Análisis de polimorfismos en genes que codifican para enzimas que regulan el estrés oxidativo y su relación con la respuesta al tratamiento y la supervivencia en pacientes con cáncer de pulmón

Los mecanismos de estrés oxidativo están implicados en numerosas condiciones patológicas, entre ellas el inicio, la promoción y la progresión del proceso de carcinogénesis. Los pulmones, son órganos susceptibles de sufrir daños por oxidantes exógenos y por las especies reactivas del oxígeno endógenas generadas por las células inflamatorias. De hecho, en el cáncer de pulmón se ha relacionado el nivel de estrés oxidativo con el pronóstico y el tratamiento y se ha sugerido que los estadios avanzados de cáncer de pulmón exhiben un nivel de estrés oxidativo más elevado que los estadios iniciales, lo que contribuiría a explicar la baja supervivencia en la enfermedad avanzada. Por otra parte, los tratamientos empleados en el cáncer de pulmón generan especies reactivas del oxígeno y, además, las combinaciones de quimioterapia con cisplatino inducen una disminución de los niveles plasmáticos de antioxidantes. Es también frecuente observar una gran variabilidad entre individuos, tanto en la susceptibilidad para desarrollar un cáncer de pulmón como en la supervivencia y en la tasa de respuesta al tratamiento antitumoral. Los polimorfismos de un solo nucleótido (SNPs) pueden ser los responsables de esta variabilidad genética. Prácticamente no existen trabajos que aborden el estudio de variantes genéticas en genes relacionados con el estrés oxidativo en la población con cáncer de pulmón. Por tanto, esta tesis se plantea investigar si la diversidad genética heredada en los genes relacionados con el estrés oxidativo puede tener relación con las características de la enfermedad en el momento del diagnóstico, con la respuesta al tratamiento y con la supervivencia. Con esa finalidad, el presente trabajo examina la asociación de 14 SNPs en 7 genes relacionados con el estrés oxidativo que codifican para proteínas productoras de radicales libres, con los factores pronósticos clásicos, la respuesta al tratamiento y la supervivencia de una población de 219 pacientes con cáncer de pulmón. Se trata de un estudio observacional retrospectivo de casos-casos, con pacientes diagnosticados de cáncer de pulmón, todos ellos procedentes del Hospital Clínico Universitario de Valencia. La población de estudio procede del grupo de pacientes reclutados en dos proyectos de investigación puestos en marcha por el Servicio de Neumología en 2002, dirigidos a evaluar la relación entre el riesgo de cáncer de pulmón y la presencia de polimorfismos en genes relacionados con el estrés oxidativo y el metabolismo de los carcinógenos del humo del tabaco. Partiendo del grupo de genes relacionados con el estrés oxidativo que formó parte de los proyectos de investigación iniciales, se realizó la selección de polimorfismos candidatos a estudiar, entre aquellos que estuvieran localizados en genes que codificaran proteínas productoras de radicales libres. En estos genes se realizó la búsqueda de polimorfismos de un único nucleótido (SNPs) que estuvieran localizados en la región codificante (SNPs exónicos), tanto no sinónimos, con cambio de sentido (“SNPs missense”), como sinónimos, con una frecuencia mínima del alelo menor del 5% para los SNPs missense y del 10% para los SNPs sinónimos en la población general. Fruto de esta búsqueda se encontraron un total de 14 SNPs que cumplían los criterios anteriores, localizados en los siguientes genes: NCF2 (1 SNP) NCF4 (2 SNPs), NOX3 (3 SNPs), NOX5 (2 SNPs), XDH (2 SNPs), NOS2 (2 SNPs ) y RAC2 (2 SNPs). Todos los análisis se realizaron en la población global de los 219 pacientes y la población de cáncer de pulmón no microcítico de 180 pacientes. Por primera vez, se detectaron 3 asociaciones relevantes. El SNP rs2075939(C>T) del gen NCF4 presentó una asociación estadísticamente significativa con el estadio. El SNP rs231954 (T>C) del gen NOX3 presentó una asociación estadísticamente significativa con la respuesta y el SNP rs2075939(C>T) del ge nNCF4 se asoció significativamente con la supervivencia en los estadios I-III de CPNM

Cost-effectiveness of adjuvant atezolizumab versus best supportive care in the treatment of patients with resectable early-stage non-small cell lung cancer and overexpression of PD-L1

Cost-effectiveness analysis; Economic evaluation; ImmunotherapiesAnàlisi cost-efectivitat; Avaluació econòmica; ImmunoteràpiesAnálisis costo-efectividad; Evaluación económica; InmunoterapiasAims To assess the cost-effectiveness of adjuvant atezolizumab in the treatment of early-stage NSCLC patients (stage II–IIIA) with expression PD-L1 ≥ 50% without mutations in EGFR or ALK rearrangements in Spain. Materials and methods A 5-states Markov model (DFS, locoregional recurrence, 1 L-metastatic recurrence, 2 L-metastatic recurrence, and death states) was adapted to the Spanish setting. Demographic characteristics of the hypothetical cohort, transition probabilities from the DFS state, and safety parameters were obtained from IMpower010 study (GO29527). Transition probabilities from locoregional and metastatic health states were obtained from the literature. The usual clinical practice in Spain (use of health resources, management of the disease, etc.) was obtained from a previous analysis carried out by the authors of this study. A societal perspective was considered so both direct and indirect costs were included (expressed in € of 2021). A lifetime horizon was used, so costs and health outcomes were discounted at 3% per year. Sensitivity analyses were performed to evaluate uncertainty. Results Over a lifetime horizon, treatment with adjuvant atezolizumab provided greater effectiveness (+2.61 life years [LY] and +1.95 quality-adjusted life years [QALY]) and higher cost (€+22,538) than BSC. The incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratios (ICUR) of the analysis were €8,625/LY gained and €11,583/QALY gained, respectively. Robustness of these base-case results was confirmed by the sensitivity analyses performed. In the probabilistic sensitivity analysis, 90% of the simulations performed showed that adjuvant atezolizumab is cost-effective versus BSC, considering a threshold of €30,000/QALY. Conclusions Our results showed that adjuvant treatment with atezolizumab in patients with early-stage resected NSCLC with overexpression of PD-L1 and without EGFR and ALK mutations is cost-effective versus BSC as the ICERs and ICURs obtained are below the cost-effectiveness thresholds commonly considered in Spain, thus offering a new treatment alternative for these patients

Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy

Gene expression profiling; Lung neoplasms; Tumor biomarkersPerfil d'expressió gènica; Neoplàsies pulmonars; Biomarcadors tumoralsPerfil de expresión génica; Neoplasias pulmonares; Biomarcadores tumoralesBackground Neoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC) has improved pathological responses and survival rates compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of nivolumab plus chemotherapy for resectable stage IB-IIIA NSCLC (AJCC 7th edition) without ALK or EGFR alterations. Unfortunately, a considerable percentage of tumors do not completely respond to therapy, which has been associated with early disease progression. So far, it is impossible to predict these events due to lack of knowledge. In this study, we characterized the gene expression profile of tumor samples to identify new biomarkers and mechanisms behind tumor responses to neoadjuvant chemoimmunotherapy and disease recurrence after surgery. Methods Tumor bulk RNA sequencing was performed in 16 pretreatment and 36 post-treatment tissue samples from 41 patients with resectable stage IIIA NSCLC treated with neoadjuvant chemoimmunotherapy from NADIM trial. A panel targeting 395 genes related to immunological processes was used. Tumors were classified as complete pathological response (CPR) and non-CPR, based on the total absence of viable tumor cells in tumor bed and lymph nodes tested at surgery. Differential-expressed genes between groups and pathway enrichment analysis were assessed using DESeq2 and gene set enrichment analysis. CIBERSORTx was used to estimate the proportions of immune cell subtypes. Results CPR tumors had a stronger pre-established immune infiltrate at baseline than non-CPR, characterized by higher levels of IFNG, GZMB, NKG7, and M1 macrophages, all with a significant area under the receiver operating characteristic curve (ROC) >0.9 for CPR prediction. A greater effect of neoadjuvant therapy was also seen in CPR tumors with a reduction of tumor markers and IFNγ signaling after treatment. Additionally, the higher expression of several genes, including AKT1, BST2, OAS3, or CD8B; or higher dendritic cells and neutrophils proportions in post-treatment non-CPR samples, were associated with relapse after surgery. Also, high pretreatment PD-L1 and tumor mutational burden levels influenced the post-treatment immune landscape with the downregulation of proliferation markers and type I interferon signaling molecules in surgery samples. Conclusions Our results reinforce the differences between CPR and non-CPR responses, describing possible response and relapse immune mechanisms, opening the possibility of therapy personalization of immunotherapy-based regimens in the neoadjuvant setting of NSCLC.Work in the authors’ laboratories was supported by '‘Instituto de Salud Carlos III’' (ISCIII) PI19/01652 grant cofunded by European Regional Development Fund (ERDF), Bristol-Myers Squibb (BMS), Ministry of Science and Innovation RTC2017-6502-1 'INmunoSIGHT', RTC2019-007359-1 'BLI-O' and European Union’s Horizon 2020 research and innovation programme, CLARIFY 875160 grant, to MP. ThermoFisher provided reagents for RNA sequencing. AC-B received a Spanish Lung Cancer Group (SLCG) grant and is supported by a ISCIII-“Sara Borrell” contract CD19/00170. MCa is supported by PEJD-2019-PRE/BMD-17006 contract granted to AC-B

Comprehensive cross-platform comparison of methods for non-invasive EGFR mutation testing: results of the RING observational trial

Several platforms for noninvasive EGFR testing are currently used in the clinical setting with sensitivities ranging from 30% to 100%. Prospective studies evaluating agreement and sources for discordant results remain lacking. Herein, seven methodologies including two next-generation sequencing (NGS)-based methods, three high-sensitivity PCR-based platforms, and two FDA-approved methods were compared using 72 plasma samples, from EGFR-mutant non-small-cell lung cancer (NSCLC) patients progressing on a first-line tyrosine kinase inhibitor (TKI). NGS platforms as well as high-sensitivity PCR-based methodologies showed excellent agreement for EGFR-sensitizing mutations (K = 0.80–0.89) and substantial agreement for T790M testing (K = 0.77 and 0.68, respectively). Mutant allele frequencies (MAFs) obtained by different quantitative methods showed an excellent reproducibility (intraclass correlation coefficients 0.86–0.98). Among other technical factors, discordant calls mostly occurred at mutant allele frequencies (MAFs) ≤ 0.5%. Agreement significantly improved when discarding samples with MAF ≤ 0.5%. EGFR mutations were detected at significantly lower MAFs in patients with brain metastases, suggesting that these patients risk for a false-positive result. Our results support the use of liquid biopsies for noninvasive EGFR testing and highlight the need to systematically report MAFs

Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II trial)

Càncer de pulmó; Quimioteràpia neoadjuvantCáncer de pulmón; Quimioterapia neoadyuvanteLung cancer; Neoadjuvant chemotherapyPURPOSE Neoadjuvant chemotherapy plus nivolumab has been shown to be effective in resectable non–small-cell lung cancer (NSCLC) in the NADIM trial (ClinicalTrials.gov identifier: NCT03081689). The 3-year overall survival (OS) and circulating tumor DNA (ctDNA) analysis have not been reported. METHODS This was an open-label, multicenter, single-arm, phase II trial in which patients with stage IIIA NSCLC, who were deemed to be surgically resectable, were treated with neoadjuvant paclitaxel (200 mg/m2 once a day) and carboplatin (area under curve 6) plus nivolumab (360 mg) once on day 1 of each 21-day cycle, for three cycles, followed by adjuvant nivolumab monotherapy for 1 year (240 mg once every 2 weeks for 4 months, followed by 480 mg once every 4 weeks for 8 months). The 3-year OS and ctDNA analysis were secondary objectives of the trial. RESULTS OS at 36 months was 81.9% (95% CI, 66.8 to 90.6) in the intention-to-treat population, rising to 91.0% (95% CI, 74.2 to 97.0) in the per-protocol population. Neither tumor mutation burden nor programmed cell death ligand-1 staining was predictive of survival. Conversely, low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and OS (hazard ratio [HR], 0.20; 95% CI, 0.06 to 0.63, and HR, 0.07; 95% CI, 0.01 to 0.39, respectively). Clinical responses according to RECIST v1.1 criteria did not predict survival outcomes. However, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and OS (HR, 0.26; 95% CI, 0.07 to 0.93, and HR, 0.04; 95% CI, 0.00 to 0.55, respectively). The C-index to predict OS for ctDNA levels after neoadjuvant treatment (0.82) was superior to that of RECIST criteria (0.72). CONCLUSION The efficacy of neoadjuvant chemotherapy plus nivolumab in resectable NSCLC is supported by 3-year OS. ctDNA levels were significantly associated with OS and outperformed radiologic assessments in the prediction of survival

Economic burden of locoregional and metastatic relapses in resectable early-stage non-small cell lung cancer in Spain

Early-stage NSCLC; Economic burden; Metastatic relapseNSCLC en fase inicial; Carga económica; Recaída metastásicaNSCLC en fase inicial; Càrrega econòmica; Recaiguda metastàticaBackground There are scarce data of the costs of non-small cell lung cancer (NSCLC) recurrence in Spain. The objective of this study is to assess the economic burden of disease recurrence, for both locoregional and/or metastatic relapses, after appropriate early-stage NSCLC treatment in Spain. Materials and methods A two-round consensus panel of Spanish oncologists and hospital pharmacists was conducted to collect information on patient’s flow, treatments, use of healthcare resources and sick leaves in patients with relapsed NSCLC. A decision-tree model was developed to calculate the economic burden of disease recurrence after appropriate early-stage NSCLC. Both direct and indirect costs were considered. Direct costs included drug acquisition and healthcare resources costs. Indirect costs were estimated using the human-capital approach. Unit costs were obtained from national databases (euros of 2022). A multi-way sensitivity analysis was performed to provide a range to the mean values. Results Among a cohort of 100 patients with relapsed NSCLC, 45 patients would have locoregional relapse (36.3 would eventually progress to metastasis and 8.7 would be considered in remission) and 55 patients would have metastatic relapse. Over time, 91.3 patients would experience a metastatic relapse (55 as first relapse and 36.6 after previous locoregional relapse). The overall cost incurred by the 100-patients cohort is €10,095,846 (€9,336,782 direct costs, €795,064 indirect costs). The average cost of a locoregional relapse is €25,194 (€19,658 direct costs, €5536 indirect costs), while the average cost a patient with metastasis who receives up to 4 lines of treatment is €127,167 (€117,328 direct, €9839 indirect). Conclusions To our knowledge, this is the first study that specifically quantifies the cost of relapse in NSCLC in Spain. Our findings shown that the overall cost of a relapse after appropriate treatment of early-stage NSCLC patients is substantial, and it increases considerably in the metastatic relapse setting, mainly due to the high cost and long duration of first-line treatments.This work was supported by Roche Farma S.A. Roche Farma S.A played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript

Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non–Small-Cell Lung Cancer (NADIM phase II trial)

PURPOSE Neoadjuvant chemotherapy plus nivolumab has been shown to be effective in resectable non–small cell lung cancer (NSCLC) in the NADIM trial (ClinicalTrials.gov identifier: NCT03081689). The 3-year overall survival (OS) and circulating tumor DNA (ctDNA) analysis have not been reported. METHODS This was an open-label, multicenter, single-arm, phase II trial in which patients with stage IIIA NSCLC, who were deemed to be surgically resectable, were treated with neoadjuvant paclitaxel (200 mg/m2 once a day) and carboplatin (area under curve 6) plus nivolumab (360 mg) once on day 1 of each 21-day cycle, for three cycles, followed by adjuvant nivolumab monotherapy for 1 year (240 mg once every 2 weeks for 4 months, followed by 480 mg once every 4 weeks for 8 months). The 3-year OS and ctDNA analysis were secondary objectives of the trial. RESULTS OS at 36 months was 81.9% (95% CI, 66.8 to 90.6) in the intention-to-treat population, rising to 91.0% (95% CI, 74.2 to 97.0) in the per-protocol population. Neither tumor mutation burden nor programmed cell death ligand-1 staining was predictive of survival. Conversely, low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and OS (hazard ratio [HR], 0.20; 95% CI, 0.06 to 0.63, and HR, 0.07; 95% CI, 0.01 to 0.39, respectively). Clinical responses according to RECIST v1.1 criteria did not predict survival outcomes. However, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and OS (HR, 0.26; 95% CI, 0.07 to 0.93, and HR, 0.04; 95% CI, 0.00 to 0.55, respectively). The C-index to predict OS for ctDNA levels after neoadjuvant treatment (0.82) was superior to that of RECIST criteria (0.72). CONCLUSION The efficacy of neoadjuvant chemotherapy plus nivolumab in resectable NSCLC is supported by 3- year OS. ctDNA levels were significantly associated with OS and outperformed radiologic assessments in the prediction of survival

Pretreatment Tissue TCR Repertoire Evenness Is Associated with Complete Pathologic Response in Patients with NSCLC Receiving Neoadjuvant Chemoimmunotherapy

Neoadjuvant Chemoimmunotherapy; Lung cancer; T-cell receptorQuimioimmunoteràpia neoadjuvant; Càncer de pulmó; Receptor de cèl·lules TQuimioinmunoterapia neoadyuvante; Cáncer de pulmón; Receptor de células TPurpose: Characterization of the T-cell receptor (TCR) repertoire may be a promising source for predictive biomarkers of pathologic response to immunotherapy in locally advanced non–small cell lung cancer (NSCLC). Experimental Design: In this study, next-generation TCR sequencing was performed in peripheral blood and tissue samples of 40 patients with NSCLC, before and after neoadjuvant chemoimmunotherapy (NADIM clinical trial, NCT03081689), considering their complete pathologic response (CPR) or non-CPR. Beyond TCR metrics, tissue clones were ranked by their frequency and spatiotemporal evolution of top 1% clones was determined. Results: We have found a positive association between an uneven TCR repertoire in tissue samples at diagnosis and CPR at surgery. Moreover, TCR most frequently ranked clones (top 1%) present in diagnostic biopsies occupied greater frequency in the total clonal space of CPR patients, achieving an AUC ROC to identify CPR patients of 0.967 (95% confidence interval, 0.897–1.000; P = 0.001), and improving the results of PD-L1 tumor proportion score (TPS; AUC = 0.767; P = 0.026) or tumor mutational burden (TMB; AUC = 0.550; P = 0.687). Furthermore, tumors with high pretreatment top 1% clonal space showed similar immune cell populations but a higher immune reactive gene expression profile. Finally, the selective expansion of pretreatment tissue top 1% clones in peripheral blood of CPR patients suggests also a peripheral immunosurveillance, which could explain the high survival rate of these patients. Conclusions: We have identified two parameters derived from TCR repertoire analysis that could outperform PD-L1 TPS and TMB as predictive biomarkers of CPR after neoadjuvant chemoimmunotherapy, and unraveled possible mechanisms of CPR involving enhanced tumor immunogenicity and peripheral immunosurveillance

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

Delphi method; Non-small cell lung cancer; OsimertinibMétodo Delphi; Cáncer de pulmón de células no pequeñas; OsimertinibMètode Delphi; Càncer de pulmó de cèl·lules no petites; OsimertinibPurpose 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.The project was funded by ICAPEM (for its acronym in Spanish of Asociación para la Investigación de Cáncer de Pulmón en Mujeres). The opinions expressed are those of the authors. The funding party did not influence any aspect of the study design, collection, analysis or interpretation of data, or decision to submit the manuscript for publication

Blood biomarkers associated to complete pathologicalresponse on NSCLC patients treated with neoadjuvantchemoimmunotherapy included in NADIM clinical trial

Background:Immunotherapy is being tested in early-stage non-small cell lungcancer (NSCLC), and achieving higher rates of complete pathological responses(CPR) as compared to standard of care. Early identification of CPR patients hasvital clinical implications. In this study, we focused on basal peripheral immunecells and their treatment-related changes to find biomarkers associated toCPR.Methods:Blood from 29 stage IIIA NSCLC patients participating in the NADIMtrial (NCT03081689) was collected at diagnosis and post neoadjuvant treatment.More than 400 parameters of peripheral blood mononuclear cells (PBMCs) phe-notype and plasma soluble factors were analyzed.Results:Neoadjuvant chemoimmunotherapy altered more than 150 immuneparameters. At diagnosis, 11 biomarkers associated to CPR were described, withan area under the ROC curve>0.70 andp-value<.05. CPR patients had sig-nificantly higher levels of CD4+PD-1+cells, NKG2D, and CD56 expression onT CD56 cells, intensity of CD25 expression on CD4+CD25hi+cells and CD69expression on intermediate monocytes; but lower levels of CD3+CD56–CTLA-4+cells, CD14++CD16+CTLA-4+cells, CTLA-4 expression on T CD56 cells andlower levels of b-NGF, NT-3, and VEGF-D in plasma compared to non-CPR. Posttreatment, CPR patients had significantly higher levels of CD19 expression on Bcells, BCMA, 4-1BB, MCSF, and PARC and lower levels of MPIF-1 and Flt-3L inplasma compared to non-CPR.Conclusions:Patients achieving CPR seem to have a distinctive peripheralblood immune status at diagnosis, even showing different immune response totreatment.TheseresultsreinforcethedifferentbiologybehindCPRandnon-CPRresponses