Recaída locorregional en mujeres con cáncer de mama portadoras de mutación BRCA tratadas mediante cirugía conservadora

El cáncer de mama (CM) representa la quinta causa de muerte por cáncer en todo el mundo y la segunda en los países desarrollados. El conocimiento de los factores de riesgo que predisponen a padecerlo permite poder desarrollar una prevención primaria y secundaria adecuada, con el fin de disminuir la incidencia de CM en el primer caso y realizar un diagnóstico precoz en el segundo. Entre un 5-10% de los casos de CM presentan una causa hereditaria asociándose a mutaciones principalmente en los genes BRCA1 y BRCA2 ocasionando el conocido Síndrome de CM y cáncer de Ovario (CO) Hereditario. Las personas portadoras de estas alteraciones presentan un alto riesgo de padecer CM , que oscila entre el 55 y el 85%, y CO , entre 16-59%, a lo largo de su vida, junto a otros tumores como el de páncreas y colon. Así mismo, numerosos estudios han objetivado que las mujeres que han padecido CM y son portadoras de una mutación genética patogénica en BRCA presentan un riesgo incrementado de tener un cáncer de mama contralateral, alcanzando este porcentaje el 30-40% a lo largo de la vida. Entre las estrategias de prevención que se ofrece a estas mujeres se encuentra la mastectomía contralateral profiláctica y la salpingooforectomía bilateral profiláctica, sin embargo, tras casi dos décadas de investigación, continua siendo controvertido cuál es el mejor tratamiento local en estas mujeres que han sido intervenidas mediante cirugía conservadora (CC) y han sido posteriormente tratadas con radioterapia (RT). En múltiples estudios se ha intentado determinar la tasa de recaída locorregional (RLR) en estas pacientes y el tiempo a la recaída. Mientras que algunos de ellos abogan por un mayor riesgo de RLR en estas mujeres, otros asumen que es comparable a la de aquéllas con CM y cirugía local no portadoras de mutación sin historia familiar (CM esporádico). Actualmente no existe un acuerdo establecido sobre el tipo de cirugía a realizar sobre esa mama en estas mujeres. Ante dichos hallazgos, hemos planteado un estudio observacional, multicéntrico y retrospectivo de casos y controles. Hemos considerado para este estudio 986 pacientes diagnosticadas de CM antes del 01/01/2010 tratadas con CC y RT adyuvante. Entre ellas, 173 resultaron portadoras de una mutación patogénica en BRCA1/2 tras ser estudiadas en una de las cinco Unidades de Consejo Genético en Cáncer de la Comunidad Valenciana y 813 padecieron CM esporádico y fueron tratadas en la Fundación Instituto Valenciano de Oncología. El objetivo principal del estudio ha sido analizar la tasa de RLR y las características de la misma en el grupo de los casos y compararla con la del grupo control. Los objetivos secundarios han sido : evaluar las características clínico-patológicas que predispongan a una RLR y compararlas con el grupo control, así como evaluar en el seguimiento de ambas poblaciones la supervivencia libre de recaída, supervivencia libre de RLR y supervivencia global. Por una parte, se ha llevado a cabo un análisis multivariante para aislar el efecto de la mutación controlando el del resto de factores mientras que, por otra parte, se ha complementado con un estudio emparejado donde se han pareado a nivel de individuo las pacientes con mutación y sin mutación que poseían determinadas características Los resultados de nuestro estudio nos permiten concluir que las mujeres con CM portadoras de mutación BRCA tratadas con CC y RT presentan un riesgo incrementado de recaída ipsilateral con respecto a las mujeres con CM esporádico que han recibido similar tratamiento (13,3% versus 3.3%, p=0,03). La CC seguida de RT en mujeres con CM portadoras de mutación patogénica puede no ser la opción más segura para evitar el riesgo de RLR.Breast cancer is the fifth cause of cancer death worldwide and the second one in developed countries. The knowledge of the risk factors predisposing to suffer it , allows to develop a suitable primary and secondary prevention, in order to disminish the incidente of BC in the first case and establish an early diagnosis in the second one. Between 5-10% of BC are hereditary, mainly by BRCA1 and BRCA2 mutations causing the Hereditary Breast and Ovarian Cancer Syndrome. Women who carry these alterations have an increased BC risk than general population, with ranges between 55 and 85%. As well, they have a high risk of ovarian cancer estimated between 16 and 59% lifelong, and risk of developing other tumours as colon or pancreatic cancer. Also, several studies have evidenced that women who have suffered a BC and have a deleterious BRCA mutation present an increased risk of having contralateral BC, ranging between 30 and 40%. Among preventive strategies offered to these women we have contralateral prophylactic mastectomy and prophylactic bilateral salpingoophorectomy.However, after nearly two decades of research, it remains controversial which is the best local treatment we can offer to these women who have received breast conserving surgery and adjuvant radiotherapy (RT). Multiple studies have attempted to determine the rate of locorregional recurrence (RLR) in these patients, as well as the time to relapse.While some of them advocate to a greater risk of RLR in these women, others assume that is comparable to RLR in sporadic BC women. Currently, there is no agreement reached on the type of surgery to be performed in these patients. Given these findings, we raised a multicenter retrospective case-control observational study. We considered for this study 986 patients diagnosed with BC before January 2010 and who received breast-conserving surgery and RT.Among them, 173 patients were carriers of a pathogenic mutation in BRCA 1 / 2 after being studied in one of the five Genetic Counselling Cancer Unit in Valencia and 813 patients were women with sporadic BC treated at the Oncologic Valencian Institution. The main objective of the study was to analyze the rate of RLR and its characteristics in case´s group and to compare it to control study, as well as evaluate the follow-up of both populations in terms of relapse-free survival, locorregional relapse-free survival and overall survival. On one hand, a multivariated analysis has been conducted to isolate the effect of the mutation controlling the other factors. On the other hand, this study has been complemented by another one where individuals from the two study groups were matched one by one according clínical tumoral stage, clinical ganglionar stage and her2 status. The results of our study allow us to conclude that women with BC conserving-surgery and BRCA mutation have an increased risk of ipsilateral recurrence compared to women with sporadic BC who have received the same treatment (13,3% vs 3,3%, p=0,03). BC conserving-surgery and RT in women with BRCA 1 /2 mutation could not be the safer option to avoid locorregional relapse risk

Novel potential predictive markers of sunitinib outcomes in long-term responders versus primary refractory patients with metastatic clear-cell renal cell carcinoma

Background: several potential predictive markers of efficacy of targeted agents in patients with metastatic renal cell carcinoma (mRCC) have been identified. Interindividual heterogeneity warrants further investigation. Patients and methods: multicenter, observational, retrospective study in patients with clear-cell mRCC treated with sunitinib. Patients were classified in two groups: long-term responders (LR) (progression-free survival (PFS)≥22 months and at least stable disease), and primary refractory (PR) (progressive disease within 3-months of sunitinib onset). Objectives were to compare baseline clinical factors in both populations and to correlate tumor expression of selected signaling pathways components with sunitinib PFS. Results: 123 patients were analyzed (97 LR, 26 PR). In the LR cohort, overall response rate was 79% and median duration of best response was 30 months. Median PFS and overall survival were 43.2 (95% confidence intervals[CI]:37.2-49.3) and 63.5 months (95%CI:55.1-71.9), respectively. At baseline PR patients had a significantly lower proportion of nephrectomies, higher lactate dehydrogenase and platelets levels, lower hemoglobin, shorter time to and higher presence of metastases, and increased Fuhrman grade. Higher levels of HEYL, HEY and HES1 were observed in LR, although only HEYL discriminated populations significantly (AUC[ROC]=0.704; cut-off=34.85). Increased levels of hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p were also associated with prolonged survival. No statistical significant associations between hsa-miR-23b or hsa-miR-27b and the expression of c-Met were found. Conclusions: certain mRCC patients treated with sunitinib achieve extremely long-term responses. Favorable baseline hematology values and longer time to metastasis may predict longer PFS. HEYL, hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p could be potentially used as biomarkers of sunitinib response

Novel potential predictive markers of sunitinib outcomes in long-term responders versus primary refractory patients with metastatic clear-cell renal cell carcinoma

Background: Several potential predictive markers of efficacy of targeted agents in patients with metastatic renal cell carcinoma (mRCC) have been identified. Interindividual heterogeneity warrants further investigation. Patients and methods: Multicenter, observational, retrospective study in patients with clear-cell mRCC treated with sunitinib. Patients were classified in two groups: long-term responders (LR) (progression-free survival (PFS)=22 months and at least stable disease), and primary refractory (PR) (progressive disease within 3-months of sunitinib onset). Objectives were to compare baseline clinical factors in both populations and to correlate tumor expression of selected signaling pathways components with sunitinib PFS. Results: 123 patients were analyzed (97 LR, 26 PR). In the LR cohort, overall response rate was 79% and median duration of best response was 30 months. Median PFS and overall survival were 43.2 (95% confidence intervals[CI]:37.2-49.3) and 63.5 months (95%CI:55.1-71.9), respectively. At baseline PR patients had a significantly lower proportion of nephrectomies, higher lactate dehydrogenase and platelets levels, lower hemoglobin, shorter time to and higher presence of metastases, and increased Fuhrman grade. Higher levels of HEYL, HEY and HES1 were observed in LR, although only HEYL discriminated populations significantly (AUC[ROC]=0.704; cut-off=34.85). Increased levels of hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p were also associated with prolonged survival. No statistical significant associations between hsa-miR-23b or hsa-miR-27b and the expression of c-Met were found. Conclusions: Certain mRCC patients treated with sunitinib achieve extremely long-term responses. Favorable baseline hematology values and longer time to metastasis may predict longer PFS. HEYL, hsa-miR-27b, hsa-miR-23b and hsa-miR- 628-5p could be potentially used as biomarkers of sunitinib response

Mammographic density and breast cancer in women from high risk families

Introduction: Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype. Methods: The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants' density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. Results: We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value<0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers (P-value=0.48). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes. Conclusions: Our study, the largest to date on this issue, confirms that MD is an independent risk factor for all BC subtypes in either BRCA1 and BRCA2 mutation carriers, and should be considered a phenotype risk marker in this context

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Más allá de la genética: Factores ambientales y cáncer

El cáncer es uno de los problemas sanitarios más importantes de los países occidentales, dada su alta incidencia y elevada mortalidad. Constituye la segunda causa de muerte después de las enfermedades cardiovasculares, y la primera causa en la población menor de 70 años. En este artículo nos ocuparemos de los factores externos capaces de inducir el desarrollo de un cáncer: agentes químicos, físicos y biológico

Phase II Trial Evaluating Olaparib Maintenance in Patients with Metastatic Castration-Resistant Prostate Cancer Responsive or Stabilized on Docetaxel Treatment: SOGUG-IMANOL Study

In this study, based on the results of chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) maintenance in other tumors, we explore whether olaparib, a PARP inhibitor, could be useful in terms of prolonging radiographic progression of the disease in patients with metastatic castration-resistant prostate cancer with specific mutations whose illness had not progressed under treatment with docetaxel—A standard chemotherapy for these patients. In the 14 patients included in this study harboring mutations in homologous recombination genes, olaparib maintenance was an effective option, stabilizing the metastasis and extending the radiographic and clinical progression of the disease with tolerable and manageable adverse events. Overall, the results suggest this alternative could be useful for selected patients.This work was supported by AstraZeneca Farmacéutica Spain, S.A. (Madrid, Spain).Medicin

Monitoring the pozzolanic effect of fly ash in blended OPC mortars by electrical impedance spectroscopy

[EN] Fly ash (FA) is a pozzolanic material widely used to replace ordinary Portland cement (OPC) in mortars and concretes. The main purpose of this replacement is to improve the durability of these materials in a sustainable way from an environmental and economical perspective. Main technical advantages, such as the improvement in durability and the enhancement of mechanical properties with long-time hydration, are derived from the pozzolanic activity. Several studies aimed to evaluate the pozzolanic reaction extent have been reported by using thermogravimetric analysis (TGA), mechanical compressive strength and mercury intrusion porosimetry (MIP). Besides, other complementary non-destructive techniques that reflect the effect of FA on microstructure are of great scientific and technical interest. In this work, an alternative non-destructive method, the electrical impedance spectroscopy (EIS) followed by the equivalent circuit (EC) analysis has been applied to identify two electrical relaxations, which are strongly associated to microstructural properties. The high frequency relaxation was assigned to the electrical conductivity of the calcium silicate hydrate (C-S H) gel. Additionally, this C-S-H gel conductivity was separated into dc-conductivity and frequency-dependent conductivity, that provided information regarding the periods of early pozzolanic reaction (around 12 days) and high pozzolanic activity (around 28 days). This research provides conclusive evidence of the validity of the applied EIS-EC method on account of the significative relationships found between electrical parameters and physicochemical properties determined by TGA, compressive strength and MIP. Specifically, non-evaporable water, compressive strength and gel-pore-volume of diameter less than 10 nm exhibited significative exponential correlations with dc-electrical resistivity of the high frequency relaxation. These correlations validated the appropriate allocation of the high frequency relaxation to C-S-H gel.Fita Fernández, IC.; Cruz González, JM.; Bouzon, N.; Borrachero Rosado, MV.; Paya Bernabeu, JJ. (2022). Monitoring the pozzolanic effect of fly ash in blended OPC mortars by electrical impedance spectroscopy. Construction and Building Materials. 314:1-12. https://doi.org/10.1016/j.conbuildmat.2021.12563211231

Mammographic density and breast cancer in women from high risk families

INTRODUCTION: Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype. METHODS: The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants' density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. RESULTS: We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value<0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers (P-value=0.48). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes. CONCLUSIONS: Our study, the largest to date on this issue, confirms that MD is an independent risk factor for all BC subtypes in either BRCA1 and BRCA2 mutation carriers, and should be considered a phenotype risk marker in this context.This work was supported by three research grants, PS09/01006, PS09/01024 and PS09/01721, from Spain’s Health Research Fund (Fondo de Investigación Sanitaria); and a grant from the Spanish Federation of Breast Cancer Patients (Federación Española de Cáncer de Mama) (FECMA 485 EPY 1170–10). The authors also acknowledge the contribution of the Asociación Española contra el Cáncer (AECC), Carlos III Health Institute; RTICC; and the Catalan Health Institute and Autonomous Government of Catalonia (grant numbers: RD06/0020/1051, RD06/0020/1050, RD12/0036/0008, RD12/0036/0031, PI10/01422, PI13/00285, PIE13/00022 and SGR290). This project was approved by the following ethical boards: Comité de Ética de la Investigación y de Bienestar Animal CEIyBA, Instituto de Salud Carlos III; Comité de Ética de la Investigación Clínica Hospital de la Santa Creu y Sant Pau, Barcelona; Comité de Ética de la Investigación Clínica Hospital Universitari de Girona Doctor Josep Trueta, Girona; Comité de Ética de la Fundación INCLIVA, Hospital Clínico Universitario, Valencia; Comité de Ética de la Investigación Clínica del Hospital Universitario 12 de Octubre, Madrid, and Comité de Ética de la Investigación Clínica del Hospital Ramón y Cajal, Madrid.S