Role of the Intracellular pH in the Metabolic Switch between Oxidative Phosphorylation and AerobicGlycolysis - Relevance to Cancer

Cellular energy in the form of ATP can be produced through oxidative phosphorylation and through glycolysis. Since oxidative phosphorylation requires oxygen and generates ATP more efficiently than glycolysis, it has been assumed for many years that the presence or absence of oxygen determines that cells generate energy through oxidative phosphorylation or through glycolysis. Although cells must activate glycolysis in the absence of oxygen to produce ATP, it is now accepted that they can activate both glycolysis and oxidative phosphorylation in the presence of oxygen. In fact, normal proliferating cells and tumor cells are known to have a high glycolytic activity in the presence of adequate oxygen levels, a phenomenon known as aerobic glycolysis or the Warburg effect. Recent observations have demonstrated that the activation of aerobic glycolysis plays a major role in carcinogenesis and tumor growth. Understanding the mechanisms involved in the metabolic switch between oxidative phosphorylation and aerobic glycolysis may therefore be important for the development of potential preventive and therapeutic interventions. In this article, we discuss the role of the intracellular pH in the metabolic switch between oxidative phosphorylation and aerobic glycolysis. We propose that, in the presence of adequate oxygen levels, the intracellular pH may play a key role in determining the way cells obtain energy, an alkaline pH driving aerobic glycolysis and an acidic pH driving oxidative phosphorylation

Safety and efficacy of ribociclib plus letrozole in patients with HR+, HER2– advanced breast cancer: Results from the Spanish sub-population of the phase 3b CompLEEment-1 trial

Advanced breast cancer; CDK4/6 inhibitor; PostmenopausalCáncer de mama avanzado; Inhibidor de CDK4/6; PosmenopáusicaCàncer de mama avançat; Inhibidor de CDK4/6; PostmenopàusicaBackground Breast cancer is the most common malignancy and the second leading cause of cancer-related mortality in Spanish women. Ribociclib in combination with endocrine therapy (ET) has shown superiority in prolonging survival in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) vs. ET alone. Methods CompLEEment-1 is a single-arm, open-label phase 3b trial evaluating ribociclib plus letrozole in a broad population of patients with HR+, HER2– ABC. The primary endpoints were safety and tolerability. Here we report data for Spanish patients enrolled in CompLEEment-1. Results A total of 526 patients were evaluated (median follow-up: 26.97 months). Baseline characteristics showed a diverse population with a median age of 54 years. At study entry, 56.5% of patients had visceral metastases and 8.7% had received prior chemotherapy for advanced disease. Rates of all-grade and Grade ≥3 adverse events (AEs) were 99.0% and 76.2%, respectively; 21.3% of patients experienced a serious AE, and 15.8% of AEs led to treatment discontinuation. AEs of special interest of neutropenia, increased alanine aminotransferase, increased aspartate aminotransferase and QTcF prolongation occurred in 77.8%, 14.8%, 11.4% and 4.0% of patients, respectively. Patients aged >70 years experienced increased rates of all-grade and Grade ≥3 neutropenia and anemia. Efficacy results were consistent with the global study. Conclusions Results from Spanish patients enrolled in CompLEEment-1 are consistent with global data showing efficacy and a manageable safety profile for ribociclib plus letrozole treatment in patients with HR+, HER2− ABC, including populations of interest (NCT02941926).This study was funded by Novartis Pharmaceuticals. The sponsor was involved in the study design, the collection, analysis, and interpretation of data, and the writing of the manuscript

Equity, barriers and cancer disparities: study of the Spanish Society of Medical Oncology on the access to oncologic drugs in the Spanish Regions

[Purpose] The Spanish Society of Medical Oncology (SEOM) has conducted a study on the access to oncologic drugs across the 17 Spanish Regions with the aim of identifying potential heterogeneities and making proposals for eliminating the barriers identified at the different levels.[Methods] An Expert Panel made up of medical oncologists designed a survey on certain indications approved for 11 drugs in the approach of breast cancer, melanoma, lung cancer, prostate cancer and support treatment. This survey was sent to 144 National Health System (NHS) hospitals. [Results] 77 hospitals answered the survey. The information modules analysed were: scope of the Commission that establishes binding decisions related to drug access; conditions, stages and periods of drug application, approval and administration processes; barriers to accessing drugs. [Conclusions] The study shows variability in drug access. The SEOM makes proposals addressed to reducing the differences identified and homogenizing drug access conditions.This study was funded by SEOM

Treatment of cancer with oral drugs: a position statement by the Spanish Society of Medical Oncology (SEOM)

Cancer treatment involves the participation of multiple medical specialties and, as our knowledge of the disease increases, this fact becomes even more apparent. The degree of multidisciplinarity is determined by several factors, which include the severity and type of disease, the increasing diversity in the available pharmacological and non-pharmacological therapies, and the range of specialists involved in cancer therapy, such as medical oncologists, radiotherapists, gynecologists, gastroenterologists, urologists, surgeons, and pneumologists, among others. Across Europe, the situation of cancer care can be variable due to the diversity of health systems, differences in drug reimbursement, and the degree of establishment of Medical Oncology as a medical specialty in the European Union states

SOLTI-1805 TOT-HER3 Study Concept: A Window-of-Opportunity Trial of Patritumab Deruxtecan, a HER3 Directed Antibody Drug Conjugate, in Patients With Early Breast Cancer

Background: Preclinical data support a key role for the human epidermal growth factor receptor 3 (HER3) pathway in hormone receptor (HR)-positive breast cancer. Recently, new HER3 directed antibody drug conjugates have shown activity in breast cancer. Given the need to better understand the molecular biology, tumor microenvironment, and mechanisms of drug resistance in breast cancer, we designed this window-of-opportunity study with the HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402). Trial Design: Based on these data, a prospective, multicenter, single-arm, window-of-opportunity study was designed to evaluate the biological effect of patritumab deruxtecan in the treatment of naïve patients with HR-positive/HER2-negative early breast cancer whose primary tumors are ≥1 cm by ultrasound evaluation. Patients will be enrolled in four cohorts according to the mRNA-based ERBB3 expression by central assessment. The primary endpoint is a CelTIL score after one single dose. A translational research plan is also included to provide biological information and to evaluate secondary and exploratory objectives of the study

Safety and efficacy of ribociclib plus letrozole in patients with HR+, HER2– advanced breast cancer: Results from the Spanish sub-population of the phase 3b CompLEEment-1 trial

Background: Breast cancer is the most common malignancy and the second leading cause of cancer-related mortality in Spanish women. Ribociclib in combination with endocrine therapy (ET) has shown superiority in prolonging survival in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) vs. ET alone.Methods: CompLEEment-1 is a single-arm, open-label phase 3b trial evaluating ribociclib plus letrozole in a broad population of patients with HR+, HER2- ABC. The primary endpoints were safety and tolerability. Here we report data for Spanish patients enrolled in CompLEEment-1.Results: A total of 526 patients were evaluated (median follow-up: 26.97 months). Baseline characteristics showed a diverse population with a median age of 54 years. At study entry, 56.5% of patients had visceral metastases and 8.7% had received prior chemotherapy for advanced disease. Rates of all-grade and Grade >= 3 adverse events (AEs) were 99.0% and 76.2%, respectively; 21.3% of patients experienced a serious AE, and 15.8% of AEs led to treatment discontinuation. AEs of special interest of neutropenia, increased alanine aminotransferase, increased aspartate aminotransferase and QTcF prolongation occurred in 77.8%, 14.8%, 11.4% and 4.0% of patients, respectively. Patients aged >70 years experienced increased rates of all-grade and Grade >= 3 neutropenia and anemia. Efficacy results were consistent with the global study.Conclusions: Results from Spanish patients enrolled in CompLEEment-1 are consistent with global data showing efficacy and a manageable safety profile for ribociclib plus letrozole treatment in patients with HR+, HER2-ABC, including populations of interest (NCT02941926).Trial registration: ClinicalTrials.gov NCT0294192

Patients' preferences for subcutaneous trastuzumab versus conventional intravenous infusion for the adjuvant treatment of HER2-positive early breast cancer: final analysis of 488 patients in the international, randomized, two-cohort PrefHer study

PrefHer revealed compelling and consistent patient preference for subcutaneous (s.c.) trastuzumab, regardless of delivery by single-use injection device or hand-held syringe. s.c. trastuzumab was well-tolerated and safety data, including immunogenicity, were consistent with previous reports. No new safety signals were identified compared with the known intravenous trastuzumab profile in early breast cance

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Tratamiento del cáncer de mama avanzado con 5-fluorouacilo en infusión continua ambulatoria mediante bomba de infusión

Las pacientes con cáncer de mama muy evolucionado, a menudo están politratadas con diversas líneas de poliquimioterapia, y presentan una esperanza de vida de varios meses. A estos pacientes es muy difícil poder ofrecerle un tratamiento específico a que la toxicidad que ocasionaría su administración, sería inaceptable para conseguir el objetivo primordial de un tratamiento en estas etapas de la enfermedad: aumentar la calidad de vida. En la mayoría de los tumores del adulto, el porcentaje de células que se encuentran bajo división celular en un momento determinado es bajo. Por ello durante la administración de quimioterapia con los esquemas habituales, serán pocas las células que se encuentren en división celular. Debido a que el tratamiento quimioterápico es más efectivo durante la división celular, la infusión continua de un fármaco específico de fase podría aportar una mayor actividad terapéutica, además de la menor toxicidad que se produce cuando el tratamiento en infusión prolongada. Dado que el cáncer de mama metastásico es incurable, y que el principal objetivo es la paliación de síntomas con la mínima toxicidad posible, esta idea se hace aún más importante en pacientes con múltiples terapias previas y con la enfermedad muy evolucionadas. La farmacocinética del 5-FU hacen de esta droga un fármaco ideal para su administración en infusión continua, al ser específico de fase, y poder incrementar la dosis sin ocasionar más toxicidad en comparación con la infusión corta o en bolo. Además tiene una excelente tolerancia, y escasa mielosupresión. En base a estos datos hemos tratado a 34 pacientes con cáncer de mama muy evolucionados, petrados, con una esperanza de vida superior a tres meses, en progresión clínica sintomática, a los que era muy difícil poder ofrecerle un tratamiento específico para controlar la enfermedad sin ocasionarle una importante toxicidad. Treinta y uno de ellos recibieron 2 o más ciclos por lo que fueron evaluables para respuesta. Tres recibieron un solo ciclo por lo que fueron evaluables para toxicidad. Todas las pacientes habían recibido al menos 2 líneas de quimioterapia, y las 34 recibieron previamente tratamiento hormonal. El tratamiento aplicado ha sido la infusión continua ambulatoria de 5-FU (4000-5000 mg/m2) en 96 – 120 con bombas de infusión acopladas a reservorios subcutáneos conectados a catéteres venosos centrales. Dicho esquema se repetía cada 21 días. El índice de respuestas parciales ha sido del 25.8% con un intervalo de confianza entre el 12%-45% para un 95% de seguridad. Todas las respuestas parciales objetivadas habían respondido a la anterior línea de tratamiento. La enfermedad se estabilizó en el 48% de las pacientes con un intervalo de confianza entre 28%-65% para 95% de seguridad. La supervivencia global ha sido de 7,1 meses con un intervalo de confianza entre 5,8-8,4 para el 95% de seguridad. El tiempo medio hasta la progresión fue de 16 semanas con un rango de 8-48. El estado general ha influido en la supervivencia, de forma que esta ha sido mayor en los pacientes con nivel funcional (Escala de ECOG) de 1 que los que presentaron un valor de 2 ó 3. La toxicidad ha sido leve y escasa, y no se han presentado complicaciones con los catéteres venosos centrales, reservorios subcutáneos, ni con las bombas de infusión ambulatorias. La aplicación del 5-FU en infusión de 96 – 120 horas, es un tratamiento activo en el cáncer de mama, aunque tuviera previa exposición al 5-FU, y con una escasa toxicidad y una excelente tolerancia, consiguiendo el objetivo fundamental del tratamiento del cáncer de mama en estas etapas, que es aumentar la calidad de vida. Los pacientes con cáncer de mama metastásico previamente politratados con quimioterapia, se encuentran a veces con una esperanza de vida de varios meses, y presentan una progresión sintomática de la enfermedad. La aplicación en estos momentos de un régimen de quimioterapia es muy difícil de administrar ya que los que fundamentalmente ocasionaría sería toxicidad, en vez de paliar los síntomas. Las infusiones continuas de fármacos antineoplásicos específicos de fase, permiten incrementar la dosis sin ocasionar más toxicidad, en comparación con la infusión corta o en bolo. Hasta el momento actual, en la enfermedad metastásica de la mama se ha usado el 5-FU casi siempre en combinación a otros quimioterápicos, o bien solo en dosis relativamente bajas, crecientes hasta toxicidad. Dado que el cáncer de mama metastásico es incurable, y que los objetivos fundamentales del tratamiento son la paliación de síntomas con la mínima toxicidad posible, y aumentar la supervivencia con buena calidad de vida, ésta idea primordial lo es mucho más en pacientes con la enfermedad muy evolucionada, y con múltiples terapias previas. El objetivo de nuestro estudio ha sido investigar la eficacia de un esquema de tratamiento en infusión continua, aplicable en nuestro medio, con la utilización de catéteres venosos centrales acoplados a reservorios subcutáneos. La infusión se realizaba mediante una bomba de infusión facilitando la estancia del enfermo en su domicilio. Los objetivos concretos han sido: 1.- Comprobar que en pacientes con cáncer de mama metastásico, politratadas, se puede aplicar un tratamiento específico que consigue el objetivo primordial del tratamiento del cáncer de mama en estas fases: el control y la paliación de síntomas. 2.- Comprobar las escasas complicaciones de la quimioterapia ambulatoria mediante bombas de infusión conectada a catéteres venosos centrales mediante reservorio subcutáneo que evitan la hospitalización cuando se administra una infusión continua. 3.- Valorar una mayor actividad del 5-FU en infusión de 96 – 120 horas, en pacientes con carcinoma de mama pretratadas. 4.- Valorar la toxicidad del tratamiento que pretende mejorar la calidad de vida en pacientes en tratamiento de soporte. 5.- Demostrar que la infusión continua del 5-FU en estas fases de la enfermedad, es un óptimo tratamiento paliativo, de fácil manejo, poco tóxico, que evitar la hospitalización para su administración. 6.- Conseguir que esta forma de administración nos sirva para poder aplicarlo a fases más tempranas de la enfermedad en combinación con otros quimioterápicos, y a otras neoplasias como las de cabeza y cuello, donde el f-FU es una de las drogas más activas

Long non-coding RNAs as monitoring tools and therapeutic targets in breast cancer

[Background] Current therapeutic strategies that are used to combat breast cancer vary widely and largely depend on its clinicopathological features, including tumor subtype, size, stage, lymph node involvement, the presence of hormone receptors and/or HER2, as well as the degree of proliferative activity. Recent work has focused on improving our knowledge on the molecular mechanisms that underlie this complex disease. Most of the human genome is transcribed into RNAs that do not encode proteins. These noncoding RNAs may act as mediators in the regulation of gene expression. Based on their size and function, noncoding RNAs are classified into small noncoding RNAs (sncRNAs) and long noncoding RNAs (lncRNAs). LncRNAs have been found to play key roles in relevant biological processes, including breast cancer. As such, lncRNAs have been proposed as diagnostic and prognostic biomarkers, as predictive biomarkers and as putative therapeutic targets.[Conclusions] In this review, we discuss the potential application of lncRNAs for the monitoring and treatment of breast cancer. We conclude that lncRNAs play important roles in the pathophysiology of this disease and may serve as putative therapeutic targets. As such, tumor-specific lncRNAs may be instrumental for improving current breast cancer clinical practices.SMP was supported by the Consejería de Salud y Bienestar Social of Junta de Andalucía through the “‘Nicolás Monardes’” program [C-0040-2016].Peer reviewe