RESUMEN
Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer1. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.
Asunto(s)
ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Fragmentación del ADN , Genoma Humano/genética , Neoplasias/diagnóstico , Neoplasias/genética , Estudios de Casos y Controles , Estudios de Cohortes , Análisis Mutacional de ADN , Humanos , Aprendizaje Automático , Mutación , Neoplasias/sangre , Neoplasias/patologíaRESUMEN
Tumor heterogeneity was associated with treatment outcome of metastatic cancers but few studies have examined whether tumor heterogeneity in circulating tumor DNA (ctDNA) can be used to predict treatment outcome. ctDNA analysis was performed in 37 HER2-positive metastatic breast cancer patients treated with pyrotinib. Patients with high tumor heterogeneity had significantly worse PFS outcomes, with a median PFS of 30.0 weeks vs. 60.0 weeks for patients with low tumor heterogeneity (hazard ratio [HR], 2.9; p = 0.02). Patients with trunk resistance mutations receiving pyrotinib monotherapy had worse outcomes (HR, 4.5; p = 0.03), with a median PFS of 7.8 weeks vs. 27.4 weeks for those with branch resistance mutations or without any resistance mutations in baseline ctDNA. Longitudinal monitoring of 21 patients during treatment showed that the molecular tumor burden index ([mTBI] a measure of the percentage of ctDNA in samples) was positively correlated with tumor size as evaluated by computed tomography (p < 0.0001, Pearson r = 0.52) and detected disease progression 8-16 weeks earlier. Our current findings suggested that ctDNA could be used to assess tumor heterogeneity and predict treatment outcomes. Furthermore, the mTBI is better for assessing therapeutic response than single gene mutations and might supplement the current therapeutic response evaluation system.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , ADN Tumoral Circulante/genética , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Adulto , Aminoquinolinas/farmacología , Aminoquinolinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Capecitabina/farmacología , Capecitabina/uso terapéutico , ADN Tumoral Circulante/sangre , Estudios de Cohortes , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple , Pronóstico , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Adulto JovenRESUMEN
Brain metastases are common in patients with non-small-cell lung cancer (NSCLC). Because of associated poor prognosis and limited specific treatment options, there is a real need for the development of medical therapies and strategies for affected patients. Novel compounds for epidermal growth factor receptor-dependent and anaplastic lymphoma kinase-dependent lung cancer have demonstrated blood-brain barrier permeability and have led to important improvements in central nervous system outcomes. Studies of targeted therapies for oncogene-driven tumors and of immunotherapies in patients with brain metastases have shown promise and, allied with novel radiation techniques, are driving a rapid evolution in treatment and prognosis for NSCLC brain metastases.
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/secundario , Neoplasias Pulmonares/patología , Quinasa de Linfoma Anaplásico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Humanos , Inmunoterapia , Mutación , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidoresRESUMEN
OPINION STATEMENT: Brain metastases are common in patients with non-small cell lung cancer (NSCLC), and due to associated poor prognosis, this field is an important area of need for the development of innovative medical therapies. Therapies including local approaches through surgical intervention and/or radiation and evolving systemic therapies have led to improvements in the treatment of brain metastases in patients with lung cancer. Strategies that consider applying advanced radiation techniques to minimize toxicity, intervening early with effective systemic therapies to spare radiation/surgery, testing radiosensitization combinations, and developing drug penetrant molecules have and will continue to define new practice patterns. We believe that in carefully considered asymptomatic patients, first-line systemic therapy may be considered before radiation therapy and small-molecule targeted therapy may provide an opportunity to defer radiation therapy for recurrence or progression of disease. The next several years in oncology drug development will see the reporting on of brain penetrant molecules in oncogene-defined non-small cell lung cancer. Ongoing studies will evaluate immunotherapies in patients with brain metastases with associated endpoints. We hope that continued drug development and carefully designed clinical trials may afford an opportunity to improve the lives of patients with brain metastases.
Asunto(s)
Neoplasias Encefálicas/terapia , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/patología , Animales , Antineoplásicos/uso terapéutico , Barrera Hematoencefálica , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/secundario , Humanos , Inmunoterapia , Neoplasias Pulmonares/terapiaRESUMEN
PURPOSE: KRAS is the most commonly mutated driver oncogene in non-small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRASG12C inhibitors, have been granted accelerated US approval; however, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy. The aim of this study was to assess the feasibility and safety of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity through real-world and clinical cases. METHODS: Medical records from five patients treated in real-world settings were retrospectively reviewed. Patients had locally advanced or metastatic KRASG12C-mutated NSCLC and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with KRASG12C-mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. The end points associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of therapy. RESULTS: All patients were treated with CPIs followed by sotorasib (initiated 0-64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients from KRYSTAL-1 transitioned from sotorasib to adagrasib because of hepatotoxicity; one experienced grade 3 ALT elevation on adagrasib that resolved with therapy interruption and dose reduction. CONCLUSION: Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRASG12C inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.
Asunto(s)
Acetonitrilos , Carcinoma de Pulmón de Células no Pequeñas , Enfermedad Hepática Inducida por Sustancias y Drogas , Neoplasias Pulmonares , Piperazinas , Piridinas , Pirimidinas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Estudios RetrospectivosRESUMEN
PURPOSE: Liquid biopsy (LBx) for tumor profiling is increasingly used, but concerns remain regarding negative results. A lack of results may truly reflect tumor genomics, or it may be a false negative that would be clarified by tissue testing. A method of distinguishing between these scenarios could help clarify when follow-on tissue testing is valuable. EXPERIMENTAL DESIGN: Here we evaluate circulating tumor DNA (ctDNA) tumor fraction (TF), a quantification of ctDNA in LBx samples, for utility in identifying true negative results. We assessed concordance between LBx and tissue-based results, stratified by ctDNA TF, in a real-world genomic dataset of paired samples across multiple disease types. We also evaluated the frequency of tissue results identifying driver alterations in patients with lung cancer after negative LBx in a real-world clinicogenomic database. RESULTS: The positive percent agreement and negative predictive value between liquid and tissue samples for driver alterations increased from 63% and 66% for all samples to 98% and 97% in samples with ctDNA TF ≥1%. Among 505 patients with lung cancer with no targetable driver alterations found by LBx who had subsequent tissue-based profiling, 37% had a driver, all of which had ctDNA TF <1%. CONCLUSIONS: Patients with lung cancer with negative LBx and ctDNA TF ≥1% are unlikely to have a driver detected on confirmatory tissue testing; such informative negative results may benefit instead from prompt treatment initiation. Conversely, negative LBx with ctDNA TF <1% will commonly have a driver identified by follow-up tissue testing and should be prioritized for reflex testing.
Asunto(s)
Biomarcadores de Tumor , ADN Tumoral Circulante , Humanos , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Biopsia Líquida/métodos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Neoplasias/genética , Neoplasias/sangre , Neoplasias/diagnóstico , Neoplasias/patología , Mutación , Genómica/métodos , FemeninoRESUMEN
Background: Kirsten rat sarcoma homolog (KRAS) mutations are one of the key drivers in non-small cell lung cancer (NSCLC) and FDA-approved specific inhibitors of KRAS-G12C mutation are available clinically. However, inhibitors of certain KRAS mutation subtypes remain unavailable, especially rare KRAS mutations including G13C, G13D, and Q61H. In this study, we retrospectively investigated the outcomes of NSCLC patients with rare KRAS-mutation to determine if they may benefit from immune checkpoint inhibitors (ICIs). Methods: Our retrospective study involved 240 advanced NSCLC patients with KRAS mutations, who visited Shanghai Chest Hospital from July 2018 to July 2021. Complete clinical and pathological data were recorded and progression-free survival (PFS) and overall survival (OS) were adopted as primary endpoints. Results: The median follow-up time was 36.5 months (range, 30.8-42.1 months) and the median OS was 9.7 months (range, 7.6-11.8 months). Of the 240 patients evaluated, 130 (54.2%) received chemotherapy and 110 (45.8%) received ICI-based treatment. Among the patients who received chemotherapy, patients with rare KRAS-mutations presented worse survival outcomes (median PFS, 3.4 vs. 4.1 months, P=0.047; median OS, 5.2 vs. 7.1 months, P=0.02) than conventional KRAS-mutant patients. PFS and OS of rare KRAS-mutation patients were prolonged after immunotherapy (median PFS 7.3 vs. 3.4 months, P<0.001; median OS, 13.3 vs. 5.2 months, P<0.001) and had no significant difference compared with conventional KRAS-mutant patients, in part of them whose programmed death-ligand 1 (PD-L1) expression data before immunotherapy were available (n=72), patients with a higher rate of PD-L1 positive tumor cells (≥50%) presented elevated PFS and OS. Conclusions: Despite having potential survival disadvantage compared with other NSCLC patients, rare KRAS-mutant patients (other than G12A, C, D, V) could benefit specifically from ICI-based therapy and survival outcomes are correlated with PD-L1 expression.
RESUMEN
Background: Non-alcoholic fatty liver disease (NAFLD) is the global most common chronic liver disease. Non-alcoholic steatohepatitis (NASH), an inflammatory subtype of NAFLD, has been shown to significantly increase the risk of colorectal adenoma (CRA). Therefore, from the perspective of bioinformatics analysis, the potential mechanisms of NASH/NAFLD-CRA can be explored. Methods: In this study, we screened the differentially expressed genes (DEGs) and core effect pathways between NASH and CRA by analyzing the single-cell data of CRA patients and the high-throughput sequencing data (GSE37364 and GSE89632) in the online database. We screened therapeutic targets and biomarkers through gene function classification, pathway enrichment analysis, and protein-protein interaction network analysis. In terms of single cell data, we screened the core effect pathway and specific signal pathway of cell communication through cell annotation and cell communication analyses. The purpose of the study was to find potential biomarkers, therapeutic targets, and related effect pathways of NASH-CRA. Results: NASH-CRA comorbidities were concentrated in inflammatory regulation-related pathways, and the core genes of disease progression included IL1B, FOSL1, EGR1, MYC, PTGS2, and FOS. The results suggested the key pathway of NASH-CRA might be the WNT pathway. The main cell signal communication pathways included WNT2B - (FZD6 + LRP5) and WNT2B - (FZD6 + LRP6). The send-receive process occurred in embryonic stem cells. Conclusions: The core genes of NASH-CRA (FOS, EGR1, MYC, PTGS2, FOSL1, and IL1B) may participate in inflammation and immune responses through up-regulation in the process of disease occurrence, interfering with the pathophysiological process of CRA and NASH. NASH-CRA produces cell signal communication in the WNT pathway sent by WNT2B and received by FZD6, LRP5, and LRP6 in embryonic stem cells. These findings may help formulate early diagnosis and treatment strategies for CRA in NAFLD/NASH patients, and further explore corresponding prognostic markers and potential approaches. The significance of scRNA-seq in exploring tumor heterogeneity lies in promoting our understanding of the expression program of tumor related genes in tumor development patterns. However, the biggest challenge is that this analysis may miss out on some biologically significant gene expression programs.
RESUMEN
Background: The optimal timing of intubation has been debated among healthcare professionals, current studies do not show any differences between early and late intubation. most studies failed to show any significant difference in clinical outcomes between early or late intubation. Methods: The study was conducted as a retrospective review of subjects with confirmed coronavirus disease 2019 admitted to the Dubai Hospital intensive care unit (ICU). Study variables included time to intubation, duration of supplemental oxygen requirement >15 L/min, and cumulative duration of tachypnea and tachycardia while on the aforementioned oxygen requirement on this oxygen usage level. Each time duration was assessed for correlation with clinical variables including mortality and length of stay in ICU and hospital. Results: Subjects who require endotracheal intubation within 4 h after the start of oxygen >15 L/min have lower survival (P = 0.03). Subjects who have tachypnea on the aforementioned oxygen requirement for 6-19.5 h (P = 0.01) before they require intubation have better survival. No duration of tachycardia has any significant effect on survival. Only the duration of invasive mechanical ventilation (MV) correlated with the hospital length of stay. Conclusions: Subjects who require endotracheal intubation within 4 h after the start of oxygen >15 L/min have lower survival. The optimal time for intubation is after tachypnea of 6 h but before 19.5 h. No duration of tachycardia has any significant effect on survival. Only the duration of invasive MV correlated with the hospital length of stay.
RESUMEN
Introduction: EGFR mutations drive a subset of NSCLC. Patients harboring the common EGFR mutations, deletion of exon 19 and L858R, respond well to osimertinib, a third-generation tyrosine kinase inhibitor. Nevertheless, the effect of osimertinib on NSCLC with atypical EGFR mutations is not well described. This multicenter retrospective study evaluates the efficacy of osimertinib among patients with NSCLC harboring atypical EGFR mutations. Methods: Patients with metastatic NSCLC treated with osimertinib, harboring at least one atypical EGFR mutation, excluding concurrent deletion of exon 19, L858R, or T790M mutations, from six U.S. academic cancer centers were included. Baseline clinical characteristics were collected. The primary end point was the time to treatment discontinuation (TTD) of osimertinib. Objective response rate by the Response Evaluation Criteria in Solid Tumors version 1.1 was also assessed. Results: A total of 50 patients with NSCLC with uncommon EGFR mutations were identified. The most frequent EGFR mutations were L861Q (40%, n = 18), G719X (28%, n = 14), and exon 20 insertion (14%, n = 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5-12.9 mo) overall and 10.7 months (95% CI: 3.2-18.1 mo) in the first-line setting (n = 20). The objective response rate was 31.7% (95% CI: 18.1%-48.1%) overall and 41.2% (95% CI: 18.4%-67.1%) in the first-line setting. The median TTD varied among patients with L861Q (17.2 mo), G719X (7.8 mo), and exon 20 insertion (1.5 mo) mutations. Conclusions: Osimertinib has activity in patients with NSCLC harboring atypical EGFR mutations. Osimertinib activity differs by the type of atypical EGFR-activating mutation.
RESUMEN
Background: In the phase 3 FLAURA trial, osimertinib was compared with first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as a first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib showed longer progression-free survival (PFS), overall survival (OS), and a similar safety profile. However, more studies demonstrating the effectiveness and safety of osimertinib as a first-line strategy are needed in real-world populations. Methods: We enrolled 1,556 patients with EGFR-mutated stage IIIc-IV NSCLC from the CAPTRA-Lung database. All patients received either osimertinib (n=202) or a first-generation EGFR-TKI (n=1,354) as their initial treatment. To adjust for differences in baseline characteristics between two groups, 1:2 propensity score matching (PSM) was performed. Propensity scores included gender, age, Eastern Cooperative Oncology Group performance status score, smoking history, family history of tumor, pathology, EGFR mutations, and central nervous system (CNS) metastases. The standardized mean differences (SMD) before and after PSM were calculated to examine the balance of covariate distributions between two groups. Results: After PSM, 202 patients receiving osimertinib and 404 patients receiving first-generation EGFR-TKIs were finally identified. SMD of each matched variable is less than 0.10. The median PFS was 19.4 months [95% confidence interval (CI): 14.3-24.4] in the osimertinib arm and 10.9 months (95% CI: 9.3-12.5) in the comparator arm [hazard ratio (HR) for progression, 0.47; 95% CI: 0.38-0.59; P<0.001). The median OS was 40.5 months (95% CI: 27.1-54.0) vs. 34.3 months (95% CI: 30.6-38.0) in two groups, respectively (HR for death, 0.76; 95% CI: 0.58-1.00; P=0.045). The incidence of grade 3 adverse events (AEs) between the two groups was 1% and 4.2%, respectively. No grade 4 AEs and treatment-related deaths were reported in both groups. Conclusions: In real-world settings, osimertinib demonstrates longer PFS and OS, with a similar safety profile to that of comparator EGFR-TKIs when used as a first-line strategy in NSCLC patients.
RESUMEN
Therapies that disrupt or repair blood-brain barrier integrity can result in major changes in MRI images even when the tumor volume remains constant. Thus, a reliable blood-based tumor biomarker could significantly improve clinical care and research studies in these patients. This study was performed to assess plasma concentrations of glial fibrillary acidic protein (GFAP) in patients with high- and low-grade gliomas before and after debulking surgery. Pre-operative plasma was collected from 33 patients with radiation- and chemotherapy-naïve gliomas. Additional plasma was collected 24-48 h post-operatively from 23 of these patients. Plasma GFAP (pGFAP) concentrations were determined using an electrochemiluminescent immunoassay and were analyzed as a function of tumor grade, tumor GFAP expression, the integrity of the blood-brain barrier, and post-operative status. Detectable pGFAP levels (≥ 0.04 ng/mL) were found pre-operatively in 52 % of patients and post-operatively in 96 %. Detectable pGFAP was more common in patients with WHO grade IV (100 %) than WHO grade III (56 %) or WHO grade II gliomas (20 %). No patient with undetectable GFAP had WHO grade IV glioma. Higher pGFAP concentrations were also associated with contrast enhancement but not related to tumor GFAP expression. GFAP is commonly detected in the plasma of patients with high-grade gliomas. pGFAP levels rise rather than fall following debulking surgery which is probably a result of surgical trauma. GFAP remains a potentially informative plasma biomarker for gliomas. Longitudinal studies are required to correlate pGFAP levels with patient outcomes.
Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias Encefálicas/sangre , Proteína Ácida Fibrilar de la Glía/sangre , Glioma/sangre , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/cirugía , Electroquímica , Femenino , Glioma/diagnóstico , Glioma/cirugía , Humanos , Técnicas para Inmunoenzimas , Mediciones Luminiscentes , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Periodo Posoperatorio , Pronóstico , Adulto JovenRESUMEN
Background: Circulating tumor DNA (ctDNA) is receiving more and more attention for its role in tumor screening and disease surveillance in cancer patients. However, it is unclear whether ctDNA can be used to predict recurrence and metastasis in patients after radical resection due to the resulting lower tumor burden. The published literature on postoperative ctDNA levels is also currently limited. Case Description: In this article, we report a rare case in which ctDNA accurately predicted relapse, disease progression and mechanism of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in adjuvant setting in an EGFR-mutated lung adenocarcinoma patient. The 49-year-old male patient was a current smoker and denied any family history. Chest computed tomography (CT) scans revealed a 5.7×4.3 mass in the left upper lobe. He received adjuvant gefitinib after surgery for a stage IIIB (pT3N2M0) pulmonary adenocarcinoma. The ctDNA detection showed that the EGFR exon 19 deletion (EGFR del19) gene mutation frequencies decreased gradually and even disappeared. However, 8 months after the operation, the EGFR del19 mutation re-emerged in the blood, accompanied by a newly emerged solitary nodule (2 mm) that was later confirmed to be metastatic. Soon afterward, ctDNA detection revealed the EGFR T790M mutation, and the mediastinal lymph nodes rapidly enlarged. The patient's treatment was switched to Osimertinib and the ctDNA detection results showed the EGFR T790M gene mutation frequencies steadily decreased to zero. During the treatment period, ctDNA detection accurately predicted each change in disease burden and revealed genotype alterations. The patient ultimately developed severe metastases in the liver after developing resistance to Osimertinib. Conclusions: This report suggests that ctDNA help monitor disease recurrence and identify genotypes in patients undergoing postoperative adjuvant EGFR-TKI therapy. More clinical researches are needed to support ctDNA is a promising tool for predicting disease progressive.
RESUMEN
Background: KRAS gene mutations are the most common driver oncogenes in non-small cell lung cancer (NSCLC). We conducted an analysis of the immunological characteristics including tumor mutation burden and programmed death-ligand 1 (PD-L1) expression of different subtypes of KRAS in 2880 KRAS-mutant NSCLC patients. Methods: A total of 2,880 patients with NSCLC were included in the study. Somatic mutation data were provided by Berry Oncology (Fujian, China), Geneplus BioTech (Beijing, China), Nanjing Geneseeq Technology Inc (Nanjing, China), and Burning Rock Biotech (Guangzhou, China). Z-scores were used to unify all data. SPSS 20.0 (SPSS, Chicago, IL, USA) software was used for statistical analyses. All scatter plots and boxplot maps were drawn using GraphPad Prism 8. Tumor mutation burden (TMB) expression was defined by the number of somatic mutations. The PD-L1 clone 22C3 pharmDx kit was used to measure the expression level of PD-L1. Mann-Whitney U test was used for statistical analysis. P value <0.05 was considered statistically significant. Results: We identified 2,880 patients with KRAS-mutant NSCLC. The percentage level of TMB and expression of PD-L1 was significantly decreased in KRAS Q61X-mutant lung cancer tissue and blood samples (n=162). The percentage level of TMB and expression of PD-L1 in KRAS G13X-mutant lung cancer specimens was significantly increased (n=190). Conclusions: The findings demonstrate a decreased level of TMB and expression of PD-L1 in KRAS Q61X-mutant lung cancer and the increased level of TMB and expression of PD-L1 in KRAS G13X-mutant lung cancer. Further work is needed to identify if the subtype of KRAS mutation could be a potential therapeutic biomarker in lung cancer patients with KRAS mutation. TMB data was consistently verified in tissue and blood samples and confirmed the feasibility of next-generation sequencing (NGS) verification in plasma samples. Our research may help to provide more individualized treatment options for NSCLC patients.
RESUMEN
INTRODUCTION: This Phase 1/2 study (NCT02349633) explored the safety and antitumor activity of PF-06747775 (oral, third-generation epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer after progression on an EGFR inhibitor. METHODS: Phase 1 was a dose-escalation study of PF-06747775 monotherapy (starting dose: 25 mg once daily [QD]). Phase 1b/2 evaluated PF-06747775 monotherapy at recommended Phase 2 dose (RP2D; Cohort 1); PF-06747775 200 mg QD plus palbociclib (starting dose: 100 mg QD orally; Cohort 2A); and PF-06747775 monotherapy at RP2D in a Japanese lead-in cohort. RESULTS: Sixty-five patients were treated. Median treatment duration was 40.1 weeks. Monotherapy maximum tolerated dose was not determined. Two patients in Cohort 2A had dose-limiting toxicities. The monotherapy RP2D was estimated to be 200 mg QD. Most frequently reported adverse events (AEs) were diarrhea (69.2%), paronychia (69.2%), and rash (60.0%). Most AEs were grades 1-3. Overall, objective response rate (90% confidence interval [CI]) was 41.5% (31.2-52.5%). Median (range) duration of response was 11.09 (2.70-34.57) months. Median progression-free survival (90% CI) was 8.1 (5.4-23.3) months. CONCLUSIONS: PF-06747775 had a manageable safety profile and the study design highlights important considerations for future anti-EGFR agent development.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , PiridinasRESUMEN
PURPOSE: Profiling of circulating tumor DNA (ctDNA) is increasingly adopted in the management of solid tumors, concurrent with increased availability of more comprehensive ctDNA panels. However, variable ctDNA shed can result in variable assay sensitivity. We studied the relationship between ctDNA tumor fraction (TF) and detection of actionable alterations across cancer types. METHODS: A total of 23,482 liquid biopsies (LBx) submitted between September 2020 and October 2021 were sequenced using a hybrid capture panel that reports genomic alterations (GAs) and genomic biomarkers across 324 cancer-related genes. The primary end points were the prevalence of targetable GAs by cancer type and detection in relationship to ctDNA TF. Sensitivity of detection in LBx was assessed in 1,289 patients with available tissue results. RESULTS: 94% (n = 22,130) of LBx had detectable ctDNA, with a median TF of 2.2%. LBx profiling detected GAs in National Comprehensive Cancer Network category 1 genes in 37% of lung, 30% of prostate, 36% of breast, and 51% of colon cancer cases. Potential germline GAs flagged on clinical reports were detected in genes including BRCA1/2, PALB2, CHEK2, and ATM. Polyclonal mutations in genes associated with resistance such as AR, ESR1, RB1, and NF1 were detected. The sensitivity of LBx to detect driver alterations identified in tissue biopsy from the same patient ranged from 58% to 86% but was consistently at or near 100% in cases with TF ≥ 10%. CONCLUSION: Elevated ctDNA shed is associated with both high sensitivity and negative predictive value for detection of actionable GAs. The presence of elevated TF suggests adequate tumor profiling and may reduce the value of subsequent reflex to confirmatory tissue testing in patients with negative LBx results.
Asunto(s)
ADN Tumoral Circulante , Neoplasias , Humanos , Masculino , ADN Tumoral Circulante/genética , Neoplasias/diagnóstico , Biopsia Líquida , Biomarcadores de Tumor/genética , Genómica/métodosRESUMEN
Introduction: This multicenter review evaluated the efficacy and safety of osimertinib dose escalation for central nervous system (CNS) progression developing on osimertinib 80 mg in EGFR-mutant NSCLC. Methods: Retrospective review identified 105 patients from eight institutions with advanced EGFR-mutant NSCLC treated with osimertinib 160 mg daily between October 2013 and January 2020. Radiographic responses were clinically assessed, and Kaplan-Meier analyses were used. We defined CNS disease control as the interval from osimertinib 160 mg initiation to CNS progression or discontinuation of osimertinib 160 mg. Results: Among 105 patients treated with osimertinib 160 mg, 69 were escalated for CNS progression, including 24 treated with dose escalation alone (cohort A), 34 who received dose-escalated osimertinib plus concurrent chemotherapy and/or radiation (cohort B), and 11 who received osimertinib 160 mg without any prior 80 mg exposure. The median duration of CNS control was 3.8 months (95% confidence interval [CI], 1.7-5.8) in cohort A, 5.1 months (95% CI, 3.1-6.5) in cohort B, and 4.2 months (95% CI 1.6-not reached) in cohort C. Across all cohorts, the median duration of CNS control was 6.0 months (95% CI, 5.1-9.0) in isolated leptomeningeal progression (n = 27) and 3.3 months (95% CI, 1.0-3.1) among those with parenchymal-only metastases (n = 23). Patients on osimertinib 160 mg experienced no severe or unexpected side effects. Conclusion: Among patients with EGFR-mutant NSCLC experiencing CNS progression on osimertinib 80 mg daily, dose escalation to 160 mg provided modest benefit with CNS control lasting approximately 3 to 6 months and seemed more effective in patients with isolated leptomeningeal CNS progression.
RESUMEN
Background: Anlotinib demonstrated improved overall survival (OS) and progression-free survival (PFS) compared with placebo as a third-line or subsequent therapy in patients with non-small cell lung cancer (NSCLC) in the ALTER0303 trial. The status of epidermal growth factor receptor (EGFR) mutation, different previous treatment may affect the efficacy of subsequent therapy, and we did this subgroup analysis to characterize the efficacy of anlotinib in patients with and without EGFR mutation. Methods: The ALTER0303 trial was a randomized, double-blind, phase 3 study of anlotinib in patients with NSCLC who failed at least 2 lines of treatment. In the study, 138 of 437 randomized patients were EGFR mutation positive. A Cox model was used to examine the influence of previous treatment on the efficacy of anlotinib according to EGFR mutation status. Results: For patients with EGFR mutation, the OS was 10.7 and 6.3 months (HR 0.59; 95% CI: 0.38-0.94, P=0.025) in the anlotinib and placebo group, respectively. The PFS was 5.6 and 0.8 months (HR 0.21; 95% CI: 0.13-0.32, P<0.0001) in the anlotinib and placebo group, respectively. For patients without EGFR mutation, the OS was 8.9 months for anlotinib and 6.5 months for placebo (HR 0.73; 95% CI: 0.55-0.97, P=0.029), and the PFS was 5.4 months for anlotinib and 1.6 months for placebo (HR 0.29; 95% CI: 0.22-0.39, P<0.0001). In the anlotinib group, the OS and PFS for patients with and without EGFR mutation was 10.7 and 8.9 months (HR 0.69; 95% CI: 0.50-0.95, P=0.021), 5.6 and 5.4 months (HR 1.00; 95% CI: 0.75-1.34, P=1.000), respectively. The incidence of adverse events was similar in subgroups. Conclusions: This analysis demonstrated that the benefit of anlotinib as a third-line therapy for patients with NSCLC was independent of EGFR mutation status.
RESUMEN
Lung cancer remains the leading cause of cancer-related death in the United States. Ongoing research into the molecular basis of lung cancer has yielded insight into various critical pathways that are deregulated in lung tumorigenesis, and in particular key driver mutations integral to cancer cell survival and proliferation. One of the most recent examples of this has been definition of translocations and functional dysregulation of the anaplastic lymphoma kinase (ALK) gene in a subset of patients with non-small-cell lung cancer. The pace of research progress in this area has been remarkable: chromosomal rearrangements involving this gene in lung cancer were first reported in 2007 by a team of investigators in Japan. Less than 3 years later, an early-phase clinical trial of a targeted ALK inhibitor has yielded impressive responses in patients with advanced lung cancer containing ALK rearrangements, and mechanisms of acquired resistance to ALK-targeted therapy are being reported. A definitive study randomizing patients with ALK-mutant lung cancer to crizotinib (also known as PF-02341066 or 1066) versus standard therapy has recently completed enrollment.Taken together, these data describe a trajectory of research progress from basic discovery science to real-world implementation that should serve as a model for future integration of preclinical and clinical therapeutic research.