PTEN mutations prevalence in HER2-positive breast cancer patients / Prevalencia de mutaciones en pten en pacientes con cáncer de mama HER2-positivo

Introduction: HER2-positive tumors is one of the aggressive subtypes of breast cancer that indicate bad prognosis. Trastuzumab is one of the targeted therapy which inhibit HER2 receptors. Mutations/expression deregulations of the downstream of HER2 receptors could cause resistance to trastuzumab. PTEN is a tumor suppressor gene which directly regulates PI3K pathway which renders it one of the predictive markers of trastuzumab. Methods: In the present study, PTEN mutations were screened in 51 patients with HER2-positive breast cancer. Also, 16 patients were further analyzed for protein expression. Results: The mutations were detected in 3 out of 51 patients (5.9%). In addition, 56.3% of the 16 patients showed downregulation/loss of PTEN protein expression. The loss of PTEN was found in 75% of estrogen-receptor negative patients (p =0.130). Conclusions: The downregulation/loss of PTEN protein has the tendency to be associated with ER-negative reflecting its value as a treatment prediction marker. (AU)

Introducción: Los tumores HER2 positivos son uno de los subtipos agresivos de cáncer de mama que indican un mal pronóstico. Trastuzumab es una de las terapias dirigidas que inhiben los receptores HER2. Las mutaciones/desregulaciones de la expresión aguas abajo de los receptores HER2 podrían causar resistencia a trastuzumab. PTEN es un gen supresor de tumores que regula directamente la vía PI3K, lo que lo convierte en uno de los marcadores predictivos de trastuzumab. Metodos: En el presente estudio, las mutaciones de PTEN se examinaron en cincuenta y un pacientes con cáncer de mama positivo para HER2. Además, dieciséis pacientes fueron analizados más a fondo para determinar la expresión de proteínas. Resultados: Las mutaciones se detectaron en tres de 51 pacientes (5.9%). Además, el 56,3 % de los dieciséis pacientes mostró regulación baja/pérdida de la expresión de la proteína PTEN. También se encontró pérdida de PTEN en el 75% de los pacientes con receptores de estrógeno negativos. Conclusiones: La regulación baja/pérdida de la proteína PTEN tiende a asociarse con ER-negativo, lo que refleja su valor como marcador de predicción de tratamiento. (AU)

Molecular mechanism of XB130 adaptor protein mediates trastuzumab resistance in gastric cancer

Background Recent studies have shown that the activation of PI3K/AKT signaling pathway is an essential molecular mechanism participating in trastuzumab resistance in HER2 + GC (gastric cancer). However, how can we effectively inhibit AKT activity associated with drug resistance during trastuzumab treatment? Screening inhibitors against the upstream receptors of PI3K/AKT signaling pathway or interacting proteins of members has become an important way. Methods In this study, western blot, qRT-PCR, CCK8, Co-IP and other techniques were used to explore possible mechanisms participating in trastuzumab resistance in vitro. Besides, the xenograft mouse model and GC tissue samples from patients were used to further validate the in-vitro results. Results The expression of XB130 adaptor protein was remarkably increased in GC cell lines resistant to trastuzumab, and knockdown of XB130 could reverse the resistance via downregulating p-AKT. In addition, p-SRC (Tyr416) was increased in resistant cells, which could facilitate the binding of XB130 to PI3K p85α. It was also discovered that XB130 could negatively regulate PTEN gene transcription, and thus a positive feedback loop was formed between SRC-XB130-PTEN. Conclusions In HER2 + GC, XB130 contributes to trastuzumab resistance by stimulating the PI3K/AKT signaling pathway through binding to PI3K p85α under the mediation of SRC kinase and regulating PTEN gene transcription, and in turn forming a positive feedback loop between SRC-XB130-PTEN (AU)

Blockade of exosome release alters HER2 trafficking to the plasma membrane and gives a boost to Trastuzumab

Objective(s) Exosomal HER2 has been evidenced to interfere with antibody-induced anti-tumor effects. However, whether the blockade of HER2+ exosomes release would affect antibody-mediated tumor inhibition has yet to be investigated. Methods Exosomes derived from BT-474, SK-BR3 and SK-OV3 (HER2-overexpressing tumor cells) and MDA-MB-231 cells (HER2 negative) were purified and characterized by bicinchoninic acid (BCA) assay, western blotting and Transmission electron microscopy (TEM). Inhibition of exosome release was achieved by neutral sphingomyelinase-2 (nSMase-2) inhibitor, GW4869. The effects of exosome blockade on the anti-proliferative effects, apoptosis induction, and antibody-mediated cellular cytotoxicity (ADCC) activity of Trastuzumab were examined using MTT, flow cytometry, and LDH release assays. Also, the effects of exosome inhibition on the surface expression and endocytosis/internalization of HER2 were studied by flow cytometry. Results Purified exosomes derived from HER2 overexpressing cancer cells were positive for HER2 protein. Blockade of exosome release was able to significantly improve apoptosis induction, anti-proliferative and ADCC responses of Trastuzumab dose dependently. The pretreatment of Trastuzumab/purified NK cells, but not PBMCs, with HER2+ exosomes could also decrease the ADCC effects of Trastuzumab. Exosome inhibition also remarkably downregulated surface HER2 levels in a time-dependent manner, but does not affect its endocytosis/internalization. Conclusion Based on our findings, HER2+ exosomes may benefit tumor progression by dually suppressing Trastuzumab-induced tumor growth inhibition and cytotoxicity of NK cells. It seems that concomitant blocking of exosome release might be an effective approach for improving the therapeutic effects of Trastuzumab, and potentially other HER2-directed mAbs (AU)

Discordance of positive immunohistochemical results among different primary HER2 antibodies used in breast cancer: A comparison between Histofine® HER2 Kit (MONO) SV2-61γ antibody and Ventana I-VIEW PATHWAY™ HER2 4B5 antibody / Discordancia de los resultados inmunohistoquímicos positivos entre los diferentes anticuerpos primarios HER2 utilizados en el cáncer de mama: comparación entre el anticuerpo Histofine® HER2 Kit (MONO) SV2-61γ y el anticuerpo Ventana I-VIEW PATHWAY™ HER2 4B5

Introduction: Immunohistochemical (IHC) testing for human epidermal growth factor receptor 2 (HER2) expression status renders variable scores among different primary antibodies. Materials and methods: We assessed HER2 expression status by IHC score using two types of kits, i.e., Roche Ventana I-VIEW PATHWAY™ HER2 using the 4B5 antibody that recognizes the intracellular domain (ICD) and Nichirei Biosciences Histofine® HER2 Kit (MONO) using the SV2-61γ antibody that recognizes the extracellular domain (ECD). In addition, we determined the presence or absence of the ECD in samples by Western blotting (WB) and examined its relationship with the IHC score. Results: Of 101 samples, 44 and 9 samples received a score of 2+/3+ by IHC with 4B5 and SV2-61γ, respectively. A verification by WB in samples with a discrepancy of IHC scores found that samples with the score of 2+/3+ with SV2-61γ showed a significantly higher protein intensity of p185HER2 with the ECD, whereas samples with a score of 2+/3+ with 4B5 but as 0/1+ with SV2-61γ showed a significantly higher protein intensity of p95HER2 without the ECD. Conclusion: The nature of primary antibodies used for IHC and the presence or absence of the ECD in samples may contribute to different positive rates between 4B5 and SV2-61γ.(AU)

Introducción: Para el ensayo de inmunohistoquímica (IHC) para evaluar el estado de expresión del receptor 2 del factor de crecimiento epidérmico humano (HER2), diferentes anticuerpos primarios causan diferentes puntuaciones de IHC. Materiales y métodos: Evaluamos el estado de expresión de HER2 mediante la puntuación IHC usando dos tipos de kits, es decir, Roche Ventana I-VIEW PATHWAY™ HER2 usando el anticuerpo 4B5 que reconoce el dominio intracelular (ICD) y Nichirei Biosciences Histofine® HER2 Kit (MONO) usando el SV2-Anticuerpo 61γ que reconoce el dominio extracelular (ECD). Además, determinamos la presencia o ausencia de ECD en las muestras mediante Western Blot (WB) y examinamos su relación con la puntuación IHC. Resultados: De las 101 muestras, 44 y 9 de ellas recibieron una puntuación de 2+/3+ por IHC con 4B5 y SV2-61γ, respectivamente. Una verificación por WB en muestras con una discrepancia en las puntuaciones de IHC encontró que las muestras con una puntuación de 2+/3+ con SV2-61γ mostraron una intensidad de proteína de p185HER2 significativamente mayor con el ECD, mientras que las muestras con una puntuación de 2+/3+ con 4B5 pero como 0/1+ con SV2-61γ mostraron una intensidad de proteína significativamente mayor de p95HER2 sin ECD. Conclusión: La naturaleza de los anticuerpos primarios utilizados para IHC y la presencia o ausencia de ECD en las muestras pueden contribuir a diferentes tasas positivas por IHC entre 4B5 y SV2-61γ.(AU)

Tumor-associated macrophages (TAMs) modulate response to HER2-targeted agents in a humanized mouse model of breast cancer

PurposeTumor-associated macrophages (TAM) may participate to antitumor activity of anti-HER2-targeted therapies (Pertuzumab, Trastuzumab) in breast cancers harbouring HER-2 overexpression through antibody-dependent phagocytosis. Additive antitumor effect of concurrent cytotoxic chemotherapies, including Paclitaxel, may be counterbalanced by alteration in TAM infiltrate. The aim of this study is to evaluate the role of TAM in tumor response to anti-HER2-targeted therapies and chemotherapy in an experimental model of HER2-amplified breast cancer.MethodsA xenograft mouse model was built by subcutaneous injection of the SKBR-3 human HER2-amplified breast cancer cell line in Hu-CD34+ mice. Animals were randomized to receive weekly administration of Cremophor (control), Trastuzumab+Pertuzumab (TP), and Paclitaxel+Trastuzumab+Pertuzumab (PTP) with or without macrophage depletion with clodronate (C). At week 4, mice were euthanised and tumors were harvested for immunohistochemical analysis of TAM infiltration (RBP-J CD163 and CD68 for M1, M2, and overall TAM, respectively).ResultsTumor size was significantly lower in mice treated with TP, PTP, and PTP+C as compared to control, while no meaningful difference was observed in the TP+C arm. Analysis of TAM infiltrate showed significantly lower CD68 and CD163 expression in PTP, TP+C, and PTP+C as compared to TP and control arm. RBP-J expression was significantly decreased in mice treated with clodronate depletion.ConclusionsActivity of TP is modulated by TAM infiltrate, that is inhibited by concurrent administration of Paclitaxel. To enhance the effect of anti-HER2-targeted therapies and minimize chemotherapy-related side effects, modulation of TAM should be considered in novel therapeutic combinations.

Current status and future perspectives in HER2 positive advanced gastric cancer

Gastric cancer is one of the most common malignancy worldwide with a prognosis less than 1 year in unresectable or metastatic disease. HER2 expression is the main biomarker to lead the addition of trastuzumab to first line systemic chemotherapy improving the overall survival in advanced HER2-positivegastric adenocarcinoma. The inevitable development of resistance to trastuzumab remains a great problem inasmuch several treatment strategies that have proven effective in breast cancer failed to show clinical benefit in advanced gastric cancer. In this review, we summarize the available data on the mechanisms underlying primary and secondary resistance toHER2-targeted therapy and current challenges in the treatment of HER2-positive advanced gastric cancer refractory to trastuzumab. Further, we describe the prognostic value of new non-invasive screening techniques, the current development of novel agents such us HER2 antibody–drug conjugates and bispecific antibodies, and the strategies with antitumor activity on going.

Estudio en vida real de pertuzumab-trastuzumabquimioterapia frente a trastuzumab-quimioterapia en neoadyuvancia en cáncer de mama / Real world study of pertuzumab-trastuzumab-chemotherapy versus trastuzumab-chemotherapy in neoadjuvant treatment of breast cance

OBJETIVO: El objetivo primario del estudio es comparar la efectividad de trastuzumab-quimioterapia con y sin pertuzumab. Como objetivo secunda-rio se busca evaluar la seguridad cardiaca del tratamiento. MÉTODO: Estudio observacional retrospectivo que incluyó todas las pa-cientes tratadas con pertuzumab-trastuzumab-quimioterapia (n = 10) o trastuzumab-quimioterapia (n = 13) (enero 2015-diciembre 2018) en un hospital de especialidades, que cumplían los criterios establecidos por la Comisión Central para la Optimización y Armonización de la farma-coterapia del Servicio Andaluz de Salud para uso de pertuzumab en neoadyuvancia: tumor HER2 positivo, receptores hormonales negativos, con alto riesgo de recaída (tumor > 2 cm o afectación ganglionar). Para valorar la efectividad se utilizó la respuesta completa patológica, y para la seguridad cardiaca, el descenso de la fracción de eyección del ven-trículo izquierdo superior al 10%. RESULTADOS: La respuesta completa patológica fue superior en el grupo con pertuzumab (70,0% versus 30,8%). La seguridad cardiaca fue similar en ambos. CONCLUSIONES: Para las pacientes con tumores HER2 positivo y recep-tores hormonales negativos con criterios de alto riesgo que reciben pertu-zumab, la respuesta completa patológica resulta superior, sin observarse incremento de la toxicidad cardiaca

OBJECTIVE: The primary objective of the study is to compare the effec-tiveness of trastuzumab-chemotherapy with and without pertuzumab. As a secondary objective, we seek to evaluate the cardiac safety of the treatment. METHOD: Retrospective observational study including all patients treated with either pertuzumab-trastuzumab-chemotherapy (n = 10) or trastuzu-mab-chemotherapy (n = 13) (January 2015-December 2018) in a special-ty hospital, which met the criteria established by the Commission Central for the Optimization and Harmonization of the pharmacotherapy of the Andalusian Health Service for the use of pertuzumab in neoadjuvance: HER2 positive tumor, negative hormonal receptors, with high risk of relapse (tumor > 2 cm or lymph node involvement). To assess effectiveness, the complete pathological response was used. For cardiac safety, the de-crease in left ventricular ejection fraction greater than 10% was employed. RESULTS: Complete pathological response was superior in the pertuzu-mab group (70.0% vs. 30.8%). Cardiac safety was similar in both.CONCLUSIONS: For patients with HER2 positive tumors and negative hormonal receptors with high risk criteria that receive pertuzumab, the complete pathological response is superior, with no increase in cardiac toxicity

Protocol for desensitization to trastuzumab in a patient with anaphylaxis and stage IV breast cancer: a case report

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Long-term stability of trastuzumab in plasma and whole blood samples stored under different conditions / Estabilidad a largo plazo del trastuzumab en plasma y suero almacenados bajo diferentes condiciones

Objective: The present work analyzed the stability of trastuzumab concentrations in blood and plasma samples stored at 4°C and -20°C. Method: Blood samples of patients treated with trastuzumab (Herceptin(R)) were analyzed. Stability of trastuzumab was analyzed under different conditions: whole blood stored at 4°C during 72 hours, blood plasma stored at 4°C during 120 hours and blood plasma stored at -20°C during 365 days. Results: In whole blood trastuzumab concentration at 72 hours was 99.01 ± 0.02%, and in plasma samples at 120 hours it was 98.6 ± 2.0%. The concentration of trastuzumab was 95.22 ± 3.20% after 12 months' storage at -20ºC. Conclusions: The concentration of trastuzumab remains stable for at least 72 hours in whole blood stored at 4°C, five days in plasma stored at 4°C and one year in plasma stored at -20°C

Objetivo: Analizar la estabilidad del trastuzumab en sangre y plasma a 4°C y -20°C. Método: Se determinó la concentración plasmática de trastuzumab en las muestras de sangre y plasma de pacientes con cáncer de mama HER2 positivo tratados con trastuzumab (Herceptin(R)). Se analizó la estabilidad del trastuzumab en sangre a 4°C durante 72 horas. En el caso de las muestras de plasma, se estudió la estabilidad a 4°C durante 72 y 120 horas, así como durante 365 días congeladas a -20°C. Resultados: En sangre, la concentración de trastuzumab a las 72 horas fue de 99,01 ± 0,02%, y en las muestras de plasma a las 120 horas fue de 98,6 ± 2,0%. La concentración de trastuzumab fue de 95,22 ± 3,20% después de 12 meses de almacenamiento a -20°C. Conclusiones: El trastuzumab permanece estable durante al menos 72 horas en sangre total almacenada a 4°C, cinco días en plasma almacenado a 4°C y un año en plasma almacenado a -20°C

Evaluación positiva de medicamentos: marzo y abril 2018 / Possitive assesment of drugs: March and April 2018

Se reseñan los medicamentos evaluados y con dictamen positivo por comisión de expertos de la Agencia Española de Medicamentos y Productos Sanitarios o de la Agencia Europea del Medicamento publicados en marzo y abril de 2018, considerados de mayor interés para el profesional sanitario. Se trata de opiniones técnicas positivas que son previas a la autorización y puesta en el mercado del medicamento

The drugs assessed by the Spanish Agency for Medicines and Health Products or European Medicines Agency made public in March, April and May of 2018, and considered of interest to the healthcare profesional, are reviewed. These are positive technical reports prior to the authorization and placing on the market of the product

Predictive factors of trastuzumab-based chemotherapy in HER2 positive advanced gastric cancer: a single-center prospective observational study

Purpose: Trastuzumab plus chemotherapy is an effective therapy in HER2 positive advanced gastric cancer (AGC). However, the clinicopathologic factors that predict the outcome of routine trastuzumab therapy remain unclear. Methods: The outcome and safety profile of trastuzumab therapy in untreated HER2 positive AGC was evaluated in this prospective observational study. Clinical and pathological data including demographics, treatment profiles, expression level of HER2 were analyzed to identify predictive factors of trastuzumab-based first-line therapy for their progression-free survival (PFS). Results: Overall, 107 patients were eligible. The median number of treatment cycles was 9 (range 1-44), the median PFS and median overall survival (OS) were 7.7 months (95% CI 6.5-8.9) and 16.0 months (95% CI 13.2-18.8), respectively. The confirmed response rate was 58.9%, and the disease control rate was 82.2%. Patients with liver metastasis (HR 1.616) and poor performance status (PS, HR 2.518) were independently associated with a worse PFS, while the other clinicopathological factors including demographics, treatment profiles and some other clinical characteristics did not predict the survival. Conclusions: In routine clinical practice, the addition of trastuzumab to chemotherapy was effective and safe in real-world setting in Chinese patients with HER2 positive AGC, regardless of most of the clinicopathological factors. Further studies are needed to improve the prognosis of HER2 positive patients with liver metastasis or poor PS

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Cost minimization analysis of treatment with intravenous or subcutaneous trastuzumab in patients with HER2-positive breast cancer in Spain

Purpose. To describe healthcare professional (HCP) and patient time and related costs associated with trastuzumab intravenous infusion (IV) and trastuzumab subcutaneous (SC) formulations in patients with HER2-positive early breast cancer. Methods. This prospective, observational time, and motion study in three Spanish centers was run as a substudy of the PrefHer trial. We recorded active HCP time for trastuzumab SC and IV-related tasks and calculated HCP time as the mean sum of task times over 154 administrations (80 IV, 74 SC). We calculated mean patient infusion chair time and treatment room time. Staff costs were calculated using fully loaded salary costs based on Spanish salaries (Euros 2012). Results. The transition from trastuzumab IV to SC led to a 50% reduction in active HCP time [27.2 min (95% CI 21.8-32.6) vs. 13.2 min (95% CI 8.9-17.5) per cycle]. Time savings resulted from avoiding IV catheter installation and removal, line flushing, and drug reconstitution. SC administration led to a fivefold reduction (78-85%) in chair time and a fourfold reduction (59–81%) in patient treatment room time, resulting in 24 h free-up time in the total treatment course (18 cycles). Total estimated direct costs were Euros 29,431.75 and Euros 28,452.12 for IV and SC, respectively, a saving of EUROS 979.60 over a full treatment course. Conclusions. Trastuzumab SC provided substantial time savings for HCP and patients, and reduced staff costs vs. trastuzumab IV. Reducing the use of hospital facilities may result in further savings and improved quality of medical care (AU)

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Adverse reactions for the use of the monoclonal trastuzumab antibody in the treatment of patients with HER2 positive breast cancer / Reacciones adversas por el uso del anticuerpo monoclonal trastuzumab en el tratamiento de pacientes con cáncer de mama HER2 positivo

Objective: identify the main adverse reactions presented by patients with HER2 positive breast cancer from an outpatient clinic specialized in chemotherapy in the city of Caruaru-PE, after the use of Trastuzumab. Methods: The data were obtained through the analysis of the medical records of the patients attended at the outpatient clinic from January 2015 to December 2016. Results: Twenty-four patients were selected, of whom 12.5% presented cardiotoxicity and 4.16% presented abdominal pain, nausea among other adverse events. Conclusion: Identifying such adverse events makes it possible to better assist the oncological patient and to better adhesion to the treatment. Because they are specific target drugs, few studies are concerned with evaluating these adverse events, which often makes clinical care difficult

Objetivo: identificar las principales reacciones adversas presentadas por pacientes con cáncer de mama HER2 positivo desde una clínica ambulatoria especializada en quimioterapia en la ciudad de Caruaru- PE (Brasil), después del uso de Trastuzumab. Métodos: los datos se obtuvieron mediante el análisis de los registros médicos de los pacientes atendidos en la consulta externa entre enero de 2015 y diciembre de 2016. Resultados: se seleccionaron 24 pacientes, de los cuales 12.5% presentaron cardiotoxicidad y 4.16% presentaron dolor abdominal, náuseas entre otros eventos adversos. Conclusión: la identificación de tales eventos adversos permite una mejor asistencia al paciente oncológico y una mejor adhesión al tratamiento. Debido a que son medicamentos específicos, pocos estudios se preocupan por evaluar estos efectos adversos, lo que a menudo dificulta la atención clínica

Carcinomatosis meníngea en el cáncer de mama: del diagnóstico al tratamiento / Meningeal carcinomatosis in breast cancer: from diagnosis to treatment

La aparición de carcinomatosis meníngea en el cáncer de mama es un suceso cada vez más comunicado en la bibliografía. Parece relacionarse con el alargamiento de la vida de las pacientes, la mejor sensibilidad al diagnóstico por imagen y la impermeabilidad de la barrera hematoencefálica a los agentes quimioterápicos. Es una forma evolutiva que afirma la invasión metastásica del espacio subaracnoideo y se correlaciona con una supervivencia limitada. El diagnóstico es difícil, debido a la inespecificidad de los signos clínicos dominados por cefaleas, trastornos cognitivos, y posibles síntomas y signos de lesiones focales progresivas. La resonancia magnética del cerebro y de la médula espinal interpretada por un especialista en neurooncología es el examen de elección en esta indicación, en búsqueda de un incremento en la captación meníngea. El análisis biológico del líquido cefalorraquídeo es un elemento esencial en el diagnóstico. Además del estudio bioquímico, la presencia de células neoplásicas es por sí sola suficiente para confirmar el diagnóstico. El número de falsos negativos es muy común y representa un gran problema diagnóstico que requiere una repetición de las punciones lumbares. Los métodos terapéuticos son estándares, a menudo invasivos, dominados por la quimioterapia intratecal y se basan sobre una evidencia científica de bajo nivel. Se analiza la epidemiología, los factores pronósticos, las herramientas diagnósticas, los tratamientos disponibles en la actualidad y las posibles terapias futuras de la carcinomatosis meníngea en el cáncer de mama (AU)

The appearance of meningeal carcinomatosis in breast cancer is an event that is being reported increasingly more frequently in the literature. It seems to be related with the lengthening of the patients’ lives, improved sensitivity to diagnostic imaging and impermeability of the blood-brain barrier to the chemotherapeutic agents. It is an evolutionary form that affirms the metastatic invasion of the subarachnoidal space and is correlated with limited survival. Its diagnosis is difficult, due to the lack of specificity of the clinical signs dominated by headaches, cognitive disorders and possible signs and symptoms of progressive focal lesions. Magnetic resonance imaging of the brain and the spinal cord interpreted by a specialist in neuro-oncology is the preferred examination in this indication, in the search for an increase in meningeal enhancement. Biological analysis of the cerebrospinal fluid is an essential element in the diagnosis. In addition to the biochemical study, the presence of neoplastic cells is in itself enough to confirm the diagnosis. False negatives are very common and represent an important diagnostic problem that entails the need to repeat the lumbar punctures. The therapeutic methods are standard, often invasive, dominated by intrathecal chemotherapy and are based on low-level scientific evidence. This study analyses the epidemiology, the prognostic factors, the diagnostic tools, currently available treatments and the possible future therapies of meningeal carcinomatosis in breast cancer (AU)

Hypofractionated boost after whole breast irradiation in breast carcinoma: chronic toxicity results and cosmesis

Purpose. To evaluate the impact of hypofractionated boost after hypofractionated whole breast irradiation in breast carcinoma. Methods and materials. Patients after breast conservative surgery were treated all time with hypofractionation of 2.67 Gy/day. Whole breast dose was 40.05 Gy followed in case of risk of local relapse by a boost of 16.02 Gy or 8.01 Gy. Acute and chronic toxicity results were evaluated including cosmetic software-assisted assessment and objective evaluation of fibrosis parameters (elasticity and hydration) by means of a skin tester. Results. A total of 362 patients were evaluated. Acute toxicities comprised grade 1 dermatitis in 48.1 %, grade 2 in 44.5 % and grade 3 in 17 patients 4.7 %, respectively. After a median follow-up of 4.5 years, in 308 cases (86.6 %) there was no chronic skin or subcutaneous changes. In the first consecutive 50 patients, measures with skin tester showed no statistical differences in parameters for skin and subcutaneous fibrosis. Cosmetic results were considered excellent and good in 26 and 62 %, respectively. Conclusions. Boost to tumour bed with hypofractionated doses is well tolerated and acute and chronic toxicities are mild with good cosmetic results. Objective systems are encouraging methods to assess skin quality and cosmesis (AU)

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Impact of HER2 expression on outcome in gastric cancer patients with liver metastasis

Purpose. We aim to investigate the correlation of HER2 expression with liver metastasis and the impact of HER2 status and trastuzumab therapy on the prognosis of gastric cancer with liver metastasis (GCLM) patients. Methods. This prospective observational study was carried out in Shanghai Zhongshan Hospital, Fudan University, from January 2012 to June 2015. HER2 status and baseline characteristics were collected from the patient record. GCLM patients were divided into three groups according to HER2 status and trastuzumab therapy. Results. A total of 290 patients were included, and94 patients were diagnosed with liver metastasis. The HER2 positivity was 37.2 % (35/94) in GCLM patients and 21 % (61/290) in the overall GC patients. Among 94 GCLM patients, 28 HER2-positive patients received trastuzumab-based therapy (group A), 7 HER2-positive patients received chemotherapy alone (group B) and the other 59 patients were HER2 negative (group C). The median progression-free survival (PFS) for groups A, B and C was 7.83, 6.30 and 5.33 months, respectively (P = 0.007). The median overall survival (OS) for groups A, B and C was 12.00, 10.47 and 8.67 months, respectively (P = 0.056). Further Cox analysis showed that there was no significant difference in OS (P = 0.917) and PFS (P = 0.456) between group B and C. Conclusions. HER2 positivity was higher in GCLM patients. HER2 status itself was not an independent prognostic factor in GCLM patients. Trastuzumab-based therapy could significantly improve survival in HER2-positive GCLM patients (AU)

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The combinational therapy of trastuzumab and cetuximab inhibits tumor growth in a patient-derived tumor xenograft model of gastric cancer

Purpose: Gastric cancer (GC) is one of the leading causes of cancer mortality worldwide. Although therapeutic strategies for GC have improved, the prognosis for advanced GC remains poor. Herein, the present study sought to design a personalized cancer therapy specific to a stage III GC patient. Methods: The tumor was surgically removed and was used to establish a patient-derived tumor xenograft (PDTX) model utilizing nude mice. Various molecular-targeted anticancer treatments were tested in the study, including control (no treatment), bevacizumab, cetuximab, bevacizumab + cetuximab, trastuzumab, and trastuzumab + cetuximab. Results: Trastuzumab + cetuximab treatment exhibited the best antitumor growth effect, followed by trastuzumab, bevacizumab + cetuximab, cetuximab, and bevacizumab. Similarly, trastuzumab + cetuximab was also the most effective treatment at inducing apoptosis and cell cycle arrest in primary cultures of the patient’s gastric cancer cells. Among all treatments tested in the study, trastuzumab + cetuximab showed the most profound effect in reducing the protein expression of proliferation and metastatic markers (VEGF, MMP-7, EGFT, Ki-67 and, PCNA) in tumors obtained from PDTX models, which may be the mechanism underlying the profound antitumor growth effect exerted by trastuzumab + cetuximab. Conclusions: The data indicate that trastuzumab + cetuximab combinational therapy should be the most effective antitumor growth therapy for the GC patient whom we took the cancer cells from (AU)

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