Metformin and Breast Cancer: Where Are We Now?

Breast cancer is the most prevalent cancer and the leading cause of cancer-related death among women worldwide. Type 2 diabetes-associated metabolic traits such as hyperglycemia, hyperinsulinemia, inflammation, oxidative stress, and obesity are well-known risk factors for breast cancer. The insulin sensitizer metformin, one of the most prescribed oral antidiabetic drugs, has been suggested to function as an antitumoral agent, based on epidemiological and retrospective clinical data as well as preclinical studies showing an antiproliferative effect in cultured breast cancer cells and animal models. These benefits provided a strong rationale to study the effects of metformin in routine clinical care of breast cancer patients. However, the initial enthusiasm was tempered after disappointing results in randomized controlled trials, particularly in the metastatic setting. Here, we revisit the current state of the art of metformin mechanisms of action, critically review past and current metformin-based clinical trials, and briefly discuss future perspectives on how to incorporate metformin into the oncologist's armamentarium for the prevention and treatment of breast cancer

Metformin induces a fasting- and antifolate-mimicking modification of systemic host metabolism in breast cancer patients

Homocisteïna; Càncer de mama; Dieta cetogènicaHomocisteína; Cáncer de mama; Dieta cetogénicaHomocysteine; Breast cancer; Ketogenic dietCertain dietary interventions might improve the therapeutic index of cancer treatments. An alternative to the “drug plus diet” approach is the pharmacological reproduction of the metabolic traits of such diets. Here we explored the impact of adding metformin to an established therapeutic regimen on the systemic host metabolism of cancer patients. A panel of 11 serum metabolites including markers of mitochondrial function and intermediates/products of folate-dependent one-carbon metabolism were measured in paired baseline and post-treatment sera obtained from HER2-positive breast cancer patients randomized to receive either metformin combined with neoadjuvant chemotherapy and trastuzumab or an equivalent regimen without metformin. Metabolite profiles revealed a significant increase of the ketone body β-hydroxybutyrate and of the TCA intermediate α-ketoglutarate in the metformin-containing arm. A significant relationship was found between the follow-up levels of homocysteine and the ability of treatment arms to achieve a pathological complete response (pCR). In the metformin-containing arm, patients with significant elevations of homocysteine tended to have a higher probability of pCR. The addition of metformin to an established anti-cancer therapeutic regimen causes a fasting-mimicking modification of systemic host metabolism. Circulating homocysteine could be explored as a clinical pharmacodynamic biomarker linking the antifolate-like activity of metformin and biological tumor response.This work was supported by grants from the Ministerio de Sanidad, Servicios Sociales e Igualdad (EC10-125, Ayudas para el Fomento de la Investigación Clínica Independiente to Begoña Martin-Castillo). Work in the Menendez laboratory is supported by the Ministerio de Ciencia e Innovación (Grant SAF2016-80639-P, Plan Nacional de l+D+I, founded by the European Regional Development Fund [EU FEDER], Spain) and by an unrestricted research grant from the Fundació Oncolliga Girona (Lliga catalana d’ajuda al malalt de càncer, Girona)

Trends on epidemiological, virological, and clinical features among newly diagnosed HIV-1 persons in Northwest Spain over the last 10 years

[Abstract] To describe temporal trend and characteristics of newly HIV-diagnosed patients in a medical care area in Northwest Spain over the last 10 years. All newly diagnosed patients for HIV-infection from 2004 to 2013 at a reference medical care area in Northwest of Spain were identified. Epidemiological, virological, immunological, and clinical data, as well as HIV genotype and drug resistance information were recorded. A total of 565 newly HIV-diagnosed patients were identified. The number of new cases increased in the last 5 years (66 cases/year). Overall, 53.1% had a median CD4 counts < 350 cells/µl and 33.6% had an AIDS defining criteria. Non-B variants were found in 34.4% of patients being subtype F (25.8%) the most common non-B subtype. The rate of transmitted drug resistance (TDR) over the study period was 3.7%, but a decreased to 2.6% was observed in the last 5 years. The most prevalent TDR mutations were: T215 revertants (1.5%), K219QENR (1.2%), for NRTIs; K103N (1.9%), for NNRTIs; L90M (0.3%), for PIs. Overall, 73.2% of patients started antiretroviral treatment and 9.9% of patients died during follow-up. The number of newly HIV diagnosed patients increased since year 2009. There is a high prevalence of late diagnosis (53%) and 33% had an AIDS defining criteria. Interestingly, the most prevalent non-B subtype in our population was F (25.8%). These findings support the need to facilitate the access for HIV testing to reduce the rate of late HIV diagnosis, improve the clinical outcome and prevent HIV transmission.Instituto de Salud Carlos III; CP08/00214Instituto de Salud Carlos III; PI10/02166Instituto de Salud Carlos III; CM13/00328Instituto de Salud Carlos III; PI13/0226

Characterization of chronic HCV infection in Northwest Spain: impact of the treatment strategic plan of the Spanish National Health Service on HCV cure

[Abstract] The aim of the study was to characterize HCV infection in Northwest Spain and assess the impact of the Spanish Strategic Plan to cure HCV infection. Overall, 387 patients were included (60.9% HIV/HCV coinfected and 28.2% cirrhotic). Of these, 72.9% of patients that were recognized as priority for HCV treatment according to the Spanish Strategic Plan (≥F2, transplant or extrahepatic manifestations), initiated treatment during 2015. Globally, SVR12 was achieved in 96.5% of patients. The implementation of the Spanish Strategic Plan has been critical to advance in HCV cure, but 27.1% of priority patients still remain awaiting HCV treatment initiation.Instituto de Salud Carlos III; CPII14/00014Instituto de Salud Carlos III; PI10/02166Instituto de Salud Carlos III; PI13/02266Instituto de Salud Carlos III; CM15/00233Instituto de Salud Carlos III; FI14/0055

Printability Study of a Conductive Polyaniline/Acrylic Formulation for 3D Printing

[Abstract] There is need for developing novel conductive polymers for Digital Light Processing (DLP) 3D printing. In this work, photorheology, in combination with Jacobs working curves, efficaciously predict the printability of polyaniline (PANI)/acrylate formulations with different contents of PANI and photoinitiator. The adjustment of the layer thickness according to cure depth values (Cd) allows printing of most formulations, except those with the highest gel point times determined by photorheology. In the working conditions, the maximum amount of PANI embedded within the resin was ≃3 wt% with a conductivity of 10−5 S cm−1, three orders of magnitude higher than the pure resin. Higher PANI loadings hinder printing quality without improving electrical conductivity. The optimal photoinitiator concentration was found between 6 and 7 wt%. The mechanical properties of the acrylic matrix are maintained in the composites, confirming the viability of these simple, low-cost, conductive composites for applications in flexible electronic devices.Xunta de Galicia; ED481A-2019/001Xunta de Galicia; ED431C 2019/17Goretti Arias-Ferreiro thanks the financial funding received from the Xunta de Galicia and the European Union (Program to support the predoctoral stage at SUG 2019 (ED481A-2019/001)). The authors would like to thank the financial support from Xunta de Galicia-FEDER (Program of Consolidation and structuring competitive research units (ED431C 2019/17))

Any impact of blips and low-level viraemia episodes among HIV-infected patients with sustained virological suppression on ART?

[Abstract] Objectives. The objective of this study was to evaluate the prevalence of blips and risk of virological failure (VF) among HIV-infected patients with sustained virological suppression (HIV-RNA <50 copies/mL) on ART. Methods. Newly diagnosed (2004–13) HIV-infected patients with sustained virological suppression on ART (minimum follow-up of 3 months) were identified. Risk of VF was evaluated according to different plasma HIV-RNA quantification values based on the limits of quantification/detection of current commercial assays (20 copies/mL). Kaplan–Meier and Cox proportional hazards models were used to compare the cumulative incidence of VF. Results. A total of 565 newly diagnosed HIV-infected patients were identified: 453 started ART and 354 achieved virological suppression. Prevalence of blips (isolated HIV-RNA ranging from 50 to 200 copies/mL) and VF (HIV-RNA ≥50 copies/mL) was 22.7% and 8.8%, respectively (mean follow-up of 42 months). Multivariate analysis identified differences between HIV-RNA values as an independent predictor of VF (P = 0.008); risk of VF was higher for patients with blips [HR 2.500 (95% CI 0.524–11.926)] and for those with at least three consecutive detected, but not quantified, HIV-RNA determinations (HIV-RNA 200 copies/mL [33.7% at 24 and 60 months versus <5% for other HIV-RNA values; HR 6.943 (0.728–66.261), P = 0.092]. Conclusions. Blips are frequent (22.7%) among HIV-infected patients with sustained virological suppression on ART. HIV patients with blips and at least three consecutive detected, but not quantified, HIV-RNA determinations (<20 copies/mL) had a higher risk of VF. These findings highlight the relevance of maintaining HIV-RNA levels below the limits of quantification of current assays (<20 copies/mL).Instituto de Salud Carlos III; CPII14/00014Instituto de Salud Carlos III; PI10/02166Instituto de Salud Carlos III; PI13/0226

First Nationwide Molecular Screening Program in Spain for Patients With Advanced Breast Cancer: Results From the AGATA SOLTI-1301 Study

Anàlisi de seqüències d'ADN; Subtipus PAM50; Genètica molecularAnálisis de secuencias de ADN; Subtipo PAM50; Genética molecularDNA sequence analyses; PAM50 subtype; Molecular geneticBackground: The SOLTI-1301 AGATA study aimed to assess the feasibility of a multi-institutional molecular screening program to better characterize the genomic landscape of advanced breast cancer (ABC) and to facilitate patient access to matched-targeted therapies in Spain. Methods: DNA sequencing of 74 cancer-related genes was performed using FFPE tumor samples in three different laboratories with three different gene panels. A multidisciplinary advisory board prospectively recommended potential targeted treatments. The primary objective was to determine the success of matching somatic DNA alteration to an experimental drug/drug class. Results: Between September 2014 and July 2017, 305 patients with ABC from 10 institutions were enrolled. Tumor sequencing was successful in 260 (85.3%) patients. Median age was 54 (29-80); most tumors were hormone receptor-positive/HER2-negative (74%), followed by triple-negative (14.5%) and HER2-positive (11.5%). Ninety-seven (37%) tumor samples analyzed proceeded from metastatic sites. Somatic mutations were identified in 163 (62.7%) patients, mostly in PIK3CA (34%), TP53 (22%), AKT1 (5%), ESR1 (3%), and ERBB2 (3%) genes. Significant enrichment of AKT1 mutation was observed in metastatic versus primary samples (9% vs. 2%; p=0.01). Genome-driven cancer therapy was recommended in 45% (n=116) of successfully screened patients, 11% (n=13) of whom finally received it. Among these patients, 46.2% had a PFS of ≥6 months on matched therapy. Conclusions: AGATA is the first nationwide molecular screening program carried out in Spain and we proved that implementing molecular data in the management of ABC is feasible. Although these results are promising, only 11% of the patients with genome-driven cancer therapy received it.This study was supported by a grant from Novartis. This study was funded, in part, by the project PI 15/01508, integrated in the Plan Estatal I+D+I and co-funded by Instituto de Salud Carlos III - Subdirección General de Evaluación and European Regional Development Fund (ERDF) (to EC) and by a grant from Mutua Madrileña Foundation (to EC). The decisions and responsibilities of this study were all under the sponsor: SOLTI Breast Cancer Research Group

Efectividad y seguridad de daclatasvir/ sofosbuvir con o sin ribavirina en pacientes infectados por el genotipo 3 del virus de la hepatitis C: resultados en práctica clínica real

[Abstract] OBJECTIVE: Direct-acting antivirals have shown high efficacy in all hepatitis C virus (HCV) genotypes, but genotype 3 (G3) treatments continue to be a challenge, mainly in cirrhotic patients. The aim of this study is to analyse effectiveness and safety of daclatasvir associated with sofosbuvir with or without ribavirin in G3-HCV infected patients in real clinical practice. METHODS: An observational, prospective, cohort study over 2.5 years, in G3-HCV infected adult patients, in all fibrosis stages including patients with decompensated cirrhosis. Treatment was a combination of sofosbuvir 400 mg/day + daclatasvir 60 mg/day, with or without a weight-adjusted dosing of ribavirin for 12 or 24 weeks. The primary efficacy endpoint was sustained virologic response rates 12 weeks after therapy (SVR12). The primary safety endpoint was treatment withdrawal rates secondary to severe adverse events. RESULTS: A total of 111 patients were enrolled, 32.4% cirrhotics and 29.9% treatment-experienced. The global SVR12 rate was 94.6%, while the SVR12 rate in F3-4 fibrosis stage patients was 90.8% versus 100% in patients with F0-2 fibrosis (p=0.03). In cirrhotic patients, SVR12 was 100% versus 40% depending on whether ribavirin was added or not to daclatasvir/sofosbuvir (p=0.001). No other patient or treatment basal variables influenced the treatment effectiveness. No patient treatment withdrawal secondary to severe adverse events was observed. CONCLUSIONS: Daclatasvir/sofosbuvir ± ribavirin is highly effective in G3-HCV infected patients. Advanced degrees of fibrosis significantly decrease the effectiveness of this treatment, which motivates the need for the addition of ribavirin in cirrhotic patients. The regimen was safe and well tolerated.[Resumen] OBJETIVOS: Los antivirales de acción directa han demostrado una alta eficacia en todos los genotipos del virus de la hepatitis C (VHC), pero los tratamientos para el genotipo 3 (G3) siguen siendo un desafío, principalmente en pacientes cirróticos. El objetivo de este estudio es analizar la efectividad y la seguridad del daclatasvir asociado con sofosbuvir con o sin ribavirina en pacientes infectados por G3-VHC en la práctica clínica real. PACIENTES Y MÉTODOS: Estudio observacional, prospectivo, de cohorte de más de 2,5 años, en pacientes adultos infectados con G3-VHC, en todos los estadios de fibrosis, incluidos los pacientes con cirrosis descompensada. El tratamiento fue una combinación de sofosbuvir 400 mg / día + daclatasvir 60 mg / día, con o sin una dosis de ribavirina ajustada por peso durante 12 o 24 semanas. El criterio de valoración principal de eficacia fue la tasa de respuesta virológica sostenida 12 semanas después del tratamiento (RVS12). La variable principal de seguridad fue la tasa de suspensiones de tratamiento secundaria a eventos adversos graves. RESULTADOS: Se incluyeron 111 pacientes, 32.4% cirróticos y 29.9% con experiencia previa de tratamiento antiviral. La tasa global de RVS12 fue del 94,6%, mientras que la tasa de RVS12 en pacientes con estadio de fibrosis F3-4 fue del 90,8% frente al 100% en pacientes con fibrosis F0-2 (p = 0,03). En pacientes cirróticos, la RVS12 fue del 100% en comparación con el 40%, dependiendo de si se agregó o no ribavirina a daclatasvir / sofosbuvir (p = 0,001). Ninguna otra variable basal del paciente o del tratamiento influyó en la efectividad del tratamiento. No se observó ninguna suspensión del tratamiento secundario a eventos adversos graves. CONCLUSIONES: Daclatasvir / sofosbuvir ± ribavirina es altamente efectivo en pacientes infectados por G3-VHC. Los grados avanzados de fibrosis disminuyen significativamente la efectividad de este tratamiento, lo que motiva la necesidad de la adición de ribavirina en pacientes cirróticos. El régimen fue seguro y bien tolerado

Towards a Sustainable Campus: Working Together to Achieve the Green Campus Flag on the UDC Peripheral Campus of Ferrol

[Abstract] Purpose. This paper aims to present and describe the main actions carried out in six different faculties and common areas such as cultural and research centres and administrative buildings in the Ferrol campus at the University of A Coruña to achieve the second green flag on a Galician University. Design/methodology/approach. A case study describing the steps for implementing a green campus programme in a medium-size, young university campus integrated into a small city. An Environmental Campus Committee was created to assess the main factors that affect environmental footprint, discuss sustainability initiatives and develop a guide to action regarding different goals related to sustainable transport options, energy, water conservation and waste reduction. The actions included several fields such as education, circular economy and healthy life and involved the on and off-campus community. Findings. The programme achieved a decrease in water consumption and electrical energy. An important change in educational values and behaviours regarding sustainability was observed in and out of the campus community. The measurements adopted mainly in waste management, mobility and education led the Ferrol campus to achieve a green campus flag on November 2019. Originality/value. This experiment can serve as a guide to establish the Green Campus philosophy in other similar university campuses.The authors of this article want to thank the finantial and institutional support of Environmental Office of University of A Coruña to develop talks, activities and to implement different actions in Ferrol Campus. The authors of this article want to thank the finantial and institutional support of Vicerrectorado del Campus de Ferrol y Responsabilidad Social of University of A Coruña to achieve the Green Flag. Ana Ares-Pernas wants to thank the financial support of Vicerrectorado de Planificación Académica e Innovación Docente of University of A Coruña obtained in the I Edition of the Prizes for Teaching Innovation Projects in Service-Learning to develop Service-Learning activitie