RESUMEN
PURPOSE: The monarchE trial showed that the addition of abemaciclib improves efficacy in patients with high-risk early breast cancer (EBC). We analyzed the long-term outcomes of a population similar to the monarchE trial to put into context the potential benefit of abemaciclib. METHODS: HR-positive/HER2-negative EBC patients eligible for the monarchE study were selected from 3 adjuvant clinical trials and a breast cancer registry. Patients with ≥ 4 positive axillary lymph nodes (N +) or 1-3 N + with tumor size ≥ 5 cm and/or histologic grade 3 and/or Ki67 ≥ 20%, who had undergone surgery with curative intent and had received anthracyclines ± taxanes and endocrine therapy in the neoadjuvant and /or adjuvant setting were included. We performed analysis of Invasive Disease-Free Survival (iDFS), Distant Disease-Free Survival (dDFS) and Overall Survival (OS) at 5 and 10 years, as well as yearly (up to 10) of Invasive Relapse Rate (IRR), Distant Relapse Rate (DRR) and Death Rate (DR). RESULTS: A total of 1,617 patients were analyzed from the GEICAM-9906 (312), GEICAM-2003-10 (210), and GEICAM-2006-10 (160) trials plus 935 from El Álamo IV. With a median follow-up of 10.1 years, the 5 and 10 years iDFS rates were 75.2% and 57.0%, respectively. The dDFS and OS rates at 5 years were 77.4% and 88.8% and the respective figures at 10 years were 59.7% and 70.9%. CONCLUSIONS: This data points out the need for new therapies for those patients. A longer follow-up of the monarchE study to see the real final benefit with abemaciclib is warranted. TRIAL REGISTRATION: ClinTrials.gov: GEICAM/9906: NCT00129922; GEICAM/ 2003-10: NCT00129935 and GEICAM/ 2006-10: NCT00543127.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Quimioterapia Adyuvante , Recurrencia Local de Neoplasia/tratamiento farmacológico , Aminopiridinas/uso terapéutico , Supervivencia sin Enfermedad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptor ErbB-2/genéticaRESUMEN
D-amino acid oxidase (DAAO) is an enzyme that catalyzes the oxidation of D-amino acids generating H2O2. The enzymatic chimera formed by DAAO bound to the choline-binding domain of N-acetylmuramoyl-L-alanine amidase (CLytA) induces cytotoxicity in several pancreatic and colorectal carcinoma and glioblastoma cell models. In the current work, we determined whether the effect of CLytA-DAAO immobilized in magnetic nanoparticles, gold nanoparticles, and alginate capsules offered some advantages as compared to the free CLytA-DAAO. Results indicate that the immobilization of CLytA-DAAO in magnetic nanoparticles increases the stability of the enzyme, extending its time of action. Besides, we compared the effect induced by CLytA-DAAO with the direct addition of hydrogen peroxide, demonstrating that the progressive generation of reactive oxygen species by CLytA-DAAO is more effective in inducing cytotoxicity than the direct addition of H2O2. Furthermore, a pilot study has been initiated in biopsies obtained from pancreatic and colorectal carcinoma and glioblastoma patients to evaluate the expression of the main genes involved in resistance to CLytA-DAAO cytotoxicity. Based on our findings, we propose that CLytA-DAAO immobilized in magnetic nanoparticles could be effective in a high percentage of patients and, therefore, be used as an anti-cancer therapy for pancreatic and colorectal carcinoma and glioblastoma.
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D-Aminoácido Oxidasa/metabolismo , Nanopartículas de Magnetita/química , Neoplasias/terapia , Especies Reactivas de Oxígeno/metabolismo , Proteínas Recombinantes de Fusión/química , Línea Celular Tumoral , Neoplasias Colorrectales/terapia , D-Aminoácido Oxidasa/uso terapéutico , Glioblastoma/terapia , Humanos , Peróxido de Hidrógeno/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias Pancreáticas/terapia , Especies Reactivas de Oxígeno/toxicidad , Neoplasias PancreáticasRESUMEN
BACKGROUND: We recently showed PAM50 gene expression data can be represented by five quantitative, orthogonal, multi-gene breast tumor traits. These novel tumor 'dimensions' were superior to categorical intrinsic subtypes for clustering in high-risk breast cancer pedigrees, indicating potential to represent underlying genetic susceptibilities and biological pathways. Here we explore the prognostic and predictive utility of these dimensions in a sub-study of GEICAM/9906, a Phase III randomized prospective clinical trial of paclitaxel in breast cancer. METHODS: Tumor dimensions, PC1-PC5, were calculated using pre-defined coefficients. Univariable and multivariable Cox proportional hazards (PH) models for disease-free survival (DFS) were used to identify associations between quantitative dimensions and prognosis or response to the addition of paclitaxel. Results were illustrated using Kaplan-Meier curves. RESULTS: Dimensions PC1 and PC5 were associated with DFS (Cox PH p = 6.7 [Formula: see text] 10-7 and p = 0.036), remaining significant after correction for standard clinical-pathological prognostic characteristics. Both dimensions were selected in the optimal multivariable model, together with nodal status and tumor size (Cox PH p = 1.4 [Formula: see text] 10-12). Interactions with treatment were identified for PC3 and PC4. Response to paclitaxel was restricted to tumors with low PC3 and PC4 (log-rank p = 0.0021). Women with tumors high for PC3 or PC4 showed no survival advantage. CONCLUSIONS: Our proof-of-concept application of quantitative dimensions illustrated novel findings and clinical utility beyond standard clinical-pathological characteristics and categorical intrinsic subtypes for prognosis and predicting chemotherapy response. Consideration of expression data as quantitative tumor dimensions offers new potential to identify clinically important patient subsets in clinical trials and advance precision medicine.
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Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Perfilación de la Expresión Génica , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Clasificación del Tumor , Metástasis de la Neoplasia , Pronóstico , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto , Carga TumoralRESUMEN
PURPOSE: EndoPredict (EPclin) is a prognostic test validated to inform decisions on adjuvant chemotherapy to endocrine therapy alone for patients with oestrogen receptor-positive, HER2-negative breast cancer. Here, we determine the performance of EPclin for estimating 10-year distant recurrence-free interval (DRFI) rates for those who received adjuvant endocrine therapy (ET) alone compared to those with chemotherapy plus endocrine therapy (ET + C). METHODS: A total of 3746 women were included in this joint analysis. 2630 patients received 5 years of ET alone (ABCSG-6/8, TransATAC) and 1116 patients received ET + C (GEICAM 2003-02/9906). The primary objective was to evaluate the ability of EPclin to provide an estimate of the 10-year DR rate as a continuous function of EPclin separately for ET alone and ET + C. Cox proportional hazard models were used for these analyses. RESULTS: EPclin was highly prognostic for DR in women who received ET alone (HR 2.79 (2.49-3.13), P < 0.0001) as well as in those who received ET + C (HR 2.27 (1.99-2.59), P < 0.0001). Women who received ET + C had significantly smaller increases in 10-year DR rates with the increasing EPclin score than those receiving ET alone (EPclin = 5; 12% ET + C vs. 20% ET alone). We observed a significant positive interaction between EPclin and treatment groups (P-interaction = 0.022). CONCLUSIONS: In this comparative non-randomised analysis, the rate of increase in DR with EPclin score was significantly reduced in women who received ET + C versus ET alone. Our indirect comparisons suggest that a high EPclin score can predict chemotherapy benefit in women with ER-positive, HER2-negative disease.
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Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Anciano , Neoplasias de la Mama/metabolismo , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Terapia Combinada , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Estudios Retrospectivos , Medición de Riesgo , Resultado del TratamientoRESUMEN
PURPOSE: GEICAM/2006-10 compared anastrozole (A) versus fulvestrant plus anastrozole (A + F) to test the hypothesis of whether a complete oestrogen blockade is superior to aromatase inhibitors alone in breast cancer patients receiving hormone adjuvant therapy. METHODS: Multicenter, open label, phase III study. HR+/HER2- EBC postmenopausal patients were randomized 1:1 to adjuvant A (5 years [year]) or A + F (A plus F 250 mg/4 weeks for 3 year followed by 2 year of A). Stratification factors: prior chemotherapy (yes/no); number of positive lymph nodes (0/1-3/≥ 4); HR status (both positive/one positive) and site. PRIMARY OBJECTIVE: disease-free survival (DFS). Planned sample size: 2852 patients. RESULTS: The study has an early stop due to the financer decision with 870 patients (437 randomized to A and 433 to A + F). Patient characteristics were well balanced. After a median follow-up of 6.24y and 111 DFS events (62 in A and 49 in A + F) the Hazard Ratio for DFS (combination vs. anastrozole) was 0.84 (95% CI 0.58-1.22; p = 0.352). The proportion of patients disease-free in arms A and A + F at 5 year and 7 year were 90.8% versus 91% and 83.6% versus 86.7%, respectively. Most relevant G2-4 toxicities (≥ 5% in either arm) with A versus A + F were joint pain (14.7%; 13.7%), fatigue (2.5%; 7.2%), bone pain (3%; 6.5%), hot flushes (3.5%; 5%) and muscle pain (2.8%; 5.1%). CONCLUSIONS: The GEICAM/2006-10 study did not show a statistically significant increase in DFS by adding adjuvant F to A, though no firm conclusions can be drawn because of the limited sample size due to the early stop of the trial. ClinicalTrials.gov: NCT00543127.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Anastrozol/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Fulvestrant/administración & dosificación , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Posmenopausia , Resultado del TratamientoRESUMEN
Gliomas are the most common brain tumors and include a variety of histologic types and grades of malignancy. They arise from glial cells and represent approximately 70% of the primary brain tumors. According to the criteria of the World Health Organization (WHO), the majority of gliomas can be classified into four grades of malignancy (I-IV). Virus infection, especially by DNA viruses and retroviruses, which may cause insertion of viral DNA sequences into the host genome, often triggers the host defense mechanisms. Particularly, the DNA methylation machinery can be activated to cause the methylation of foreign movable viral sequences and, therefore, silence viral gene expression. Several studies have shown the presence of Human Cytomegalovirus (HCMV) in glioblastoma, suggesting that the virus may participate in tumor pathogenesis. But this relationship is controversial because many other studies did not detect HCMV in these tumors. This study aims to detect the presence of HCMV in several samples of human glioma (94 formalin-fixed, paraffin-embedded samples and 28 snap-frozen samples) by different sensitive techniques. We have been unable to detect HCMV DNA and proteins in glioma samples. Therefore, arguments used so far to conclude that HCMV is an oncomodulator virus in gliomas must be, in our view, seriously reconsidered.
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Astrocitoma/virología , Neoplasias Encefálicas/virología , Citomegalovirus/aislamiento & purificación , Astrocitoma/patología , Neoplasias Encefálicas/patología , Citomegalovirus/genética , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/virología , ADN de Neoplasias/genética , ADN Viral/análisis , Femenino , Regulación Viral de la Expresión Génica , Humanos , Masculino , Clasificación del Tumor , Carga Viral , Proteínas Virales/análisis , Organización Mundial de la SaludRESUMEN
There are several prognostic multigene-based tests for managing breast cancer (BC), but limited data comparing them in the same cohort. We compared the prognostic performance of the EndoPredict (EP) test (standardized for pathology laboratory) with the research-based PAM50 non-standardized qRT-PCR assay in node-positive estrogen receptor-positive (ER+) and HER2-negative (HER2-) BC patients receiving adjuvant chemotherapy followed by endocrine therapy (ET) in the GEICAM/9906 trial. EP and PAM50 risk of recurrence (ROR) scores [based on subtype (ROR-S) and on subtype and proliferation (ROR-P)] were compared in 536 ER+/HER2- patients. Scores combined with clinical information were evaluated: ROR-T (ROR-S, tumor size), ROR-PT (ROR-P, tumor size), and EPclin (EP, tumor size, nodal status). Patients were assigned to risk-categories according to prespecified cutoffs. Distant metastasis-free survival (MFS) was analyzed by Kaplan-Meier. ROR-S, ROR-P, and EP scores identified a low-risk group with a relative better outcome (10-year MFS: ROR-S 87 %; ROR-P 89 %; EP 93 %). There was no significant difference between tests. Predictors including clinical information showed superior prognostic performance compared to molecular scores alone (10-year MFS, low-risk group: ROR-T 88 %; ROR-PT 92 %; EPclin 100 %). The EPclin-based risk stratification achieved a significantly improved prediction of MFS compared to ROR-T, but not ROR-PT. All signatures added prognostic information to common clinical parameters. EPclin provided independent prognostic information beyond ROR-T and ROR-PT. ROR and EP can reliably predict risk of distant metastasis in node-positive ER+/HER2- BC patients treated with chemotherapy and ET. Addition of clinical parameters into risk scores improves their prognostic ability.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante/métodos , Receptor ErbB-2/genética , Receptores de Estrógenos/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Pronóstico , Medición de Riesgo/métodos , Resultado del TratamientoRESUMEN
PURPOSE: To determine intrinsic breast cancer subtypes represented within categories defined by quantitative hormone receptor (HR) and HER2 expression. METHODS: We merged 1,557 cases from three randomized phase III trials into a single data set. These breast tumors were centrally reviewed in each trial for quantitative ER, PR, and HER2 expression by immunohistochemistry (IHC) stain and by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), with intrinsic subtyping by research-based PAM50 RT-qPCR assay. RESULTS: Among 283 HER2-negative tumors with <1% HR expression by IHC, 207 (73%) were basal-like; other subtypes, particularly HER2-enriched (48, 17%), were present. Among the 1,298 HER2-negative tumors, borderline HR (1%-9% staining) was uncommon (n = 39), and these tumors were heterogeneous: 17 (44%) luminal A/B, 12 (31%) HER2-enriched, and only 7 (18%) basal-like. Including them in the definition of triple-negative breast cancer significantly diminished enrichment for basal-like cancer (p < .05). Among 106 HER2-positive tumors with <1% HR expression by IHC, the HER2-enriched subtype was the most frequent (87, 82%), whereas among 127 HER2-positive tumors with strong HR (>10%) expression, only 69 (54%) were HER2-enriched and 55 (43%) were luminal (39 luminal B, 16 luminal A). Quantitative HR expression by RT-qPCR gave similar results. Regardless of methodology, basal-like cases seldom expressed ER/ESR1 or PR/PGR and were associated with the lowest expression level of HER2/ERBB2 relative to other subtypes. CONCLUSION: Significant discordance remains between clinical assay-defined subsets and intrinsic subtype. For identifying basal-like breast cancer, the optimal HR IHC cut point was <1%, matching the American Society of Clinical Oncology and College of American Pathologists guidelines. Tumors with borderline HR staining are molecularly diverse and may require additional assays to clarify underlying biology.
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Receptor ErbB-2/genética , Receptores de Estrógenos/genética , Receptores de Progesterona/genética , Neoplasias de la Mama Triple Negativas/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estadificación de Neoplasias , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptor ErbB-2/biosíntesis , Receptores de Estrógenos/biosíntesis , Receptores de Progesterona/biosíntesis , Neoplasias de la Mama Triple Negativas/clasificación , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
INTRODUCTION: EndoPredict (EP) is an RNA-based multigene test that predicts the likelihood of distant recurrence in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC) who are being treated with adjuvant endocrine therapy. Herein we report the prospective-retrospective clinical validation of EP in the node-positive, chemotherapy-treated, ER+/HER2- BC patients in the GEICAM 9906 trial. METHODS: The patients (N = 1,246) were treated either with six cycles of fluorouracil, epirubicin and cyclophosphamide (FEC) or with four cycles of FEC followed by eight weekly courses of paclitaxel (FEC-P), as well as with endocrine therapy if they had hormone receptor-positive disease. The patients were assigned to EP risk categories (low or high) according to prespecified cutoff levels. The primary endpoint in the clinical validation of EP was distant metastasis-free survival (MFS). Metastasis rates were estimated using the Kaplan-Meier method, and multivariate analysis was performed using Cox regression. RESULTS: The molecular EP score and the combined molecular and clinical EPclin score were successfully determined in 555 ER+/HER2- tumors from the 800 available samples in the GEICAM 9906 trial. On the basis of the EP, 25% of patients (n = 141) were classified as low risk. MFS was 93% in the low-risk group and 70% in the high-risk group (absolute risk reduction = 23%, hazard ratio (HR) = 4.8, 95% confidence interval (CI) = 2.5 to 9.5; P < 0.0001). Multivariate analysis showed that, in this ER+/HER2- cohort, EP results are an independent prognostic parameter after adjustment for age, grade, lymph node status, tumor size, treatment arm, ER and progesterone receptor (PR) status and proliferation index (Ki67). Using the predefined EPclin score, 13% of patients (n = 74) were assigned to the low-risk group, who had excellent outcomes and no distant recurrence events (absolute risk reduction vs high-risk group = 28%; P < 0.0001). Furthermore, EP was prognostic in premenopausal patients (HR = 6.7, 95% CI = 2.4 to 18.3; P = 0.0002) and postmenopausal patients (HR = 3.3, 95% CI = 1.3 to 8.5; P = 0.0109). There were no statistically significant differences in MFS between treatment arms (FEC vs FEC-P) in either the high- or low-risk groups. The interaction test results between the chemotherapy arm and the EP score were not significant. CONCLUSIONS: EP is an independent prognostic parameter in node-positive, ER+/HER2- BC patients treated with adjuvant chemotherapy followed by hormone therapy. EP did not predict a greater efficacy of FEC-P compared to FEC alone.
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Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud/métodos , Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ensayos Clínicos Fase III como Asunto , Ciclofosfamida/administración & dosificación , Epirrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Metástasis Linfática , Estudios Multicéntricos como Asunto , Paclitaxel/administración & dosificación , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
BACKGROUND: We compared standard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy in women with operable node-positive breast cancer. Here we report the final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety. METHODS: BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18-70 years with node-positive, early breast cancer and a Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based on the intention-to-treat principle. BCIRG 001 is registered with ClinicalTrials.gov, number NCT00688740. FINDINGS: Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC. After a median follow-up of 124 months (IQR 90-126), disease-free survival was 62% (95% CI 58-65) for patients in the TAC group and 55% (51-59) for patients in the FAC group (hazard ratio [HR] 0·80, 95% CI 0·68-0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72-79) for patients in the TAC group and 69% (65-72) for patients in the FAC group (HR 0·74, 0·61-0·90; log-rank p=0·0020). TAC improved disease-free survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup analyses. Grade 3-4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC. INTERPRETATION: Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by anthracycline therapy, which warrants further investigation. FUNDING: Sanofi.
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Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Taxoides/administración & dosificación , Adolescente , Adulto , Anciano , Antraciclinas/administración & dosificación , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Docetaxel , Doxorrubicina/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Estado de Ejecución de Karnofsky , Metástasis Linfática/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Receptor ErbB-2/metabolismo , Taxoides/efectos adversos , Resultado del TratamientoRESUMEN
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that targets human epidermal growth factor receptor 2 (HER2) and has shown promising results in the treatment of advanced/metastatic breast cancer. The objective of this report is to provide guidance on the prophylaxis, monitoring, and management of adverse events (AEs) in patients with breast cancer treated with T-DXd, and to emphasize that proper management of AEs is needed to optimize the effectiveness of T-DXd treatment and reduce the number of discontinuations. The article covers various aspects of T-DXd treatment, including its clinical efficacy, safety profile, and dosing considerations, and provides practical recommendations for managing AEs, such as nausea/vomiting, interstitial lung disease, and hematologic toxicity. Although there are still many knowledge gaps about the cause and incidence of AEs in real-world patients, this document may serve as a valuable resource for clinicians who are involved in the care of breast cancer patients receiving T-DXd treatment.
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Neoplasias de la Mama , Camptotecina , Inmunoconjugados , Trastuzumab , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Trastuzumab/efectos adversos , Trastuzumab/uso terapéutico , Femenino , Inmunoconjugados/uso terapéutico , Inmunoconjugados/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Receptor ErbB-2/metabolismo , Testimonio de ExpertoRESUMEN
PURPOSE: Growing complexity and demand for cancer care entail increased challenges for Medical Oncology (MO). The Spanish Society of Medical Oncology (SEOM) has promoted studies to provide updated data to estimate the need for medical oncologists in 2040 and to analyse current professional standing of young medical oncologists. METHODS: Two national, online surveys were conducted. The first (2021) targeted 146 Heads of MO Departments, and the second (2022), 775 young medical oncologists who had completed their MO residency between 2014 and 2021. Participants were contacted individually, and data were processed anonymously. RESULTS: Participation rates reached 78.8% and 48.8%, respectively. The updated data suggest that 87-110 new medical oncologist full-time equivalents (FTEs) should be recruited each year to achieve an optimal ratio of 110-130 new cases per medical oncologist FTE by 2040. The professional standing analysis reveals that 9.1% of medical oncologists trained in Spain do not work in clinical care in the country, with tremendous employment instability (only 15.2% have a permanent contract). A high percentage of young medical oncologists have contemplated career paths other than clinical care (64.5%) or working in other countries (51.7%). CONCLUSIONS: Optimal ratios of medical oncologists must be achieved to tackle the evolution of MO workloads and challenges in comprehensive cancer care. However, the incorporation and permanence of medical oncologists in the national healthcare system in Spain could be compromised by their current sub-optimal professional standing.
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Oncólogos , Carga de Trabajo , Humanos , España , Censos , Oncología Médica , Recursos Humanos , Encuestas y CuestionariosRESUMEN
This study provides a comprehensive perspective on the deregulated pathways and impaired biological functions prevalent in human glioblastoma (GBM). In order to characterize differences in gene expression between individuals diagnosed with GBM and healthy brain tissue, we have designed and manufactured a specific, custom DNA microarray. The results obtained from differential gene expression analysis were validated by RT-qPCR. The datasets obtained from the analysis of common differential expressed genes in our cohort of patients were used to generate protein-protein interaction networks of functionally enriched genes and their biological functions. This network analysis, let us to identify 16 genes that exhibited either up-regulation (CDK4, MYC, FOXM1, FN1, E2F7, HDAC1, TNC, LAMC1, EIF4EBP1 and ITGB3) or down-regulation (PRKACB, MEF2C, CAMK2B, MAPK3, MAP2K1 and PENK) in all GBM patients. Further investigation of these genes and enriched pathways uncovered in this investigation promises to serve as a foundational step in advancing our comprehension of the molecular mechanisms underpinning GBM pathogenesis. Consequently, the present work emphasizes the critical role that the unveiled molecular pathways likely play in shaping innovative therapeutic approaches for GBM management. We finally proposed in this study a list of compounds that target hub of GBM-related genes, some of which are already in clinical use, underscoring the potential of those genes as targets for GBM treatment.
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Neoplasias Encefálicas , Glioblastoma , Análisis de Secuencia por Matrices de Oligonucleótidos , Humanos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/terapia , Glioblastoma/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión Génica , Masculino , Femenino , Mapas de Interacción de Proteínas/genética , Persona de Mediana EdadRESUMEN
BACKGROUND: Retrospective data suggest an association between bevacizumab efficacy and the incidence of arterial hypertension (AHT). Additionally, epigenetic mechanisms have been related to AHT. METHODS: This prospective observational study conducted by GEICAM Spanish Breast Cancer Research Group included metastatic breast (MBC) or colorectal (mCRC) cancer patients treated with bevacizumab-containing chemotherapy as first-line treatment. Blood pressure (BP) levels were measured (conventional and 24-h Holter monitoring) at baseline and up to cycle 3. Primary endpoint assessed BP levels increase as predictive factor for progression-free survival (PFS). Germline DNA methylation profile was explored in pre-treatment blood samples; principal component analysis was used to define an epigenetic predictive score for increased BP levels. RESULTS: From Oct-2012 to Jul-2016, 143 (78 MBC and 65 mCRC) patients were included. The incidence of AHT according to guidelines was neither predictive of PFS nor of best overall tumor response (BOR). No statistically significant association was observed with systolic BP nor diastolic BP increment for PFS or BOR. Grade 3 and 4 adverse events were observed in 37 and 5% of patients, respectively. We identified 27 sites which baseline methylation status was significantly associated to BP levels increase secondary to bevacizumab-containing chemotherapy. CONCLUSIONS: Neither the frequency of AHT nor the increase of BP levels were predictive of efficacy in MBC and mCRC patients treated with bevacizumab-containing chemotherapy. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT01733628.
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Bevacizumab , Neoplasias de la Mama , Neoplasias Colorrectales , Hipertensión , Humanos , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Femenino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Persona de Mediana Edad , Hipertensión/inducido químicamente , Estudios Prospectivos , Anciano , Masculino , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Supervivencia sin Progresión , Metilación de ADNRESUMEN
INTRODUCTION: Obesity is an unfavorable prognostic factor in breast cancer (BC) patients regardless of menopausal status and treatment received. However, the association between obesity and survival outcome by pathological subtype requires further clarification. METHODS: We performed a retrospective analysis including 5,683 operable BC patients enrolled in four randomized clinical trials (GEICAM/9906, GEICAM/9805, GEICAM/2003-02, and BCIRG 001) evaluating anthracyclines and taxanes as adjuvant treatments. Our primary aim was to assess the prognostic effect of body mass index (BMI) on disease recurrence, breast cancer mortality (BCM), and overall mortality (OM). A secondary aim was to detect differences of such prognostic effects by subtype. RESULTS: Multivariate survival analyses adjusting for age, tumor size, nodal status, menopausal status, surgery type, histological grade, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, chemotherapy regimen, and under-treatment showed that obese patients (BMI 30.0 to 34.9) had similar prognoses to that of patients with a BMI < 25 (reference group) in terms of recurrence (Hazard Ratio [HR] = 1.08, 95% Confidence Interval [CI] = 0.90 to 1.30), BCM (HR = 1.02, 0.81 to 1.29), and OM (HR = 0.97, 0.78 to 1.19). Patients with severe obesity (BMI ≥ 35) had a significantly increased risk of recurrence (HR = 1.26, 1.00 to 1.59, P = 0.048), BCM (HR = 1.32, 1.00 to 1.74, P = 0.050), and OM (HR = 1.35, 1.06 to 1.71, P = 0.016) compared to our reference group. The prognostic effect of severe obesity did not vary by subtype. CONCLUSIONS: Severely obese patients treated with anthracyclines and taxanes present a worse prognosis regarding recurrence, BCM, and OM than patients with BMI < 25. The magnitude of the harmful effect of BMI on survival-related outcomes was similar across subtypes.
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Antraciclinas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Obesidad/etiología , Taxoides/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Índice de Masa Corporal , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pronóstico , Receptor ErbB-2/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: A regimen of docetaxel, doxorubicin, and cyclophosphamide (TAC) is superior to a regimen of fluorouracil, doxorubicin, and cyclophosphamide (FAC) when used as adjuvant therapy in women with node-positive breast cancer. The value of taxanes in the treatment of node-negative disease has not been determined. METHODS: We randomly assigned 1060 women with axillary-node-negative breast cancer and at least one high-risk factor for recurrence (according to the 1998 St. Gallen criteria) to treatment with TAC or FAC every 3 weeks for six cycles after surgery. The primary end point was disease-free survival after at least 5 years of follow-up. Secondary end points included overall survival and toxicity. RESULTS: At a median follow-up of 77 months, the proportion of patients alive and disease-free was higher among the 539 women in the TAC group (87.8%) than among the 521 women in the FAC group (81.8%), representing a 32% reduction in the risk of recurrence with TAC (hazard ratio, 0.68; 95% confidence interval [CI], 0.49 to 0.93; P=0.01 by the log-rank test). This benefit was consistent, regardless of hormone-receptor status, menopausal status, or number of high-risk factors. The difference in survival rates (TAC, 95.2%; FAC, 93.5%) was not significant (hazard ratio, 0.76; 95% CI, 0.45 to 1.26); however, the number of events was small (TAC, 26; FAC, 34). Rates of grade 3 or 4 adverse events were 28.2% with TAC and 17.0% with FAC (P<0.001). Toxicity associated with TAC was diminished when primary prophylaxis with granulocyte colony-stimulating factor was provided. CONCLUSIONS: As compared with adjuvant FAC, adjuvant TAC improved the rate of disease-free survival among women with high-risk, node-negative breast cancer. (Funded by GEICAM and Sanofi-Aventis; ClinicalTrials.gov number, NCT00121992.).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Taxoides/administración & dosificación , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Docetaxel , Doxorrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Receptor ErbB-2/análisis , Receptores de Estrógenos/análisis , Factores de Riesgo , Taxoides/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
To identify a group of patients who might benefit from the addition of weekly paclitaxel to conventional anthracycline-containing chemotherapy as adjuvant therapy of node-positive operable breast cancer. The predictive value of PAM50 subtypes and the 11-gene proliferation score contained within the PAM50 assay were evaluated in 820 patients from the GEICAM/9906 randomized phase III trial comparing adjuvant FEC to FEC followed by weekly paclitaxel (FEC-P). Multivariable Cox regression analyses of the secondary endpoint of overall survival (OS) were performed to determine the significance of the interaction between treatment and the (1) PAM50 subtypes, (2) PAM50 proliferation score, and (3) clinical and pathological variables. Similar OS analyses were performed in 222 patients treated with weekly paclitaxel versus paclitaxel every 3 weeks in the CALGB/9342 and 9840 metastatic clinical trials. In GEICAM/9906, with a median follow up of 8.7 years, OS of the FEC-P arm was significantly superior compared to the FEC arm (unadjusted HR = 0.693, p = 0.013). A benefit from paclitaxel was only observed in the group of patients with a low PAM50 proliferation score (unadjusted HR = 0.23, p < 0.001; and interaction test, p = 0.006). No significant interactions between treatment and the PAM50 subtypes or the various clinical-pathological variables, including Ki-67 and histologic grade, were identified. Finally, similar OS results were obtained in the CALGB data set, although the interaction test did not reach statistical significance (p = 0.109). The PAM50 proliferation score identifies a subset of patients with a low proliferation status that may derive a larger benefit from weekly paclitaxel.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Proliferación Celular , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Ensayos Clínicos Fase III como Asunto , Ciclofosfamida/uso terapéutico , Epirrubicina/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Humanos , Estimación de Kaplan-Meier , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Análisis Multivariante , Paclitaxel/administración & dosificación , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
The activity of bevacizumab (BVZ) in advanced lines is not well known. In the treatment of metastatic breast cancer, the response rate and time to treatment failure (TTF) decrease with progression through successive therapeutic lines. The objective of this study was to compare BVZ activity in advanced treatment lines with that achieved in the previous line in routine clinical practice. Ninety-six patients who had received BVZ treatment in second or subsequent treatment lines were selected from five Spanish hospitals. Analysis was carried out of the differences in TTF and response rate in the lines with BVZ and those in earlier lines. Data analysis was carried out in two different ways: (a) by comparing treatment groups according to the treatment line received, using a Cox regression model with random effects, and the McNemar test to analysis the response rate, and (b) by comparing intrapatient data, using the Wilcoxon signed-rank test. In 62 patients, the TTF (adjusted for treatment line) was longer in the BVZ treatment line than that in the previous line. In the BVZ lines, there was a significant reduction in the probability of treatment failure [hazard ratio 0.52; 95% confidence interval (CI) 0.38-0.71]. The median TTF was 4.27 months (95% CI 3.7-5) in the previous line and 6.18 months (95% CI 5.5-7.93) in the BVZ line. The percentage of patients with an objective response was 33.3% in the previous lines and 52.1% (P=0.005) in the BVZ line. Contrary to expectation, more patients showed better results with the BVZ line than with the previous line. BVZ treatment in advanced lines improves the results obtained in previous treatment lines. This suggests that BVZ is active in advanced lines and that it produces favourable changes in the natural history of patients with metastatic breast carcinoma.
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Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Glándulas Mamarias Humanas/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab , Neoplasias de la Mama/patología , Carcinoma/patología , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/patología , Monitoreo de Drogas , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Humanos , Glándulas Mamarias Humanas/patología , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: We aimed to determine the effect of dual anti-HER2 blockade compared to monotherapy on clinically important outcomes. METHODS: We carried out a systematic review updated until July 2022. The outcomes included pathological complete response (pCR), clinical response, event-free survival, and overall survival. RESULTS: We identified eleven randomized clinical trials (2836 patients). When comparing paclitaxel plus dual treatment versus paclitaxel plus trastuzumab or lapatinib, dual treatment was associated with a higher probability of achieving a pathological complete response (OR 2.88, 95% CI 2.02-4.10). Addition of a taxane to an anthracycline plus cyclophosphamide and fluorouracil, plus lapatinib or trastuzumab, showed that the dual treatment was better than lapatinib alone (OR 2.47, 95% CI 1.41-4.34), or trastuzumab alone (OR 1.89, 95% CI 1.13-3.16). Dual treatment may result in an increase in survival outcomes and tumour clinical response, although such benefits are not consistent for all the combinations studied. CONCLUSIONS: The use of dual blockade with combinations of trastuzumab and pertuzumab can be recommended for the neoadjuvant treatment of women with HER2-positive breast cancer. PROSPERO Registration number: CRD42018110273.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Lapatinib/uso terapéutico , Terapia Neoadyuvante , Receptor ErbB-2/análisis , Quinazolinas , Resultado del Tratamiento , Trastuzumab/uso terapéutico , Paclitaxel , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: There is a lack of knowledge about the career paths and employment situation of young medical oncologists. The aim of our study was to evaluate the current professional standing of these professionals in Spain. METHODS: The Spanish Society of Medical Oncology + MIR section conducted a national online survey in May 2021 of young medical oncology consultants (< 6 years of expertise) and final year medical oncology residents. RESULTS: A total of 162 responses were eligible for analysis and included participants from 16 autonomous communities; 64% were women, 80% were consultants, and 20% were residents. More than half of the participants performed routine healthcare activity and only 7% research activity. Almost three quarters (73%) were subspecialized in a main area of interest and almost half of these chose this area because it was the only option available after residency. Half of the respondents (51%) considered working abroad and 81% believed the professional standing in Spain was worse than in other countries. After finishing their residency, only 22 were offered a job at their training hospital. Just 16% of participants had a permanent employment contract and 87% were concerned (score of ≥ 5 on a scale of 1-10) about their job stability. In addition, one quarter of the participants in our study showed an interest in increasing their research activity. CONCLUSIONS: The choice of subspecialty in medical oncology may depend on job opportunities after residency rather than personal interest. The abundance of temporary contracts may have influenced the job stability concerns observed. Future mentoring strategies should engage in building a long-term career path for young medical oncologists.