RESUMEN
BACKGROUND: The prognostic relevance of early immune-related adverse events (irAEs) in patients affected by non-small cell lung cancer (NSCLC) upon immunotherapy is not fully understood. METHODS: The Leading to Treatment Discontinuation cohort included 24 patients experiencing severe irAEs after one of two administrations of single anti-PD-1/PD-L1 in any line setting for metastatic NSCLC between November 2015 and June 2019. The control cohort was composed of 526 patients treated with single anti-PD-1/PD-L1 in any line setting with no severe irAE reported. The primary end points were median progression-free survival, overall survival, objective response rate, risk of progression of disease and risk of death. The correlation of clinic pathological features with early severe irAEs represented the secondary end point. RESULTS: Median PFS was 9.3 and 8.4 months, median OS was 12.0 months and 14.2 months at a median follow-up of 18.1 and 22.6 months in the LTD cohort and in the control cohort, respectively. The ORR was 40% (95% CI 17.2-78.8) in the LTD cohort and 32.7% (95% CI 27.8-38.2) in the control cohort. The risk of disease progression was higher in the LTD cohort (HR 2.52 [95% 1.10-5.78], P = .0288). CONCLUSIONS: We found no survival benefit in LTD cohort compared to the control cohort. However, early and severe irAEs might underly an immune anti-tumor activation. We identified a significant association with first-line immune checkpoints inhibitors treatment and good PS. Further studies on risk prediction and management of serious and early irAEs in NSCLC patients are needed.
Asunto(s)
Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Antineoplásicos Inmunológicos/efectos adversos , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/patología , Receptor de Muerte Celular Programada 1 , Estudios RetrospectivosRESUMEN
BACKGROUND: High circulating levels of cellular adhesion molecules (CAMs) in non-small cell lung cancer (NSCLC) have been supposed to act as a negative prognostic factor. Here, we explored the predictive role of pre-treatment levels of CAMs in previously treated patients receiving nivolumab for NSCLC. MATERIALS AND METHODS: Seventy one patients with advanced NSCLC, treated with nivolumab at the dose of 3 mg/kg every 14 days, were enrolled. Maximum follow-up time was 3 years. Serum levels of Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intracellular Adhesion Molecule-1 (ICAM-1) were measured at baseline and before each nivolumab administration. Endpoints of the study were a composite outcome of survival ≥2 years or absence of disease progression at the end of the follow-up, and the overall survival. RESULTS: Composite outcome and overall survival were positively associated with VCAM-1 baseline levels and with the reduction of VCAM-1 during the treatment. After adjustment for potential confounders, the change in VCAM-1 serum levels during the treatment was an independent predictor of overall survival. CONCLUSIONS: High baseline serum levels of VCAM-1 are associated with a longer survival in patients treated with nivolumab as second line treatment for NSCLC. Surviving patients experience also a significant reduction in CAMs expression during the treatment. Hence, CAMs might be promising prognostic factors in patients with NSCLC underoing immunotherapy.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Nivolumab/uso terapéutico , Molécula 1 de Adhesión Celular Vascular/sangre , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: Patients with cancer are considered at high risk for the novel respiratory illness coronavirus disease 2019 (COVID-19). General measures to keep COVID-19-free cancer divisions have been adopted worldwide. The objective of this study was to evaluate the efficacy of triage to identify COVID-19 among patients with cancer. METHODS: From March 20 to April 17, 2020, data were collected from patients who were treated or followed at the authors' institution in a prospective clinical trial. The primary endpoint was to estimate the cumulative incidence of COVID-19-positive patients who were identified using a triage process through the aid of medical and patient questionnaires. Based on a diagnostic algorithm, patients with suspect symptoms underwent an infectious disease specialist's evaluation and a COVID-19 swab. Serologic tests were proposed for patients who had symptoms or altered laboratory tests that did not fall into the diagnostic algorithm but were suspicious for COVID-19. RESULTS: Overall, 562 patients were enrolled. Six patients (1%) were diagnosed with COVID-19, of whom 4 (67%) had the disease detected through telehealth triage, and 2 patients (33%) without suspect symptoms at triage had the disease detected later. Seventy-one patients (13%) had suspect symptoms and/or altered laboratory tests that were not included in the diagnostic algorithm and, of these, 47 patients (73%) underwent testing for severe acute respiratory syndrome coronavirus 2 antibody: 6 (13%) were positive for IgG (n = 5) or for both IgM and IgG (n = 1), and antibody tests were negative in the remaining 41 patients. CONCLUSIONS: The triage process had a positive effect on the detection of COVID-19 in patients with cancer. Telehealth triage was helpful in detecting suspect patients and to keep a COVID-19-free cancer center. The overall incidence of COVID-19 diagnosis (1%) and antibody positivity (13%) in patients with suspect symptoms was similar to that observed in the general population.
Asunto(s)
Prueba de COVID-19/estadística & datos numéricos , COVID-19/diagnóstico , Neoplasias/terapia , Triaje/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/complicaciones , COVID-19/virología , Prueba de COVID-19/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/diagnóstico , Estudios Prospectivos , Reproducibilidad de los Resultados , SARS-CoV-2/fisiología , Sensibilidad y Especificidad , Triaje/métodosRESUMEN
HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody drug conjugate showing significant anti-tumor activity in heavily pre-treated HER2-positive breast and gastric cancer patients. Preliminary data have shown promising objective response rates in patients with HER2-positive NSCLC and colorectal cancer. T-DXd has an acceptable safety profile, however with concerns regarding potentially serious treatment-emergent adverse events. In this review we focus on the pharmacologic characteristics and toxicity profile of T-Dxd, and provide an update on the most recent results of clinical trials of T-DXd in solid tumors. The referenced papers were selected through a PubMed search performed on 16 March 2021 with the following searching terms: T-DXd and breast cancer, or gastric cancer, or non-small cell lung cancer (NSCLC), or colorectal cancer. Oral presentation, abstracts, and posters presented at the American Society of Clinical Oncology (ASCO, Alexandria, VA, USA) 2020 and the European Society for Medical Oncology (ESMO, Lugano, Switzerland) 2020 annual meetings were retrieved for data on T-DXd. We also overview ongoing research and data of combination therapies currently under investigation, which will impact on future therapeutic strategies. Clinicaltrials.gov was searched to identify ongoing clinical trials of T-DXd alone or in combination in solid tumors.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Camptotecina/análogos & derivados , Inmunoconjugados/uso terapéutico , Neoplasias/tratamiento farmacológico , Receptor ErbB-2/análisis , Trastuzumab/uso terapéutico , Animales , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/farmacología , Camptotecina/efectos adversos , Camptotecina/farmacología , Camptotecina/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/farmacología , Neoplasias/patología , Trastuzumab/efectos adversos , Trastuzumab/farmacologíaRESUMEN
Growing research has focused on obesity as a prognostic factor during therapy with immune-checkpoint inhibitors (ICIs). The role of body-mass index (BMI) in predicting response and toxicity to ICIs is not clear, as studies have shown inconsistent results and significant interpretation biases. We performed a systematic review to evaluate the relationship between BMI and survival outcomes during ICIs, with a side focus on the incidence of immune-related adverse events (irAEs). A total of 17 studies were included in this systematic review. Altogether, the current evidence does not support a clearly positive association of BMI with survival outcomes. Regarding toxicities, available studies confirm a superimposable rate of irAEs among obese and normal weight patients. Intrinsic limitations of the analyzed studies include the retrospective nature, the heterogeneity of patients' cohorts, and differences in BMI categorization for obese patients across different studies. These factors might explain the heterogeneity of available results, and the subsequent absence of a well-established role of baseline BMI on the efficacy of ICIs among cancer patients. Further prospective studies are needed, in order to clarify the role of obesity in cancer patients treated with immunotherapy.
Asunto(s)
Índice de Masa Corporal , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia , Neoplasias/mortalidad , Neoplasias/terapia , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Tasa de SupervivenciaRESUMEN
BACKGROUND: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%. METHODS: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naïve NSCLC and a PD-L1 expression of ≥ 50%. RESULTS: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis. CONCLUSION: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Antígeno B7-H1/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Estudios RetrospectivosRESUMEN
Monoclonal antibodies targeting PD-1 are used for treating NSCLC. To date, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been poorly investigated in the oncologic field. Here, we aimed at evaluating whether serum PCSK9 might represent a predictive factor for OS in older patients with advanced NSCLC under nivolumab treatment. Among 78 patients with advanced, pre-treated NSCLC previously enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 44 patients have been included in this sub-analysis due to the availability of serum samples for the measurement of PCSK9. Before each nivolumab administration, clinical information and blood samples were collected. Median age was 71, with a prevalence of the male sex. The most represented histological type of lung cancer was adenocarcinoma. The majority of patients were former smokers (72.1%). Median PCSK9 levels were 123.59 (86.32-169.89) ng/mL and 117.17 (80.46-147.79) ng/mL at cycle 1 and 2, respectively. Based on a receiver operating characteristic curve analysis, a PCSK9 value at cycle 2 of 95 ng/mL was found as the best cutoff point for OS. Kaplan-Meier analysis demonstrated that patients below the PCSK9 cutoff (< 95 ng/mL) experienced a better OS, as confirmed by Cox proportional hazard regression analysis. In this pilot study, circulating levels of PCSK9 < 95 ng/mL at the time of the second cycle of nivolumab treatment could independently predict a better OS in elderly patients with advanced, pre-treated NSCLC. However, further studies are warranted to validate these preliminary results.
Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Inmunoterapia/métodos , Neoplasias Pulmonares/diagnóstico , Nivolumab/uso terapéutico , Proproteína Convertasa 9/sangre , Anciano , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Humanos , Italia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Masculino , Estadificación de Neoplasias , Proyectos Piloto , Pronóstico , Estudios Prospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Immunotherapy has become the standard-of-care in many solid tumors. Despite the significant recent achievements in the diagnosis and treatment of cancer, several issues related to patients' selection for immunotherapy remain unsolved. Multiple lines of evidence suggest that, in this setting, the vision of a single biomarker is somewhat naïve and imprecise, given that immunotherapy does not follow the rules that we have experienced in the past for targeted therapies. On the other hand, additional immune-related biomarkers that are reliable in real-life clinical practice remain to be identified. Recently, the immune-checkpoint blockade has been approved in the US irrespective of the tumor site of origin. Further histology-agnostic approvals, coupled with with tumor-specific companion diagnostics and guidelines, are expected in this field. In addition, immune-related biomarkers can also have a significant prognostic value. In this review, we provide an overview of the role of these biomarkers and their characterization in the management of lung cancer, melanoma, colorectal cancer, gastric cancer, head and neck cancer, renal cell carcinoma, urothelial cancers, and breast cancer.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Inmunoterapia/métodos , Neoplasias/metabolismo , Neoplasias/terapia , Antígeno B7-H1/metabolismo , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Antígeno CTLA-4/metabolismo , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/terapia , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/metabolismo , Neoplasias Renales/terapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Melanoma/diagnóstico , Melanoma/metabolismo , Melanoma/terapia , Neoplasias/diagnóstico , PronósticoRESUMEN
BACKGROUND: Rare cases of severe myocarditis are reported during treatment with nivolumab. Troponin, a biomarker of cardiac damage, is a key component of the diagnostic workup of many cardiac disorders, including myocarditis. This study investigates the role of troponin to assess cardiac involvement during nivolumab therapy for non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We evaluated 59 NSCLC patients, analyzing serum samples collected within a translational research study. Troponin above the upper normal limit (0.046 ng/mL) was defined as Tn+, whereas normal but detectable troponin (0.015-0.045) was defined as Tndet. Troponin alterations were interpreted on the grounds of the following elements: peak values and time curve, cardiac comorbidities, signs and symptoms coincident to troponin elevation, ECG, echocardiography, and disease progression. RESULTS: No patient had cardiovascular events. Among 362 available blood samples, Tn+ (max 0.317 ng/mL) was found in 13 determinations belonging to 6 patients. Seven other patients had isolated Tndet. In five patients, Tn+ was attributed to cardiac comorbidities, disease progression, or worsening clinical status. One patient without cardiac history and in good clinical condition had a sustained troponin increase-soon after the start of therapy-and after careful evaluation of all relevant elements, it was interpreted as a marker of nivolumab-related subclinical myocarditis. CONCLUSION: Tn+ may occur in NSCLC patients treated with nivolumab, but in most cases it does not indicate nivolumab cardiotoxicity. In some cases, however, a careful interpretation of troponin alteration, especially at the beginning of therapy, enables identification of subclinical myocarditis, thus allowing early cardiac treatment. IMPLICATIONS FOR PRACTICE: Myocarditis is a rare but serious adverse event of immune checkpoint blockade with nivolumab, which needs to be recognized as soon as possible. This article suggests that troponin, a user-friendly biomarker of myocardial cytotoxicity, might be useful for early detection of immune-mediated myocarditis. However, because troponin abnormalities might also be related to a number of conditions capable of causing myocardial oxygen demand-supply mismatch, a careful cardiac assessment should be performed in non-small cell lung cancer patients in order to properly interpret any troponin increase. According to the available evidence, monitoring troponin during the first weeks of treatment can be considered reasonable.
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Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Nivolumab/uso terapéutico , Troponina/sangre , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Cardiotoxicidad , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Nivolumab/farmacologíaRESUMEN
Cell-free DNA (cfDNA) and circulating tumor cells (CTCs) are promising prognostic and predictive biomarkers in non-small cell lung cancer (NSCLC). In this study, we examined the prognostic role of cfDNA and CTCs, in separate and joint analyses, in NSCLC patients receiving first line chemotherapy. Seventy-three patients with advanced NSCLC were enrolled in this study. CfDNA and CTC were analyzed at baseline and after two cycles of chemotherapy. Plasma cfDNA quantification was performed by quantitative PCR (qPCR) whereas CTCs were isolated by the ScreenCell Cyto (ScreenCell, Paris, France) device and enumerated according to malignant features. Patients with baseline cfDNA higher than the median value (96.3 hTERT copy number) had a significantly worse overall survival (OS) and double the risk of death (hazard ratio (HR): 2.14; 95% confidence limits (CL) = 1.24-3.68; p-value = 0.006). Conversely, an inverse relationship between CTC median baseline number (6 CTC/3 mL of blood) and OS was observed. In addition, we found that in patients reporting stable disease (SD), the baseline cfDNA and CTCs were able to discriminate patients at high risk of poor survival. cfDNA demonstrated a more reliable biomarker than CTCs in the overall population. In the subgroup of SD patients, both biomarkers identified patients at high risk of poor prognosis who might deserve additional/alternative therapeutic interventions.
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Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Ácidos Nucleicos Libres de Células/sangre , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Células Neoplásicas Circulantes/patología , Adulto , Anciano , Estudios de Cohortes , Quimioterapia , Femenino , Humanos , Estimación de Kaplan-Meier , Biopsia Líquida , Masculino , Persona de Mediana Edad , Pronóstico , Resultado del TratamientoRESUMEN
PURPOSE OF REVIEW: Most patients affected by lung cancer are treated with chemotherapy, and hence are at risk of myelosuppression. Hematopoietic growth factors have a relevant role in this setting, as they can improve quality of life, reduce the rate of chemotherapy-induced complications and allow the administration of full-dose chemotherapy. RECENT FINDINGS: Most data of hematologic growth factors in lung cancer come from dated publications or large trials involving different malignancies, thus limiting specific information for lung neoplasms. Nonetheless, most studies consistently identified myeloid growth factors as effective on specific end-points such as the duration and severity of neutropenia, or complications such as hospitalizations and febrile neutropenia; on the other hand, erythropoiesis-stimulating agents (ESAs) consistently improved anemia-specific end-points including hemoglobin values, transfusions rate and fatigue, although some specific safety issues characterized this drug class. The most recent international guidelines address these characteristics and include the main indications for hematologic growth factors in solid neoplasms, including lung cancer. SUMMARY: Myeloid growth factors and ESAs have a relevant role in selected patients undergoing chemotherapy for nonsmall cell lung cancer and small cell lung cancer. Notably, a comprehensive risk-benefit assessment is required in the specific case of ESAs.
Asunto(s)
Anemia/tratamiento farmacológico , Neutropenia Febril Inducida por Quimioterapia/prevención & control , Hematínicos/uso terapéutico , Fármacos Hematológicos/uso terapéutico , Factores de Crecimiento de Célula Hematopoyética/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Anemia/inducido químicamente , Anemia/prevención & control , Neutropenia Febril Inducida por Quimioterapia/tratamiento farmacológico , HumanosRESUMEN
BACKGROUND: Next Generation Sequencing (NGS) has become a valuable tool for molecular landscape characterization of cancer genomes, leading to a better understanding of tumor onset and progression, and opening new avenues in translational oncology. Formalin-fixed paraffin-embedded (FFPE) tissue is the method of choice for storage of clinical samples, however low quality of FFPE genomic DNA (gDNA) can limit its use for downstream applications. METHODS: To investigate the FFPE specimen suitability for NGS analysis and to establish the performance of two solution-based exome capture technologies, we compared the whole-exome sequencing (WES) data of gDNA extracted from 5 fresh frozen (FF) and 5 matched FFPE lung adenocarcinoma tissues using: SeqCap EZ Human Exome v.3.0 (Roche NimbleGen) and SureSelect XT Human All Exon v.5 (Agilent Technologies). RESULTS: Sequencing metrics on Illumina HiSeq were optimal for both exome systems and comparable among FFPE and FF samples, with a slight increase of PCR duplicates in FFPE, mainly in Roche NimbleGen libraries. Comparison of single nucleotide variants (SNVs) between FFPE-FF pairs reached overlapping values >90 % in both systems. Both WES showed high concordance with target re-sequencing data by Ion PGM™ in 22 lung-cancer genes, regardless the source of samples. Exon coverage of 623 cancer-related genes revealed high coverage efficiency of both kits, proposing WES as a valid alternative to target re-sequencing. CONCLUSIONS: High-quality and reliable data can be successfully obtained from WES of FFPE samples starting from a relatively low amount of input gDNA, suggesting the inclusion of NGS-based tests into clinical contest. In conclusion, our analysis suggests that the WES approach could be extended to a translational research context as well as to the clinic (e.g. to study rare malignancies), where the simultaneous analysis of the whole coding region of the genome may help in the detection of cancer-linked variants.
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Adenocarcinoma/genética , ADN de Neoplasias/análisis , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias Pulmonares/genética , Juego de Reactivos para Diagnóstico , Adenocarcinoma del Pulmón , Exoma , Formaldehído , Humanos , Adhesión en Parafina , Fijación del TejidoRESUMEN
Next-generation sequencing (NGS) is a cost-effective technology capable of screening several genes simultaneously; however, its application in a clinical context requires an established workflow to acquire reliable sequencing results. Here, we report an optimized NGS workflow analyzing 22 lung cancer-related genes to sequence critical samples such as DNA from formalin-fixed paraffin-embedded (FFPE) blocks and circulating free DNA (cfDNA). Snap frozen and matched FFPE gDNA from 12 non-small cell lung cancer (NSCLC) patients, whose gDNA fragmentation status was previously evaluated using a multiplex PCR-based quality control, were successfully sequenced with Ion Torrent PGM™. The robust bioinformatic pipeline allowed us to correctly call both Single Nucleotide Variants (SNVs) and indels with a detection limit of 5%, achieving 100% specificity and 96% sensitivity. This workflow was also validated in 13 FFPE NSCLC biopsies. Furthermore, a specific protocol for low input gDNA capable of producing good sequencing data with high coverage, high uniformity, and a low error rate was also optimized. In conclusion, we demonstrate the feasibility of obtaining gDNA from FFPE samples suitable for NGS by performing appropriate quality controls. The optimized workflow, capable of screening low input gDNA, highlights NGS as a potential tool in the detection, disease monitoring, and treatment of NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Biología Computacional/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Pulmonares/genética , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Biología Computacional/normas , Humanos , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Polimorfismo de Nucleótido Simple , Control de Calidad , Sensibilidad y Especificidad , Flujo de TrabajoRESUMEN
After several decades of modest results with nonspecific immune stimulants, immunotherapy has become an exciting approach in the treatment of cancer. Although non-small-cell lung cancer has not been considered an immunogenic disease for very long, a better understanding of tumor immunology and the identification of new targets have led to the development of many clinical trials of immune-based therapies for this neoplasm. Promising results from many clinical trials suggest that immunotherapy could be an effective strategy in the management of advanced non-small-cell lung cancer. Further studies are required to help clinicians in the selection of patients who are more likely to benefit from immunotherapy strategies by the identification of biomarkers and to understand when the combination of immunotherapy with other agents should be recommended.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/terapia , Inmunoterapia/métodos , Neoplasias Pulmonares/terapia , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antígeno CTLA-4/inmunología , Vacunas contra el Cáncer/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Humanos , Ipilimumab , Neoplasias Pulmonares/metabolismo , Terapia Molecular Dirigida/métodos , Nivolumab , Oligodesoxirribonucleótidos/farmacología , Oligodesoxirribonucleótidos/uso terapéutico , Receptor de Muerte Celular Programada 1/inmunología , Receptor Toll-Like 9/inmunología , Receptor Toll-Like 9/metabolismoRESUMEN
Immunotherapy has improved survival outcomes of patients with advanced melanoma. Lower gastrointestinal tract immune-related adverse events (irAEs) are common during treatment; however, gastritis is not frequently observed. Herein, we report a case of severe cytomegalovirus (CMV)-related gastritis in a patient treated with ipilimumab and nivolumab for metastatic melanoma. This report presents a 60-year-old woman with stage IV BRAF wild-type melanoma. After the second course of ipilimumab-nivolumab, the patient reported epigastric discomfort after meals, anorexia, and subsequent nausea, vomiting, epigastric pain, and weight loss. Disease staging with PET/CT scan showed very good partial response and diffuse gastroduodenitis. The patient underwent esophagogastroduodenoscopy, showing severe esophageal candidiasis and diffuse hemorrhagic, edematous, and ulcerative mucosa in the whole gastric wall. Biopsies of the gastric wall were obtained. Before receipt of the final pathology report, the patient was empirically started on corticosteroids based on the clinical suspicion of immune-related gastritis, without improvement of symptoms. The hematoxylin-eosin staining demonstrated active gastritis with diffuse nuclear cytopathic viral inclusions in epithelial and interstitial cells; CMV infection was confirmed with immunohistochemical staining. The patient started ganciclovir and fluconazole, with rapid improvement of symptoms. This case presents a rare instance of CMV gastritis in a patient receiving combined anti-PD1 and anti-CTLA4 , in the absence of immune-suppression to manage an irAE. In the case of suggestive symptoms of irAEs, a high index of clinical suspicion is required to rule out concomitant or isolated infective disease. Guidelines for prophylaxis and treatment of these patients are needed, to optimize treatment results.
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Infecciones por Citomegalovirus , Gastritis , Ipilimumab , Melanoma , Nivolumab , Humanos , Melanoma/tratamiento farmacológico , Melanoma/complicaciones , Ipilimumab/efectos adversos , Femenino , Persona de Mediana Edad , Gastritis/inducido químicamente , Nivolumab/efectos adversos , Infecciones por Citomegalovirus/inducido químicamente , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , CitomegalovirusRESUMEN
BACKGROUND: Immunotherapy represented a turning point for treating extensive small-cell lung cancer (ES-SCLC). Although, many issues remain debated. METHODS: A group of Italian medical and radiation oncologists with expertise in managing patients with ES-SCLC developed a list of statements divided in six areas of interest. The Delphi method was used to assess the consensus on the defined list of statements. RESULTS: 32 statements were included in the final list to be voted by the Delphi panel, and 26 reached a consensus on the agreement. A prompt involvement of a multidisciplinary team is a priority to provide an integrated treatment strategy. First-line recommended treatment is immunotherapy in combination with platinum-based chemotherapy and etoposide for four cycles followed by maintenance immunotherapy. CONCLUSIONS: While awaiting new data from clinical trials and real-world studies, these recommendations can represent a useful tool to guide the management of ES-SCLC patients in daily practice.
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Consenso , Técnica Delphi , Inmunoterapia , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/terapia , Carcinoma Pulmonar de Células Pequeñas/patología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Inmunoterapia/métodos , Italia/epidemiología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Manejo de la EnfermedadRESUMEN
Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced non-small cell lung cancer (NSCLC), although patient survival is still unsatisfactory. Accurate predictive markers capable of personalizing the treatment of patients with NSCLC are still lacking. Circulating extracellular vesicles involved in cell-to-cell communications through miRNAs (EV-miRs) transfer are promising markers. Plasma from 245 patients with advanced NSCLC who received nivolumab as second-line therapy was collected and analyzed. EV-miRnome was profiled on 174/245 patients by microarray platform, and selected EV-miRs were validated by qPCR. A prognostic model combining EV-miR and clinical variables was built using stepwise Cox regression analysis and tested on an independent patient cohort (71/245). EV-PD-L1 gene copy number was assessed by digital PCR. For 54 patients with disease control, EV-miR changes at best response versus baseline were investigated by microarray and validated by qPCR. EV-miRNome profiling at baseline identified two EV-miRs (miR-181a-5p and miR-574-5p) that, combined with performance status, are capable of discriminating patients unlikely from those that are likely to benefit from immunotherapy (median overall survival of 4 months or higher than 9 months, respectively). EV-PD-L1 digital evaluation reported higher baseline copy number in patients at increased risk of mortality, without improving the prognostic score. Best response EV-miRNome profiling selected six deregulated EV-miRs (miR19a-3p, miR-20a-5p, miR-142-3p, miR-1260a, miR-1260b, and miR-5100) in responding patients. Their longitudinal monitoring highlighted a significant downmodulation already in the first treatment cycles, which lasted more than 6 months. Our results demonstrate that EV-miRs are promising prognostic markers for NSCLC patients treated with nivolumab.
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Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Vesículas Extracelulares , Neoplasias Pulmonares , MicroARNs , Nivolumab , Humanos , MicroARNs/genética , MicroARNs/sangre , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Anciano , Nivolumab/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Biomarcadores de Tumor/genética , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Anciano de 80 o más Años , Adulto , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéuticoRESUMEN
BACKGROUND: Glycolysis in presence of oxygen with high glucose consumption is known to be the metabolism of choice in many tumors. In lung cancer this phenomenon is routinely exploited in diagnostic PET imaging of fluorodeoxyglucose uptake, but not much is known about the prognostic capabilities of glycolysis level assessment in resected lung tumor samples. METHODS: In this retrospective study, we used real time polymerase chain reaction(RQ-PCR) to assess the expression level of the gene for Glyceraldehyde 3-phosphate dehydrogenase(GAPDH), key enzyme for glucose breakdown, in tumor samples from 82 consecutive early stages resected non small cell lung cancer(NSCLC) patients. We then compared our results in six large publicly available NSCLC microarray datasets collecting data from over 1250 total patients. RESULTS: In our study GAPDH gene over expression was found to be an adverse prognostic factor in early stages NSCLC (n = 82 HR = 1.30 p = 0.050). This result was confirmed in 5 of 6 public datasets analyzed: Shedden et al. 2008: n = 442 HR = 1.54 p < 0.0001; Lee et al. 2008: n = 138 HR = 1.31 p = 0.043; Tomida et al. 2009: n = 117 HR = 1.59 p = 0.004; Roepman et al. 2009: n = 172 (TPI1 gene) HR = 1.51 p = 0.009; Okayama et al. 2012: n = 226 HR = 3.19 p < 0.0001; Botling et al. 2013: n = 196 HR = 1.00 p = 0.97). Furthermore, in the large and clinically well annotated Shedden et al. microarray dataset, GAPDH hazard ratio did not change whether calculated for the whole dataset or for the subgroup of adjuvant naive patients only (n = 330 HR = 1.49 p < 0.0001). CONCLUSION: GAPDH gene over expression in resected tumor samples is an adverse prognostic factor in NSCLC. Our results confirm the prognostic value of glucose metabolism assessment in NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/enzimología , Expresión Génica , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/metabolismo , Neoplasias Pulmonares/enzimología , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/genética , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
The treatment of non-small cell lung cancer (NSCLC) has changed dramatically with the advent of immune checkpoint inhibitors (ICIs). Despite encouraging results, their efficacy remains limited to a subgroup of patients. Circulating immune checkpoints in soluble (s) form and associated with extracellular vesicles (EVs) represent promising markers, especially in ICI-based therapeutic settings. We evaluated the prognostic role of PD-L1 and of two B7 family members (B7-H3, B7-H4), both soluble and EV-associated, in a cohort of advanced NSCLC patients treated with first- (n = 56) or second-line (n = 126) ICIs. In treatment-naïve patients, high baseline concentrations of sPD-L1 (>24.2 pg/mL) were linked to worse survival, whereas high levels of sB7-H3 (>0.5 ng/mL) and sB7-H4 (>63.9 pg/mL) were associated with better outcomes. EV characterization confirmed the presence of EVs positive for PD-L1 and B7-H3, while only a small portion of EVs expressed B7-H4. The comparison between biomarker levels at the baseline and in the first radiological assessment under ICI-based treatment showed a significant decrease in EV-PD-L1 and an increase in EV-B7H3 in patients in the disease response to ICIs. Our study shows that sPD-L1, sB7-H3 and sB7-H4 levels are emerging prognostic markers in patients with advanced NSCLC treated with ICIs and suggests potential EV involvement in the disease response to ICIs.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Antígeno B7-H1 , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , PronósticoRESUMEN
BACKGROUND: CheckMate 817, a phase 3B study, evaluated flat-dose nivolumab plus weight-based ipilimumab in patients with metastatic non-small cell lung cancer (NSCLC). Here, in this research, we report on first-line treatment in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (cohort A) and special populations (cohort A1: ECOG PS 2; or ECOG PS 0-1 with untreated brain metastases, renal impairment, hepatic impairment, or controlled HIV infection). METHODS: Cohorts A and A1 received nivolumab 240 mg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary endpoint was the incidence of grade 3-4 and grade 5 immune-mediated adverse events (IMAEs; adverse events (AEs) deemed potentially immune-related, occurring <100 days of last dose, and treated with immune-modulating medication (except endocrine events)) and treatment-related select AEs (treatment-related AEs with potential immunological etiology requiring frequent monitoring/intervention, reported between first dose and 30 days after the last dose) in cohort A; efficacy endpoints were secondary/exploratory. In cohort A1, safety/efficacy assessment was exploratory. RESULTS: The most common grade 3-4 IMAEs were pneumonitis (5.1%), diarrhea/colitis (4.9%), and hepatitis (4.6%) in cohort A (N=391) and diarrhea/colitis (3.5%), hepatitis (3.5%), and rash (3.0%) in cohort A1 (N=198). The most common grade 3-4 treatment-related select AEs were hepatic (5.9%), gastrointestinal (4.9%), and pulmonary (4.6%) events in cohort A and gastrointestinal (4.0%), skin (3.5%), and endocrine (3.0%) events in cohort A1. No grade 5 IMAEs or treatment-related select AEs occurred. Treatment-related deaths occurred in 4 (1.0%) and 3 (1.5%) patients in cohorts A and A1, respectively. Three-year overall survival (OS) rates were 33.7% and 20.5%, respectively. CONCLUSIONS: Flat-dose nivolumab plus weight-based ipilimumab was associated with manageable safety and durable efficacy in cohort A, consistent with data from phase 3 metastatic NSCLC studies. Special populations of cohort A1 including patients with ECOG PS 2 or ECOG PS 0-1 with untreated brain metastases had manageable treatment-related toxicity and clinically meaningful 3-year OS rate. TRIAL REGISTRATION NUMBER: NCT02869789.