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ExteNET showed that neratinib, an irreversible pan-HER tyrosine ki- nase inhibitor, given for 1 year after trastuzumab-based therapy significantly improved inva- sive disease-free survival in women with early-stage HER2-positive breast cancer. We report the final analysis of overall survival in ExteNET.

Funding Information: This project was initiated at the Endeavour Breast Project coordinated by Daiichi Sankyo (special thanks to Christian Opitz and Britta Mazur from Daiichi Sankyo). We thank all participants and the steering committee members of the Endeavour Breast Meeting who are not listed as co-authors ( Supplementary Table S4 , available at https://doi.org/10.1016/j.esmoop.2022.100747 ). The authors gratefully acknowledge the support from the AGMT office (particularly Mag. Katrin Dorfinger, Mag. Alexandra Keuschnig, Sebastian Schütz, and Dr. Daniela Wolkersdorfer) and all trial coordinators at the contributing centers. Publisher Copyright: © 2022 The Authors Background: Triple-negative breast cancer (TNBC) is associated with poor prognosis, and new treatment options are urgently needed. About 34%-39% of primary TNBCs show a low expression of human epidermal growth factor receptor 2 (HER2-low), which is a target for new anti-HER2 drugs. However, little is known about the frequency and the prognostic value of HER2-low in metastatic TNBC. Patients and methods: We retrospectively included patients with TNBC from five European countries for this international, multicenter analysis. Triple-negativity had to be shown in a metastatic site or in the primary breast tumor diagnosed simultaneously or within 3 years before metastatic disease. HER2-low was defined as immunohistochemically (IHC) 1+ or 2+ without ERBB2 gene amplification. Survival probabilities were calculated by the Kaplan–Meier method, and multivariable hazard ratios (HRs) were estimated by Cox regression models. Results: In total, 691 patients, diagnosed between January 2006 and February 2021, were assessable. The incidence of HER2-low was 32.0% [95% confidence interval (CI) 28.5% to 35.5%], with similar proportions in metastases (n = 265; 29.8%) and primary tumors (n = 425; 33.4%; P = 0.324). The median overall survival (OS) in HER2-low and HER2-0 TNBC was 18.6 and 16.1 months, respectively (HR 1.00; 95% CI 0.83-1.19; P = 0.969). Similarly, in multivariable analysis, HER2-low had no significant impact on OS (HR 0.95; 95% CI 0.79-1.13; P = 0.545). No difference in prognosis was observed between HER2 IHC 0/1+ and IHC 2+ tumors (HR 0.89; 95% CI 0.69-1.17; P = 0.414). Conclusions: In this large international dataset of metastatic TNBC, the frequency of HER2-low was 32.0%. Neither in univariable nor in multivariable analysis HER2-low showed any influence on OS. publishersversion published

Purpose We sought to expand the currently limited, Canadian, population-based data on the characteristics, treatment pathways, and health care costs according to stage in patients with human epidermal growth factor receptor-2 positive (HER2+) breast cancer (BC). Methods We extracted data from the publicly funded health care system in Ontario. Baseline characteristics, treatment patterns, and health care costs were descriptively compared by cancer stage (I–III vs. IV) for adult women diagnosed with invasive HER2+ BC between 2012 and 2016. Resource use was multiplied by unit costs for publicly funded health care services to calculate costs. Results Overall, 4535 patients with stage I–III and 354 with stage IV HER2+ BC were identified. Most patients with stage I–III disease were treated with surgery (4372, 96.4%), with the majority having a lumpectomy, and 3521 (77.6%) received radiation. Neoadjuvant (NAT) and adjuvant (AT) systemic treatment rates were 20.1% (n = 920) and 88.8% (n = 3065), respectively. Systemic treatment was received by 311 patients (87.9%) with metastatic HER2+ BC, 264 of whom (84.9%) received trastuzumab. Annual health care costs per patient were nearly 3 times higher for stage IV vs. stage I–III HER2+ BC. Conclusion Per-patient annual costs were substantially higher for women with metastatic HER2+ BC, despite less frequent exposure to surgery and radiation compared to those with early stage disease. Increasing NAT rates in early stage disease represent a critical opportunity to prevent recurrence and reduce the costs associated with treating metastatic HER2+ BC.

Currently the oncological mortality takes the second place globally, the leading cause being cardiovascular diseases. The statistics of malignant neoplasms is rather negative all over the world. 10 million of cases of oncological disorders are diagnosed annually; this means that 27 million people fall sick with oncological diseases annually. It was established in 2019 that there are 14 million people suffering from oncological diseases, 8.2 million of these die. WHO anticipates that in 20 years’ time the malignant neoplasm incidence statistics will be on an increase as the number of new cases will reach 20 million, 12 million out of which will die. Regardless of such formidable figures medicine does not stand still; keeping up with the times, the science attempts to develop cutting edge methods of treating malignant tumours. As a result, the treatment of malignant neoplasms is continuing to improve. However, the number of side effects is also growing, thus requiring research attention. Therefore, the significance of the impact that oncological drugs have on a patient’s body is becoming more and more urgent for further discussion. While current tumour treatment methods involving drugs such as tyrosine kinase inhibitors, anthracycline chemotherapy and immunotherapy protocols are effective for the treatment of various forms of cancer, these drugs affect the DNA replication process thus resulting in endothelial dysfunction and nonspecific immune response. This causes cardiotoxic side effects. Cardiotoxicity, in its turn, is a notion that includes various adverse events involving the cardiovascular system of oncological patients receiving drug treatment. Cardiotoxicity may develop during treatment or following its completion.

Orientadores: Luis Otávio Zanatta Sarian, Sophie Françoise Mauricette Derchain Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: Introdução: o câncer de ovário é comumente diagnosticado em estágios avançados, sendo atualmente a neoplasia ginecológica de maior letalidade. As pesquisas têm direcionado esforços na tentativa de descobrir novos fatores prognósticos e métodos terapêuticos. Muitos trabalhos estudam a expressão dos receptores de esteróides (dentre eles, estrógeno (RE), progesterona (RP) e andrógeno (RA)) e HER2 (receptor estimulador de crescimento epitelial - subtipo 2) como fatores prognósticos e associados à resposta terapêutica, apresentando; entretanto, resultados conflitantes. Até onde conhecemos, não há estudos desta natureza no Brasil. Objetivo: Correlacionar à expressão dos RE, RP, RA e HER2 aos fatores clínico patológicos, ao intervalo livre de doença e à sobrevida nos cânceres epiteliais de ovário. Material e métodos: Este é um estudo observacional de coorte retrospectiva. Foram incluídas 152 mulheres com tumores epiteliais malignos, selecionados através dos prontuários no período de 1993 a 2008, no Centro de Atenção Integral à Saúde da Mulher (CAISM) da Universidade Estadual de Campinas - UNICAMP, São Paulo, Brasil. A avaliação da expressão dos RE [subtipos alfa (RE?) e beta (RE?)], RP, RA e HER2 foram realizadas por imunoistoquímica através da construção de microarranjos de tecidos (TMA). Inicialmente, foi realizada análise uni variada da expressão dos receptores acima quanto à idade, estado menopausal, índice de massa corpórea (IMC), tipo histológico, grau histológico, estadiamento inicial de acordo com a classificação proposta pela FIGO e presença de doença residual pós-tratamento cirúrgico. Em seguida, as pacientes foram divididas em dois grupos: ausência da expressão de RE?, RP e HER2 (triplo negativo) e positividade para pelo menos um desses receptores (não triplo negativo); e, avaliadas em relação aos critérios clínicos e epidemiológicos acima. Foram, então, realizadas análises multivariadas dos padrões de expressão de RE ? e ?, RP, RA, HER2 e triplo negativo em relação a estes mesmos critérios. Por fim, análise de sobrevida multivariada foi realizada utilizando-se todos os padrões de expressão e os fatores clínicos epidemiológicos estudados. Resultados: Nas análises multivariadas, mostraram-se significativas as seguintes associações: do receptor de estrógeno alfa (ER?) com tumores de grau histológico menos diferenciado (p=0.01); do receptor de progesterona (RP) à obesidade (p= 0.01); do receptor de andrógeno (RA) com tumores do subtipo seroso (p= 0.01); do receptor de HER2 com tumores dos graus histológicos II-III (p=0.02); do subgrupo triplo negativo com tumores de grau histológico menos diferenciado (II-III) (p

El cáncer de mama sigue constituyendo uno de los tumores con mayor morbi-mortalidad entre la población femenina. Sin embargo, en los últimos años, gracias al avance en la biología molecular y la secuenciación del genoma, se ha podido precisar el enfoque terapéutico de los distintos subtipos moleculares del cáncer de mama. Las nuevas terapias dirigidas contra el receptor HER2, sobreexpresado/amplificado en un porcentaje minoritario de cáncer de mama, ha permitido mejorar la evolución de la enfermedad, aumentando significativamente la esperanza de las pacientes con este subtipo. Por lo tanto, este trabajo tiene como objetivo revisar la literatura científica disponible acerca de la eficacia y seguridad de las terapias anti-HER2. Para ello, se ha realizado una búsqueda extensiva en la base de datos Medline a través del buscador Pubmed, utilizando palabras claves tales como: “cáncer de mama”, “receptor, ErbB-2”, “anticuerpos monoclonales, humanizados”, “proteínas Tirosina Quinasas Receptoras”, “eficacia” y “efecto adverso”. Los resultados obtenidos de la búsqueda han sido estructurados de manera organizada en cuatro bloques. De tal modo que finalmente se puede concluir que las terapias dirigidas contra el receptor HER2, en especial el anticuerpo monoclonal trastuzumab, han supuesto un beneficio terapéutico para este subtipo molecular cuando se administra junto con las terapias convencionales estándares especialmente en estados precoces. A pesar de ello, es necesario seguir investigando nuevas opciones terapéuticas para un mejor abordaje del cáncer de mama HER2-positivo en estados avanzados con el fin de mejorar la calidad y esperanza de vida de estas pacientes.

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Karcinom dojke je najčešći maligni tumor u žena. Ciljevi: Istražiti utjecaj statusa receptora za humani epidermalni čimbenik rasta 2 (HER2) na zahvaćenost limfnih čvorova aksile metastazama u bolesnica s invazivnim duktalnim karcinomom dojke nespecificiranog tipa (IDK-NST), pri operaciji dojke te tijekom četverogodišnjeg postoperacijskog razdoblja. Ispitanici i metode: U studiju je retrospektivno uključeno 375 žena u ranom kliničkom stadiju IDK-NST kojima je od 2007. do 2013. godine u Kliničkom bolničkom centru Rijeka učinjen operacijski zahvat na dojci. One su, ovisno o molekularnom podtipu tumora, razvrstane u grupe: HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-. Samo kod makrometastaza u limfnim čvorovima čuvarima učinjena je i disekcija aksile. Adjuvantna radioterapija je primijenjena u žena s poštednom operacijom dojke te u onih s mastektomijom koje su imale >3 pozitivna limfna čvora. Sve ispitanice primile su adjuvantnu kemoterapiju, one s HER2+ tumorima i trastuzumab, a one s pozitivnim hormonskim receptorima (HR+) hormonsku terapiju. Rezultati: Veći tumori, viši histološki gradus, HR+, HER2+ status te limfovaskularna invazija bili su prediktori aksilarnih metastaza pri operaciji. Najlošija preživljenja: ukupno, bez relapsa i bez udaljenog relapsa, bila su u HR-/HER2-, a najlošije preživljenje bez lokoregionalnog relapsa u HR-/HER2- i HR-/HER2+ grupama. Histološki gradus, HR status, omjer broja pozitivnih i odstranjenih limfnih čvorova te veličina tumora bili su prediktori preživljenja, no ne i HER2 status. Zaključak: HER2+ status, unatoč prediktivnom kapacitetu za zahvaćenost limfnih čvorova aksile pri operaciji dojke, nije utjecao na preživljenja: ukupno, bez relapsa, bez lokoregionalnog relapsa te bez udaljenog relapsa, u bolesnica s IDK-NST liječenih adjuvantnom sistemskom terapijom prema preporukama konferencija iz St. Gallena.

Objective: To evaluate the accuracy of magnetic resonance imaging (MRI) of the breasts in the identification of a pathological complete response in patients with breast cancer undergoing neoadjuvant chemotherapy (NAC). Materials and Methods: This was a single-center, retrospective, observational study designed to validate a diagnostic test. The following variables were evaluated: age; results of the histological and immunohistochemical analysis of the biopsy; post-NAC MRI findings; and results of the histological analysis of the surgical specimen, using the residual cancer burden index. The radiological response, as assessed by MRI, was compared with the pathological response, as assessed by histological analysis of the surgical specimen (the gold standard method). Results: We evaluated 310 tumors in 308 patients. The mean age of the patients was 47 years (range, 27-85 years). For identifying a pathological complete response, breast MRI had an overall accuracy of 79%, with a sensitivity of 75%, specificity of 83%, positive predictive value of 75%, and negative predictive value of 83%. When that accuracy was stratified by molecular subtype, it was best for the HER2 subtype, with a sensitivity and specificity of 82% and 89%, respectively, followed by the triple-negative subtype, with a sensitivity and specificity of 78% and 83%, respectively. Conclusion: Breast MRI showed good accuracy in the prediction of a pathological complete response after NAC. The sensitivity and positive predictive value were highest for the HER2 and triple-negative subtypes. Resumo Objetivo: Avaliar a acurácia da ressonância magnética (RM) das mamas na identificação de resposta patológica completa em pacientes com câncer de mama submetidas a quimioterapia neoadjuvante (QTN). Materiais e Métodos: Teste de validação diagnóstica, realizado por meio de estudo observacional, unicêntrico e retrospectivo. As variáveis avaliadas no estudo foram idade, resultado histológico e imuno-histoquímico da biópsia, análise da RM após QTN e análise histológica da peça cirúrgica, com cálculo do índice residual cancer burden. Os resultados da resposta radiológica pela RM foram comparados com a resposta patológica na peça cirúrgica (padrão ouro). Resultados: Foram incluídos 310 tumores de 308 pacientes com média de idade de 47 anos (variação: 27 a 85 anos). A acurácia da RM foi 79%, com sensibilidade de 75%, especificidade de 83%, valor preditivo positivo de 75% e valor preditivo negativo de 83%. Estratificando-se por subtipo molecular, a detecção da resposta patológica pela RM obteve os melhores porcentuais de acerto no subtipo HER2 superexpresso, com sensibilidade e especificidade de 82% e 89%, respectivamente, seguido do subtipo triplo negativo, com sensibilidade e especificidade de 78% e 83%, respectivamente. Conclusão: A RM demonstrou boa acurácia na predição de resposta patológica completa após QTN. A sensibilidade e o valor preditivo positivo foram mais altos nos subtipos triplo negativo e HER2 superexpresso.

Background: Breast cancer (BC) is the most common malignancy in women. Aim: To assess the impact of HER2 status on axillary lymph node (ALN) involvement in patients with invasive ductal carcinoma of no special type (IDC-NST) both at diagnosis and during the 4-year postoperative period. Patients and Methods: We retrospectively included 375 women with an early clinical stage of non-luminal IDC-NST who between 2007 and 2013 underwent breast surgery at a clinical hospital. They were divided into phenotype-based groups: HR+HER2-, HR+HER2+, HR-HER2+ and HR-HER2-. Only patients with sentinel lymph node (SLN) macrometastases underwent ALN dissection. If > 3 ALNs were positive, radiotherapy was delivered. All patients were treated with chemotherapy, HER2+ BC patients received trastuzumab, and hormone receptor (HR)-positive BC patients received hormonal therapy. Results: Larger tumor size, higher grade, HR+, HER2+ status, and lymphovascular invasion (LVI) were predictive for ALN metastases at diagnosis. The poorest overall, disease-free, and distant recurrence-free survival (OS, DFS, DRFS) were found in the HR-HER2- group, while the poorest locoregional recurrence-free survival (LRFS) was observed in HR-HER2+ and HR-HER2- groups. HER2 status was not predictor of survival. Conclusions: HER2+ status was predictive for ALN involvement at diagnosis but had no effect on 4-year LRFS in these patients. Antecedentes: El cáncer de mama es el tumor maligno más común en mujeres. Objetivo: Conocer el impacto del estado HER2 sobre el compromiso ganglionar axilar al momento del diagnóstico y durante los primeros cuatro años después de la cirugía en mujeres con carcinoma ductal invasivo de tipo no especial (IDC-NST). Pacientes y Métodos: Incluimos retrospectivamente a 375 mujeres en etapas clínicas iniciales de IDC-NST que fueron operadas en un hospital clínico. Ellas se dividieron en grupos de acuerdo al fenotipo: HR+HER2-, HR+HER2+, HR-HER2+y HR-HER2-. La disección de ganglios axilares se efectuó solo en las pacientes con macrometástasis en el ganglio centinela. Si había más de tres ganglios comprometidos, se efectuó radioterapia. Todas las pacientes se trataron con quimioterapia. Las pacientes HER2+ recibieron trastuzumab y las pacientes HR+ recibieron hormonoterapia. Resultados: Tumores más grandes, de mayor grado de malignidad, HR+, HER2+ y la invasión linfovascular fueron predictivos de la presencia de metástasis axilares al momento del diagnóstico. La sobrevida más baja se observó en pacientes HR-HER2+. La sobrevida libre de recurrencia locorregional más baja, se observó en pacientes HR-HER2+ y HR-HER2-. HER2 no fue predictor de sobrevida. Conclusiones: En estas mujeres, HER2+fue predictor de la presencia de compromiso ganglionar axilar al momento del diagnóstico pero no de la sobrevida a cuatro años.

Resumen Introducción: La hibridación in situ fluorescente (FISH) es una herramienta fundamental en oncopatología para confirmar el diagnóstico de algunas patologías, al igual que determinar el pronóstico y el tratamiento. Objetivo: Describir la experiencia del Instituto Nacional de Cancerología de Colombia (INC) con la técnica de FISH en las diferentes neoplasias hematológicas y tumores sólidos para conocer el comportamiento molecular de nuestra población. Materiales y métodos: Se realizó un estudio descriptivo retrospectivo de todos los resultados de FISH que se han realizado en tumores hematológicos y tumores sólidos en el laboratorio de Genética y Oncología Molecular del INC, entre 2012 y 2016. Resultados: En total se realizaron 1.713 pruebas de FISH, 1.010 (59%) fueron desarrolladas en neoplasias de origen hematolinfoide y 703 (41%) en tumores sólidos, de estos 428 (61%) correspondieron para HER2 de cáncer de seno. En tumores de tejidos blandos fueron evaluadas las sondas MDM2/CDK4, EWSR1, SS18, FUS, CHOP observando positividad en el 10%, el 43%, el 44%, el 20% y el 63%, respectivamente. En cáncer de pulmón se observó positividad en el 12%. Además se realizó estudios para la detección de melanoma y para la detección la codeleción del 1p/19q en gliomas. Discusión: En el INC de Colombia se confirmó la utilidad de la técnica de FISH como complemento en el diagnóstico, el pronóstico y el factor predictivo en el manejo de pacientes con cáncer. Observamos que la prevalencia de algunas pruebas varían de la reportadas en la literatura médica (C-MYC para linfomas, ALK para cáncer de pulmón). Abstract Introduction: Fluorescent in situ hybridization (FISH) is a fundamental tool in oncopathology to confirm the diagnosis of some pathologies, as well as to determine the prognosis and treatment. Keywords: FISH; Hybridization; Lymphomas; Leukemia; Sarcomas; HER2 Objective: To describe the experience of the FISH in the National Institute of Cancerology of Colombia (INC) in different hematological malignancies and solid tumors to know the molecular behavior of our population. Materials and methods: A retrospective descriptive study was conducted of all the FISH results that have been carried out in the Genetics and Molecular Oncology laboratory of the INC between 2012 and 2016 in hematological tumors and solid tumors. Results: A total of 1713 FISH tests were performed, 1010 (59%) were developed in neoplasms of hematolymphoid origin and 703 (41%) in solid tumors, of these 428 (61%) corresponded to breast cancer (HER2). In soft tissue tumors, MDM2 / CDK4, EWSR1, SS18, FUS, CHOP probes were evaluated, observing positivity in 10%, 43%, 44%, 20% and 63%, respectively. In lung cancer, it has observed positivity in 12%. In addition, studies have been carried out to detect melanoma and to detect the 1p / 19q deletions in gliomas. Discussion: The INC of Colombia confirms the usefulness of the FISH technique as a complement in the diagnosis, prognosis and predictive factor in the management of patients with cancer. We observed that the prevalence of some tests varies from that reported in the medical literature (C-MYC for lymphomas, ALK for lung cancer).

Intertumor heterogeneity has been proposed as a potential mechanism to account for variability in cognitive performance in women diagnosed with breast cancer. The purpose of this study was to explore associations between variation in pathologic tumor features (PTFs) and variability in preadjuvant therapy cognitive performance in postmenopausal women newly diagnosed with early‐stage breast cancer. Participants (N = 329) completed a comprehensive battery of neuropsychological tests to evaluate cognitive performance after primary surgery but prior to initiation of adjuvant anastrozole±chemotherapy. PTF data were abstracted from medical records. Robust multiple linear regression models were fit to estimate associations between individual PTFs and the cognitive function composite domain scores. All models controlled for age, estimated intelligence, and levels of depressive symptoms, anxiety, fatigue, and pain. Diagnosis of a HER2‐positive tumor contributed to poorer verbal (b = −0.287, P = 0.018), visual (b = −0.270, P = 0.001), and visual working (b = −0.490, P

Background Phospholipase Cγ1 (PLCγ1) is highly expressed in human tumours. Our previous studies reported that both stable and inducible PLCγ1 down-regulation can inhibit formation of breast-cancer-derived experimental lung metastasis. Further, high expression of PLCγ1 and its constitutively activated forms (i.e., PLCγ1-pY1253, PLCγ1-pY783) is associated with worse clinical outcome in terms of incidence of distant metastases, but not of local relapse in T1-T2, N0 breast cancer patients. Methods In the present retrospective study, we analysed the prognostic role of PLCγ1 in early breast cancer patients stratified according to the St. Gallen criteria and to their menopausal status. PLCγ1-pY1253 and PLCγ1-pY783 protein expression levels were determined by immunohistochemistry on tissue microarrays, and were correlated with patients’ clinical data, using univariate and multivariate statistical analyses. Results In our series, the prognostic value of PLCγ1 overexpression was restricted to Luminal type tumours. From multivariate analyses, pY1253-PLCγ1High was an independent prognostic factor only in postmenopausal patients with Luminal-B tumours (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.1–5.3; P = 0.034). Conversely, PLCγ1-pY783High was a remarkably strong risk factor (HR, 20.1; 95% CI, 2.2–178.4; P = 0.003) for pre/perimenopausal patients with Luminal-A tumours. Conclusions PLCγ1 overexpression is a strong predictive surrogate marker of development of metastases in early Luminal-A and -B breast cancer patients, being able to discriminate patients with high and low risk of metastases. Therefore, targeting the PLCγ1 pathway can be considered of potential benefit for prevention of metastatic disease. Electronic supplementary material The online version of this article (10.1186/s12885-019-5949-x) contains supplementary material, which is available to authorized users.

Primjena inhibitora CDK4/6 u liječenju hormonski ovisnoga metastatskog raka dojke negativnog na HER-2 dovela je do bitnog poboljšanja kontrole bolesti, i to ponajprije znatnim produljenjem preživljenja bez progresije bolesti, uz prihvatljiv profil toksičnosti. Osnovno djelovanje inhibitora CDK4/6 jest odgađanje razvoja rezistencije na endokrinu terapiju, odnosno reverziju već nastale rezistencije. Medijani preživljenja bez progresije bolesti kreću se oko 20 i više mjeseci u prvoj liniji liječenja i 10-ak mjeseci i više u drugoj liniji. U prvoj liniji liječenja kombinirani su s aromataznim inhibitorima, a u drugoj s fulvestrantom. Produljenjem vremena bez napredovanja bolesti odgađa se primjena kemoterapije, a bolesnicama se osigurava bolja kvaliteta života. Zbog svega navedenoga ovi lijekovi u kombinaciji s endokrinom terapijom nova su, visokovrijedna terapijska opcija u liječenju metastatskog raka dojke. Međutim, ostaju brojna otvorena pitanja za svakodnevnu kliničku praksu kao što su optimalan odabir bolesnica za prvolinijsko i drugolinijsko liječenje, sekvenciranje drugih lijekova nakon progresije bolesti na inhibitore CDK4/6 te dostupnost i cijena liječenja., Implementation of CDK4/6 inhibitors in metastatic hormone receptor positive, HER2 negative breast cancer treatment significantly improves progression free survival. CDK4/6 inhibitors are characterized by favorable toxicity profile. CDK4/6 inhibitor administration delays and/or overcomes endocrine therapy resistance in metastatic breast cancer. CDK4/6 inhibitors were tested in both first line treatment in combination with aromatase inhibitors, and in second line treatment in combination with fulvestrant. Progression free survival longer than 20 months in the first and longer than 10 months in the second treatment line has been achieved. Progression free survival prolongation may delay chemotherapy administration and consequently enable longer period with maintained quality of life. CDK4/6 inhibitors in combination with endocrine therapy represent a new valuable treatment option for metastatic hormone receptor positive HER2 negative breast cancer. However , many questions such as optimal patient selection as well as positioning of the CDK4/6 inhibitors and other endocrine therapy options during the course of metastatic disease treatment, remain unanswered. Furthermore, availability and cost of CDK4/6 inhibitors are also important issues.

Resumen Introducción: Existen múltiples factores pronóstico de la supervivencia en el cáncer de mama metastásico (CMM). Los dos factores mejor estudiados son la expresión de receptores hormonales (RH) y el estatus HER2, por lo que su determinación es obligada en toda paciente con diagnóstico de CMM. El 80% de los tumores expresan RH y el 20% son HER2-positivo. El objetivo de este estudio es determinar los factores pronóstico de la supervivencia global (SG) de pacientes con diagnóstico de CMM HER2-positivo atendidos entre 2009 y 2015 en el Instituto de Cancerología de Medellín (Colombia). Métodos: Estudio observacional retrospectivo. Se realizaron las curvas de supervivencia mediante el método de Kaplan-Meier comparadas con Log-Rank test y se analizaron los factores que influyeron en la supervivencia mediante la regresión de Cox. Resultados: Se incluyeron 101 pacientes. La mediana de seguimiento fue 46,6 meses (rango 13-155 meses), la SG a cinco años fue 41% (IC95%: 31%-50%) y a diez años 13% (IC95%: 4%-30%). Tuvieron mayor SG pacientes con enfermedad en recaída, con estadios I y II, las mayores de 40 años, menopáusicas, con tumores con grado histológico bajo y co-expresión de receptores hormonales. Las pacientes que recayeron tuvieron mayor SG que las que hicieron metástasis de novo (HR: 0,47, IC95%: 0,27-0,81) ajustado por las otras variables. Conclusiones: La supervivencia de estas pacientes fue semejante al de otros países, al igual que las líneas de tratamiento y la terapia recibida. Abstract Introduction: There are multiple risk factors associated with the prognosis of survival of metastatic breast cancer (MBC). The two major risk factors are the expression of hormonal receptors (HR) and HER 2 neu, and the reason why they are requested in every MBC patient. The large majority (80%) of breast tumors are HR positive, and 20% are HER 2 positive. The aim of this study was to determine the prognostic factors associated with the overall survival (OS) of patients diagnosed with HER 2 positive MBC seen between January 2009 and December 2015 in the Instituto de Cancerología (Medellín-Colombia). Methods: A retrospective observational study was conducted, with survival analysis using the Kaplan-Meier method. The survival curves were compared using the Log-Rank Test, and factors associated with survival were analyzed using the Cox regression. Results: 101 patients were included in the study. The median survival time was 46.6 months (Range 13-155 months), the 5-year OS was 41% (95% CI; 31%-50%) and the 10-year OS 13% (95% CI; 4%-30%). Higher overall survival was found for patients with relapsed disease, those with stages I and II, patients older than 40 years, postmenopausal, tumors with low histological grade and with co-expression of hormonal receptors. The patients with relapse of disease had a higher OS than the de novo patients after being adjusted for the other factors (HR: 0.47, 95% CI; 0.27-0.1). Discussion: The overall survival time is similar to that of other countries, as well as the lines of treatment and therapy received.

Orientadores: Luís Otávio Zanatta Sarian, Sophie Françoise Mauricette Derchain Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: O carcinoma de ovário está dividido em subtipos I (serosos de baixo grau e mucinosos) e II (serosos de alto grau e carcinossarcomas). Os tumores do subtipo I apresentam-se de forma indolente e evoluem a partir de tumores borderline serosos e mucinosos; podendo estes serem considerados lesões precursoras daqueles. Atualmente, há uma procura por características histológicos nos tumores borderline relacionadas ao maior risco de progressão para invasão; e, marcadores proteicos nos carcinomas com valor terapêutico. Os objetivos dessa tese foram: 1) comparar as características histológicas dos tumores borderline serosos/seromucinosos e mucinosos com as características clínicas dessas mulheres; 2) comparar as expressões do RE (receptor de estrógeno), RP (receptor de progesterona), HER2 (Human Epidermal growth factor Receptor 2) e VEGF (fator de crescimento endotelial vascular) entre as áreas benignas, borderline e invasoras dos carcinomas serosos de baixo grau e carcinomas mucinosos; e, relacionar essas expressões com as características clínicas dessas mulheres. Foram selecionados todos os blocos de parafina e prontuários de mulheres com diagnóstico de tumor borderline seroso/seromucinoso e mucinoso, carcinoma seroso de baixo grau e carcinoma mucinoso tratadas no CAISM de 1995 a 2015, seguidas até fevereiro de 2017. A análise estatística foi feita através do programa R®, com nível de significância de 5%. Como resultado do objetivo 1 encontramos associação significativa da microinvasão com os níveis de CA125 (p=0,04) e com os subtipos serosos/seromucinosos (p=0,02). Como resultados do objetivo 2 encontramos: a) aumento da expressão do RP, HER2 e VEGF na transição de adenoma ¿ borderline ¿ carcinoma dos carcinomas serosos de baixo grau e carcinomas mucinosos (p< 0,05); b) associação significativa dos níveis de CA125 com as expressões do RE, RP, HER2 e VEGF nas transições de adenoma para borderline e borderline para carcinoma (p

Background: Several (neo)adjuvant treatments for patients with HER2-positive breast cancer have been compared in different randomized clinical trials. Since it is not feasible to conduct adequate pairwise comparative trials of all these therapeutic options, network meta-analysis offers an opportunity for more detailed inference for evidence-based therapy. Methods: Phase II/III randomized clinical trials comparing two or more different (neo) adjuvant treatments for HER2-positive breast cancer patients were included. Relative treatment effects were pooled in two separate network meta-analyses for overall survival (OS) and disease-free survival (DFS). Results: 17 clinical trials met our eligibility criteria. Two different networks of trials were created based on the availability of the outcomes: OS network (15 trials: 37,837 patients); and DFS network (17 trials: 40,992 patients). Two studies—the ExteNET and the NeoSphere trials—were included only in this DFS network because OS data have not yet been reported. The concept of the dual anti-HER2 blockade proved to be the best option in terms of OS and DFS. Chemotherapy (CT) plus trastuzumab (T) and lapatinib (L) and CT + T + Pertuzumab (P) are probably the best treatment options in terms of OS, with 62.47% and 22.06%, respectively. In the DFS network, CT + T + Neratinib (N) was the best treatment option with 50.55%, followed by CT + T + P (26.59%) and CT + T + L (20.62%). Conclusion: This network meta-analysis suggests that dual anti-HER2 blockade with trastuzumab plus either lapatinib or pertuzumab are probably the best treatment options in the (neo)adjuvant setting for HER2-positive breast cancer patients in terms of OS gain. Mature OS results are still expected for the Aphinity trial and for the sequential use of trastuzumab followed by neratinib, the treatment that showed the best performance in terms of DFS in our analysis.

OBJETIVO: Descrever as principais características em mulheres com câncer de mama, de acordo com o perfil imuno-histoquímico. MÉTODOS: A população foi composta a partir de coorte hospitalar formada por mulheres com diagnóstico de câncer de mama efetuado entre 2003 e 2005 (n = 601) e atendidas em centro de referência em assistência oncológica de Juiz de Fora-MG. Foram selecionadas apenas 397 mulheres que possuíam imunohistoquímica completa. Para definição dos grupos segundo perfil imuno-histoquímico, optou-se por classificação baseada na avaliação dos receptores de estrógeno e de progesterona, índice de proliferação celular Ki67 e superexpressão de HER2. De acordo com os diferentes fenótipos, foram definidos cinco subtipos: luminal A, luminal B-HER2 negativo, luminal B-HER2 positivo, triplo negativo e HER2 superexpresso. RESULTADOS: A maioria dos pacientes tinha pele branca (80,7%) e era pós-menopausada (64,9%), com idade média de 57,4 anos (±13,5). Ao diagnóstico, 57,5% delas tinha tumor de tamanho > 2,0 cm, e 41,7% exibiam comprometimento linfonodal. Os subtipos mais frequentes foram luminal B-HER2 negativo (41,8%) e triplo negativo (24,2%). No subtipo luminal A, 72,1% das pacientes eram pós-menopausadas, enquanto que os maiores percentuais na pré-menopausa foram observados nos subtipos luminal B-HER2 positivo e triplo negativo (45,2% e 44,2%, respectivamente). Verificou-se maior frequência de tumores > 2,0 cm e com linfonodos comprometidos nos subtipos triplo negativo e HER2 positivo. CONCLUSÃO: Esta pesquisa possibilitou avaliar a distribuição das principais características clinicopatológicas e relacionadas aos serviços de saúde em coorte de mulheres brasileiras com câncer de mama, segundo os subtipos tumorais imuno-histoquímicos.OBJECTIVE: To describe the main characteristics of women with breast cancer, according to the immunohistochemical profile. METHODS: The population comprised a hospital cohort, consisting of women diagnosed with breast cancer between 2003 and 2005 (n = 601) and treated at a referral center for cancer care in Juiz de Fora, MG, Brazil. Only 397 women who had complete immunohistochemistry analysis were selected. To define the groups according to the immunohistochemical profile, the assessment of estrogen and progesterone receptors, Ki-67 cell proliferation index, and overexpression of human epidermal growth factor receptor 2 (HER2) was chosen. According to the different phenotypes, five subtypes were defined: luminal A, luminal B HER2 negative, luminal B HER2 positive, triple negative, and HER2 overexpression. RESULTS: Most patients were white (80.7%) and post-menopausal (64.9%), with a mean age of 57.4 years (± 13.5). At diagnosis, 57.5% had tumor size > 2.0 cm, and 41.7% had lymph node involvement. The most common subtypes were luminal B - HER2 negative (41.8%) and triple negative (24.2%). In the luminal A subtype, 72.1% of patients were post-menopausal, while the highest percentage of premenopausal women were observed in the luminal B - HER2 positive and triple negative subtypes (45.2% and 44.2%, respectively). A higher frequency of tumors > 2.0 cm and lymph node involvement was observed in triple negative and HER2 positive subtypes. CONCLUSION: This study allowed the distribution assessment of the main clinical and pathological characteristics and those related to health services in a cohort of Brazilian women with breast cancer, according to the immunohistochemical tumor subtypes.

OBJETIVO: Descrever as principais características em mulheres com câncer de mama, de acordo com o perfil imuno-histoquímico. MÉTODOS: A população foi composta a partir de coorte hospitalar formada por mulheres com diagnóstico de câncer de mama efetuado entre 2003 e 2005 (n = 601) e atendidas em centro de referência em assistência oncológica de Juiz de Fora-MG. Foram selecionadas apenas 397 mulheres que possuíam imunohistoquímica completa. Para definição dos grupos segundo perfil imuno-histoquímico, optou-se por classificação baseada na avaliação dos receptores de estrógeno e de progesterona, índice de proliferação celular Ki67 e superexpressão de HER2. De acordo com os diferentes fenótipos, foram definidos cinco subtipos: luminal A, luminal B-HER2 negativo, luminal B-HER2 positivo, triplo negativo e HER2 superexpresso. RESULTADOS: A maioria dos pacientes tinha pele branca (80,7%) e era pós-menopausada (64,9%), com idade média de 57,4 anos (±13,5). Ao diagnóstico, 57,5% delas tinha tumor de tamanho > 2,0 cm, e 41,7% exibiam comprometimento linfonodal. Os subtipos mais frequentes foram luminal B-HER2 negativo (41,8%) e triplo negativo (24,2%). No subtipo luminal A, 72,1% das pacientes eram pós-menopausadas, enquanto que os maiores percentuais na pré-menopausa foram observados nos subtipos luminal B-HER2 positivo e triplo negativo (45,2% e 44,2%, respectivamente). Verificou-se maior frequência de tumores > 2,0 cm e com linfonodos comprometidos nos subtipos triplo negativo e HER2 positivo. CONCLUSÃO: Esta pesquisa possibilitou avaliar a distribuição das principais características clinicopatológicas e relacionadas aos serviços de saúde em coorte de mulheres brasileiras com câncer de mama, segundo os subtipos tumorais imuno-histoquímicos. OBJECTIVE: To describe the main characteristics of women with breast cancer, according to the immunohistochemical profile. METHODS: The population comprised a hospital cohort, consisting of women diagnosed with breast cancer between 2003 and 2005 (n = 601) and treated at a referral center for cancer care in Juiz de Fora, MG, Brazil. Only 397 women who had complete immunohistochemistry analysis were selected. To define the groups according to the immunohistochemical profile, the assessment of estrogen and progesterone receptors, Ki-67 cell proliferation index, and overexpression of human epidermal growth factor receptor 2 (HER2) was chosen. According to the different phenotypes, five subtypes were defined: luminal A, luminal B HER2 negative, luminal B HER2 positive, triple negative, and HER2 overexpression. RESULTS: Most patients were white (80.7%) and post-menopausal (64.9%), with a mean age of 57.4 years (± 13.5). At diagnosis, 57.5% had tumor size > 2.0 cm, and 41.7% had lymph node involvement. The most common subtypes were luminal B - HER2 negative (41.8%) and triple negative (24.2%). In the luminal A subtype, 72.1% of patients were post-menopausal, while the highest percentage of premenopausal women were observed in the luminal B - HER2 positive and triple negative subtypes (45.2% and 44.2%, respectively). A higher frequency of tumors > 2.0 cm and lymph node involvement was observed in triple negative and HER2 positive subtypes. CONCLUSION: This study allowed the distribution assessment of the main clinical and pathological characteristics and those related to health services in a cohort of Brazilian women with breast cancer, according to the immunohistochemical tumor subtypes.

OBJETIVO: Descrever as principais características em mulheres com câncer de mama, de acordo com o perfil imuno-histoquímico. MÉTODOS: A população foi composta a partir de coorte hospitalar formada por mulheres com diagnóstico de câncer de mama efetuado entre 2003 e 2005 (n = 601) e atendidas em centro de referência em assistência oncológica de Juiz de Fora-MG. Foram selecionadas apenas 397 mulheres que possuíam imunohistoquímica completa. Para definição dos grupos segundo perfil imuno-histoquímico, optou-se por classificação baseada na avaliação dos receptores de estrógeno e de progesterona, índice de proliferação celular Ki67 e superexpressão de HER2. De acordo com os diferentes fenótipos, foram definidos cinco subtipos: luminal A, luminal B-HER2 negativo, luminal B-HER2 positivo, triplo negativo e HER2 superexpresso. RESULTADOS: A maioria dos pacientes tinha pele branca (80,7%) e era pós-menopausada (64,9%), com idade média de 57,4 anos (±13,5). Ao diagnóstico, 57,5% delas tinha tumor de tamanho > 2,0 cm, e 41,7% exibiam comprometimento linfonodal. Os subtipos mais frequentes foram luminal B-HER2 negativo (41,8%) e triplo negativo (24,2%). No subtipo luminal A, 72,1% das pacientes eram pós-menopausadas, enquanto que os maiores percentuais na pré-menopausa foram observados nos subtipos luminal B-HER2 positivo e triplo negativo (45,2% e 44,2%, respectivamente). Verificou-se maior frequência de tumores > 2,0 cm e com linfonodos comprometidos nos subtipos triplo negativo e HER2 positivo. CONCLUSÃO: Esta pesquisa possibilitou avaliar a distribuição das principais características clinicopatológicas e relacionadas aos serviços de saúde em coorte de mulheres brasileiras com câncer de mama, segundo os subtipos tumorais imuno-histoquímicos. Objective: To describe the main characteristics of women with breast cancer, according to the immunohis- tochemical profile. Methods: The population comprised a hospital cohort, consisting of women diagnosed with breast cancer between 2003 and 2005 (n = 601) and treated at a referral center for cancer care in Juiz de Fora, MG, Brazil. Only 397 women who had complete immunohistochemistry analysis were selected. To define the groups according to the immunohistochemical profile, the assessment of estrogen and proges- terone receptors, Ki-67 cell proliferation index, and overexpression of human epidermal growth factor re- ceptor 2 (HER2) was chosen. According to the different phenotypes, five subtypes were defined: luminal A, luminal B HER2 negative, luminal B HER2 positive, triple negative, and HER2 overexpression. Results: Most patients were white (80.7%) and post-menopausal (64.9%), with a mean age of 57.4 years (± 13.5). At diagnosis, 57.5% had tumor size ≥ 2.0 cm, and 41.7% had lymph node involvement. The most common subtypes were luminal B - HER2 negative (41.8%) and triple negative (24.2%). In the luminal A subtype, 72.1% of patients were post-menopausal, while the highest percentage of premenopausal women were observed in the luminal B - HER2 positive and triple negative subtypes (45.2% and 44.2%, respectively). A higher frequency of tumors > 2.0 cm and lymph node involvement was observed in triple negative and HER2 positive subtypes. Conclusion: This study allowed the distribution assessment of the main clinical and pathological characteristics and those related to health services in a cohort of Brazilian women with breast cancer, according to the immu- nohistochemical tumor subtypes.

CONTEXT AND OBJECTIVE: Cyclooxygenase-2 (COX-2) and human epidermal growth factor receptor type 2 (HER-2) are associated with tumorigenesis. Studies have shown that HER-2 can regulate COX-2 expression. The aim of this study was to evaluate the correlation between COX-2 and HER-2 expression in normal breast epithelium and in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) present in the same breast. DESIGN AND SETTING: Cross-sectional study at the Mastology Unit of the Department of Gynecology and Obstetrics, Santa Casa de Misericórdia de São Paulo Hospital. METHODS: COX-2 and HER-2 were detected using immunohistochemistry on 100 tissue fragments. HER-2 > +2 was subjected to fluorescence in situ hybridization (FISH). RESULTS: COX-2 expression was detected in 87%, 85% and 75% of IDC, DCIS and normal epithelium, respectively. HER-2 expression was detected in 34% of IDC and 34% of DCIS. COX-2 in DCIS correlated with HER-2 in IDC (P = 0.049) and DCIS (P = 0.049). COX-2 in normal epithelium correlated with HER-2 in IDC (P = 0.046) and DCIS (P = 0.046). COX-2 in IDC was not associated with HER-2 (P = 0.235). Comparison between COX-2 and HER-2 in DCIS showed that there was a statistically significant difference with regard to nuclear grades II and III and presence of comedonecrosis (P < 0.001). In IDC, there was significant expression with nuclear grades II and III and histological grade II (P < 0.001). CONCLUSIONS: Our findings provide evidence that HER-2 and COX-2 regulate each other CONTEXTO E OBJETIVO: Ciclo-oxigenase (COX-2) e receptor tipo 2 do fator de crescimento epidérmico humano (HER-2) estão associados com tumorigênese. Estudos mostraram que HER-2 pode regular a expressão de COX-2. O objetivo deste estudo foi avaliar a correlação entre expressão da COX-2 e HER-2 no epitélio normal de mama, no carcinoma ductal in situ (DCIS) e carcinoma ductal invasivo (IDC) presentes na mesma mama. TIPO DE ESTUDO E LOCAL: Estudo transversal na clínica de Mastologia do Departamento de Obstetrícia e Ginecologia do Hospital da Santa Casa de Misericórdia de São Paulo. MÉTODOS: A detecção da COX-2 e HER-2 foi realizada por imunoistoquímica em 100 fragmentos teciduais. HER-2 > +2 foi submetido a hibridização fluorescente in situ (FISH). RESULTADOS: Expressão de COX-2 foi detectada em 87%, 85% e 75% dos IDC, DCIS e epitélio normal, respectivamente. Expressão de HER-2 foi detectada em 34% dos IDC e 34% de DCIS. COX-2 em DCIS correlacionou-se com HER-2 em IDC (P = 0,049) e DCIS (P = 0,049). COX-2 no epitélio normal correlacionou-se com HER-2 em IDC (P = 0,046) e DCIS (P = 0,046). COX-2 no IDC não foi associada com HER-2 (P = 0,235). Quando comparado COX-2 com HER-2 em DCIS houve diferença estatisticamente significante com relação ao grau nuclear II e III e presença de comedonecrose (P < 0,001) e no IDC, houve expressão significativa no grau nuclear II e III e histológico II (P < 0,001). CONCLUSÕES: Nossos achados mostram evidências que HER-2 e COX-2 se autorregulam.

A prognostic interpretation of preneoplastic lesions would have impact in bronchial carcinoma early diagnosis and through the study of Erb-B family receptors as they have an important role in lung carcinogenesis. The existence of drugs as tyrosine kinase inhibitors stressed the importance of studying gene alterations for selected chemoprevention schemes and characterization of carcinogenesis. Bronchial preneoplastic lesions were characterized by immunohistochemistry using the antibodies LP34 (high weigh molecular cytokeratin), CK7, chromogranin A, Ki67, p53, C-erbB-2 and EGFR. HER2 and EGFR gene copy number was also evaluated by fluorescent in situ hybridization in those lesions. The expected results defined the origin cell for basal cell hyperplasia and squamous metaplasia as adaptative lesions and dysplasia. By known experiences and published data, beyond the stem cell, the spectral evolution of bronchial preneoplastic lesions was demonstrated by characterizing basal cells (LP34) and their neoplastic potentiality. Dysplasias showed a higher expression of EGFR, Ki67 and p53 with a stepwise increase with the gravity of the respective grading. C-erbB-2 immunohistochemical overexpression was a rare event in preneoplastic lesions. Polysomy was the main mechanism for EGFR and HER2/neu higher gene copy number and together with increased proliferation index (Ki67) will account to preview bronchial carcinogenesis. info:eu-repo/semantics/publishedVersion

PURPOSE: To investigate the immunohistochemical expression (IGF-1, EGFr, EGF, c-erbB-2/HER-2/neu, PDGF-A, PDGF-B, FGF and VEGF) in patients with Graves' ophthalmopathy. METHODS: Twenty-four samples (Graves' ophthalmopathy patients) underwent lateral rectus muscle and surrounding fibrous and adipose tissue biopsy. The control group was obtained by strabismus surgery. Correlation between clinical- ophthalmologic, endocrinological, ultrasonographic findings, and immunohistochemical expression was performed. RESULTS: IGF-1: There were 7 positive cases (29.2%). There was a direct relation with higher CAS (clinical activity score) in all of them and if only CAS equal or higher than 5 was considered, this was 54.5%. FGF: There was expression in 5 cases (20.8%) with a direct relation in all those with higher CAS (>5) (45.4%). VEGF: There were two positive cases (8.3%) for VEGF in endothelial cells, in these cases the patients also presented CAS higher than 5. There was no expressions of all growth factors in the control group. CONCLUSIONS: All patients, except one, with positive expression of FGF, IGF-1 and VEGF showed CAS greater than 5, suggesting in this way an important role of these growth factors in the pathogenesis and severity of Graves' ophthalmopathy. However, statistical analysis revealed only significant association between IGF-1 and male sex (P=0.034). Low ultrasound reflectivity and endocrine status may not correlate directly with disease activity or with immunoexpression of growth factors and c-erbB-2/HER-2/neu.OBJETIVO: Investigar a expressão imuno-histoquímica de IGF-1, EGFr, EGF, c-erbB-2/HER-2/neu, PDGF-A, PDGF-B, FGF e VEGF na oftalmopatia de Graves. MÉTODOS: Vinte e dois pacientes (oftalmopatia de Graves) foram submetidos à biópsia do músculo reto lateral e tecido fibroso e adiposo adjacente. O grupo controle foi de pacientes de cirurgia de estrabismo. Foi feita correlação entre achados clínico-oftalmológicos, endocrinológicos, ultra-sonográficos e da expressão imuno-histoquímica dos fatores de crescimento. RESULTADOS: IGF-1: Houve 7 casos positivos (29,2%). Houve correlação direta com o CAS (clinical activity score) elevado em todos os casos e em que consideramos CAS apenas acima de 5, em 54,5%. FGF: Houve expressão em 5 casos (20,8%) com relação direta com CAS elevado em todos os casos e em que consideramos CAS maior que 5 (45,4%). VEGF: Houve dois casos positivos (8,3%) para VEGF nas células endoteliais e estes casos também apresentavam CAS maior que 5. A imunorreatividade foi negativa em todo grupo controle. CONCLUSÃO: Todos os pacientes, com exceção de um, com expressão positiva para FGF, IGF-1 e VEGF mostraram CAS maior que 5, sugerindo importante papel destes fatores de crescimento na patogênese e gravidade da oftalmopatia de Graves. Entretanto, a análise estatística demonstrou associação significativa entre IGF-1 e o sexo masculino (P=0,034). Baixa refletividade ao ultra-som e condição endócrina não estiveram correlacionadas.

Clinical Trial, Phase III; Comparative Study; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't; BACKGROUND Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting. METHODS After breast cancer surgery, women with lymph node-positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study-5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided. RESULTS Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P < .001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment. CONCLUSIONS Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy. Yes

CONTEXT: Prostate cancer is the most frequent solid genitourinary neoplasm in men. Involvement of several genes has been described in the promotion and progression of prostate carcinoma. OBJECTIVE: To study the expression of the oncogenes HER2/neu and BCL2, tumor suppressor gene p53 and the tumor proliferation rate in 150 radical prostatectomy specimens, in order to define their role as prognostic parameters in localized prostate cancer. TYPE OF STUDY: Prospective study. SETTING: Universidade Federal de São Paulo and Hospital Sírio Libanês, Sao Paulo PARTICIPANTS: One hundred and fifty men who were submitted to radical prostatectomy between August 1997 and August 1998, for localized prostate cancer. MAIN MEASUREMENTS: All specimens underwent evaluation in their entirety, to determine tumor volume percentage, tumor extent and Gleason score. Immunohistochemistry was performed to determine gene expression using anti- HER2/neu, BCL2 and p53 antibodies, and proliferating cell nuclear antigen. The chi-squared test was used for correlation between gene expression, proliferative activity and histological variables. RESULTS: Thirty percent of the cases were p53 positive. There was positive correlation between p53 expression and tumor stage. The p53 expression was 22.9% and 42.6% for pT2 and pT3 tumors, respectively (p = 0.01). Expression of HER2/neu, BCL2 and proliferating cell nuclear antigen was identified in 66%, 23% and 43% of patients, respectively. There was no correlation between these three parameters and tumor volume, Gleason score or tumor stage. CONCLUSION: One-third of prostate adenocarcinomas express p53 protein, and this characteristic is related to tumor stage. HER2/neu is frequently expressed in prostate carcinomas, with no correlation with histological parameters. BCL2 is rarely expressed, and together with proliferative activity has no relationship with prognostic pathological variables in these neoplasms. CONTEXTO: Câncer de próstata é a neoplasia geniturinária sólida mais freqüente no homem. Alguns genes foram identificados na iniciação e progressão do carcinoma de próstata. OBJETIVO: Estudar a expressão dos oncogenes HER2/neu e BCL2, do gene supressor p53, e da taxa de proliferação tumoral em 150 espécimes de prostatectomia radical, para definir o papel prognóstico desses parâmetros no câncer de próstata localizado. TIPO DE ESTUDO: Estudo prospectivo. LOCAL: Universidade Federal de São Paulo e Hospital Sírio Libanês, São Paulo. PARTICIPANTES: Cento e cinqüenta homens foram submetidos a prostatectomia radical entre agosto 1997 e agosto 1998, por câncer de próstata localizado. VARIÁVEIS ESTUDADAS: Todos os espécimes foram submetidos à avaliação da porcentagem de volume tumoral, da extensão do tumor e da escala de Gleason. Imunohistoquímica foi realizada para determinar a expressão genética dos seguintes anticorpos: anti-HER2/neu, BCL2, p53, e proteína nuclear de proliferação celular. O teste qui-quadrado foi utilizado na correlação entre a expressão genética, a atividade proliferativa e as variáveis histológicas. RESULTADOS: Trinta por cento dos casos eram p53 positivos. Houve correlação positiva entre a expressão do p53 e o estágio tumoral. A porcentagem de expressão do p53 foi de 22.9% e de 42.6% para tumores pT2 e pT3, respectivamente, (p = 0,01). As expressões de HER2/neu, BCL2 e proteína nuclear de proliferação celular foram identificadas em 66%, 23% e 43% dos pacientes, respectivamente. Não houve correlação entre esses três parâmetros e o volume tumoral, a escala de Gleason ou o estágio da neoplasia. CONCLUSÃO: Um terço dos adenocarcinomas prostáticos expressam a proteína p53, e essa característica está relacionada ao estágio tumoral. HER2/neu está freqüentemente expressado nos carcinomas de próstata, mas não existe correlação com os parâmetros histológicos. BCL2 e proteína nuclear de proliferação celular raramente estão expressados, não havendo correlação destes com as variáveis de prognóstico patológicos nessa neoplasia.