Circulating Tumor Cells Identify Early Recurrence in Patients with Non-Small Cell Lung Cancer Undergoing Radical Resection

This work was supported by Fundacion de Investigacion Basica Alenjando Otero (www.Fibao.es) (MJS). The funders had no role in study design, data collection and analyses, decision to publish or preparation of the manuscript.Background Surgery is the treatment of choice for patients with non-small cell lung cancer (NSCLC) stages I-IIIA. However, more than 20% of these patients develop recurrence and die due to their disease. The release of tumor cells into peripheral blood (CTCs) is one of the main causes of recurrence of cancer. The objectives of this study are to identify the prognostic value of the presence and characterization of CTCs in peripheral blood in patients undergoing radical resection for NSCLC. Patients and Methods 56 patients who underwent radical surgery for previously untreated NSCLC were enrolled in this prospective study. Peripheral blood samples for CTC analysis were obtained before and one month after surgery. In addition CTCs were phenotypically characterized by epidermal growth factor receptor (EGFR) expression. Results 51.8% of the patients evaluated were positive with the presence of CTCs at baseline. A decrease in the detection rate of CTCs was observed in these patients one month after surgery (32.1%) (p = 0.035). The mean number of CTCs was 3.16 per 10 ml (range 0-84) preoperatively and 0.66 (range 0-3) in postoperative determination. EGFR expression was found in 89.7% of the patients at baseline and in 38.9% patients one month after surgery. The presence of CTCs after surgery was significantly associated with early recurrence (p = 0.018) and a shorter disease free survival (DFS) (p =.008). In multivariate analysis CTC presence after surgery (HR = 5.750, 95% CI: 1.50-21.946, p = 0.010) and N status (HR = 0.296, 95% CI: 0.091-0.961, p = 0.043) were independent prognostic factors for DFS. Conclusion CTCs can be detected and characterized in patients undergoing radical resection for non-small cell lung cancer. Their presence might be used to identify patients with increased risk of early recurrence.Fundacion de Investigación Básica Alenjando Oter

Cooperative and Escaping Mechanisms between Circulating Tumor Cells and Blood Constituents

Metastasis is the leading cause of cancer-related deaths and despite measurable progress in the field, underlying mechanisms are still not fully understood. Circulating tumor cells (CTCs) disseminate within the bloodstream, where most of them die due to the attack of the immune system. On the other hand, recent evidence shows active interactions between CTCs and platelets, myeloid cells, macrophages, neutrophils, and other hematopoietic cells that secrete immunosuppressive cytokines, which aid CTCs to evade the immune system and enable metastasis. Platelets, for instance, regulate inflammation, recruit neutrophils, and cause fibrin clots, which may protect CTCs from the attack of Natural Killer cells or macrophages and facilitate extravasation. Recently, a correlation between the commensal microbiota and the inflammatory/immune tone of the organism has been stablished. Thus, the microbiota may affect the development of cancer-promoting conditions. Furthermore, CTCs may suffer phenotypic changes, as those caused by the epithelial–mesenchymal transition, that also contribute to the immune escape and resistance to immunotherapy. In this review,we discuss the findings regarding the collaborative biological events among CTCs, immune cells, and microbiome associated to immune escape and metastatic progression

Valor pronóstico de la detención y caracterización de células tumorales circulantes en pacientes con cáncer de pulmón no microcítico sometidos a tratamiento quirúrgico radical

El cáncer de pulmón representa la principal causa de muerte atribuída a cáncer a nivel mundial. Las variantes no microcíticas representan más del 80%. La resección quirúrgica constituye el tratamiento de elección del cáncer de pulmón no microcítico y a pesar de que con la cirugía se consiguen las mejores tasas de supervivencia, el alto porcentaje de recurrencias incluso en estadios iniciales y tras resección completa ha llevado a plantear la necesidad de investigar nuevos factores pronósticos. Diversos estudios han demostrado el papel clave que la detección de celulas tumorales circulantes (CTCs) tienen en el proceso metastásico y el papel pronóstico y predictivo que la determinación de estas CTCs puede tener en diferentes tumores de origen epitelial, como en el cáncer de mama, colon o próstata. El origen de la recurrencia local o de la diseminación metastásica podría relacionarse con la presencia de estas células tumorales circulantes, que son capaces de desprenderse del tumor primario ya en estadios iniciales En lo que respecta al cáncer de pulmón varios grupos han investigado el valor pronóstico de la detección de CTCs en pacientes con estadios avanzados sometidos a tratamiento quimioterápico. Sin embargo son escasas las publicaciones en en estadios iniciales sometidos a resección quirúrgica, sus reslutados apuntan a un posible valor pronóstico de la determianción de CTCs, requiriéndose de nuevos estudios para confirmar dichos hallazgos. Con estos antecedentes se planteó este estudio con el objetivo general de analizar el valor pronóstico de la detección y caracterización de CTCs en pacientes con tratamiento quirúrgico radical de un cáncer de pulmón no microcítico.Tesis Univ. Granada. Programa Oficial de Doctorado en: Cirugí

Post-Surgery Circulating Tumor Cells and AXL Overexpression as New Poor Prognostic Biomarkers in Resected Lung Adenocarcinoma

Background: The prognosis of early stage non-small cell lung cancer (NSCLC) is quite disappointing and the benefits of adjuvant therapy are relatively small. Thus, there is an urgent need to identify novel prognostic and predictive biomarkers. Lung adenocarcinoma has distinct clinical–pathological characteristics and novel therapeutic strategies are under active evaluation in the adjuvant setting. Here, we investigated the prognostic impact of circulating tumor cells (CTCs) and gene and miRNA tissue expression in resectable NSCLC. Results: ADC (n = 47) and SCC (n = 50) revealed different tissue expression profiles, resulting in the presence of different CTC subpopulations. In ADC, miR-155 correlated with AXL and IL6R expression, which were related to the presence of EMT CTC1 (p = 0.014 and p = 0.004). In the multivariate analysis, CTC2 was an independent prognostic factor for relapse-free survival, and CTC3 and AXL were independent prognostic for overall survival only in ADC. Neither the surgery nor the adjuvant treatment influenced the prognosis of these patients. Conclusions: Our study elucidate the prognostic impact of tissue AXL expression and the presence of CTCs after surgery in adenocarcinoma patients. Tissue AXL expression and CTC EMT activation could potentially represent biomarkers for the stratification of ADC patients that might benefit from new adjuvant therapies.This work was supported by the Department of Health and SocialWelfare of the Regional Government of Andalusia [PI-0294-2012] and Diego de Miguel Perez was supported by the PhD (2014) and the PhD International Mobility (2019) grants from the University of Granada, Spain