Estudio de variantes genéticas en 169 pacientes de cáncer de pulmón no microcítico / Study of genetic variants in 169 non-small cell lung cancer patients

Introducción: El cáncer de pulmón es la principal causa de muerte por cáncer en nuestro país. El cáncer de pulmón de células no pequeñas (CPCNP) representa el paradigma de la medicina personalizada. El objetivo principal de este trabajo es estudiar la frecuencia en nuestro medio de las variantes clínicamente significativas más frecuentemente descritas en CPCNP. Material y métodos: Se estudia la expresión inmunohistoquímica de TTF1, p40 y PD-L1 y la frecuencia de variantes genéticas mediante secuenciación masiva (NGS) con un panel de 52 genes, en 174 muestras incluidas en parafina de CPNCP en 169 pacientes (111 hombres y 52 mujeres) de la provincia de Cádiz. Resultados: La expresión inmunohistoquímica de TTF1, p40 y PD-L1 fue positiva en el 87%, el 0% y el 46% de los adenocarcinomas y en el 0%, el 100% y el 41% de los carcinomas escamosos. En NGS, las variantes de un solo nucleótido (SNV) más frecuentes fueron KRAS (36%), EGFR (14%), BRAF (10%), PIK3CA (8%) y MET (3%). Las variantes en el número de copias (CNV) más frecuentes fueron las amplificaciones en NF1 (30%), EGFR (18%), CCND1 (9%), MYC (9%) y KRAS (7%). En mujeres, las SNV en EGFR fueron más frecuentes que en hombres (p<0,0001). El adenocarcinoma es el tipo histológico más frecuente con SNV en KRAS (p=0,007361) o en EGFR (p<0,0001). En 16 pacientes (9,47%) se detectaron fusiones génicas, 9 casos en el gen MET. Conclusiones: Detectamos nuevas asociaciones entre expresión inmunohistoquímica y algunas variantes génicas, que podrían tener impacto en el tratamiento de pacientes de CPNCP.(AU)

Introduction: Lung cancer is the leading cause of cancer death in our country. Non-small cell lung cancer (NSCLC) represents the paradigm of personalized medicine. The main objective of this study is analysing the distribution of the most frequently described clinically significant variants in NSCLC, in our environment. Material and methods: We studied the immunohistochemical expression of TTF1, p40 and PD-L1 and the genetic variants frequency using Next-Generation Sequencing (NGS) with a panel of 52 genes, in 174 NSCLC paraffin-embedded samples in 169 patients (111 men and 52 women) from the province of Cádiz. Results: The immunohistochemical expression of TTF1, p40 and PD-L1 was positive in 87%, 0% and 46% in adenocarcinoma, and 0%, 100% and 41% in squamous cell carcinoma. In NGS, the most common single nucleotide variants (SNVs) were KRAS (36%), EGFR (14%), BRAF (10%), PIK3CA (8%), and MET (3%). The most frequent copy number variants (CNVs) were amplifications in NF1 (30%), EGFR (18%), CCND1 (9%), MYC (9%) and KRAS (7%). In women, SNV in EGFR are more frequent than in men (P<.0001). Adenocarcinoma is the most frequent histological type with SNV in KRAS (P=.007361) or in EGFR (P<.0001). Gene fusions were detected in 16 patients (9.47%), in 9 cases in the MET gene. Conclusions: We detected associations, not described so far, between immunohistochemical expression and specific gene variants, which could have an impact on the treatment of NSCLC patients.(AU)

A Delphi consensus panel about clinical management of early-stage EGFR-mutated non-small cell lung cancer (NSCLC) in Spain: a Delphi consensus panel study

Purpose This Delphi panel study assessed the level of consensus between medical oncologists on the clinical management of patients with early-stage EGFR-mutated non-small cell lung cancer (NSCLC). Methods A modified two-round Delphi approach was used. A scientific committee comprised of medical oncologists developed an online questionnaire. Delphi panel experts rated their level of agreement with each questionnaire statement on a 9-point Likert scale. The questionnaire included 36 statements from 3 domains (clinical management of early-stage NSCLC: 15 statements; role of adjuvant therapy in early-stage NSCLC: 9 statements; and role of adjuvant therapy in early-stage NSCLC with sensitizing EGFR mutation: 12 statements). Results In round 1, consensus was reached for 24/36 statements (66.7%). Nine statements that did not achieve consensus after the first round were evaluated in round 2, and none of them reached consensus. Overall, 84.4% of the panelists agreed that EGFR mutation testing should be done after surgery. Consensus was not achieved on whether the implementation of EGFR mutation testing in resected early-stage NSCLC could limit the use of adjuvant osimertinib. The panelists recognized the rationale for the use of osimertinib in the adjuvant scenario (88%) and 72% agreed that it may change the treatment paradigm in stage IB–IIIA EGFR-mutated NSCLC. Consensus was not reached on the inconvenience of prolonged duration of osimertinib. Conclusions This Delphi study provides valuable insights into relevant questions in the management of early-stage EGFR-mutated NSCLC. However, specific issues remain unresolved. The expert consensus emphasizes the role of adjuvant treatment with osimertinib in this scenario. (AU)

PARP inhibitor niraparib as a radiosensitizer promotes antitumor immunity of radiotherapy in EGFR-mutated non-small cell lung cancer

Background Poly-(ADP-Ribose)-Polymerase inhibitors (PARPi) were reported as radiosensitizers in non-small cell lung cancer (NSCLC) with wide-type epidermal growth factor receptor (EGFR), but the effects of radiation combined with PARPi were not investigated in EGFR-mutated NSCLC. Moreover, the underlying mechanisms were not well examined. This study aimed to study the efficacy of radiation combined with niraparib in EGFR-mutated NSCLC and explore their influence on the immune system. Methods Clone formation and apoptosis assay were conducted to explore the effects of niraparib and radiation. Immunofluorescence was conducted to detect the double-strand DNA breaks. Real-time PCR and immunoblotting were employed to evaluate the activation of STING/TBK1/TRF3 pathway and the expression levels of interferon β, CCL5 and CXCL10. Immunocompetent mice model bearing with subcutaneous Lewis lung cancer was established to confirm the results in vivo. Results Niraparib and radiation were synergistic to inhibit tumor both in vitro and in vivo. Radiation plus niraparib could activate anti-tumor immunity, which appeared as increased CD8+ T lymphocytes and activated STING/TBK1/IRF3 pathway. Conclusion PARPi not only as a radiosensitizer inhibited EGFR-mutated NSCLC tumor growth, but also cooperated with radiation to promote anti-tumor immune responses (AU)

Valor pronóstico de la ruta de EGFR-PI3K-pAKT-mTOR-pS6 en los carcinomas epidermoides nasosinusales / Predictive value of EGFR-PI3K-pAKT-mTOR-pS6 pathway in sinonasal squamous cell carcinomas

Antecedentes y objetivos: En estudios previos hemos indicado que EGFR tiene un papel en la carcinogénesis en un subgrupo de carcinomas epidermoides nasosinusales (CENS). Además, EGFR activa a 2 de las más importantes vías de señalización intracelular como son la PI3K/pAKT/mTOR/pS6 y la vía MAP-cinasas. El objetivo de este estudio fue evaluar la participación de la ruta de EGFR/PI3K/pAKT/mTOR/pS6 y su relación con parámetros clínico-patológicos y de seguimiento de los CENS. Material y métodos: La expresión proteica de PTEN, pAKT, mTOR y pS6 fue analizada mediante inmunohistoquímica en 54 CENS. Los resultados fueron relacionados con diversos parámetros clínico-patológicos y la supervivencia. Resultados: La pérdida de expresión de PTEN se observó en 33/54 casos (61%) y la sobreexpresión de pAKT, mTOR y pS6 se observó en 19/54 casos (35%), 8/54 casos (15%) y 47/54 casos (87%), respectivamente. La pérdida de expresión de PTEN se relacionó con la invasión intracraneal y el desarrollo de metástasis regionales (p = 0,005). La ausencia de sobreexpresión de pS6 se relacionó con una supervivencia específica (p = 0,008) y global (p = 0,007) más favorables y la ausencia de recidivas locales (p = 0,055). No se observaron relaciones significativas entre la expresión de pAKT y mTOR y los parámetros clínico-patológicos estudiados. Conclusiones: Las alteraciones en la expresión de los componentes de la vía EGFR/PI3K/pAKT/mTOR/pS6 son frecuentes en un subgrupo de CENS. Este estudio revela que la ausencia de sobreexpresión de pS6 se relaciona con mejores resultados clínicos, por lo que la expresión pS6 podría considerarse como un marcador pronóstico

Background and objectives: We have previously indicated that EGFR has a role in carcinogenesis in a subgroup of sinonasal squamous cell carcinomas (SNSCC). In addition, EGFR activates 2 of the most important intracellular signalling pathways: PI3K/pAKT/mTOR/pS6 and MAP pathway kinases. The objective of this study was to evaluate the involvement of the EGFR/PI3K/pAKT/mTOR/pS6 pathway and its relationship with clinical-pathological parameters and follow-up of sinonasal squamous cell carcinoma. Material and methods: The immunohistochemical expression of different components of the PI3K/AKT/mTOR/pS6 pathway and its relationship with various clinical-pathological parameters was studied in a series of 54 patients with SNSCC. Results: Loss of PTEN expression was observed in 33/54 cases (61%) and pAKT, mTOR and pS6 pre-expression was observed in 19/54 cases (35%), 8/54 cases (15%), and 47/54 cases (87%), respectively. Loss of PTEN expression was related to intracranial invasion and development of regional metastases (p=0.005). Overexpression of pS6 was associated with a decrease in survival (p=0.008), presence of local recurrences (p=0.055), and worsening of overall prognosis (p=0.007). No significant relationships were observed between pAKT and mTOR expression and the clinicopathological parameters studied. Conclusions: Alterations in the expression of EGFR/PI3K/pAKT/mTOR/pS6 pathway components are common in a subgroup of SNSCC. This study reveals that the absence of pS6 overexpression is associated with better clinical outcomes. Therefore, pS6 expression could be considered as an unfavourable prognostic marker

Radiolabeled F(ab')2-cetuximab for theranostic purposes in colorectal and skin tumor-bearing mice models

Purpose: This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111In and 177Lu, respectively. Methods: We designed F(ab′)2-fragments of cetuximab radiolabeled with 111In and 177Lu. 111In-F(ab′)2-cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111In-F(ab′)2-cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177Lu-F(ab′)2-cetuximab was evaluated in SWISS nude mice bearing A431 tumors. Results: Radiolabeling procedure did not change F(ab′)2-cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111In-DOTAGA-F(ab′)2-cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab′)2-cetuximab. SPECT imaging of 111In-DOTAGA-F(ab′)2-cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177Lu-DOTAGA-F(ab′)2-cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses. Conclusions: 111In-DOTAGA-F(ab′)2-cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177Lu-DOTAGA-F(ab′)2-cetuximab is an interesting theranostic tool allowing therapy and imaging

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Long-term clinical benefit from salvage EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer patients with EGFR wild-type tumors

Background. Erlotinib has been approved for the management of NSCLC patients after failure of the first or subsequent line of chemotherapy. Although the efficacy of erlotinib is clearly associated with the presence of EGFR mutations, there is a subset of patients with EGFR wild-type (EGFRwt) tumors who impressively respond. Patients and methods. Patients with EGFRwt NSCLC who received salvage (≥2nd line) treatment with erlotinib for a prolonged period (>6 months), were sought from the database of the Hellenic Oncology Research Group. We retrospectively analyzed the clinical, pathological and molecular characteristics of the patients with available tumor material. Results. Forty-four patients that received erlotinib for >6 months (median 10.1 months) were enrolled in the study. The majority of them were male, never-smokers with adenocarcinoma histology and a good performance status. KRAS and PIK3CA mutations were detected in 21% (9/42 tested) and 13% (4/30 tested) of the patients, respectively. The ALK-EML4 translocation was found in 10% (2/20 tested); there was no patient with HER2 or BRAF mutated tumor. Twelve (54.5%) tumor specimens were considered positive for EGFR-overexpression. Eleven patients experienced a partial response (objective response rate 25%; 95% CI 12-38%) and the remaining 33 had stable disease. The median progression-free survival and overall survival were 10.1 (95% CI 8.6-11.6 months) and 24.1 (95% CI 11.2-37 months), respectively. Conclusions. Treatment with erlotinib significantly improves the clinical outcome in a subset of NSCLC patients with EGFRwt tumors. Further molecular analysis of such tumor specimens could provide a more comprehensive characterization of this particular group of patients. Nevertheless, the presence of other mutations should not prevent the treating physician from using erlotinib at later lines of salvage therapy for NSCLC patients (AU)

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Bevacizumab plus chemotherapy for patients with advanced pulmonary adenocarcinoma harboring EGFR mutations

Purpose. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and bevacizumab plus chemotherapy were effective for EGFR-mutant patients. However, the appropriated treatment orders remained controvertible. We investigated the efficacy of treatment orders between bevacizumab plus chemotherapy and EGFR-TKIs for EGFR-mutant patients with advanced pulmonary adenocarcinoma. Patients and methods. This study involved 40 EGFR-mutant patients with advanced pulmonary adenocarcinoma who were treated with bevacizumab plus carboplatin and paclitaxel (Bev + CP) and EGFR-TKIs in different treatment orders or gemcitabine plus cisplatin (GP) in first-line setting. Seventeen patients were treated with Bev + CP and 10 cases with GP in first-line treatment. Thirteen patients received EGFR-TKIs after first-line Bev + CP regimen, while 13 patients were treated with first-line EGFR-TKIs. Progression-free survival (PFS), the response rate (ORR) and overall survival (OS) were evaluated. Results. Median PFS of Bev + CP treatment was significantly longer in first-line than non-first-line settings (11.7 vs. 5.6 months, P = 0.003). Median OS was 37.8 months for EGFR-mutant patients with first-line Bev + CP followed by second-line EGFR-TKIs and 31.0 months for those with first-line EGFR-TKIs and non-first-line Bev + CP, respectively (P = 0.509). Median PFS was 11.7 (95% CI 10.6-12.8) months for Bev + CP group and 4.7 (95% CI 4.4-5.0) months for GP group with the hazard ratio of 0.17 (P = 0.001). ORR was 70.6 and 50.0% in the two groups, respectively (P = 0.415). However, there was no significant difference in median OS (33.7 vs 27.8 months, P = 0.293). Conclusions. First-line Bev + CP followed by EGFR-TKIs might possibly provide favorable prognosis for EGFR-mutant patients. Bev + CP regimen significantly prolonged PFS in first-line than non-first-line settings. These findings warrant further investigations (AU)

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Overall Survival Analysis and Characterization of an EGFR Mutated Non-Small Cell Lung Cancer (NSCLC) Population / Análisis de la supervivencia global y caracterización del perfil mutacional del gen EGFR en una población con cáncer de pulmón no microcítico

Background: Patients with activating somatic mutations in the Epidermal Growth Factor Receptor (EGFR) have better clinical outcomes when treated with Tyrosine Kinase Inhibitors (TKI) over chemotherapy. However, the impact of the use of TKIs on overall survival outside clinical trials is not well established. Objective: To characterize and analyze the overall survival of a Caucasian population with NSCLC and EGFR mutations. Methods: A retrospective cohort analysis of patients with NSCLC screened for EGFR mutations (exons 18-21) between October 2009 and July 2013 was conducted. Clinical and pathological characteristics, mutational EGFR status, treatment and overall survival were evaluated. Results: From the 285 patients which performed screening for EGFR mutations, 54 (18.9%) had mutations, 25 (46.3%) of which in exon 19 and 20 of which (37.0%) in exon 21. The occurrence of mutations was associated with female sex and non-smoking habits (both, P < .001). The median survival of the global population was 12.0 months, with a better overall survival in mutated than non-mutated patients (20.0 vs 11.0 months, respectively; P = .007). Conclusion: These data contribute for a better knowledge of our lung cancer population concerning the mutational status and clinical outcomes, confirming a better overall survival for the patients with EGFR TKI sensible mutations (AU)

Antecedentes: Los pacientes con mutaciones somáticas activantes en el receptor del factor de crecimiento epidérmico (EGFR) obtienen mejor resultado clínico cuando se tratan con inhibidores de la tirosina cinasa (TQ) frente a quimioterapia. Sin embargo, el impacto de la terapia en inhibidores de TQ en la supervivencia global de los pacientes no está del todo establecido en la práctica clínica habitual. Objetivo: Caracterizar y analizar la supervivencia global de una población caucásica con cáncer de pulmón no microcítico y mutaciones en el gen EGFR. Métodos: Se realizó un análisis retrospectivo de una cohorte de pacientes con cáncer de pulmón no microcítico con mutaciones en el gen EGFR (exones 18-21) entre octubre de 2009 y julio de 2013. Se evaluaron las características clínicas y patológicas, el estatus mutacional del gen EGFR, el tratamiento y la supervivencia global. Resultados: De los 285 pacientes que se cribaron para caracterización de mutaciones en el gen EGFR, 54 (18,9%) presentaron mutaciones, de los cuales 25 (46,3%) tenían mutaciones en el exón 19 y 20 (37,0%) en el exón 21. Se observó que la ocurrencia de mutaciones estaba asociada al género femenino y al no consumo de tabaco (p < 0,001 en ambos casos). La supervivencia media de la población global fue de 12 meses, con una mejor supervivencia global en pacientes que presentaron mutaciones que en los que no las presentaron (20 vs. 11 meses, respectivamente, p = 0,007). Conclusión: Estos datos contribuyen a mejorar el conocimiento de nuestra población con cáncer de pulmón con relación a su estatus mutacional y el resultado clínico, confirmando una mayor tasa de supervivencia global en los pacientes con mutaciones en el gen EGFR sensibles a inhibidores de TQ (AU)

Carcinomatosis meníngea: forma inusual de presentación del adenocarcinoma de pulmón / Meningeal carcinomatosis: unusual presentation of adenocarcinoma of the lung

Se presenta el caso de una paciente con antecedentes de ser fumadora de baja intensidad, con índice acumulado de tabaco menor de 5 paquetes/año y sin otros antecedentes personales de interés. Acudió en diversas ocasiones durante 2 meses a urgencias, refiriendo cefalea difusa, opresiva e intermitente y diplopía acompañada de visión borrosa ocasional, siendo diagnosticada de parálisis isquémica del IV par craneal del ojo izquierdo e iniciando tratamiento con antiagregante. A pesar del tratamiento, a la semana acudió de nuevo a urgencias, ya que progresivamente había ido presentado mareos, inestabilidad en la marcha, pérdida de visión con predominio en ojo izquierdo y mayor sensación de debilidad en miembros superiores, Finalmente, se decidió ingreso en Neurología ante la sospecha de meningoencefalitis subaguda tuberculosa, pero tras diversas pruebas diagnósticas se llegó a la conclusión de que se trataba de un adenocarcinoma pulmonar, que debutó en forma de carcinomatosis meníngea sin haber presentado sintomatología respiratoria asociada

A case is presented of a patient with a history of low-intensity smoking, with an accumulated tobacco index of less than 5 packs-year and without other personal history of interest. She went to the emergency room several times over 2 months, complaining of a diffuse, oppressive and intermittent headache and diplopia accompanied by occasional blurred vision, being diagnosed with ischemic paralysis of the fourth cranial nerve of the left eye and initiating treatment with antiplatelets. Despite treatment, she returned to the emergency room within a week, as she had been suffering from progressive dizziness, instability when walking, loss of vision mainly in the left eye and a greater feeling of weakness in the upper limbs. Finally, admission to Neurology was decided upon with the suspicion of subacute tuberculous meningoencephalitis. However, after various diagnostic tests, it was concluded that it was a pulmonary adenocarcinoma, which began as meningeal carcinomatosis without presenting associated respiratory symptoms

Utility of urinary circulating tumor DNA for EGFR mutation detection in different stages of non-small cell lung cancer patients

Purpose. Non-invasive methods of molecular profiling for non-small cell lung cancer (NSCLC) are useful for monitoring disease progression. The aim of the current study was to ascertain if transrenal DNA is sensitive for clinical correlation and EGFR detection in NSCLC patients. Methods. 160 patients at various stages of the disease participated and samples were collected prospectively at 2-month intervals. A baseline sample was taken before treatment commencement. To ascertain the sensitivity of transrenal DNA, we compared its results with plasma DNA. ddPCR was used to profile the urine and blood samples for key EGFR mutations. Results. Using tumor tissues as references, our study showed good concordance in EGFR mutations with transrenal DNA before treatment. Results were highly matching in late-stage NSCLC patients, with stage III/IV patients yielding an agreement of more than 90%. The assay was also sensitive to detect early-stage patients after surgical procedures. Profiles were highly concordant with results derived from plasma DNA, demonstrating the specificity of transrenal DNA assays. Serial monitoring of these patients showed stable molecular signatures and correlated to different treatments. Survival analysis showed good prognostic utility for late-stage patients with high transrenal DNA variations and patients that acquired T790M mutation. Conclusion. The study demonstrated the feasibility of using transrenal DNA in mutation profiling for different stages of NSCLC patients. It highlights the importance of continual monitoring and has potential clinical utility in the clinical management of NSCLC (AU)

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High early growth response 1 (EGR1) expression correlates with resistance to anti-EGFR treatment in vitro and with poorer outcome in metastatic colorectal cancer patients treated with cetuximab

Purpose. Biomarkers, such as mutant RAS, predict resistance to anti-EGFR therapy in only a proportion of patients, and hence, other predictive biomarkers are needed. The aims were to identify candidate genes upregulated in colorectal cancer cell lines resistant to anti-EGFR monoclonal antibody treatment, to knockdown (KD) these genes in the resistant cell lines to determine if sensitivity to anti-EGFR antibody was restored, and finally to perform a pilot correlative study of EGR1 expression and outcomes in a cohort of metastatic colorectal cancer (mCRC) patients given cetuximab therapy. Methods. Comparative expression array analysis of resistant cell lines (SW48, COLO-320DM, and SNU-C1) vs sensitive cell lines (LIM1215, CaCo2, and SW948) was performed. The highest up-regulated gene in each resistant cell line was knocked down (KD) using RNA interference, and effect on proliferation was assessed with and without anti-EGFR treatment. Expression of the candidate genes in patients’ tumours treated with cetuximab was assessed by immunohistochemistry; survival analyses were performed comparing high vs low expression. Results. Genes significantly upregulated in resistant cell lines were EGR1 (early growth response protein 1), HBEGF (heparin-binding epidermal growth factor-like growth factor), and AKT3 (AKT serine/threonine kinase 3). KD of each gene resulted in the respective cells being more sensitive to anti-EGFR treatment, suggesting that the resistant phenotype was reversed. In the pilot study of mCRC patients treated with cetuximab, both median PFS (1.38 months vs 6.79 months; HR 2.77 95% CI 1.2-19.4) and median OS (2.59 months vs 9.82 months; HR 3.0 95% CI 1.3-23.2) were significantly worse for those patients with high EGR1 expression. Conclusion. High EGR1 expression may be a candidate biomarker of resistance to anti-EGFR therapy (AU)

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A consensus statement on the gender perspective in lung cancer

Lung cancer is the most common cancer globally and has the highest mortality. Although this disease is not associated with a particular gender, its incidence is rising among women, who are diagnosed at an increasingly younger age compared with men. One of the main reasons for this rise is women taking up smoking. However, many non-smoking women also develop this disease. Other risk factors implicated in the differential development of lung cancer in women are genetic predisposition, tumour histology and molecular profile. Proportionally more women than men with lung cancer have a mutation in the EGFR gene. This consensus statement reviews the available evidence about the epidemiological, biological, diagnostic, therapeutic, social and psychological aspects of lung cancer in women (AU)

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Urinary circulating DNA detection for dynamic tracking of EGFR mutations for NSCLC patients treated with EGFR-TKIs

Purpose. Changes in EGFR profiles of non small cell lung cancer (NSCLC) patients correlates to clinical outcome. Extracting quality tumor tissue remains a challenge for molecular profiling. Our study aims to ascertain the clinical relevance of urinary cell free DNA as an alternative tumor material source. Methods. 150 patients with activating EGFR mutation and received EGFR-TKIs were recruited to participate in the serial monitoring study. Matched primary tumor samples were taken together with blood and urine specimens before the initiation of TKIs. The EGFR mutation testing was performed and quantified using ddPCR. For serial time point measurements, urine and blood samples were extracted at 1-month intervals for duration of 9 months. Results. Urinary ctDNA yielded a close agreement of 88 % on EGFR mutation status when compared to primary tissue at baseline. Almost all samples detected via urine specimens were uncovered in plasma samples. Analysis of urinary cell free DNA at different time points showed a strong correlation to treatment efficacy. Interestingly, a secondary EGFR mutation T790M was detected for 53 % of the patients during monitoring. The results were corroborated with the plasma ctDNA analysis. The T790M+ group had a reduced median survival when compared to the wildtype group. Conclusion. Urinary cell free DNA may be a potential alternative to conventional primary tissue based EGFR mutation testing. Our findings showed that the assay sensitivity was comparable to results from blood plasma. Urinary samples being noninvasive and readily available have clinical utility for monitoring of EGFR TKI treatment (AU)

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Difícil manejo en paciente con adenocarcinoma de pulmón con mutación de EGFR y enfermedad cerebral / Management difficulties in a patient with EGFR-mutation positive lung adenocarcinoma and cerebral metastases

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Mutación en heterocigosis en el gen del receptor de la hormona de crecimiento como causa de la talla baja / Heterozygous mutation in the receptor gene of the growth hormone as cause of short stature

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EGFR mutations in lung cancer / Mutaciones de EGFR en cancer de pulmón

The study of epidermal growth factor receptor mutations has become essential for the treatment of lung cancer. The aim of this study was to find a correlation between morphological changes and EGFR mutational status using both immunohistochemistry and molecular techniques. We also analyzed the cross-reaction of the L858R mutation-specific monoclonal antibody in cases with HER2 amplification described previously in breast and gastric cancer. A series of 100 primary lung adenocarcinomas were examined. Exon 19 E746_A750del and exon 21 L858R mutations were studied using immunohistochemistry with two specific monoclonal antibodies. Gene mutational status was determined using real-time PCR or Sanger sequencing followed by real-time PCR when negative. EGFR mutations were detected in 22 cases (22%) by molecular techniques, being significantly more frequent in women, low grade carcinoma and lepidic subtype, (p-value <0.05 in all cases). In addition, in our series presence of tumoral necrosis correlated with absence of mutations. The anti-E746_A750del antibody achieved a 100% positive predictive value and a negative predictive value of 97.7% which could restrict the use of molecular techniques to the 7% of cases with an equivocal result. The antibody for L858R mutation showed inconsistent results compared to molecular techniques, giving false positive result in two adenocarcinomas with HER2 amplification. However, its negative predictive value was very high (98.9%). The use of real-time PCR identifies mutations not detected by the other two techniques. These new antibodies could be useful as a screening tool prior to EGFR molecular techniques (AU)

El estudio de las mutaciones de EGFR ha resultado ser esencial en el tratamiento del cáncer de pulmón. La finalidad de este trabajo ha sido estudiar la correlación entre los cambios morfológicos y el estado mutacional de EGFR utilizando técnicas de inmunohistoquímica y moleculares. Asimismo se analizó la reacción cruzada del anticuerpo anti-L858R en casos con amplificación de HER2 descrita previamente en cáncer de mama y gástrico. La serie consta de 100 adenocarcinomas pulmonares primarios. Las mutaciones E746_A750del exón-19 y L858R exón-21 se estudiaron por inmunohistoquímica con dos anticuerpos monoclonales específicos. El estado mutacional del gen se determinó mediante PCR en tiempo-real o secuenciación por Sanger seguida de PCR en tiempo-real cuando resultó negativa. Se detectaron mutaciones de EGFR en 22 casos (22%) por técnicas moleculares, siendo significativamente más frecuente en mujeres, carcinoma de bajo grado y subtipo lepídico, (p-valor<0,05 en todos los casos). Además, en nuestra serie la presencia de necrosis tumoral se correlaciona con ausencia de mutaciones. El anticuerpo anti-E746_A750del presentó un valor-predictivo-positivo del 100% y un valor-predictivo-negativo del 97,7%, lo que podría restringir el uso de técnicas moleculares al 7% de casos no-concluyentes. El anticuerpo anti-L858R mostró resultados inconsistentes en comparación con las técnicas moleculares, dando resultado falso-positivo en dos adenocarcinomas con amplificación de HER2. Sin embargo, su valor-predictivo-negativo es muy alto (98,9%). El uso de PCR en tiempo-real rescata mutaciones no detectadas por las otras dos técnicas. Estos nuevos anticuerpos podrían ser útiles como herramienta de cribado previo al estudio de EGFR mediante técnicas moleculares (AU)

Síndrome neurológico progresivo inusual en adenocarcinoma de pulmón epidermal growth factor receptor mutado: carcinomatosis meníngea invasiva, un diagnóstico de autopsia / Unusual progressive neurological syndrome in epidermal growth factor receptor-mutated lung adenocarcinoma, diagnosed at autopsy as invasive meningeal carcinomatosis

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Contexto actual de los inhibidores de EGFR/ErbB en carcinoma de pulmón no microcítico / Current status of EGFR/ErbB inhibitors in non-small cell lung carcinoma

Durante los últimos 10 años hemos asistido a un cambio importante en el tratamiento del cáncer de pulmón. El descubrimiento en 2004 de las mutaciones activadoras del receptor del factor de crecimiento epidérmico (EGFR) en alguno de los subgrupos histológicos del cáncer de pulmón y su sensibilidad frente a los inhibidores de la tirosincinasa, ha supuesto un avance importante en el tratamiento del cáncer de pulmón. Hasta este momento, la única opción disponible para tratar este tipo de tumores se basaba en la quimioterapia, con un impacto beneficioso limitado pero significativo, tanto en la supervivencia como en la calidad de vida de los pacientes. La llegada de estos nuevos agentes dirigidos frente a las mutaciones activadoras del EGFR dio comienzo a la era de la «medicina de precisión», con terapias dirigidas capaces de actuar en el origen del tumor, permitiendo asegurar un beneficio terapéutico minimizando los efectos adversos y retrasando la administración de quimioterapia. Asimismo, esto ha producido un cambio en el paradigma diagnóstico del cáncer de pulmón (y también de todos los tumores) y se ha pasado de un diagnóstico meramente histológico a una clasificación de los tumores en función de sus características mutacionales. Esto ha sido posible gracias al desarrollo tecnológico, que permite realizar complejos análisis del ADN. Estas técnicas, junto con el esfuerzo conjunto de investigadores de todo el mundo, permiten seguir descubriendo alteraciones genéticas que pueden ser diana de nuevos medicamentos, así como definir los mecanismos de actividad y de resistencia a los tratamientos. Este desarrollo extraordinario de los tratamientos dirigidos no puede cambiar el hecho de que el cáncer de pulmón metastásico sigue siendo una enfermedad incurable y aún son pocos los pacientes que se benefician de estos tratamientos dirigidos. Las investigaciones que se siguen realizando permitirán continuar conociendo las alteraciones moleculares que dan origen al cáncer de pulmón y nos ofrecerán nuevas alternativas de tratamiento para esta enfermedad (AU)

In the last 10 years, there has been a major change in the treatment of lung cancer (LC). The discovery of activating mutations in the epidermal growth factor receptor (EGFR) in some histological subtypes of LC and its sensitivity to tyrosine kinase inhibitors (TKI) has represented a substantial advance in the treatment of this entity. Until then, the only available option to treat this type of tumour was based on chemotherapy, with a small but significant benefit in terms of survival and quality of life. The arrival of new agents that act against activating EGFR mutations gave rise to the era of precision medicine with targeted therapies able to act on the origin of the tumour, thus providing a therapeutic benefit while minimizing adverse effects and delaying administration of chemotherapy. In addition, this has produced a change in the diagnostic paradigm of lung cancer (as well as in that of all tumours), with a shift from a purely histological diagnosis to a classification of tumours based on their mutational characteristics. This shift has been made possible by the development of technologies allowing complex DNA analysis. Together with the efforts of researchers from all over the world, these techniques allow continued discovery of genetic alterations that could be the target of new drugs as well as definition of the mechanisms of activity and resistance to treatments. This extraordinary development of targeted therapies cannot change the fact that metastatic lung cancer continues to be an incurable disease and, at the present time, only a few patients will benefit from targeted therapies. Ongoing research will shed new light on the molecular alterations that give rise to LC and will provide new treatment alternatives for this disease (AU)

Tratamiento con afatinib en primera línea EGFR M+. Resultados según subtipo de mutación / Afatinib as first-line therapy in mutation-positive EGFR. Results by type of mutation

El descubrimiento de las mutaciones del receptor de factor de crecimiento epidérmico (EGFR) ha creado las bases para la medicina personalizada en el carcinoma de pulmón no microcítico (CPNM). Los inhibidores de la tirosincinasa (ITK) de primera generación, gefitinib y erlotinib, demostraron en ensayos fase III mayor eficacia comparados con la quimioterapia en los pacientes con mutaciones de EGFR, consiguiendo una supervivencia libre de progresión de 8-13,5 meses. Afatinib, un inhibidor irreversible pan-ErbB de segunda generación, es el primer ITK que ha mostrado un beneficio en la supervivencia global comparado con la quimioterapia en pacientes con CPNM con mutación de EGFR tratados en primera línea. La deleción en el exón 19 (Del19) y la mutación puntual en el exón 21 (L858R) constituyen las denominadas mutaciones activadoras, por conferir sensibilidad a los ITK, y representan aproximadamente el 90% de las mutaciones de EGFR en CPNM. Se ha observado diferente sensibilidad a los ITK según el tipo de mutación, observándose mayor supervivencia libre de progresión en pacientes con la Del19 de EGFR frente a quimioterapia. El análisis de supervivencia global de los ensayos LUX-Lung 3 y LUX-Lung 6 mostró un incremento estadísticamente significativo de la supervivencia en los pacientes tratados con afatinib y que presentaban Del19, mientras que este no fue significativo en los pacientes con mutación L858R. La comparación directa de afatinib y gefitinib en primera línea de tratamiento (ensayo LUX-Lung 7) mostró un aumento estadísticamente significativo de la supervivencia libre de progresión (hazard ratio: 0,73; intervalo de confianza del 95%, 0,57-0,95; p = 0,0165) a favor del afatinib. En el análisis por tipo de mutación, el beneficio se observó tanto para la Del19 como para la mutación L858R (AU)

The discovery of endothelial growth factor receptor (EGFR) mutations has laid the foundations for personalized medicine in non-small cell lung carcinoma (NSCLC). In phase III trials, the first-generation tyrosine kinase inhibitors (TKI), gefitinib and erlotinib, demonstrated greater efficacy compared with chemotherapy in patients with EGFR mutations, achieving progression-free survival of 8-13.5 months. Afatinib, a second-generation irreversible pan-ErbB inhibitor, is the first TKI that has shown a benefit in overall survival (OS) compared with chemotherapy in EGFR mutation-positive NSCLC when used as first-line treatment. Exon 19 deletion (Del19) and the single-point substitution mutation (L858R) in exon 21, called activating mutations due to their ability to confer sensitivity to TKI, represent approximately 90% of the EGFR mutations in NSCLC. Distinct sensitivity to TKI has been observed depending on the type of mutation, with greater progression-free survival in patients with the Del19 mutation. The analysis of OS in the LUX-Lung 3 and LUX-Lung 6 trials showed a statistically significant increase in survival in afatinib-treated patients with the Del 19 mutation, but no significant increase in that of patients with the L858R mutation. Direct comparison of afatinib and gefitinib as first-line therapy (LUX-Lung 7 trial) showed a statistically-significant increase in progression-free survival (hazard ratio: 0.73; 95% confidence interval, 0.57-0.95; p=0.0165) with afatinib. In the analysis by type of mutation, this benefit was observed for both the Del19 and the L858R mutations (AU)

Evidencia de afatinib en pacientes que progresan a un tratamiento de primera línea / Evidence on afatinib in patients progressing on a first-line treatment

Tras la descripción de la importancia de las mutaciones en EGFR en el carcinoma de pulmón no microcítico y una vez comprobado que los inhibidores de la tirosincinasa superan el beneficio producido por quimioterapia en pacientes con tumores EGFR+, el tratamiento con uno de estos fármacos se ha convertido en la recomendación estándar. A pesar de este avance, los pacientes acaban progresando, por lo que es necesario buscar alternativas de tratamiento. Existen estudios que han analizado la actividad de afatinib después de un tratamiento con un inhibidor de la tirosincinasa de primera generación e incluso de la administración también de quimioterapia convencional. Produce una tasa de respuestas y un tiempo de control de la enfermedad significativos tras la aparición de resistencia clínica, que son independientes de la existencia de la mutación de resistencia T790M y que podemos atribuir a mantener el control pan-HER. Además del ensayo clínico inicial, LUX-Lung 1, tenemos datos de utilización en la práctica clínica habitual dentro de programas de uso expandido. En conjunto, podemos esperar tasas de respuesta de entre el 7 y el 15% con una duración de alrededor de 24 semanas y una mediana del tiempo hasta progresión de unos 4 meses. Un estudio que lo combina con cetuximab ha obtenido una alta tasa de respuestas. La toxicidad de afatinib en segunda línea es semejante a cuando se utiliza en primera (fundamentalmente mucocutánea y diarreas) y manejable con las medidas habituales. En conjunto hay que considerar afatinib como una opción de tratamiento en pacientes con mutación de EGFR que progresan tras un primer inhibidor de la tirosincinasa (AU)

After description of the importance of EGFR mutations in non-small cell lung cancer and confirmation that tyrosine-kinase inhibitors are more beneficial than chemotherapy in patients with EGFR+ tumours, treatment with one of these drugs has become the standard recommendation. Despite this advance, patients continue to progress and consequently there is a need to search for alternative treatments. Some studies have analysed afatinib activity after first-generation TKI therapy, as well as its administration in combination with conventional chemotherapy. Afatinib produces significant response rates and progression-free survival times after the development of clinical resistance, which are independent of the presence of the T790M resistance mutation and can be attributed to continued pan-HER inhibition. In addition to the initial clinical trial, LUX-LUNG-1, data are available from the use of afatinib in routine clinical practice, within extended use programs. Overall, response rates of between 7 and 15% can be expected with a duration of approximately 24 months and a median progression-free time of about 4 months. A study combining afatinib with cetuximab has obtained a high response rate. Afatinib toxicity in second-line treatment is similar to that appears when the drug is used as first-line therapy (mainly mucocutaneous and diarrhoea) and can be managed with routine measures. In conclusion, afatinib should be considered as a treatment option in patients with EGFR mutations who show disease progression after a first tyrosine-kinase inhibitor (AU)