Development in the last 20 years of anti-HER2 targeted therapy for breast cancer / 中华外科杂志

Since trastuzumab was listed and approved for breast cancer in 2002, China has entered a new epoch of targeted therapy. Over the past 20 years, anti-human epidermal growth factor receptor 2 (HER2) targeted therapy for breast cancer in China has experienced the era of single-target, tyrosine kinase inhibitors, double-target and anti-HER2 plus antibody-drug conjugate. Advancement in the anti-HER2 targeted therapy is continuously changing the treatment mode of patients with HER2 positive status and even HER2 low expression, significantly improved their prognosis. In the past 20 years, Chinese scholars have participated in international clinical researches, completed a series of registration studies of imported drugs, developed new drugs with proprietary intellectual property rights, enriched the evidence of clinical research on HER2-targeted therapy, and formed a treatment system with both international standards and Chinese characteristics. In particular, the formulation of the Chinese Society of Clinical Oncology Breast Cancer Guidelines and the Chinese expert consensus on anti-HER2 targeted treatment in breast cancer are the concentrated embodiments of Chinese wisdom.

Effects of adjuvant trastuzumab on long-term survival of T1N0M0 stage human epidermal growth factor receptor 2 positive breast cancer: a real-world study / 中华肿瘤杂志

Objective: To investigate the prognosis impact of adjuvant trastuzumab treatment on human epidermal growth factor receptor 2 (HER-2) positive early breast cancer patients. Methods: A retrospective study was conducted, HER-2-positive T1N0M0 stage breast cancer patients who underwent surgery in the Affiliated Tumor Hospital of Xinjiang Medical University from January 2010 to December 2019 were divided into treatment group and control group according to whether they were treated with trastuzumab or not. Propensity score matching (PSM) was used to balance the confounding bias caused by differences in baseline characteristics between the two groups. Cox proportional hazards model was used to analyze the risk factors affecting disease-free survival (DFS). The Kaplan-Meier method was used to estimate the 3- and 5-year DFS and overall survival (OS) rates of the two groups before and after PSM. Results: There were 291 patients with HER-2 positive T1N0M0 stage breast cancer, including 21 cases in T1a (7.2%), 61 cases in T1b (21.0%), and 209 cases in T1c (71.8%). Before PSM, there were 132 cases in the treatment group and 159 cases in the control group, the 5-year DFS rate was 88.5%, and the 5-year OS rate was 91.5%. After PSM, there were 103 cases in the treatment group and 103 cases in the control group, the 5-year DFS rate was 86.0%, and the 5-year OS rate was 88.5%. Before PSM, there were significant differences in tumor size, histological grade, vascular invasion, Ki-67 index, postoperative chemotherapy or not and radiotherapy between the treatment group and the control group (P<0.05). After PSM, there were no significant difference in clinicopathological features between the treatment group and the control group (P>0.05). Multivariate analysis showed that histological grade (HR=2.927, 95 CI: 1.476, 5.805; P=0.002), vascular invasion (HR=3.410, 95 CI: 1.170, 9.940; P=0.025), menstrual status (HR=3.692, 95 CI: 1.021, 13.344, P=0.046), and chemotherapy (HR=0.238, 95 CI: 0.079, 0.720; P=0.011) were independent factors affecting DFS. After PSM, the 5-year DFS rate of the treatment group was 89.2%, while that of the control group was 83.5%(P=0.237). The 5-year OS rate of the treatment group was 96.1%, while that of the control group was 84.7%(P=0.036). Conclusion: Postoperative targeted therapy with trastuzumab can reduce the risk of recurrence and metastasis in patients with HER-2-positive T1N0M0 stage breast cancer.

A real-world study on the efficacy and safety analysis of paclitaxel liposome in advanced breast cancer / 中华肿瘤杂志

Objective: To explore the application and efficacy of paclitaxel liposome in the treatment of advanced breast cancer among Chinese population in the real world. Methods: The clinical characteristics of patients with advanced breast cancer who received paclitaxel liposome as salvage treatment from January 1, 2016 to August 31, 2019 in 11 hospitals were collected and retrospectively analyzed. The primary outcome was progression free survival (PFS), and the secondary outcome included objective response rate (ORR) and safety. The survival curve was drawn by Kaplan-Meier analysis and the Cox regression model were used for the multivariate analysis. Results: Among 647 patients with advanced breast cancer who received paclitaxel liposome, the first-line treatment accounted for 43.3% (280/647), the second-line treatment accounted for 27.7% (179/647), and the third-line and above treatment accounted for 29.1% (188/647). The median dose of first-line and second-line treatment was 260 mg per cycle, and 240 mg in third line and above treatment. The median period of paclitaxel liposome alone and combined chemotherapy or targeted therapy is 4 cycles and 6 cycles, respectively. In the whole group, 167 patients (25.8%) were treated with paclitaxel liposome combined with capecitabine±trastuzumab (TX±H), 123 patients (19.0%) were treated with paclitaxel liposome alone (T), and 119 patients (18.4%) were treated with paclitaxel liposome combined with platinum ± trastuzumab (TP±H), 108 patients (16.7%) were treated with paclitaxel liposome combined with trastuzumab ± pertuzumab (TH±P). The median PFS of first-line and second-line patients (5.5 and 5.5 months, respectively) were longer than that of patients treated with third line and above (4.9 months, P<0.05); The ORR of the first line, second line, third line and above patients were 46.7%, 36.8% and 28.2%, respectively. Multivariate analysis showed that event-free survival (EFS) and the number of treatment lines were independent prognostic factors for PFS. The common adverse events were myelosuppression, gastrointestinal reactions, hand foot syndrome and abnormal liver function. Conclusion: Paclitaxel liposomes is widely used and has promising efficacy in multi-subtype advanced breast cancer.

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.

Multiple cutaneous telangiectasias after the use of trastuzumab: a case report

We aim to report a particular case of cutaneous telangiectasias on the arms after immunotherapy with trastuzumab plus paclitaxel to treat breast cancer. New oncology therapies reflect a major advance in cancer treatment. They greatly increase survival; however, they still cause certain adverse cutaneous events that should be taken into account for their proper management.

A real world study on the relationship between drug resistance of targeted therapy and prognosis of HER-2-positive advanced breast cancer / 中华肿瘤杂志

Objective: To explore the effect of primary and acquired resistance to anti-human epidermal growth factor receptor 2 (HER-2) on the overall survival of patients with HER-2 positive advanced breast cancer. Methods: The clinical characteristics of HER-2 positive patients with advanced breast cancer admitted to Cancer Hospital of Chinese Academy of Medical Sciences from January 1998 to December 2018 were collected, and their neoadjuvant/adjuvant and advanced three-line chemotherapy were summarized. Among them, targeted drugs for HER-2 included trastuzumab, pertuzumab, T-DM1, RC48-ADC, lapatinib, pyrotinib, allitinib, sipatinib, seratinib. Based on the duration of benefit from anti HER-2 treatment, the patients were divided into two groups: primary anti HER-2 resistance group and acquired anti HER-2 resistance group. In this study, the overall survival (OS) was used as the main end point. Kaplan-Meier analysis and Cox proportional risk regression model were used to analyze the effects of different drug resistance mechanisms on the overall survival. Results: The whole group of 284 patients were included. The median age of recurrence and metastasis was 48 years old, 155 (54.6%) were hormone receptor (HR) positive and 129 (45.4%) were HR negative, 128 cases (45.1%) were premenopausal and 156 cases (54.9%) were postmenopausal, 277 cases (97.5%) had a score of 0-1 in ECoG PS and 7 cases (2.5%) had a score of more than 2 in the first diagnosis of relapse and metastasis. There were 103 cases (36.3%) in the primary drug resistance group and 181 cases (63.7%) in the secondary drug resistance group. The median overall survival time of the two groups was 24.9 months and 40.4 months, respectively, with statistical significance (P<0.001). Conclusion: Primary resistance to HER-2 is one of the factors of poor prognosis in HER-2 positive breast cancer, and its mechanism needs to be further explored.

RUNX3 regulates trastuzumab resistance of gastric cancer cells: a metabolomic analysis based on UPLC-Q Exactive Focus Orbitrap mass spectrometry / 南方医科大学学报

OBJECTIVE@#To explore the role of Runt-related transcription factor 3 (RUNX3) in metabolic regulation of trastuzumab-resistant gastric cancer cells and investigate the mechanism of RUNX3 knockdown-mediated reversal of trastuzumab resistance.@*METHODS@#We performed a metabolomic analysis of trastuzumab-resistant gastric cancer cells (NCI N87R) and RUNX3 knockdown cells (NCI N87R/RUNX3) using ultra performance liquid chromatography (UPLC) coupled with Q Exactive Focus Orbitrap mass spectrometry (MS). Multivariate combined with univariate analyses and MS/MS ion spectrums were used to screen the differential variables. MetaboAnalyst 5.0 database was employed for pathway enrichment analysis. Differential metabolites-genes regulatory relationships were constructed based on OmicsNet database. The changes in GSH/GSSG and NADPH/NADP ratios in NCI N87R/RUNX3 cells were measured using detection kits.@*RESULTS@#The metabolic profile of NCI N87R cells was significantly altered after RUNX3 knockdown, with 81 differential metabolites identified to contribute significantly to the classification, among which 43 metabolites were increased and 38 were decreased (P < 0.01). In NCI N87R cells, RUNX3 knockdown resulted in noticeable alterations in 8 pathways involving glutamine metabolism, glycolysis, glycerophospholipid, nicotinate-nicotinamide and glutathione metabolism, causing also significant reduction of intracellular GSH/GSSG and NADPH/NADP ratios (P < 0.01). The differential metabolites-genes network revealed a regulatory relationship between the metabolic molecules and genes.@*CONCLUSION@#RUNX3 reverses trastuzumab resistance in gastric cancer cells by regulating energy metabolism and oxidation-reduction homeostasis and may serve as a potential therapeutic target for trastuzumab-resistant gastric cancer.

Dihydromyricetin reverses Herceptin resistance by up-regulating miR-98-5p and inhibiting IGF1R/HER2 dimer formation in SKBR3 cells / 南方医科大学学报

OBJECTIVE@#To explore the effect of dihydromyricetin on the expression of miR-98-5p and its mechanism in the development of Herceptin resistance in SKBR3 cells.@*METHODS@#The expression of IGF2 and miR-98-5p and their interaction relationship were analyzed by bioinformatics analysis through TargetScan online databases. SKBR3 cells and drug-resistant SKBR3-R cells were cultured in cell experiments. Xenograft tumor mice were constructed by SKBR3 and SKBR3-R cells. Proteins were detected by western blotting and immunohistochemistry. Transfected cells were constructed by shRNA lentivirus vectors. RT-QPCR was used to detect RNA. Cell proliferation was detected by MTS method. Cell jnvasion was detected by Transwell assay. Luciferase reporting assays were used to verify RNA interactions. IGF-1R/HER2 heterodimer was determined by immunocoprecipitation.@*RESULTS@#The expression of IGF2, p-IGF1R, p-Akt and p-S6K in SKBR3-R cells were significantly higher than those in SKBR3 cells, while the expression of PTEN protein was lower in SKBR3-R cells (P < 0.05). IGF1R/HER2 heterodimer in SKBR3-R cells was significantly increased (P < 0.01).The expression of IGF2 and invasion ability were significantly reduced while transfected with miR-98-5p in SKBR3-R cells (P < 0.05), but the IGF2 mRNA were no difference in both cells (P > 0.05). The expression of miR-98-5p was up-regulated and IGF2 was decreased in drug-resistant xenograft tumor mice after feeding with dihydromyricetin, and the tumor became more sensitivity to Herceptin (P < 0.05).@*CONCLUSION@#Dihydromyricetin could induce the expression of miR-98-5p, which binds to IGF2 mRNA to reduce IGF2 expression, inhibit the IGF-1R/HER2 formation, thereby reversing cell resistance to Herceptin in SKBR3-R cells.

Características y manejo del cáncer de mama precoz en mujeres añosas asistidas en la Unidad Docente Asistencial de Mastología del Hospital de Clínicas en el período 2011-2018 / Characteristics and management of early breast cancer in elderly women assisted in the Mastology Care Teaching Unit of the Hospital de Clínicas in the period 2011-2018 / Características e manejo do câncer de mama precoce em idosas atendidas na Unidade de Ensino de Mastologia do Hospital de Clínicas no período de 2011-2018

Introducción: Existen pocas pautas para el tratamiento del cáncer de mama (CM) en pacientes añosas, lo que puede conducir al sub o sobre tratamiento. Objetivo: Conocer las características, manejo y la evolución del CM precoz en mujeres añosas. Material y métodos: Estudio observacional, descriptivo, transversal. Se recolectaron datos relacionados con las características clínico-patológicas y la evolución de pacientes de 70 años o más tratadas por CM en el período comprendido entre el 1/1/ 2011 y el 31/12/ 2018, asistidas en el Hospital de Clínicas. Se utilizaron herramientas de estadística descriptiva y para calcular la sobrevida global (SVG) se utilizó el método de Kaplan-Meier. Resultados: se incluyeron 31 pacientes; la edad mediana al diagnóstico fue 76,8 años; las características clínico-patológicas fueron: carcinoma ductal: 71%; GH 1-2: 74,2%; estadio I: 54,8 %; sin metástasis axilares: 80,6 %; HER2-RE/RP+ 80,6%; HER2+ 16,7%, y triple negativas 3,2%. El 29% de las pacientes fueron diagnosticadas mediante tamizaje poblacional y el 74,2% recibieron tratamiento según pautas vigentes, mientras que el 38,7% fueron subtratadas y el 16,1% sobretratadas. La mediana de SVG fue de 98,7 meses. Conclusiones: Una minoría de las pacientes fue diagnosticada mediante tamizaje poblacional, el tipo histológico más frecuente fue el ductal y la prevalencia de los tumores HER2-RE/RP+ fue mayor que en las pacientes más jóvenes. La mayoría de las pacientes recibió tratamiento estandar.

Introduction: There are few guidelines for the treatment of breast cancer (BC) in older patients, which can lead to under- or over-treatment. Objective: To understand the characteristics, management and evolution of early BC in older women. Material and methods: Observational, descriptive, cross-sectional study. Data were collected on the clinical-pathological characteristics and evolution of patients aged 70 years or older, treated for BC in the period from 1/1/ 2011 to 31/12/ 2018, at the Hospital de Clínicas. Descriptive statistical tools were used and the Kaplan-Meier method was applied to calculate the overall survival (OS) rate. Results: 31 patients were included; median age at diagnosis was 76.8 years old; the clinical-pathological characteristics were: ductal carcinoma: 71%; HG 1-2: 74.2%; stage I: 54.8%; no axillary metastases: 80.6%; HER2-ER/PR+ 80.6%; HER2+ 16.7%, and triple negative 3.2%. Of all the patients, 29% were diagnosed through screening and 74.2% were treated according to current guidelines, while 38.7% were under-treated and 16.1% over-treated. The median OS was 98.7 months. Conclusions: A minority of patients were diagnosed by screening, the most frequent histological type was ductal and the prevalence of HER2-RE/RP+ tumors was higher than in younger patients. Most patients received standard treatment.

Introdução: Existem poucas diretrizes para o tratamento do câncer de mama (CM) em pacientes idosos, o que pode levar ao sub ou excesso de tratamento. Objetivo: Conhecer as características, manejo e evolução do MC precoce em mulheres idosas. Material e métodos: estudo observacional, descritivo e transversal. Foram coletados dados relacionados às características clínico-patológicas e à evolução dos pacientes com 70 anos ou mais atendidos por CM no período de 01/01/2011 a 31/12/2018, atendidos no Hospital de Clínicas. Ferramentas de estatística descritiva foram usadas e o método de Kaplan-Meier foi usado para calcular a sobrevida global (SVG). Resultados: 31 pacientes foram incluídos; a mediana de idade ao diagnóstico foi de 76,8 anos; as características clínico-patológicas foram: carcinoma ductal: 71%; GH 1-2: 74,2%; estágio I: 54,8%; sem metástases axilares: 80,6%; HER2-RE / RP + 80,6%; HER2 + 16,7% e triplo negativo 3,2%. 29% dos pacientes foram diagnosticados por triagem populacional e 74,2% receberam tratamento de acordo com as diretrizes atuais, enquanto 38,7% foram subtratados e 16,1% supertratados. O SVG médio foi de 98,7 meses. Conclusões: A minoria dos pacientes foi diagnosticada por rastreamento populacional, o tipo histológico mais frequente foi ductal e a prevalência de tumores HER2-RE / RP + foi maior do que em pacientes mais jovens. A maioria dos pacientes recebeu tratamento padrão.

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.

La importancia de la determinación del HER2 en el cáncer gástrico avanzado: a propósito de un caso clínico / Importance of HER2 status determination in advanced gastric cancer: A case study

Resumen El cáncer gástrico avanzado es una entidad que incluye dos situaciones clínicas distintas: el cáncer gástrico localmente avanzado no resecable y la enfermedad metastásica, cuyo tratamiento estándar es la quimioterapia. La sobreexpresión del receptor 2 del factor de crecimiento epidérmico humano (HER2) se puede presentar en esta enfermedad de un 9 % a un 38 % y ha sido el primer biomarcador predictivo utilizado para el tratamiento dirigido con trastuzumab en pacientes con tumores gástricos y de la región gastroesofágica avanzados. Se presenta en este artículo el caso de un paciente con cáncer gástrico avanzado con HER2 positivo manejado con quimioterapia convencional más trastuzumab como terapia blanco con adecuada respuesta clínica.

Abstract Advanced gastric cancer (AGC) is an entity that encompasses two distinct clinical situations: locally advanced unresectable gastric cancer and metastatic disease, with chemotherapy as the standard treatment. HER2 overexpression can occur in 9% to 38% of the cases with this disease and has been the first predictive biomarker used for trastuzumab-targeted therapy in patients with advanced gastric and gastroesophageal tumors. This article presents a patient with AGC and positive HER2 treated with conventional chemotherapy plus trastuzumab as targeted therapy with adequate clinical response.

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.

Cardiotoxicidad inducida por trastuzumab en paciente con carcinoma de mama HER-2 positivo / Trastuzumab-induced cardiotoxicity in a patient with HER-2 positive breast carcinoma

Introducción: La disfunción cardíaca emerge como una de las principales causas de morbilidad y mortalidad entre los sobrevivientes de cáncer. En la actualidad, el trastuzumab se considera parte de la terapia estándar para el cáncer de mama; sin embargo, se asocia a una variada incidencia de cardiotoxicidad. Caso clínico: Paciente femenina de 52 años que recibió neoadyuvancia con antraciclinas, y luego, taxanos combinados a trastuzumab. Se le realizó una cuadrantectomía de mama izquierda por un carcinoma ducto lobulillar infiltrante, etapa IIIa, con un fenotipo: luminal B- Her2 positivo. Desarrolló una insuficiencia cardiaca congestiva, luego de dos dosis de trastuzumab posoperatorio. La fracción de eyección ventricular izquierda descendió de 65 por ciento (previo al tratamiento con antraciclinas) a 44 por ciento. Recibió tratamiento con enalapril, carvedilol, y espironolactona. Se recuperó la fracción de eyección ventricular izquierda a 57 por ciento, por lo que se reintrodujo el trastuzumab y así completar las 18 dosis planificadas, luego de cuatro meses de suspensión. Actualmente, está libre de enfermedad, en tratamiento hormonal con letrozol y sin síntomas cardiovasculares. Conclusiones: La cardiotoxicidad por trastuzumab puede ser reversible, si se trata adecuada y oportunamente, en el marco de grupos multidisciplinarios y Unidades de Cardio-Oncología(AU)

Introduction: Cardiac dysfunction emerges as one of the main causes of morbidity and mortality among cancer survivors. Currently, trastuzumab is considered part of the standard therapy for breast cancer; however, it is associated with a varied incidence of cardiotoxicity. Clinical case report: A case of a 52-year-old female patient is reported here, because she received neoadjuvant therapy with anthracyclines and later, taxanes combined with trastuzumab. She underwent a quadrantectomy of her left breast for an infiltrating lobular duct carcinoma, stage IIIa, with a phenotype: luminal B-Her2 positive. She developed congestive heart failure after two doses of postoperative trastuzumab. The left ventricular ejection fraction decreased from 65 percent (prior to anthracycline treatment) to 44 percent. She was treated with enalapril, carvedilol, and spironolactone. The left ventricular ejection fraction was recovered to 57 percent, so trastuzumab was reintroduced and thus complete the 18 planned doses, after four months of suspension. Currently, she is disease-free, on hormonal treatment with letrozole, and without cardiovascular symptoms. Conclusions: Cardiotoxicity due to trastuzumab can be reversible, if it is appropriately and timely treated, within the framework of multidisciplinary groups and Cardio-Oncology Units(AU)

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

Efficacy and safety of oral pyrotinib in HER2 positive metastatic breast cancer: real-world practice / 北京大学学报(医学版)

OBJECTIVE@#Pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising antitumor activity and acceptable tolerability in phase II and phase III randomized clinical trials. We assessed the activity and safety of oral pyrotinib for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer patients in the real world.@*METHODS@#We retrospectively analyzed 72 HER2 positive metastatic breast cancer (MBC) patients who received oral pyrotinib based regimens at Beijing Cancer Hospital and other four hospitals (Peking University First Hospital, China-Japan Friendship Hospital, General Hospital of PLA, Peking University Third Hospital) from August 2018 to September 2019. Progression free survival (PFS), objective response rate (ORR), adverse events (AE) of pyrotinib were investigated.@*RESULTS@#Seventy-two patients with HER2 positive MBC were enrolled. The median age of the patients was 55 years (range: 32-79 years). Sixty-nine (95.8%) patients had received anti-HER2 treatment in the metastatic and/or (neo) adjuvant settings; 61 (84.7%) patients had received anti-HER2 treatments in the metastatic setting in terms of trastuzumab 56 (77.8%) patients, lapatinib 36 (50.0%) patients, and T-DM1 4 (5.6%) patients. Among these 72 patients who received oral pyrotinib based regimens, 62 (86.1%) patients received pyrotinib (±trastuzumab) in combination with chemotherapy, 6 (8.3%) patients received pyrotinib (± trastuzumab) in combination with endocrine therapy and 4 (5.6%) patients received pyrotinib (±trastuzumab). Sixty-five (90.3%) patients received 400 mg pyrotinib once daily as initial dose, and 7 (9.7%) patients received 320 mg. OBJECTIVE response and safety to pyrotinib based therapy were evaluable in all the 72 patients. One (1.4%) patient achieved complete response (CR), 18 (25.0%) patients achieved partial response (PR), 41 (56.9%) patients had stable disease (SD), and 12 (16.7%) patients had progressive disease (PD). The ORR (CR+PR) was 26.4% and the median PFS was 7.6 months (95%CI: 5.5-9.7 months). Among the 36 patients with prior lapatinib therapy, the median PFS was 7.9 months (95%CI: 4.1-11.7 months). Among the 15 patients with brain metastasis, the median PFS was 6.0 months (95%CI: 2.2-9.8 months). The main toxicities related to pyrotinib were diarrhea in 57 (79.2%) cases, and 48 (66.7%) cases with grade 1-2 as well as 9 (12.5%) cases with grade 3.@*CONCLUSION@#Pyrotinib based therapy is an effective treatment for patients with HER2 positive MBC, including patients with lapatinib treatment failure and brain metastasis, and the toxicities can be tolerated.

Cardiotoxicidad de los quimioterapéuticos diferentes a antraciclinas de la lista oficial de medicamentosde la Caja Costarricense del Seguro Social / Cardiotoxicity of chemotherapeutics other than anthracyclines from the official list of medications of the Costa Rican Social Security Fund

Resumen La Cardio-oncología es una nueva disciplina que busca enfocarse en el tamizaje, monitoreo y tratamiento de los pacientes con cáncer que presentan enfermedad cardiaca durante o después de recibir tratamiento. Esto debido a que el efecto cardiotóxico asociado a los quimioterapéuticos es ampliamente conocido y respaldado por abundantes estudios clínicos. Sin embargo, no es hasta épocas recientes que en Costa Rica se desarrollaron por primera vez Unidades Cardio-oncológicas, los cuales actualmente se ubican en diversos centros médicos de nuestro sistema de salud público. A continuación, se presenta un resumen de las manifestaciones clínicas de las diversas terapias oncológicas diferentes a las antraciclinas que tenemos a disposición en la Caja Costarricense del Seguro Social (CCSS).

Abstract Cardio-oncology is a new discipline that looks to focus on the screening, monitoring and treatment of patients withcancer that show up with heart disease during and after their treatment. This is due to the fact that the cardiotoxic effectsassociated to chemotherapeutics is widely known and backed up with abundant clinical trials. Nevertheless, it is not untilrecently that in Costa Rica the Cardio-oncologic Units were created for the first time, which now can be found in multiplemedical centers of our public health system. Up next, we present a summary of the clinical manifestations of the diversenon-anthracycline oncologic therapies that are available in the "Caja Costarricense del Seguro Social".

Impacto del cambio de presentación del trastuzumab para la Seguridad Social de Costa Rica, estudio de minimización de costos / Impact of the change of presentation of the trastuzumab for the Social Security of Costa Rica, cost minimization study

Resumen Objetivo: dado que en este momento está disponible a nivel de la Seguridad Social Costarricense tanto trastuzumab para administración intravenosa como para administración subcutánea, y que la presentación para administración subcutánea ha documentado ser no inferior a la intravenosa, resulta pertinente contar con un estudio de minimización de costes que permita documentar cuál de las formulaciones resulta más conveniente mantener en el sistema público de salud, con base en criterios de eficiencia de la intervención. Métodos: se desarrolló un estudio que evaluó desde la perspectiva financiera de la Seguridad Social de Costa Rica, dos opciones diferentes de aplicación del trastuzumab en pacientes con cáncer de mama. Los procedimientos relacionados fueron identificados y documentados para los dos tipos de aplicación del tratamiento intravenosa y subcutánea. Ambas opciones de tratamiento se basaron en esquemas de diecisiete dosis, con la estimación de los suministros y el tiempo del profesional sanitario para cada posibilidad. El análisis incluyó la evaluación desde la perspectiva del paciente. Resultados: la evaluación económica del procedimiento de administración para ambas alternativas evidenció que la opción subcutánea tenía un costo de aplicación de $ 78,6 y $ 467,34 para la opción intravenosa. Desde la perspectiva financiera, la opción subcutánea constituye la alternativa con un costo menor: $ 4000,00 por tratamiento por paciente, y desde la perspectiva de este, implica un 45,0 % menos de tiempo por sesión de tratamiento por paciente, que en la opción intravenosa. Conclusiones: la formulación de trastuzumab subcutánea evidenció una reducción sustancial de tiempo y costo en comparación con la presentación intravenosa en el sistema de Seguridad Social Costarricense.

Abstract Objective: Given that at this time is available at the Costa Rican Social security both trastuzumab for intravenous as for subcutaneous administration, and that the presentation for subcutaneous administration has documented to be not inferior to the intravenous. It is relevant to have a study of cost minimization to investigate what formulation is more convenient to maintain in the public health system, based on criteria of efficiency of the intervention. Methods: A study was developed to evaluate, from the financial perspective of the Social Security of Costa Rica, two different options of application of trastuzumab in patients with breast cancer. The related procedures were identified and documented for the two types treatment application. Both treatment options were based on seventeen dose schemes, with the estimate of supplies and the time of the health professional for each possibility. The analysis also included the evaluation from the patient's perspective. Results: The economic evaluation of the application procedure for both alternatives evidenced that the subcutaneous option had an application cost of $78.6 and $467.34 for the intravenous option. From the financial perspective the subcutaneous option constitutes the alternative with lower cost, with a cost around $4000.0 by treatment per patient, and from the patient perspective implies a 45.0% less time for session than then intravenous option. Conclusions: Trastuzumab subcutaneous formulation evidenced a substantial time and cost reduction in comparison with the intravenous formulation in the Costa Rican Social Security System.

Left Ventricular Regional Wall Motion Abnormality is a Strong Predictor of Cardiotoxicity in Breast Cancer Patients Undergoing Chemotherapy / Alteração Contrátil Segmentar Ventricular Esquerda é Preditor Independente de Cardiotoxicidade em Pacientes com Câncer de Mama em Tratamento Quimioterápico

Abstract Background: Chemotherapeutic agents of anthracyclines class and humanized monoclonal antibodies are effective treatments for breast cancer, however, they present a potential risk of cardiotoxicity. Several predictors have been recognized as predictors in the development of cardiac toxicity, and the evaluation of left ventricular segmental wall motion abnormalities (LVSWMA) has not been studied. Objective: To analyze prospectively the role of LVSWMA among echocardiographic parameters in the prediction of development of cardiotoxicity in breast cancer patients undergoing treatment with chemotherapy. Methods: Prospective cohort of patients diagnosed with breast cancer and in chemotherapy treatment with potential cardiotoxicity medications including doxorubicin and trastuzumab. Transthoracic echocardiograms including speckle tracking strain echocardiography were performed at standard times before, during and after the treatment to assess the presence (or lack thereof) of cardiotoxicity. Cardiotoxicity was defined by a 10% decrease in the left ventricular ejection fraction, on at least one echocardiogram. Multivariate logistic regression models were used to verify the predictors related to the occurrence of cardiotoxicity over time. Results: Of the 112 patients selected (mean age 51,3 ± 12,9 years), 18 participants (16.1%) had cardiotoxicity. In the multivariate analysis using the logistic regression model, those with LVWMA (OR = 6.25 [CI 95%: 1.03; 37.95], p < 0,05), LV systolic dimension (1.34 [CI 95%: 1.01; 1.79], p < 0,05) and global longitudinal strain by speckle tracking (1.48 [CI 95%: 1.02; 2.12], p < 0,05) were strongly associated with cardiotoxicity. Conclusion: In the present study, we showed that LVWMA, in addition to global longitudinal strains, were strong predictors of cardiotoxicity and could be useful in the risk stratification of these patients.

Resumo Fundamento: Os agentes quimioterápicos da classe das antraciclinas e dos anticorpos monoclonais humanizados são tratamentos eficazes para o câncer de mama, entretanto, apresentam alto risco de cardiotoxicidade. Diversos parâmetros têm sido reconhecidos como preditores no desenvolvimento de toxicidade cardíaca, sendo que a avaliação da alteração contrátil segmentar ventricular esquerda (ACSVE) ainda não foi estudada. Objetivo: Analisar a associação entre o surgimento de ACSVE e o desenvolvimento de cardiotoxicidade em pacientes com câncer de mama em tratamento com quimioterapia. Métodos: Coorte prospectiva de pacientes diagnosticados com câncer de mama e em tratamento quimioterápico com doxorrubicina e/ou trastuzumab. Foram realizados ecocardiogramas transtorácicos antes, durante e depois do tratamento para avaliar a presença ou não de cardiotoxicidade. A cardiotoxicidade foi definida por um decréscimo de 10% na fração de ejeção do ventrículo esquerdo, em pelo menos um ecocardiograma. Modelos de regressão logística multivariada foram utilizados para verificar os fatores preditores na ocorrência de cardiotoxicidade ao longo do tempo. Resultados: Dos 112 pacientes selecionados (idade média = 51,3 ± 12,9 anos), 18 (16,1%) apresentaram cardiotoxicidade. Na análise multivariada os pacientes com ACSVE (OR = 6,25 [IC 95%: 1,03; 37,95], p < 0,05), diâmetro sistólico do VE (OR = 1,34 [IC 95%:1,01; 1,79], p < 0,05) e strain longitudinal global pela técnica de speckle tracking (OR = 1,48 [IC 95%: 1,02; 2,12], p < 0,05) foram preditores significativos e independentes na predição de cardiotoxidade. Conclusão: Mostramos que ACSVE, bem como a redução do strain longitudinal global foram preditores independentes para cardiotoxicidade, podendo ser úteis na estratificação de risco destes pacientes.