RESUMEN
BACKGROUND: Approximately 30% of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. We have analyzed the clinical utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. PATIENTS AND METHODS: We conducted the study in a multi-institutional prospective cohort of clinically unselected patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (n = 93). ctDNA NGS was carried out by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database and classified in four levels of actionability based on their clinical or preclinical evidence for drug response. RESULTS: Eighty-three out of 93 patients (89%) had detectable levels of ctDNA. Potentially actionable level 1-4 genomic alterations were detected in 53 cases (57%), of which 13 (14%) had level 1-2A alterations (Food and Drug Administration-approved and standard-care biomarkers according to lung cancer guidelines). Frequencies of each genomic alteration in ctDNA were consistent with those observed in unselected pulmonary adenocarcinomas. The majority of the patients (62%), particularly those with actionable alterations (87%), had more than one pathogenic variant in ctDNA. The median turnaround time to genomic results was 13 days. Twelve patients (13%) received genotype-matched therapies based on ctDNA results, deriving the expected clinical benefit. Patients with co-occurring pathogenic alterations had a significantly shorter median overall survival as compared with patients without co-occurring pathogenic alteration (multivariate hazard ratio = 5.35, P = 0.01). CONCLUSION: Digital NGS of ctDNA in lung cancers with insufficient tumor samples for tissue sequencing detects actionable variants that frequently co-occur with other potentially clinically relevant genomic alterations, allowing timely initiation of genotype-matched therapies.
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Adenocarcinoma del Pulmón/secundario , Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/sangre , ADN de Neoplasias/sangre , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas/genética , Adenocarcinoma del Pulmón/sangre , Adenocarcinoma del Pulmón/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , ADN de Neoplasias/genética , Femenino , Estudios de Seguimiento , Genoma Humano , Genómica , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Medicina de Precisión , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
Background: There has been little progress toward personalized therapy for patients with metastatic colorectal cancer (mCRC). TYMS-3' untranslated region (UTR) 6 bp ins/del and ERCC1-118C/T polymorphisms were previously reported to facilitate selecting patients for fluoropyrimidine-based treatment in combination with oxaliplatin as first-line therapy. We assessed the utility of these markers in selecting therapy for patients with mCRC. Patients and methods: This randomized, open-label phase II trial compared bevacizumab plus XELOX (control) versus treatment tailored according to TYMS-3'UTR 6 bp ins/del and ERCC1-118C/T polymorphisms. Patients randomized to the experimental treatment received bevacizumab plus FUOX, FUIRI, XELIRI, or XELOX depending on their combination of favorable polymorphisms for FUOX treatment (TYMS-3'UTR ins/del or del/del; ERCC1-118T/T). Progression-free survival (PFS) was the primary end point. Results: Overall, 195 patients were randomized (control n = 65; experimental n = 130). The primary objective was not met: median PFS was 9.4 months in the control group and 10.1 months in the experimental group (P = 0.745). Median overall survival was similar in both groups (16.5 versus 19.1 months, respectively; P = 0.797). Patients in the experimental group had a significantly higher overall response rate (ORR; 65% versus 47% in the control group; P = 0.042) and R0 resection rate (86% versus 44%, respectively; P = 0.018). Neuropathy, hand-foot syndrome, thrombocytopenia, and dysesthesia were significantly less common in the experimental group. Conclusions: This study did not show survival benefits after treatment personalization based on polymorphisms in mCRC. However, the improved ORR and R0 resection rate and fewer disabling toxicities suggest that tailoring therapy by TYMS-3'UTR and ERCC1-118 polymorphisms warrants further investigation in patients with mCRC. ClinicalTrials.gov: NCT01071655.
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Neoplasias Colorrectales/tratamiento farmacológico , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Pruebas de Farmacogenómica/métodos , Variantes Farmacogenómicas/genética , Timidilato Sintasa/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Selección de Paciente , Medicina de Precisión/métodos , Supervivencia sin Progresión , Resultado del TratamientoRESUMEN
Background: This two-stage, phase IIa study investigated the antitumor activity and safety of MOR208, an Fc-engineered, humanized, CD19 antibody, in patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is broadly expressed across the B-lymphocyte lineage, including in B-cell malignancies, but not by hematological stem cells. Patients and methods: Patients aged ≥18 years, with R-R NHL progressing after ≥1 prior rituximab-containing regimen were enrolled into subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent (i)NHL and mantle cell lymphoma (MCL). Treatment was MOR208, 12 mg/kg intravenously, weekly, for 8 weeks. Patients with at least stable disease could continue treatment for an additional 4 weeks. Those with a partial or complete response after 12 weeks could receive extended MOR208 treatment (12 mg/kg, either monthly or every second week) until progression. The primary end point was overall response rate. Results: Ninety-two patients were enrolled: DLBCL (n = 35), FL (n = 34), other iNHL (n = 11) and MCL (n = 12). Responses were observed in DLBCL, FL and other iNHL cohorts (26%, 29% and 27%, respectively). They lasted ≥12 months in 5/9 responding patients with DLBCL, 4/9 with FL and 2/3 with other iNHL. Responses in nine patients are ongoing (>26 months in five instances). Patients with rituximab refractory disease showed a similar response rate and progression-free survival time to patients with non-refractory disease. The most common adverse events (any grade) were infusion-related reactions (12%) and neutropenia (12%). One patient experienced a grade 4 infusion-related reaction and eight patients (9%) experienced grade 3/4 neutropenia. No treatment-related deaths were reported. Conclusions: MOR208 monotherapy demonstrated promising clinical activity in patients with R-R DLBCL and R-R FL, including in patients with rituximab refractory tumors. These efficacy data and the favorable safety profile support further investigation of MOR208 in phase II/III combination therapy trials in R-R DLBCL. ClinicalTrials.gov number: NCT01685008.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Antígenos CD19/inmunología , Antígenos CD19/metabolismo , Antineoplásicos Inmunológicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Reacción en el Punto de Inyección/epidemiología , Reacción en el Punto de Inyección/etiología , Linfoma de Células B/inmunología , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Supervivencia sin Progresión , Rituximab/farmacología , Rituximab/uso terapéuticoRESUMEN
BACKGROUND: In a Spanish Lung Cancer Group (SLCG) phase II trial, the combination of BRCA1 and receptor-associated protein 80 (RAP80) expression was significantly associated with outcome in Caucasian patients with nonsmall-cell lung cancer (NSCLC). The SLCG therefore undertook an industry-independent collaborative randomized phase III trial comparing nonselected cisplatin-based chemotherapy with therapy customized according to BRCA1/RAP80 expression. An analogous randomized phase II trial was carried out in China under the auspices of the SLCG to evaluate the effect of BRCA1/RAP80 expression in Asian patients. PATIENTS AND METHODS: Eligibility criteria included stage IIIB-IV NSCLC and sufficient tumor specimen for molecular analysis. Randomization to the control or experimental arm was 1 : 1 in the SLCG trial and 1 : 3 in the Chinese trial. In both trials, patients in the control arm received docetaxel/cisplatin; in the experimental arm, patients with low RAP80 expression received gemcitabine/cisplatin, those with intermediate/high RAP80 expression and low/intermediate BRCA1 expression received docetaxel/cisplatin, and those with intermediate/high RAP80 expression and high BRCA1 expression received docetaxel alone. The primary end point was progression-free survival (PFS). RESULTS: Two hundred and seventy-nine patients in the SLCG trial and 124 in the Chinese trial were assessable for PFS. PFS in the control and experimental arms in the SLCG trial was 5.49 and 4.38 months, respectively [log rank P = 0.07; hazard ratio (HR) 1.28; P = 0.03]. In the Chinese trial, PFS was 4.74 and 3.78 months, respectively (log rank P = 0.82; HR 0.95; P = 0.82). CONCLUSION: Accrual was prematurely closed on the SLCG trial due to the absence of clinical benefit in the experimental over the control arm. However, the BREC studies provide proof of concept that an international, nonindustry, biomarker-directed trial is feasible. Thanks to the groundwork laid by these studies, we expect that ongoing further research on alternative biomarkers to elucidate DNA repair mechanisms will help define novel therapeutic approaches. TRIAL REGISTRATION: NCT00617656/GECP-BREC and ChiCTR-TRC-12001860/BREC-CHINA.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Proteína BRCA1/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas Portadoras/biosíntesis , Proteínas Nucleares/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , China , Cisplatino/administración & dosificación , Proteínas de Unión al ADN , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Docetaxel , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Chaperonas de Histonas , Humanos , Masculino , Persona de Mediana Edad , Taxoides/administración & dosificación , Resultado del Tratamiento , Población Blanca , GemcitabinaRESUMEN
BACKGROUND: In 2019, we reported the first efficacy and safety analysis of EUCROSS, a phase II trial investigating crizotinib in ROS1 fusion-positive lung cancer. At that time, overall survival (OS) was immature and the effect of crizotinib on intracranial disease control remained unclear. Here, we present the final analysis of OS, systemic and intracranial activity, and the impact of co-occurring aberrations. MATERIALS AND METHODS: EUCROSS was a prospective, single-arm, phase II trial. The primary endpoint was best overall response rate (ORR) using RECIST 1.1. Secondary and exploratory endpoints were progression-free survival (PFS), OS, and efficacy in pre-defined subgroups. RESULTS: Median OS of the intention-to-treat population (N = 34) was 54.8 months [95% confidence interval (CI) 20.3 months-not reached (NR); median follow-up 81.4 months] and median all-cause PFS of the response-evaluable population (N = 30) was 19.4 months (95% CI 10.1-32.2 months). Time on treatment was significantly correlated with OS (R = 0.82; P < 0.0001). Patients with co-occurring TP53 aberrations (28%) had a significantly shorter OS [hazard ratio (HR) 11; 95% CI 2.0-56.0; P = 0.006] and all-cause PFS (HR 4.2; 95% CI 1.2-15; P = 0.025). Patients with central nervous system (CNS) involvement at baseline (N = 6; 20%) had a numerically shorter median OS and all-cause PFS. Median intracranial PFS was 32.2 months (95% CI 23.7 months-NR) and the rate of isolated CNS progression was 24%. CONCLUSIONS: Our final analysis proves the efficacy of crizotinib in ROS1-positive lung cancer, but also highlights the devastating impact of TP53 mutations on survival and treatment efficacy. Additionally, our data show that CNS disease control is durable and the risk of CNS progression while on crizotinib treatment is low.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Crizotinib/farmacología , Crizotinib/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas Tirosina Quinasas/genética , Estudios Prospectivos , Proteínas Proto-Oncogénicas/genética , Sistema Nervioso CentralRESUMEN
PURPOSE: The increase in the prevalence "long-term cancer survivor" (LCS) patients is expected to increase the cost of LCS care. The aim of this study was to obtain information that would allow to optimise the current model of health management in Spain to adapt it to one of efficient LCS patient care. METHODS: This qualitative study was carried out using Delphi methodology. An advisory committee defined the criteria for participation, select the panel of experts, prepare the questionnaire, interpret the results and draft the final report. RESULTS: 232 people took part in the study (48 oncologists). Absolute consensus was reached in three of the proposed sections: oncological epidemiology, training of health professionals and ICT functions. CONCLUSION: The role of primary care in the clinical management of LCS patients needs to be upgraded, coordination with the oncologist and hospital care is essential. The funding model needs to be adapted to determine the funding conditions for new drugs and technologies.
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Supervivientes de Cáncer , Modelos Teóricos , Neoplasias/terapia , Técnica Delphi , Humanos , Oncología Médica/normas , EspañaRESUMEN
BACKGROUND: The ETOP 10-16 BOOSTER trial failed to demonstrate a progression-free survival (PFS) benefit for adding bevacizumab to osimertinib in second line. An exploratory subgroup analysis, however, suggested a PFS benefit of the combination in patients with a smoking history and prompted us to do this study. METHODS: A systematic review and meta-analysis to evaluate the differential effect of smoking status on the benefit of adding an angiogenesis inhibitor to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor therapy was carried out. All relevant randomized controlled trials appearing in main oncology congresses or in PubMed as of 1 November 2021 were used according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Primarily PFS according to smoking status, and secondarily overall survival (OS) were of interest. Pooled and interaction hazard ratios (HRs) were estimated by fixed or random effects models, depending on the detected degree of heterogeneity. Bias was assessed using the revised Cochrane tool for randomized controlled trials (RoB 2). RESULTS: Information by smoking was available for 1291 patients for PFS (seven studies) and 678 patients for OS (four studies). The risk of bias was low for all studies. Combination treatment significantly prolonged PFS for smokers [n = 502, HR = 0.55, 95% confidence interval (CI): 0.44-0.69] but not for nonsmokers (n = 789, HR = 0.92, 95% CI: 0.66-1.27; treatment-by-smoking interaction P = 0.02). Similarly, a significant OS benefit was found for smokers (n = 271, HR = 0.66, 95% CI: 0.47-0.93) but not for nonsmokers (n = 407, HR = 1.07, 95% CI: 0.82-1.42; treatment-by-smoking interaction P = 0.03). CONCLUSION: In advanced EGFR-non-small-cell lung cancer patients, the addition of an angiogenesis inhibitor to EGFR-tyrosine kinase inhibitor therapy provides a statistically significant PFS and OS benefit in smokers, but not in non-smokers. The biological basis for this observation should be pursued and could determine whether this might be due to a specific co-mutational pattern produced by tobacco exposure.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Fumar/efectos adversos , Fumar/epidemiologíaRESUMEN
The identification of tumour biomarkers that detect the presence of disease using noninvasive diagnostic procedures is a key part of cancer research. We determined in plasma the vesicle-related microRNA (miRNA) expression profile of nonsmall cell lung cancer (NSCLC) and evaluate whether plasma miRNAs can be both discriminating (between patients and healthy controls) and prognostic markers. 365 human miRNAs were analysed by Taqman® low-density arrays (Applied Biosystems, Foster City, CA, USA) in the plasma from 28 NSCLC patients and 20 controls. Five selected miRNAs (let-7f, miR-20b, miR-30e-3p, miR-223 and miR-301) were validated independently by real-time PCR in plasma from 78 NSCLC and 48 controls and correlated with pathologic parameters and survival. Levels of let-7f, miR-20b and miR-30e-3p were decreased in plasma vesicles of NSCLC patients. Moreover, levels of let-7f and miR-30e-3p distinguished between two groups of patients for stage of disease and therefore possibility of surgery. Plasma levels of miR-30e-3p and let-7f were associated with short disease-free survival and overall survival, respectively. NSCLC patients and healthy controls differ in vesicle-related miRNAs in plasma. Levels of let-7f and miR-30e-3p in NSCLC patients are associated with poor outcome. Thus, plasma vesicle-related miRNAs obtained by noninvasive methods could serve as circulating tumour biomarkers of discriminating and prognostic value.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , MicroARNs/metabolismo , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Estudios de Casos y Controles , Supervivencia sin Enfermedad , Reacciones Falso Positivas , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Marcadores Genéticos , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , PronósticoRESUMEN
PURPOSE: Lung cancer is the leading cause of cancer death in Spain. The objective of our study was to evaluate the characteristics of patients diagnosed with stages I-III non-small-cell lung cancer, as well as the impact that epidemiological changes, diagnostic improvements and surgical therapeutic innovations have had on survival in the past 20 years. METHODS: Retrospective analysis of patients diagnosed with early and locally advanced non-small-cell lung cancer between years 2000 and 2017 in our institution. RESULTS: A total of 859 patients were included. An increase in the percentage of women diagnosed over time was observed. Statistically significant differences were observed in the mean age at diagnosis, with a progressive increase in the different periods. The percentage of current or former smokers was similar in all periods. Adenocarcinoma was the most frequent histologic type with a progressive increase in its frequency. The percentage of patients diagnosed in early stages has been increasing over the years. In stages I-II, there was a significant increase in the median survival (29.7 months: 2000-2004, 68.73 months: 2010-2014) that could be seen in stage III as well (14.7 months: 2000-2004, 30.63 months: 2015-2017). CONCLUSIONS: A variation of clinical characteristics of lung cancer in Spain has been observed in recent years, as well as an improvement in survival in early and locally advanced stages, due not only to the treatments, but also to a more accurate detection of these tumors. Little progress has been made in tobacco habit with high stable percentages over the years.
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Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Tasa de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: Ischemia-reperfusion injury in free flaps is associated with tissue damage and is one of the main factors causing flap failure in reconstructive microsurgery. The aim of this study is to assess whether any ischemia-reperfusion injury takes place during a microsurgical flap reconstruction as seen through the levels of malondialdehyde (MDA) and superoxide dismutase, biomarkers of oxidative stress, and to analyze the effect of lidocaine in this process. METHODS: Twenty-four patients operated for immediate breast reconstruction using the Deep Inferior Epigastric Perforator free flap technique were divided into two groups: one group was treated with a lidocaine intravenous perfusion and the other group with a saline perfusion. MDA and superoxide dismutase (SOD) levels were measured at several points before, during, and after surgery. RESULTS: There was an increase in MDA levels in both groups, but the lidocaine group experienced a decrease during reperfusion. On the other hand, we observed a rise in SOD levels in both groups, but a decrease during reperfusion in the placebo group. However, these differences between groups were not statistically significant. CONCLUSIONS: The decreased SOD activity and increased MDA content in our research prove a redox imbalance and high reactive oxygen species levels in flaps, indicating that tissues experience ischemia-reperfusion injury during microsurgical reconstruction. Lidocaine may have a protective effect in free flap surgery, but our results were not statistically significant, so further studies will be required.
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Anestésicos Locales/administración & dosificación , Arterias Epigástricas/trasplante , Lidocaína/administración & dosificación , Mamoplastia/métodos , Colgajo Perforante/irrigación sanguínea , Daño por Reperfusión/prevención & control , Adulto , Biomarcadores/sangre , Neoplasias de la Mama/cirugía , Método Doble Ciego , Femenino , Humanos , Infusiones Intravenosas , Malondialdehído/sangre , Microcirugia , Persona de Mediana Edad , Estrés Oxidativo , Estudios Prospectivos , Superóxido Dismutasa/sangreRESUMEN
BACKGROUND: Lung cancer is a public health problem worldwide. Small-cell lung cancer (SCLC) is the most aggressive histologic type, with a 5-year survival <10%. SCLC is closely associated with tobacco consumption and infrequent in never-smokers. We aim to describe SCLC characteristics in never-smokers recruited in a radon-prone area. PATIENTS AND METHODS: We designed a multicentric case series where SCLC cases were recruited consecutively following histologic confirmation. Detailed information was obtained for indoor radon exposure, occupation and environmental tobacco smoke. We also collected different clinical characteristics such as extended or limited disease at diagnosis. RESULTS: We recruited 32 never-smoking SCLC cases. Median age was 75 years and 87.5% were women; 47% had extended disease. Median radon concentration was 182 Bq/m3. There were no statistically significant differences in residential radon concentration neither regarding age at diagnosis nor regarding sex. The most frequent symptoms were constitutional syndrome (23.1%) and coughing (23.1%). As much as 63% of cases had an Eastern Cooperative Oncology Group Study (ECOG) status of 0-2. The 1- and 2-year survival rates were 34.4% and 21.9%, respectively. The 2-year survival rate with a localized tumor was 26.7%, compared with 18.8% for extended disease. CONCLUSIONS: These results show, for the first time, that indoor radon might not be associated with SCLC characteristics at diagnosis in never-smokers, and also confirms the low survival of this aggressive type of lung cancer also for never-smokers.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/etiología , Factores de Riesgo , Carcinoma Pulmonar de Células Pequeñas/epidemiología , Carcinoma Pulmonar de Células Pequeñas/etiología , FumadoresRESUMEN
BACKGROUND: KRAS is mutated in â¼30% of non-small-cell lung cancer (NSCLC) but it has also been identified as one of the mechanisms underlying resistance to tyrosine kinase inhibitors (TKIs) in EGFR-positive NSCLC patients. Novel KRAS inhibitors targeting KRAS p.G12C mutation have been developed recently with promising results. The proportion of EGFR-positive NSCLC tumours harbouring the KRAS p.G12C mutation upon disease progression is completely unexplored. MATERIALS AND METHODS: Plasma samples from 512 EGFR-positive advanced NSCLC patients progressing on a first first-line treatment with a TKI were collected. The presence of KRAS p.G12C mutation was assessed by digital PCR. RESULTS: Overall, KRAS p.G12C mutation was detected in 1.17% of the samples (n = 6). In two of these cases, we could confirm that the KRAS p.G12C mutation was not present in the pre-treatment plasma samples, supporting its role as an acquired resistance mutation. According to our data, KRASG12C patients showed similar clinicopathological characteristics to those of the rest of the study cohort and no statistically significant associations between any clinical features and the presence of the mutation were found. However, two out of six KRASG12C tumours harboured less common EGFR driver mutations (p.G719X/p.L861Q). All KRASG12C patients tested negative for the presence of p.T790M resistance mutation. CONCLUSIONS: The KRAS p.G12C mutation is detected in 1% of EGFR-positive NSCLC patients who progress on a first line with a TKI. All KRASG12C patients were negative for the presence of the p.T790M mutation and they did not show any distinctive clinical feature.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Stage III non-small cell lung cancer (NSCLC) is a very heterogeneous disease that encompasses patients with resected, potentially resectable and unresectable tumours. To improve the prognostic capacity of the TNM classification, it has been agreed to divide stage III into sub-stages IIIA, IIIB and IIIC that have very different 5-year survival rates (36, 26 and 13%, respectively). Currently, it is considered that both staging and optimal treatment of stage III NSCLC requires the joint work of a multidisciplinary team of expert physicians within the tumour committee. To improve the care of patients with stage III NSCLC, different scientific societies involved in the diagnosis and treatment of this disease have agreed to issue a series of recommendations that can contribute to homogenise the management of this disease, and ultimately to improve patient care.
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Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia/mortalidad , Neoplasias Pulmonares/terapia , Escisión del Ganglio Linfático/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Consenso , Manejo de la Enfermedad , Humanos , Neoplasias Pulmonares/patología , Estadificación de Neoplasias , Tasa de SupervivenciaRESUMEN
Small-cell lung cancer (SCLC) accounts for 15% of lung cancers. Only one-third of patients are diagnosed at limited stage. The median survival remains to be around 15-20 months without significative changes in the strategies of treatment for many years. In stage I and IIA, the standard treatment is the surgery followed by adjuvant therapy with platinum-etoposide. In stage IIB-IIIC, the recommended treatment is early concurrent chemotherapy with platinum-etoposide plus thoracic radiotherapy followed by prophylactic cranial irradiation in patients without progression. However, in the extensive stage, significant advances have been observed adding immunotherapy to platinum-etoposide chemotherapy to obtain a significant increase in overall survival, constituting the new recommended standard of care. In the second-line treatment, topotecan remains as the standard treatment. Reinduction with platinum-etoposide is the recommended regimen in patients with sensitive relapse (≥ 3 months) and new drugs such as lurbinectedin and immunotherapy are new treatment options. New biomarkers and new clinical trials designed according to the new classification of SCLC subtypes defined by distinct gene expression profiles are necessary.
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Ensayos Clínicos como Asunto/normas , Neoplasias Pulmonares/terapia , Guías de Práctica Clínica como Asunto/normas , Carcinoma Pulmonar de Células Pequeñas/terapia , Humanos , Oncología Médica , Sociedades MédicasRESUMEN
BACKGROUND: Malignant mesothelioma is a rare but aggressive tumor arising from the pleura, typically associated with exposure to asbestos. The purpose of this investigation was to describe mesothelioma patient characteristics, treatment patterns, and outcomes in Spain. MATERIAL AND METHODS: Patients diagnosed with malignant mesothelioma of the pleura were recorded in an anonymous online database (BEMME, Epidemiologic Spanish Malignant Mesothelioma Database) from June 2008 through May 2013. Patient and tumor characteristics at time of diagnosis, as well as subsequent treatments (surgery, radiation, and chemotherapy), were collected. Among patients treated with chemotherapy, we explored type of chemotherapy regimen and outcomes by treatments. RESULTS: A total of 560 malignant pleural mesothelioma (MPM) patients were recorded. The median age at diagnosis was 68 years, mainly with epithelioid histology (62 %), and any asbestos exposure was noted in 45 % of patients. Nearly two-thirds of patients (71 %) received chemotherapy, mainly platinum-pemetrexed combination, as part of their treatment. Surgery and radiotherapy were given in 36 % and 17 % of patients, respectively. The median overall survival (OS) in the whole cohort was 13.0 months (95 % confidence interval (CI), 11.1-14.8 months) with 1-year OS of 53.2 % (95 % CI, 48.7-57.7 %). In patients receiving first-line chemotherapy (Nâ¯=â¯315), the median OS was 13.4 months (95 % CI, 10.8-16.0 months), reaching 20.2 months (95 % CI, 17.2-23.2 months) for those 68 patients receiving maintenance chemotherapy. Results of multivariate analyses showed significant association of ECOG-performance status, histology and treatment response with improved OS in MPM patients treated with palliative chemotherapy. CONCLUSIONS: Despite multimodal therapeutic intervention, survival of patients with mesothelioma in Spain remains poor. Although it did not reach significance in the multivariate analysis, a meaningful additional survival benefit was observed among those patients receiving maintenance chemotherapy.
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Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/terapia , Mesotelioma/diagnóstico , Mesotelioma/epidemiología , Mesotelioma/terapia , Neoplasias Pleurales/epidemiología , Neoplasias Pleurales/terapia , España/epidemiologíaRESUMEN
Lung cancer is currently the most common malignancy and also the leading cause of mortality related to cancer in the world [1]. The crude incidence of lung cancer in the EU is 52.5/100,000/year, while the mortality 48.7/100,000/year. Among men the rates are 82.5 and 77.0/100,000/year, and among women 23.9 and 22.3/100,000/year, respectively. Non-small-cell lung cancer (NSCLC) accounts for 80% of all cases. In Spain, there were 16,879 deaths in men, with a mean age of 68 years, and 2634 deaths in women, with a mean age of 66 years. The incidence of lung cancer in Spain was 68.3/100,000 among men and 13.8/100,000 among women, according to the latest data published in the year 2006 by the Instituto Nacional de Estadística. About 90% of lung cancer mortality among men (and 80% among women) is attributable to smoking.
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Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Incidencia , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/patología , Masculino , Estadificación de NeoplasiasRESUMEN
INTRODUCTION: Many methods used to assess the effectiveness of immune checkpoint (programmed death-ligand 1 or cytotoxic T-lymphocyte-associated protein 4) inhibitors for non-small cell lung cancer (NSCLC) are insufficient, as the therapeutic benefit of these agents is often underestimated. Consequently, immune-related evaluation criteria have been developed to better reflect their efficacy. The aim of this consensus was to obtain the opinion of lung cancer experts on the adequacy of immune-response criteria for evaluating the efficacy of these treatments. METHODS: Through two rounds of a modified Delphi consensus, 18 Spanish lung cancer experts participated in a 15-item questionnaire regarding the use of immunotherapies for NSCLC and the assessment criteria used to evaluate their effectiveness. RESULTS: Consensus was achieved on 80% of the items in the questionnaire. The panelists agreed that although the Response Evaluation Criteria in Solid Tumors (RECIST) are standard for the evaluation of solid tumors, immune-related response criteria would be useful for measuring the efficacy of immunotherapy. In addition, they considered that an overall survival (OS) rate at 2-5 years is the most useful end point for assessing the benefit of immunotherapy, as clinical benefit may extend beyond the RECIST criteria-defined progression of disease. CONCLUSIONS: Although immune-related response criteria have been developed to better evaluate the efficacy of immunotherapy, their use has not been validated and is restricted to investigational applications. However, they may prove to be a useful tool for measuring the efficacy of immunotherapy agents in NSCLC, especially the OS rate at 2-5 years.
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Carcinoma de Pulmón de Células no Pequeñas/terapia , Consenso , Inmunoterapia/métodos , Neoplasias Pulmonares/terapia , Antígeno B7-H1/antagonistas & inhibidores , Antígeno CTLA-4/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Técnica Delphi , Progresión de la Enfermedad , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tasa de Supervivencia , Factores de TiempoRESUMEN
PURPOSE: Breast cancer patients receiving hormonal therapies face risks of relapse, increased rates of cardiovascular events, and toxicities of therapy such as aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS). C-reactive protein (CRP), a marker for inflammation, is associated with breast cancer outcomes. We evaluated whether the olive-derived polyphenol hydroxytyrosol combined with omega-3 fatty acids and curcumin would reduce CRP and musculoskeletal symptoms in breast cancer patients receiving adjuvant hormonal therapies. EXPERIMENTAL DESIGN: This prospective, multicenter, open-label, single arm, clinical trial enrolled post-menopausal breast cancer patients (n = 45) with elevated C-reactive protein (CRP) taking predominantly aromatase inhibitors to receive a combination of hydroxytyrosol, omega-3 fatty acids, and curcumin for 1 month. CRP, other inflammation-associated cytokines, and pain scores on the Brief Pain Inventory were measured before therapy, at the end of therapy and 1 month after completion of therapy. RESULTS: CRP levels declined during the therapy [from 8.2 ± 6.4 mg/L at baseline to 5.3 ± 3.2 mg/L (p = 0.014) at 30 days of treatment], and remained decreased during the additional 1 month off therapy. Subjects with the highest baseline CRP levels had the greatest decrease with the therapy. Pain scores also decreased during the therapy. There were no significant adverse events. CONCLUSIONS: The combination of hydroxytyrosol, omega-3 fatty acids, and curcumin reduced inflammation as indicated by a reduction in CRP and reduced pain in patients with aromatase-induced musculoskeletal symptoms. Longer studies comparing this combination to other anti-inflammatories in larger groups of patients with clinical outcome endpoints are warranted.
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Inhibidores de la Aromatasa/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Curcumina/administración & dosificación , Ácidos Grasos Omega-3/administración & dosificación , Inflamación/tratamiento farmacológico , Dolor Musculoesquelético/tratamiento farmacológico , Alcohol Feniletílico/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/patología , Proteína C-Reactiva/metabolismo , Quimioterapia Adyuvante/efectos adversos , Curcumina/efectos adversos , Combinación de Medicamentos , Ácidos Grasos Omega-3/efectos adversos , Femenino , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Persona de Mediana Edad , Dolor Musculoesquelético/inducido químicamente , Dolor Musculoesquelético/patología , Alcohol Feniletílico/administración & dosificación , Alcohol Feniletílico/efectos adversos , Proyectos Piloto , Posmenopausia , Estudios ProspectivosRESUMEN
PURPOSE: Our primary goal was to study the use of outpatient attendances by lung cancer patients in Hospital Universitario Puerta de Hierro Majadahonda (HUPHM), Spain, by leveraging our Electronic Patient Record (EPR) and structured clinical registry of lung cancer cases as well as assessing current Data Science methods and tools. METHODS/PATIENTS: We applied the Cross-Industry Standard Process for Data Mining (CRISP-DM) to integrate and analyze activity data extracted from the EPR (9.3 million records) and clinical data of lung cancer patients from a previous registry that was curated into a new, structured database based on REDCap. We have described and quantified factors with an influence in outpatient care use from univariate and multivariate points of view (through Poisson and negative binomial regression). RESULTS: Three cycles of CRISP-DM were performed resulting in a curated database of 522 lung cancer patients with 133 variables which generated 43,197 outpatient visits and tests, 1538 ER visits and 753 inpatient admissions. Stage and ECOG-PS at diagnosis and Charlson Comorbidity Index were major contributors to healthcare use. We also found that the patients' pattern of healthcare use (even before diagnosis), the existence of a history of cancer in first-grade relatives, smoking habits, or even age at diagnosis, could play a relevant role. CONCLUSIONS: Integrating activity data from EPR and clinical structured data from lung cancer patients and applying CRISP-DM has allowed us to describe healthcare use in connection with clinical variables that could be used to plan resources and improve quality of care.