Comparison of plasma ctDNA and tissue/cytology-based techniques for the detection of EGFR mutation status in advanced NSCLC: Spanish data subset from ASSESS

Purpose: The analysis of epidermal growth factor receptor (EGFR) mutations in many patients with advanced non-small-cell lung cancer (aNSCLC) has provided the opportunity for successful treatment with specific, targeted EGFR tyrosine kinase inhibitors. However, this therapeutic decision may be challenging when insufficient tumor tissue is available for EGFR mutation testing. Therefore, blood surrogate samples for EGFR mutation analysis have been suggested. Methods: Data were collected from the Spanish cohort of patients in the large, non-interventional, diagnostic ASSESS study (NCT01785888) evaluating the utility of circulating free tumor-derived DNA from plasma for EGFR mutation testing. The incidence of EGFR mutation in Spain and the level of concordance between matched tissue/cytology and plasma samples were evaluated. Results: In a cohort of 154 eligible patients, EGFR mutations were identified in 15.1 and 11.0% of tumor and plasma samples, respectively. The most commonly used EGFR mutation testing method for the tumor tissue samples was the QIAGEN Therascreen® EGFR RGQ PCR kit (52.1%). Fragment Length Analysis + PNA LNA Clamp was used for the plasma samples. The concordance rate for EGFR mutation status between the tissue/cytology and plasma samples was 88.8%; the sensitivity was 45.5%, and the specificity was 96.7%. Conclusions: The high concordance between the different DNA sources for EGFR mutation testing supports the use of plasma samples when tumor tissue is unavailable

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Comparison of plasma ctDNA and tissue/cytology-based techniques for the detection of EGFR mutation status in advanced NSCLC: Spanish data subset from ASSESS.

PURPOSE: The analysis of epidermal growth factor receptor (EGFR) mutations in many patients with advanced non-small-cell lung cancer (aNSCLC) has provided the opportunity for successful treatment with specific, targeted EGFR tyrosine kinase inhibitors. However, this therapeutic decision may be challenging when insufficient tumor tissue is available for EGFR mutation testing. Therefore, blood surrogate samples for EGFR mutation analysis have been suggested. METHODS: Data were collected from the Spanish cohort of patients in the large, non-interventional, diagnostic ASSESS study (NCT01785888) evaluating the utility of circulating free tumor-derived DNA from plasma for EGFR mutation testing. The incidence of EGFR mutation in Spain and the level of concordance between matched tissue/cytology and plasma samples were evaluated. RESULTS: In a cohort of 154 eligible patients, EGFR mutations were identified in 15.1 and 11.0% of tumor and plasma samples, respectively. The most commonly used EGFR mutation testing method for the tumor tissue samples was the QIAGEN Therascreen® EGFR RGQ PCR kit (52.1%). Fragment Length Analysis + PNA LNA Clamp was used for the plasma samples. The concordance rate for EGFR mutation status between the tissue/cytology and plasma samples was 88.8%; the sensitivity was 45.5%, and the specificity was 96.7%. CONCLUSIONS: The high concordance between the different DNA sources for EGFR mutation testing supports the use of plasma samples when tumor tissue is unavailable.

Expresión de proteínas relacionadas con resistencia a múltiples drogas (MDR-Proteínas) y resistencia a la quimioterapia en el cáncer de pulmón / Expression of proteins related to multiple drug resistance (MDR-proteins) in chemotherapy-resistant lung cancer

Propósito: El objetivo de este estudio es analizar la expresión de proteinas transportadoras de fármacosy la resistencia a la quimioterapia en el cáncer de pulmón.Material y métodos: Se recogieron 147 muestras tumorales procedentes de 143 pacientes (35broncoscópicas y 112 quirúrgicas). Resultaron válidas para el estudio 101 muestras correspondientes a99 pacientes. Las muestras tumorales criocongeladas fueron sometidas a análisis inmunohistoquímicopara la detección de las tres MDR-proteínas, Pgp, Mrp1 y Lrp.Resultados: No expresaron ninguna proteína, 16 casos. Expresaron una sola proteína, 32 casos: 3Pgp, 11 Mrp1 y 18 Lrp=0. Expresaban dos proteínas, 34 casos: 24 Pgp y Lrp, 5 Mrp1 y Pgp, 5 Mrp1 yLrp=0. Expresaban las tres proteínas, 17 casos. No hemos detectado relación significativa entre laedad y la expresión de Pgp (p=0.74), Mrp1 (p=0.95), o Lrp (p=0.26). No observamos diferencias significativasentre sexos, tanto al analizar por el número (p=0.72), como por el tipo (p=0.39) de proteínasexpresadas de forma simultánea.Tampoco detectamos diferencias significativas entre los diferentesestadios tumorales, tanto para el número (p=0.55), como para el tipo (p=0.21) de MDR-proteínasexpresada. Tampoco encontramos diferencias significativas entre los diferentes grados histológicos,tanto para el número (p=0.59), como para el tipo (p=0.51) de MDR-proteínas expresadas simultáneamenteesadas simultáneamente. La tendencia de Pgp y Lrp a expresase asociadas ha resultado muysignificativa (p<0.01), no ocurrió lo mismo para la sociación Pgp y Mrp1 (p=0.18) o Mrp1 y Lrp(p=0.26).Conclusiones: Pgp se expresa fundamentalmente asociada a Lrp. Solamente la expresión de Pgpy el número de proteinas expresabas simultáneamente parece guardar relación con la respuesta a laquimioterapia

Purpose: To evaluate the expression of MDR-proteins in the response to lung cancerchemotherapy.Methods: 147 tumor samples were collected from 143 patients, 35 of which were obtained bybronchoscopy and 112 from surgery; 101 samples belonging to 99 patients were considered valid forthe study. The samples were cryopreserved and immunochemistry with monoclonal murine antibodiesused to determine the MDR-proteins Pgp, Mrp1 and Lrp.Results: No MDR-proteins were expressed in 16 cases. One MDR-protein was present in 32cases: Pgp in 3, Mrp1 in 11 and Lrp in 18. Two MDR-proteins were expressed in 34 cases: Pgp andLrp in 24, Mrp1 and Pgp in 5, and Mrp and Lrp in 5. All the three MDR-proteins were present in 17cases. No differences were observed considering age (Pgp, p = 0.74; Mrp1, p = 0.95; Lrp, p = 0.26).Neither sex produced changes when considering either number of MDR-proteins (p = 0.55) or types ofthem (p = 0.21). Significant differences of MRD-proteins were also lacking for number (p = 0.59) andtype (p = 0.51) in relation to the tumor histologic grade. The tendency to the simultaneous expressionof Pgp and Lrp was very significant (p < 0.01), while the simultaneous expression of Mrp1 and Lrpshowed to be no significant (p = 0.26).Conclussions: Pgp and Lrp are frequently expressed simultaneously. Only the expression of Pgpand the number of MDR-proteins expressed simultaneously seem to be related to response tochemotherapy

Expresión de proteínas relacionadas con resistencia a múltiples drogas (MDR-Proteínas) en el cáncer de pulmón / Expression of proteins related to multiple drug resistance (MDR-proteins) in lung cancer

• Introducción: La reducción en la acumulación intracelular de los fármacos, es uno de los mecanismosmás frecuentes de resistencia a los antineoplásicos. Las proteinas transportadoras de membrana juegan un papelesencial en este fenómeno.• Material y métodos: Se recogieron 147 muestras tumorales procedentes de 143 pacientes. De éstas,35 eran broncoscópicas y 112 quirúrgicas. Resultaron válidas para el estudio 101 muestras correspondientes a99 pacientes. Las muestras tumorales criocongeladas fueron sometidas a análisis inmunohistoquímico para ladetección de las tres MDR-proteínas, Pgp, Mrp1 y Lrp• Resultados: No expresaban ninguna proteína, 16 casos. Expresaban una sola proteína, 32 casos: 3 Pgp,11 Mrp1 y 18 Lrp=0. Expresaban dos proteínas, 34 casos: 24 Pgp y Lrp, 5 Mrp1 y Pgp, 5 Mrp1 y Lrp=0. Expresabanlas tres proteínas, 17 casos. No hemos detectado relación significativa entre la edad y la expresión dePgp (p=0.74), Mrp1 (p=0.95), o Lrp (p=0.26). No detectamos diferencias significativas entre sexos, tanto alanalizar por el número (p=0.72), como por el tipo (p=0.39) de proteínas expresadas de forma simultánea.Tampocodetectamos diferencias significativas entre los diferentes estadios tumorales, tanto para el número(p=0.55), como para el tipo (p=0.21) de MDR-proteínas expresada. Tampoco detectamos diferencias significativasentre los diferentes grados histológicos, tanto para el número (p=0.59), como para el tipo (p=0.51) deMDR-proteínas expresadas simultáneamente esadas simultáneamente.La tendencia de Pgp y Lrp a expresarse asociadas ha resultado muy significativa (p<0.01), no ocurrió lo mismopara la asociación Pgp y Mrp1 (p=0.18) o Mrp1 y Lrp (p=0.26).• Conclusiones: El cáncer de pulmón expresa con frecuencia MDR-proteínas.De las tres MDR-proteínasestudiadas, Pgp Mrp1 y Lrp, es Lrp la más frecuentemente expresada. Los adenocarcinomas expresan menosMrp1 que el resto de los tipos histológicos.Los carcinomas escamosos expresan menos Lrp que los adenocarcinomasy carcinomas indiferenciados de célula grande.Una proporción importante de pacientes expresan de formasimultánea más de una MDR-proteína. Los carcinomas escamosos, son los que con más frecuencia expresanPgp, Mrp1 y Lrp de forma simultánea. Pgp se expresa fundamentalmente asociada a Lrp

• Introduction: Lowering of intracellular drug deposition plays an important role in the resistance tochemotherapy of many neoplasms. MDR-proteins regulate the process.• Material and methods: 147 tumor samples were collected from 143 patients, 35 were obtained bymeans of bronchoscopy and 112 were surgical specimens; 101 samples from 99 patients were consideredcorrect for final analysis. Samples were cryopreserved and immuno-staining techniques used for MDRproteinscharacterization (Pgp, Mrp1, and Lrp). A monoclonal murine antibody to each was employed.• Results: 16 cases failed to express any of the three analysed MDR-proteins. One protein was expressedin 32 cases: 3 Pgp, 11 Mrp1, and 18 Lrp. The expression of two proteins was observed in 34 cases: 24 Pgp andLrp, 5 Mrp1 and Pgp, and 5 Mrp1 and Lrp. All the three proteins were expressed in 17 cases. No differenceswere found in the expression according to age: Pgp (p=0.74), Mrp (p=0.95) and Lrp (p=0.26). Sex showed nodifferences when considered either number (p=0.72) or type of proteins (p=0.39). No significative differenceswere found according to tumor stage analysing either number (p=0.55) or type (p=0.21) of expressed MRDproteins.Differences were also not observed in relation to histologic grade for number (p=0.59) or type(p=0.51) of expressed proteins.A tendency to the simultaneous expression of Pgp and Lrp was very significative (p<0.01). No similartendency was observed for the association of Mrp- Lrp (p=0.26) and Pgp-Mrp1 (p=0.18).• Conclussions: Lung cancer cells frequently express MDR-proteins. Lrp was the most frequently found inour series. Adenocarcinomas rarely express Mrp1 as compared with other histological classes. Squamous-cellcarcinomas express less Lrp than adenocarcinomas and large-cell undifferentiated carcinomas. The simultaneousexpression or more than two proteins was observed in a significant number of cases. Squamous-cell carcinomastend to express Pgp, Mrp1 and Lrp simultaneously. Pgp is ussually expressed associated to Lrp