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Background: Luminal A tumours generally have a favourable prognosis but possess the highest 10‐year recurrence risk among breast cancers. Additionally, a quarter of the recurrence cases occur within 5 years post‐diagnosis. Identifying such patients is crucial as long‐term relapsers could benefit from extended hormone therapy, while early relapsers might require more aggressive treatment. Methods: We conducted a study to explore non‐structural chromosome maintenance condensin I complex subunit H’s (NCAPH) role in luminal A breast cancer pathogenesis, both in vitro and in vivo, aiming to identify an intratumoural gene expression signature, with a focus on elevated NCAPH levels, as a potential marker for unfavourable progression. Our analysis included transgenic mouse models overexpressing NCAPH and a genetically diverse mouse cohort generated by backcrossing. A least absolute shrinkage and selection operator (LASSO) multivariate regression analysis was performed on transcripts associated with elevated intratumoural NCAPH levels. Results: We found that NCAPH contributes to adverse luminal A breast cancer progression. The intratumoural gene expression signature associated with elevated NCAPH levels emerged as a potential risk identifier. Transgenic mice overexpressing NCAPH developed breast tumours with extended latency, and in Mouse Mammary Tumor Virus (MMTV)‐NCAPH ErbB2 double‐transgenic mice, luminal tumours showed increased aggressiveness. High intratumoural Ncaph levels correlated with worse breast cancer outcome and subpar chemotherapy response. A 10‐gene risk score, termed Gene Signature for Luminal A 10 (GSLA10), was derived from the LASSO analysis, correlating with adverse luminal A breast cancer progression. Conclusions: The GSLA10 signature outperformed the Oncotype DX signature in discerning tumours with unfavourable outcomes, previously categorised as luminal A by Prediction Analysis of Microarray 50 (PAM50) across three independent human cohorts. This new, Ministry of Science and Innovation/State Research Agency (MCIN/AEI), European Regional Development Fund (ERDF) “A way of making Europe”, Carlos III Health Institute, Regional Government of Castile and León, Depto. de Estadística e Investigación Operativa, Fac. de Farmacia, TRUE, pub

SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2+/ERBB2+ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2+ tumor behavior, Snai2-deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2+/ERBB2+ breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2+/ERBB2+ tumors is associated with: (i) lower levels of cyclin D1 (CCND1) and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of angiopoietin-2 (ANGPT2), and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2+ breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B HER2+/ERBB2+ breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis., Depto. de Estadística e Investigación Operativa, Fac. de Farmacia, TRUE, pub

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management., Ministerio de Ciencia, Innovación y Universidades (España), European Comission, Junta de Castilla y León, Instituto de Salud Carlos III, Ministerio de Economía, Comercio y Empresa (España), Federación Española de Enfermedades Raras, Departamento de Defensa (Estados Unidos), National Institutes of Health (Estados Unidos), Universidad de California (Estados Unidos), Instituto Nacional del Cáncer (Estados Unidos), Fundación "la Caixa", Agencia Estatal de Investigación, Depto. de Estadística e Investigación Operativa, Fac. de Farmacia, TRUE, pub

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

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).

Here we present a series of supplemental datasets that complement our study entitled "A Systems Genetics approach to identify genetic markers of cardiotoxicity due to anthracyclines in cancer patients." The datasets presented here were used to generate the main and supplementary figures and tables of the indicated study. The study consists of the identification of genetic markers of cardiotoxicity due to anthracyclines (CDA). CDA is a complex genesis disease or complex trait, and because of this, there is a component of missing heritability. Therefore, it is not possible to identify genetic markers associated with CDA risk. Here, we propose that molecular subphenotypes associated with the CDA may be a strategy for identifying some of this missing heritability and risk markers associated with it. A similar strategy could be applied to identify markers of other diseases of complex genesis. This study is done using a genetically heterogeneous cohort of mice that developed breast cancer and was treated with doxorubicin or a combined treatment of doxorubicin and docetaxel. The mouse cohort was generated by backcrossing, so each mouse is genetically unique. Post-chemotherapy heart damage was assessed by quantifying fibrosis's cardiac area and the thickness of myocardial fibers. The genetic regions associated with CDA were assessed by massive genotyping and genetic linkage analysis. Several molecular subphenotypes were quantified in the myocardium, and their association with the CDA was evaluated. Subsequently, we identified which of them were most statistically associated with CDA in multivariate models. Moreover, which complex trait loci (QTLs) associated with molecular subphenotypes best explained CDA. This strategy served to identify in the cohort of mice genes whose allelic forms could be candidates for the risk of CDA. Allelic variants of these genes were evaluated in four cohorts of cancer patients treated with anthracyclines and whose CDA was evaluated by echocardi

SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2+/ERBB2+ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2+ tumor behavior, Snai2-deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2+/ERBB2+ breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2+/ERBB2+ tumors is associated with: (i) lower levels of cyclin D1 (CCND1) and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of angiopoietin-2 (ANGPT2), and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2+ breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B HER2+/ERBB2+ breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis., Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Junta de Castilla y León, National Institutes of Health, Sandra Ibarra Foundation for Solidarity against Cancer, “We can be heroes” Foundation, Federación Española de Enfermedades Raras, Sección Deptal. de Bioquímica y Biología Molecular (Biológicas), Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Biológicas, Fac. de Ciencias Químicas, TRUE, pub

SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2+/ERBB2+ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2+ tumor behavior, Snai2-deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2+/ERBB2+ breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2+/ERBB2+ tumors is associated with: (i) lower levels of cyclin D1 (CCND1) and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of angiopoietin-2 (ANGPT2), and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2+ breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B HER2+/ERBB2+ breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis.

Introduction: In the context of radiotherapy, control of breakthrough cancer pain (BTPc) is particularly challenging. BTPc has been defined by the Spanish Society of Pain (SED), the Spanish Society of Medical Oncology (SEOM) and the Spanish Society for Palliative Care (SECPAL) as a sudden and transient exacerbation of pain of great intensity (VAS > 7) and short (less than 20-30 minutes), which appears on the basis of a stable persistent pain when it is reduced to a tolerable level (VAS < 5) by using major opioids. Objectives: The main objective of this study was to assess the intensity of BTPc induced by cancer treatments that included radiotherapy (RT), both exclusive and associated with chemotherapy (RT/CT). Secondly, the efficacy of treatment was evaluated with fentanyl sublingual scheduled for BTPc control. Material and methods: Retrospective, observational study in 110 patients recruited in 19 Spanish Radiotherapy Services. Patients must have BTPc induced by RT or RT/CT, with or without medication prescribed and with an intensity outside a VAS > 6 in the last 24-48 h. Controls were established at baseline and at 3, 7, 15 and 30 days. Results: There was a decrease in mean values ??on the VAS scale as the study progressed (VAS = 6 in the control 0 to VAS = 3 in the control 3) and the differences were significant (p < 0.0001). Treatment satisfaction was rated as good or excellent by 85.3% of patients and 92.7% of researches. Conclusions: The results of this study demonstrate the efficacy of BTPc treatment with sublingual fentanyl in the context of the radiotherapy cancer treatment, with a significant decrease in VAS from baseline values??. The high satisfaction among physicians and patients with this treatment reflects the efficacy and convenience of sublingual fentanyl in controlling BTPc., Introducción: en el contexto de la radioterapia, el control del dolor irruptivo oncológico (DIO) supone un reto especial. El DIO ha sido definido por la Sociedad Española del Dolor (SED), la Sociedad Española de Oncología Médica (SEOM) y la Sociedad Española de Cuidados Paliativos (SECPAL) como una exacerbación del dolor súbita y transitoria, de gran intensidad (EVA > 7) y de corta duración (inferior a 20-30 minutos), que aparece sobre la base de un dolor persistente estable cuando este se encuentra reducido a un nivel tolerable (EVA < 5) mediante el uso de opioides mayores. Objetivos: el objetivo principal de este estudio fue evaluar la intensidad del DIO inducido por tratamientos oncológicos que incluyeran radioterapia (RT), tanto exclusiva como asociada a quimioterapia (RT/QT). Secundariamente, se evaluó la eficacia del tratamiento con fentanilo sublingual pautado para el control del DIO. Material y métodos: estudio observacional retrospectivo realizado en 110 pacientes reclutados en 19 Servicios de Radioterapia españoles. Los pacientes debían presentar DIO inducido por RT o RT/QT, con o sin medicación pautada y cuya intensidad fuera de una EVA > 6 en las últimas 24-48 h. Se establecieron controles en el momento basal, y a los 3, 7, 15 y 30 días. Resultados: se apreció un descenso en la media de los valores en la escala EVA según avanzó el estudio (EVA = 6 en el control 0 a EVA = 3 en el control 3), y las diferencias fueron significativas (p < 0,0001). La satisfacción con el tratamiento fue calificada como buena o excelente por el 85,3% de los pacientes y por el 92,7% de los investigadores. Conclusiones: los resultados de este estudio demuestran la eficacia del tratamiento del DIO con fentanilo sublingual en el contexto del tratamiento oncológico radioterápico, con un descenso significativo en los valores EVA frente al valor basal. La elevada satisfacción de los médicos y pacientes con este tratamiento refleja la eficacia y la comodidad del fentanilo sublingual e

Introduction and objectives: Breakthrough cancer pain (BTcP) is an acute exacerbation of baseline pain. The clinicians involved in its management have different diagnostic and therapeutic criteria. In order to facilitate decision making in usual clinical practice, 8 reference experts from 4 scientific associations involved in the management of patients with cancer pain have developed this Consensus Document. Methods: After an initial search on the most relevant publications in BTcP literature, a set of preliminary recommendations were established. A working meeting was subsequently held with the experts, following the Metaplan® methodology -a structured brainstorming technique- that produced a first version of the Consensus Document which, after several review rounds, was validated by all the participants. Every statement and recommendation was sorted according to its degree of recommendation, following the categories in the SIGN (Scottish Intercollegiate Guidelines Network) system. Results: The management of BTcP requires a full anamnesis, both of BTcP itself and of baseline pain, a physical examination and the supplementary tests that are deemed necessary. The drugs of choice for the treatment of BTcP must be those with a potent and rapid analgesic effect a short duration, minimal side effects and easy administration. Transmucosal fentanyl is currently the active ingredient most fitting to the analgesic needs of BTcP, regardless of the major opioid used for control of the baseline pain. Conclusion: This Consensus can be a very useful tool to improve the quality of life in cancer patients, because it guides the clinician towards a better diagnose and treatment of BTcP., Introducción y objetivos: el dolor irruptivo oncológico (DIO) es una exacerbación aguda del dolor que presenta diferentes criterios diagnósticos y de tratamiento por parte de los distintos especialistas implicados en su manejo. Para facilitar la toma de decisiones en la práctica clínica habitual, ocho especialistas de referencia de cuatro sociedades científicas implicadas en el manejo del paciente oncológico han diseñado este documento. Métodos: tras una búsqueda bibliográfica en las publicaciones más relevantes sobre DIO se establecieron las recomendaciones preliminares. El grupo de expertos realizó una reunión de trabajo siguiendo la metodología Metaplan® en la que se debatieron las recomendaciones que incorporar al documento. Cada una de las afirmaciones y recomendaciones fueron clasificadas según su grado de recomendación, atendiendo a las categorías del sistema SIGN (Scottish Intercollegiate Guidelines Network). Resultados: el manejo del DIO requiere una anamnesis completa tanto del DIO como del dolor basal y una exploración física del paciente asociada a pruebas complementarias cuando sean precisas. Los fármacos de elección para el tratamiento del DIO deben ser aquellos que muestren una analgesia potente, con rápido inicio, de efectos secundarios mínimos y de fácil administración. El fentanilo administrado por vía transmucosa es actualmente el principio activo más adecuado a las necesidades analgésicas del dolor irruptivo, con independencia del opioide mayor utilizado para el control del dolor basal. Conclusión: este consenso puede ser una herramienta útil para la mejora de la calidad de vida del paciente con cáncer, ya que permite un mejor diagnóstico y tratamiento del DIO.

Introduction objectives: Breakthrough cancer pain (BTcP) is an acute exacerbation of baseline pain. The clinicians involved in its management have different diagnostic and therapeutic criteria. In order to facilitate decision making in usual clinical practice, 8 reference experts from 4 scientific associations involved in the management of patients with cancer pain have developed this Consensus Document. Methods: After an initial search on the most relevant publications in BTcP literature, a set of preliminary recommendations were established. A working meeting was subsequently held with the experts, following the Metaplan® methodology -a structured brainstorming technique- that produced a first version of the Consensus Document which, after several review rounds, was validated by all the participants. Every statement and recommendation was sorted according to its degree of recommendation, following the categories in the SIGN (Scottish Intercollegiate Guidelines Network) system. Outcomes: The management of BTcP requires a full anamnesis, both of BTcP itself and of baseline pain, a physical examination and the supplementary tests that are deemed necessary. The drugs of choice for the treatment of BTcP must be those with a potent and rapid analgesic effect a short duration, minimal side effects and easy administration. Transmucosal fentanyl is currently the active ingredient most fitting to the analgesic needs of BTcP, regardless of the major opioid used for control of the baseline pain. Conclusion: This Consensus can be a very useful tool to improve the quality of life in cancer patients, because it guides the clinician towards a better diagnose and treatment of BTcP., Introducción y objetivos: El dolor irruptivo oncológico (DIO) es una exacerbación aguda del dolor que presenta diferentes criterios diagnósticos y de tratamiento por parte de los diferentes especialistas implicados en su manejo. Para facilitar la toma de decisiones en la práctica clínica habitual, ocho especialistas de referencia de 4 sociedades científicas implicadas en el manejo del paciente oncológico, han diseñado este documento de consenso. Métodos: Tras una búsqueda bibliográfica en las publicaciones más relevantes sobre DIO, se establecieron las recomendaciones preliminares. El grupo de expertos realizó una reunión de trabajo siguiendo la metodología Metaplan®, donde se debatieron las recomendaciones a incorporar al documento. Cada una de las afirmaciones y recomendaciones fueron clasificadas según su grado de recomendación, atendiendo a las categorías del sistema SIGN (Scottish Intercollegiate Guidelines Network). Resultados: El manejo del DIO requiere de una anamnesis completa, tanto del DIO como del dolor basal, y una exploración física del paciente asociada a pruebas complementarias cuando sean precisas. Los fármacos de elección para el tratamiento del DIO deben ser aquellos que muestren una analgesia potente, con rápido inicio de acción, efectos secundarios mínimos y de fácil administración. El fentanilo administrado por vía transmucosa es actualmente el principio activo más adecuado a las necesidades analgésicas del dolor irruptivo, con independencia del opioide mayor utilizado para el control del dolor basal. Conclusión: Este consenso puede ser una herramienta útil para la mejora de la calidad de vida del paciente con cáncer, ya que permite un mejor diagnóstico y tratamiento del DIO.