leading cause of death from cancer in women. The purpose of the present study was to establish the predictive value of the histopathological factors present in malignant breast tumors with positive hormone receptors Her2 negative in a group of patients in an oncology reference center.Met hodology: This longitudinal study was conducted at the "Dr. Juan Tanca Marengo" National Oncology Institute in Guayaquil -Ecuador. The inclusion period was from 2007 to 2009, with an observation period until December 2020. With a non-probabilistic sample, women with hormone-positive Her2 Neu negative breast cancer who had received adjuvant treatment during a follow-up period were included. Demo-graphic, clinical, tumor-related, TNM classification and survival variables were measured. A descriptive univariate analysis of the sample is performed, a bivariate analysis comparing the group of deceased patients with the group of living patients; a correlation analysis between variables in scale; a survival analysis; and a COX regression is presented to predict survival based on the variables.R esults: 105 patients,54.1 ± 11.4 years old, entered the study. 58.1% of cases are in the early stage, and 41.9% are in a locally advanced stage. Overall survival (OS) was 67.6% at 14 years, and progression-free survival (PFS) was 59.05%. Hormone blocking therapy was associated with PFS (R=0.544, P<0.01) and OS (R=0.399, P<0.05). Lymph node involvement in stage N0 had a PFS of 11.9 ± 0.4 years; stage N3 was 6.8 ± 1.6 years (P<0.01). The Cox regression model to predict progression-free or disease-free life was statistically significant with hormone blockade therapy (R2=0.607, P<0.001).C o nclusion: Hormone blockade therapy maintained for more than five years positively impacts the sur-vival of patients with hormone-positive Her2 Neu negative breast cancer.

Grado de infiltración linfocitaria tumoral al diagnóstico como factor pronóstico de recidiva en cánceres de mama de tipos moleculares rico en Her2 y triple negativo: Revisión Narrativa / Tumor infiltrating lymphocyte grade as prognostic factor of recurrence in molecular subtypes of breast cancer (triple negative and Her2): A narrative review

El carcinoma de mama es una enfermedad común, con efectos negativos significativos en la salud predominantemente femenina. Los linfocitos infiltrantes al tumor (TILs) son una manifestación de la respuesta inmune del huésped al cáncer. Este estudio revisa y resume los reportes bibliográficos relacionados con la eficacia pronóstica del porcentaje alto de TILs en cánceres de mama de tipos moleculares rico en HER2 y triple negativo. Se incluyeron estudios y revisiones en inglés buscados en la base de datos PubMed. Un mayor nivel de TILs se corresponde con mejor supervivencia libre de enfermedad tanto en los cánceres triple negativo como los ricos en HER2; por tanto, constituye un marcador histológico que debería ser utilizado rutinariamente en los análisis microscópicos de biop-sias de mama.

Breast cancer is a common disease affecting women, with significant health-related negative effects. Tumor-infiltrating lymphocytes (TILs) are recognized as manifestations of the host's antitumor im-munity. The following study reviews and summarizes reports on the effectiveness of prognosis of high levels of tumor-infiltrating lymphocytes on triple negative and HER2-enriched breast cancer molecular subtypes. Studies and reviews in English from Pubmed's database were included. A higher percentage of tumor- infiltrating lymphocytes is associated with better prognosis and survival rate of triple negative and HER2-enriched breast cancer. Consequently, such histological marker should be routinely used in the microscopic analysis of breast biopsies.

An easy and practical prognostic parameter: tumor-stroma ratio in Luminal, Her2, and triple-negative breast cancers

SUMMARY OBJECTIVE: The stroma surrounding the tumor cells is important in tumor progression and treatment resistance, besides the properties of tumor cells. Studies on the tumor stroma characteristics will contribute to the knowledge for new treatment approaches. METHODS: A total of 363 breast cancer patients were evaluated for the tumor-stroma ratio. The percentage of stroma was visually assessed on hematoxylin-eosin stained slides. The cases of tumor-stroma ratio more than 50% were categorized as tumor-stroma ratio high, and those less than 50% and below were categorized as tumor-stroma ratio low. RESULTS: Tumor-stroma ratio-high tumors had shorter overall survival (p=0.002). Disease-free survival tended to be shorter in tumor-stroma ratio-high tumors (p=0.082) compared with tumor-stroma ratio-low tumors. Tumor-stroma ratio was an independent prognostic parameter for the total group of patients (p=0.003) and also axillary lymph node metastasis and tumor-stroma ratio was statistically associated (p=0.004). Also, tumor-stroma ratio was an independent prognostic parameter in node-positive Luminal A and B subgroups for overall survival (p<0.001). CONCLUSION: Tumor-stroma ratio is an independent prognostic parameter that can be evaluated quite easily in all molecular subtypes of all breast cancers and does not require extra cost and time to evaluate.

The production of the first functional antibody mimetic in higher plants: the chloroplast makes the DARPin G3 for HER2 imaging in oncology

BACKGROUND: Designed mimetic molecules are attractive tools in biopharmaceuticals and synthetic biology. They require mass and functional production for the assessment of upcoming challenges in the near future. The DARPin family is considered a mimetic pharmaceutical peptide group with high affinity binding to specific targets. DARPin G3 is designed to bind to the HER2 (human epidermal growth factor receptor 2) tyrosine kinase receptor. Overexpression of HER2 is common in some cancers, including breast cancer, and can be used as a prognostic and predictive tool for cancer. The chloroplasts are cost-effective alternatives, equal to, and sometimes better than, bacterial, yeast, or mammalian expression systems. This research examined the possibility of the production of the first antibody mimetic, DARPin G3, in tobacco chloroplasts for HER2 imaging in oncology. RESULTS: The chloroplast specific DARPin G3 expression cassette was constructed and transformed into N. tabacum chloroplasts. PCR and Southern blot analysis confirmed integration of transgenes as well as chloroplastic and cellular homoplasmy. The Western blot analysis and ELISA confirmed the production of DARPin G3 at the commercial scale and high dose with the rate of 20.2% in leaf TSP and 33.7% in chloroplast TSP. The functional analysis by ELISA confirmed the binding of IMAC purified chloroplast-made DARPin G3 to the extracellular domain of the HER2 receptor with highly effective picomolar affinities. The carcinoma cellular studies by flow cytometry and immunofluorescence microscopy confirmed the correct functioning by the specific binding of the chloroplast-made DARPin G3 to the HER2 receptor on the surface of HER2-positive cancer cell lines. CONCLUSION: The efficient functional bioactive production of DARPin G3 in chloroplasts led us to introduce plant chloroplasts as the site of efficient production of the first antibody mimetic molecules. This report, as the first case of the cost-effective production of mimetic molecules, enables researchers in pharmaceuticals, synthetic biology, and bio-molecular engineering to develop tool boxes by producing new molecular substitutes for diverse purposes.

Inmunohistoquímica con anticuerpos monoclonales en mujeres indígenas peruanas con cáncer de mama, para pronosticar sobrevida global / Immunohistochemistry with monoclonal antibodies in peruvian indigenous with breast cancer, to forecast Global Survival

Resumen Objetivo: Aplicar la técnica de anticuerpos monoclonales para HER2/neu (human epidermal growth 2/neuro glioblastoma), en tumores de indígenas nativos de Perú con diagnóstico de cáncer de mama, así como correlacionar la sobreexpresión molecular con la sobrevida global. Pacientes y Métodos: Estudio experimental, prospectivo y analítico. Se evaluaron 23 muestras biológicas de tumores de pacientes indígenas andinos de Arequipa, con diagnóstico definitivo de adenocarcinoma de mama. La expresión del receptor HER2/neu se determinó mediante inmunohistoquímica con anticuerpos monoclonales. Resultados: El 43,4% (10 casos) fueron positivos para sobreexpresión del receptor. Los casos negativos fueron 56,6%. La supervivencia global de las pacientes a los 3 años fue 69,9% cuando los tumores tenían HER2/neu sobreexpresados y 84,6% para los negativos, mostrando diferencia estadísticamente significativa (p=0,017). Conclusiones: La técnica de inmunohistoquímica en tumores mamarios de indígenas andinos puede aplicarse siguiendo los protocolos mundiales. Así mismo, hubo correlación entre la sobreexpresión del receptor HER2/neu con menor sobrevida global. El principal beneficio de esta técnica es justificar el uso de terapia biológica con anticuerpos monoclonales, según el perfil molecular, en población nativa de Arequipa, en un hospital cercano a su residencia.

Abstract Objective: To apply the monoclonal antibody technique for HER2/neu, in tumors of indigenous natives of Peru with breast cancer, as well as to correlate molecular overexpression with global survival. Patients and methods: Experimental, prospective and analytical study. 23 biological samples of tumors from indigenous Andean patients from Arequipa, with a definitive diagnosis of breast adenocarcinoma, were evaluated. HER2/neu expression was determined by immunohistochemistry with monoclonal antibodies. Results: 43.4% (10 cases) were positive for receptor overexpression. The negative cases were 56.6%. The overall survival of the patients at 3 years was 69.9% when the tumors had overexpressed HER2/neu and 84.6% for the negative ones, showing a statistically significant difference (p = 0.017) Conclusions: The immunohistochemical technique in Andean indigenous mammary tumors can be applied following world protocols. Likewise, there was a correlation between the overexpression of the HER2 / neu receptor with lower overall survival. The main benefit of this technique is to justify the use of biological therapy with monoclonal antibodies, according to the molecular profile, in the native population of Arequipa, in a hospital near their residence.

Spatiotemporally differential expression of HER (human epithelial growth factor receptor)-2 with sexual dimorphism in submandibular gland of mice

SUMMARY: Considering that the submandibular gland (SMG) of postnatal mice performs active cell proliferation, apoptosis and differentiation which are regulated by proto-oncogene products in cancerous cells, the expression and localization of a proto-oncogene product HER (human epidermal growth factor receptor)-2 was examined in SMG of postnatal mice. In Western blot analysis, the expression for HER-2 was high until pre-puberty, and it decreased from puberty to young adult stages with male SMG more dominant. In immunohistochemistry, the immunoreactivity was positive in acinar and ductal cells of newborn SMG with distinct localization at the intercellular apposition sites. The immunoreactivity in acinar cells progressively decreased to negligible levels by pre-pubertal stage, while it remained positive in most ductal cells throughout the postnatal time-course. The immunoreactivity in cells of terminal tubules and intercalated ducts, both of which have a high potential to produce cells, were seen at levels similar to those of more proximal ducts, while the immunoreactivity in ductal basal cells was significantly high, but the granular convoluted tubule cells were seen at negligible levels in male and at faint levels in female. In immuno-electron microscopy of excretory ducts, the immunoreactivity was dominantly localized on the basal infolding membranes as well as vesicles and vacuoles of various sizes, but rarely in Golgi apparatus and mitochondria. The immunoreactivity without association to any membranous structures were also seen, though not numerous. The relation of expression levels of HER-2 in various portions of normal SMG to those in their cancerous ones is briefly discussed.

RESUMEN: Considerando que la glándula submandibular (GSM) de ratones postnatales realiza la proliferación celular activa, apoptosis y diferenciación que están reguladas por productos protooncogénicos en células cancerosas, la expresión y localización de un producto protooncogénico HER (receptor del factor de crecimiento epidérmico humano) - 2 se examinó en GSM de estos ratones. En el análisis de Western blot, la expresión de HER-2 fue alta hasta la prepubertad, y disminuyó desde la pubertad hasta las etapas de adultos jóvenes con GSM macho más dominante. En inmunohistoquímica, la inmunorreactividad fue positiva en las células acinares y ductales de GSM de recién nacido con una localización distinta en los sitios de aposición intercelular. La inmunorreactividad en las células acinares disminuyó progresivamente a niveles insignificantes en la etapa prepuberal, mientras que permaneció positiva en la mayoría de las células ductales durante el transcurso del tiempo posnatal. La inmunorreactividad en las células de los túbulos terminales y los conductos intercalados, los cuales tienen un alto potencial para producir células, se obser- vó a niveles similares a los de los conductos más proximales, mientras que la inmunorreactividad en las células basales ductales fue significativamente alta, pero en el túbulo contorneado granular las células se observaron en niveles insignificantes en los machos y en niveles débiles en las hembras. En la microscopía inmunoelectrónica de los conductos excretores, la inmunorreactividad se localizó de manera predominante en las membranas de pliegues basales, así como en vesículas y vacuolas de varios tamaños, pero raramente en el aparato de Golgi y en las mitocondrias. También se observó la inmunorreactividad sin asociación a ninguna estructura membranosa, aunque no numerosa. Se discute brevemente la relación de los niveles de expresión de HER-2 en varias porciones de GSM normal con aquellos en sus cancerosos.

Automated breast volume scanning combined with shear wave elastography for diagnosis of triple-negative breast cancer and human epidermal growth factor receptor 2-positive breast cancer

SUMMARY OBJECTIVE To explore the values of automated breast volume scanning (ABVS) combined with shear wave elastography (SWE) in the differential diagnosis of triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2-positive breast cancers (HER2+BC). METHODS In this study, 28 patients with TNBC and 32 patients with HER2+BC were enrolled. The characteristics of ABVS and virtual touch quantification (VTQ) in SWE of all patients were reviewed. The multivariate logistic regression analysis was carried out and the receiver operating characteristic curves of ABVS and ABVS+VTQ were drawn. RESULTS In ABVS imaging, the microcalcification, posterior echo, internal echo, shape, and edge had significant difference between TNBC and HER2+BC groups (p<0.05). The regular shape was the independent factor for TNBC (p=0.04, odds ratio [OR]=4.479), and the microcalcification in mass was the independent factor for HER2+BC (p=0.01, OR=2.997). In VTQ imaging, the shear wave velocity (SWV)max, SWVmin, and SWVmean in TNBC group were significantly lower than those in HER2+BC group (p<0.001). The sensitivity, specificity, and accuracy of ABVS+VTQ in diagnosing TNBC were higher than those of ABVS alone. CONCLUSIONS ABVS combined with SWE has certain advantages in differentiating TNBC from HER2+BC, which is helpful for the treatment planning and prognosis judgment.

Factors affecting pathological complete response after neoadjuvant chemotherapy in breast cancer: a single-center experience

SUMMARY OBJECTIVE: The aim of this study was to examine the characteristics of patients admitted to our hospital with a diagnosis of breast cancer who reached pathological complete response after being operated following eight cycles of neoadjuvant chemotherapy. METHODS: Between 2015-2020, patients with pathological complete response who were operated on after neoadjuvant chemotherapy and sent to our clinic for radiotherapy were evaluated. RESULTS: The median age of the patients was 51 years. The most common histological type was invasive ductal cancer. The number of pathological complete response patients was 74 (28%), and the number of non-pathological complete response patients was 188 (72%). Patients with pathological complete response had a smaller tumor diameter than the non-pathological complete response group (p=0.001). For pathological complete response, T1 stage, N1 stage, NG 3, Ki-67 >20%, negative estrogen receptor, negative progesterone receptor, positive Cerb-B2, and adding trastuzumab to chemotherapy were statistically significant (p<0.05). Before neoadjuvant chemotherapy, stage T1-T2 (p=0.036), LN0-1 (p=0.026), Cerb-B2 positivity (p=0.025), and an initial nuclear grade of three (p=0.001) were found to be the factors affecting pathological complete response. CONCLUSIONS: With neoadjuvant chemotherapy, the size of locally advanced tumors decreases, allowing breast conserving surgery. The neoadjuvant chemotherapy response can be used as an early indicator of the prognosis of patients with breast cancer. Today, neoadjuvant chemotherapy is also used for patients with early-stage, operable breast cancer because it has been shown in many studies that reaching pathological complete response is associated with positive long-term results. If we can identify patients who have reached pathological complete response before neoadjuvant chemotherapy, we think we can also determine a patient-specific treatment plan at the beginning of treatment.

Immunohistochemical and clinicopathologic features of estrogen receptor-negative, progesterone receptor-positive, HER-2 negative breast carcinomas

SUMMARY OBJECTIVE: Currently, there is an ongoing debate whether progesterone receptor positive and estrogen receptor negative breast carcinomas represent a true distinct subtype of tumor or a mere immunohistochemical artifact. In this study, we conducted an immunohistochemistry panel with the antibodies TFF1, EGFR, and CK5 to reclassify this phenotype in a luminal or basal-like subtype. METHODS: Tumors estrogen receptor -/progesterone receptor +, Her-2 - from a large population of breast cancer patients were selected to be studied. Immunohistochemistry with the antibodies TFF1, EGFR, and CK5 was performed. Tumors showing positivity for TFF1, regardless of EGFR and CK5 results, were classified as luminal-like carcinomas. Those lesions that were negative for TFF1, but were positive for EGFR and/or CK5, were classified as basal-like triple-negative carcinomas. When the three markers were negative, tumors were classified as undetermined. Clinical pathologic characteristics of patients and tumor recurrence were evaluated. RESULTS: Out of 1188 breast carcinomas investigated, 30 cases (2.5%) presented the estrogen receptor -/progesterone receptor +/HER2- phenotype. Of them, 27 tumors (90%) were classified as basal-like triple-negative carcinomas, one as luminal-like (3.3%), and two as undetermined tumors (6.7%). The mean follow-up for the study group was 27.7 (2.7 to 50) months. Out of the 26 patients, 6 had cancer recurrence: 2 local and 4 systemic recurrences. The average time for recurrence was 17 (8 to 38) months. CONCLUSION: Estrogen receptor -/progesterone receptor +/tumors exhibit aggressive behavior, similar to triple-negative tumors. An appropriate categorization of these tumors should be made to improve their therapeutic management.

Effects of risk factors in the likelihood of breast cancer subtypes in Brazilian women / Efeitos de fatores de risco na probabilidade de subtipos do câncer de mama em mulheres brasileiras

INTRODUCTION: Breast cancer is a heterogenous disease with multiple causes and it lacks more investigation related to its risk factors. OBJECTIVE: To evaluate the likelihood of breast cancer subtypes according to the positivity to estrogen and progesterone receptors (ER+ and PR+ respectively), with or without the expression HER2, related to the following risk factors: age, parity, diabetes mellitus, arterial hypertension, occurrence of familiar cancer case and body mass index (BMI). METHODS: The sample with 79 individuals was divided into three subtypes 1 (ER+/PR-), 2 (ER+/PR+) and 3 (RE+/RP+/HER+) and then analyzed by quantitative methods using Ordinal Generalized Linear Models (OGLM) for estimating the marginal effects of risk factors for the studied subtypes, and modeling the heteroscedasticity in terms of error. RESULTS: It were observed the following statistically significant positive effects: (1) age for the tumoral subtype 1 (ER+/PR-) and (2) parity for the subtype 2 (ER+/PR+); while the significant negative effects were: (1) age for subtype 3 (ER+/PR+/HER2+); (2) parity for both 1 (ER+/PR-) and 3 (ER+/PR+/HER2+) subtypes; and arterial hypertension for subtype 1 (ER+/PR-). There were no statistically significant effects for BMI, Diabetes mellitus and occurrence of familiar cancer variables on the studied tumoral subtypes. CONCLUSION: The risk factos age and parity demonstrated varied effects for the breast cancer subtypes according the expression of estrogen, progesterone and HER2 receptors.

INTRODUÇÃO: O câncer de mama é uma doença heterogênea, multifatorial e que necessita de mais estudos relacionados aos fatores de riscos. OBJETIVO: Analisar a probabilidade dos subtipos tumorais do câncer de mama receptores de estrogênio (RE) ou progesterona (RP) positivos, com ou sem expressão de HER2, em relação aos fatores de risco: idade, parto, diabetes mellitus, hipertensão arterial, ocorrência de câncer de mama familiar e índice de massa corporal (IMC). MÉTODOS: A análise da amostra de 79 pacientes dividida nos subtipos 1 (RE+/RP-), 2 (RE+/RP+) e 3 (RE+/RP+/HER+), foi feita por meio de métodos quantitativos usando o Modelo Linear Generalizado Ordinal (MLGO) para estimar os efeitos marginais dos fatores de risco para os subtipos estudados, e ao mesmo tempo modelando a heterocedasticidade do termo de erro. RESULTADOS: Nos resultados foram observados os seguintes efeitos positivos estatisticamente significantes: (1) da idade para o subtipo tumoral 1 (RE+/RP-) e (2) do número de partos para o subtipo 2 (RE+/RP+); enquanto os efeitos negativos significativos foram os seguintes: (1) da idade para o subtipo 3 (RE+/RP+/HER2+); (2) do número de partos para o sutipos 1 (RE+/RP) e 3 (RE+/RP+/HER2+); e da hipertensão arterial para o o subtipo 1 (RE+/RP-). Não foram observados efeitos estatisticamente significativos das variáveis IMC, Diabetes mellitus e ocorrência de câncer de mama familiar sobre os subtipos tumorais estudados. CONCLUSÃO: Os fatores de risco idade e número de partos têm efeitos variados para os subtipos do câncer de mama segundo a expressão de receptores para estrogênio, progesterona e HER2.

Incidence of central nervous system metastases in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer treated with trastuzumab: A meta-analysis

This study aimed to estimate the incidence of central nervous system (CNS) metastases in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) treated with trastuzumab. Studies were identified through a literature search of electronic databases. Random-effects meta-analyses were performed to estimate the incidence rate of CNS metastases, trastuzumab therapy duration, and time from trastuzumab therapy to CNS metastasis diagnosis. A meta-analysis of odds ratios was performed to evaluate the significance of a difference in CNS metastasis incidence between patients with and without trastuzumab treatment. Thirty studies (8121 trastuzumab-treated and 3972 control patients) were included. The follow-up duration was 18.9 months (95% confidence interval [CI]: 13.8, 24.1). The trastuzumab treatment duration was 9.0 months (95% CI: 7.0, 11.0). The median interval between the start of trastuzumab therapy and CNS metastasis diagnosis was 12.2 months (95% CI: 9.5, 14.7). The incidence of CNS metastasis after the start of trastuzumab therapy was 22% (95% CI: 16, 27). The incidence of CNS metastases was significantly higher in trastuzumab-treated than in non-trastuzumab-treated patients (odds ratio: 1.39 [95% CI: 1.06, 1.82], p=0.02). The survival time from the start of the study was 23.4 months (95% CI: 19.7, 27.1) in trastuzumab-treated patients and 18.4 months (95% CI: 12.7, 24.1) in patients treated with control regimens. The survival time after the development of CNS metastases in trastuzumab-treated patients was 19.2 months (95% CI: 15.6, 25.9). Approximately 22% of patients with HER2-positive MBC who were treated with trastuzumab developed CNS metastases. However, trastuzumab-treated patients had a longer survival than patients who were not treated with trastuzumab.

Comparison of hormonal receptor expression and HER2 status between circulating tumor cells and breast cancer metastases

OBJECTIVES: Breast cancer (BC) is the most common neoplasm in women. Biopsy of metastatic lesions is recommended to confirm estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status as there are discrepancies in these patterns between primary tumors and metastases in up to 40% of the cases. Circulating tumor cells (CTCs) are related to BC outcomes and could potentially be an alternative to the invasive procedures of metastasis rebiopsy. ISET® technology is not currently employed to detect CTCs in patients with BC. Emerging data support that the characterization of CTC protein expression can refine its prognostic value. Transforming growth factor (TGF)-β plays a role in BC progression and invasiveness. Thus, in this study, we aimed to compare ER, PR, and HER2 expression in primary tumors, CTCs, and metastases and evaluate TGF-β type 1 receptor (TGF-β RI) expression in CTCs as prognostic factor for progression free survival (PFS) and overall survival (OS). METHODS: This prospective study was conducted at the A.C. Camargo Cancer Center, Brazil. Blood samples were processed in ISET® (Isolation by SizE of Tumors, Rarecells, France) before computed tomography-guided biopsy of suspected metastatic lesions. Protein expression levels in CTCs were compared to those in primary tumors/metastases (medical records). RESULTS: Of the 39 patients initially included, 27 underwent both biopsies of metastases and blood collection and were considered for analysis. The concordance rates for ER, PR, and HER2 expression between primary tumors and metastases were high. No loss of HER2 expression at any metastasis site and retention of the same pattern of protein expression in all triple-negative (TN) tumors (92.5%, 81.5% and 96.2% respectively) (p<0.0001) was observed. When metastases/CTCs were classified as TN/non-TN, CTCs showed high specificity (93%), accuracy (84.2%), and negative predictive value (88%). The median OS of patients without TGF-β RI expression in CTCs was 42.6 versus 20.8 months for TGF-β RI expression-positive ones (p>0.05). CONCLUSION: The role of CTCs detected by ISET has not yet been established in BC. Here, we suggest that this methodology may be useful to evaluate metastasis in non-TN cases as well as TGF-β RI expression in CTCs, which may impact patient survival. Due to sample limitations, future studies must focus on specific BC subtypes and an expansion of the cohort.

Gliomas de Alto Grado del Adulto, Biología Molecular (Parte I) / High-Grade Gliomas of the Adult, Molecular Biology (Part I)

Introducción: Los tumores gliales, dentro de las lesiones neuroepiteliales, son las neoplásicas intraaxiales más comunes. Representan alrededor del 45% de todos los tumores primarios del sistema nervioso central (SNC) y el 77% de todos los tumores primarios malignos del SNC. El promedio de supervivencia media de los pacientes con glioblastoma multiforme (GBM) cuando se utiliza el tratamiento multimodal es de 15-18 meses y de 2 a 5 años con gliomas anaplásicos. Los tratamientos convencionales de los tumores cerebrales incluyen cirugía, radioterapia y quimioterapia. El tratamiento quirúrgico representa la primera aproximación para la gran mayoría de tumores cerebrales, sin embargo, la resección total no siempre es alcanzable en relación con la localización del tumor, de vital importancia para preservar estructuras nerviosas o vasculares. Modalidades de tratamiento agresivas han extendido la supervivencia media, pero la supervivencia a menudo se asocia con un deterioro significativo en la calidad de vida. La eficacia de quimioterapia sistémica está limitada por la presencia de la barrera hemato encefálica (BHE), la que limita el paso de una amplia variedad de agentes anti cancerígenos, la acción de los agentes alquilantes, está limitado por la activación de metil-guanina-metil-transferasa. El advenimiento de los estudios moleculares permite una nueva evaluación de la biología de los gliomas con, un nivel de precisión que promete interesantes avances hacia el desarrollo de terapias específicas eficaces. Las terapias dirigidas bloquean la activación de vías oncogénicas, ya sea a nivel de la interacción ligando-receptor o mediante la inhibición vías de transducción de señales, corriente abajo, inhibiendo así el crecimiento y la progresión del cáncer. El objetivo del presente trabajo fue realizar una revisión bibliográfica acerca de los aspectos relacionados con la patogénesis molecular en la progresión de estos tumores en los adultos, y sus potenciales blancos terapéuticos.

Introduction:Glial tumors, within neuroepithelial lesions, are the most common intraaxial neoplastic. They represent about 45% of all primary central nervous system (CNS) tumors and 77% of all malignant primary CNS tumors. The median median survival of patients with glioblastoma multiforme (GBM) when multimodal treatment is used is 15-18 months and 2-5 years with anaplastic gliomas. Conventional treatments for brain tumors include surgery, radiation therapy, and chemotherapy. Surgical treatment represents the first approach for the vast majority of brain tumors; however, total resection is not always achievable in relation to the location of the tumor, which is vitally important to preserve nerve or vascular structures.Aggressive treatment modalities have extended median survival, but survival is often associated with a significant deterioration in quality of life. The efficacy of systemic chemotherapy is limited by the presence of the blood-brain barrier (BBB), which limits the passage of a wide variety of anticancer agents, the action of alkylating agents, is limited by the activation of methyl-guanine-methyltransferase. The advent of molecular studies allows a new evaluation of the biology of gliomas with, a level of precision that promises interesting advances towards the development of effective specific therapies. Targeted therapies block the activation of oncogenic pathways, either at the level of ligand-receptor interaction or by inhibiting downstream signal transduction pathways, thus inhibiting cancer growth and progression.The objective of the present work was to carry out a bibliographic review about the aspects related to the molecular pathogenesis in the progression of these tumors in adults, and their potential therapeutic targets.

Tratamiento Neoadyuvante en cáncer de mama HER2 positivo. La era de la terapia dirigida / Neoadjuvant treatment in HER2 positive breast cancer. The Age of Targeted Therapy

Introducción: El tratamiento neodyuvante del cáncer de mama HER2 positivo ha ido evolucionando a través del tiempo, con la implementación de nuevas estrategias de manejo terapéutico. Es de esta manera como el trastuzumab, un anticuerpo monoclonal anti-HER2sigue siendo el tratamiento estándar en este subtipo de cáncer, los primeros estudios en los que se evidencia su eficacia son el realizado por el Dr. Buzdar y el estudio NOAH en los cuales las pacientes alcanzaron mayores tasas de respuesta patológica completa en comparación con quimioterapia sola, así como también un mayor número de cirugías conservadoras de mama en lugar de mastectomía.Con el paso de los años se han ido desarrollando nuevas estrategias de manejo terapéutico, así tenemos el doble bloqueo anti-HER2 con los anticuerpos monoclonales trastuzumab y pertuzumab que han mejorado las tasas de respuesta patológica completa. Además se ha incluido al lapatinib un inhibidor de tirosina quinasa como parte de las terapias dirigidas. Se ha dilucidado si las antraciclinas confieren un beneficio adicional al tratamiento neoadyuvante y los estudios demuestran que el beneficio es el mismo queotros esquemas de quimioterapia. Es en realidad la quimioterapia indispensable en la neoadyuvancia, el estudio PHERGain demuestra que existen pacientes que pueden alcanzar respuesta patológica completa solo con el doble bloqueo anti-her2 (trastuzumab y pertuzumab) lo que evitaría la toxicidad innecesaria por quimioterapia, y se podrían desarrollar estrategias para el manejo de aquellas pacientes que no alcanzaron una respuestapatológica completa posterior al doble bloqueo. Aún queda un campo amplio por explorar y con estudios en curso al momento. Palabras claves:DsCS:Receptor ErbB-2, Trastuzumab, Neoplasias de la Mama, Quimioterapia Adyuvante, Ado-Trastuzumab Emtansina

Introduction:The neodyuvanttreatment of HER2 positive breast cancer has evolved over time, with the implementation of new therapeutic management strategies. It is in this way that trastuzumab, an anti-HER2 monoclonal antibody continues to be the standard treatment in this subtype of cancer, the first studies in which its efficacy is evidenced are the one carried out by Dr. Buzdar and the NOAH study in which patients achieved higher rates of complete pathological response compared to chemotherapy alone, as well as a higher number of breast-conserving surgeries rather than mastectomy.Over the years, new therapeutic management strategies have been developed, thus we have the double anti-HER2 blockade with the monoclonal antibodies trastuzumab and pertuzumab that have improved the ratesof complete pathological response. In addition, lapatinib, a tyrosine kinase inhibitor, has been included as part of targeted therapies. It has been elucidated whether anthracyclines confer an additional benefit to neoadjuvant treatment and studies show that the benefit is the same as other chemotherapy regimens.It is actually the essential chemotherapy in neoadjuvant therapy, the PHERGain study shows that there are patients who can achieve a complete pathological response only with the double anti-her2 blockade (trastuzumab and pertuzumab), which would avoid unnecessary toxicity due to chemotherapy, and strategies could be developed for the management of those patients who did not achieve a complete pathological response after double blockade. There is still a wide field to explore and with studies underway at the moment. Keywords:MESH:Receptor, ErbB-2;Trastuzumab; Breast Neoplasms; Chemotherapy, Adjuvant; Ado-Trastuzumab Emtansine