Circulating cell-free DNA (cfDNA) may help understand the molecular response to pharmacologic treatment and provide information on dynamics of clonal heterogeneity. Therefore, this study evaluated ...the correlation between treatment outcome and activating EGFR mutations (act-EGFR) and T790M in cfDNA in patients with advanced NSCLC given osimertinib.
Thirty-four NSCLC patients resistant to first/second-generation EGFR-TKIs, positive for both act-EGFR and T790M in cfDNA at the time of progression were enrolled in this study. Plasma samples were obtained at osimertinib baseline and after 3 months of therapy; cfDNA was analyzed by droplet digital PCR and results were expressed as mutant allele frequency (MAF).
At baseline, act-EGFR MAF was significantly higher than T790M (p < 0.0001). act-EGFR MAF and T790M/act-EGFR MAF ratio were significantly correlated with disease response (p = 0.02). Cut-off values of act-EGFR MAF and T790M/act-EGFR ratio of 2.6% and 0.22 were found, respectively. The PFS of patients with act-EGFR MAF of > 2.6% and < 2.6%, were 10 months vs. not reached, respectively (p = 0.03), whereas patients with T790M/act-EGFR ≤ 0.22 had poorer PFS than patients with a value of > 0.22 (6 months vs. not reached, respectively, p = 0.01).
act-EGFR MAF and T790M/act-EGFR MAF ratio are potential markers of outcome in patients treated with osimertinib.
EGFR-positive Non-small Cell Lung Cancer (NSCLC) is a dynamic entity and tumor progression and resistance to tyrosine kinase inhibitors (TKIs) arise from the accumulation, over time and across ...different disease sites, of subclonal genetic mutations. For instance, the occurrence of EGFR T790M is associated with resistance to gefitinib, erlotinib, and afatinib, while EGFR C797S causes osimertinib to lose activity. Sensitive technologies as radiomics and liquid biopsy have great potential to monitor tumor heterogeneity since they are both minimally invasive, easy to perform, and can be repeated over patient's follow-up, enabling the extraction of valuable information. Yet, to date, there are no reported cases associating liquid biopsy and radiomics during treatment.
In this case series, seven patients with metastatic EGFR-positive NSCLC have been monitored during target therapy. Plasma-derived cell free DNA (cfDNA) was analyzed by a digital droplet PCR (ddPCR), while radiomic analyses were performed using the validated LifeX® software on computed tomography (CT)-images. The dynamics of EGFR mutations in cfDNA was compared with that of radiomic features. Then, for each EGFR mutation, a radiomic signature was defines as the sum of the most predictive features, weighted by their corresponding regression coefficients for the least absolute shrinkage and selection operator (LASSO) model. The receiver operating characteristic (ROC) curves were computed to estimate their diagnostic performance. The signatures achieved promising performance on predicting the presence of EGFR mutations (R
= 0.447, p <0.001 EGFR activating mutations R
= 0.301, p = 0.003 for T790M; and R
= 0.354, p = 0.001 for activating plus resistance mutations), confirmed by ROC analysis.
To our knowledge, these are the first cases to highlight a potentially promising strategy to detect clonal heterogeneity and ultimately identify patients at risk of progression during treatment. Together, radiomics and liquid biopsy could detect the appearance of new mutations and therefore suggest new therapeutic management.
Resistance to EGFR tyrosin kinase inhibitors (TKI) inevitably occurs. Here it is reported the case of a young patient affected by lung adenocarcinoma harboring the L858R
EGFR
sensitive mutation. The ...patient developed multiple TKI resistance mechanisms: T790M
EGFR
resistance mutation, detected only on tumor cell-free DNA, squamous cell transformation and
MET
amplification, both detected on a tumor re-biopsy. The co-occurrence of squamous cell transformation and
de novo MET
amplification is an extremely rare event, and this case confirms how dynamic and heterogeneous can be the temporal and spatial tumor evolution under treatment pressure.
Lung cancer has become a paradigm for precision medicine in oncology, and liquid biopsy (LB) together with radiomics may have a great potential in this scenario. They are both minimally invasive, ...easy to perform, and can be repeated during patient’s follow-up. Also, increasing evidence suggest that LB and radiomics may provide an efficient way to screen and diagnose tumors at an early stage, including the monitoring of any change in the tumor molecular profile. This could allow treatment optimization, improvement of patients' quality of life, and healthcare-related costs reduction. Latest reports on lung cancer patients suggest a combination of these two strategies, along with cutting-edge data analysis, to decode valuable information regarding tumor type, aggressiveness, progression, and response to treatment. The approach seems more compatible with clinical practice than the current standard, and provides new diagnostic companions being able to suggest the best treatment strategy compared to conventional methods. To implement radiomics and liquid biopsy directly into clinical practice, an artificial intelligence (AI)-based system could help to link patients' clinical data together with tumor molecular profiles and imaging characteristics. AI could also solve problems and limitations related to LB and radiomics methodologies. Further work is needed, including new health policies and the access to large amounts of high-quality and well-organized data, allowing a complementary and synergistic combination of LB and imaging, to provide an attractive choice e in the personalized treatment of lung cancer.
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•Liquid biopsy-derived tumor components may have diagnostic, prognostic and predictive utility in lung cancer.•Growing evidence suggest radiomic analysis to decode the tumor pathophysiological processes and support patient management an.•Risk stratification and monitoring are the most promising applications for both liquid biopsy and radiomics in lung cancer.•Artificial intelligence may implement multiparametric information from radiomics and liquid biopsy into clinical practice.
A portion of this article was previously published as part of an article titled “Human C-reactive protein and the metabolic syndrome” in the following journal: Curr Opin Lipidol. 2009 ...Jun;20(3):182–9. doi: 10.1097/MOL.0b013e32832ac03e. https://insights.ovid.com/crossref?an=00041433-200906000-00007
Insights into the mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) could provide important information for further patient management, including ...the choice of second-line treatment. The EGFR T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs. Owing to its biologic relevance in the response of non–small-cell lung cancer (NSCLC) to the selective pressure of treatment, the present study investigated whether the occurrence of T790M at progression differed among patients receiving gefitinib, erlotinib, or afatinib.
The present retrospective study included patients with NSCLC with an EGFR activating mutation, who had received gefitinib, erlotinib, or afatinib as first-line treatment. Plasma samples for the analysis of cell-free DNA were taken at disease progression and analyzed using a digital droplet polymerase chain reaction EGFR mutation assay.
A total of 83 patients were enrolled; 42 had received gefitinib or erlotinib and 41afatinib. The patient characteristics were comparable across the 2 groups. The median time to progression (TTP) was 14.4 months for the gefitinib and erlotinib group and 10.2 months for the afatinib group (P = .09). Of the 83 patients, 47 (56.6%) were positive for the T790M in plasma. A greater incidence of T790M was observed in patients with progression during gefitinib or erlotinib therapy compared with patients treated with afatinib (33 79% vs. 14 34%, respectively; odds ratio, 7.1; 95% confidence interval, 2.7-18.5; P = .0001).
Although gefitinib, erlotinib, and afatinib showed a comparable TTP in patients receiving first-line therapy, the incidence of T790M differed among them, as demonstrated by the present study, which could have implications for the choice of second-line treatment.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are characterized by different pharmacologic profiles, potentially affecting the development of resistance mutations, which were investigated in the present study. We retrospectively included patients with EGFR-mutant non–small-cell lung cancer who had received EGFR TKIs as first-line therapy. Circulating cell-free DNA was analyzed at disease progression to investigate the incidence of T790M. We found a greater occurrence of T790M in patients with progression during gefitinib or erlotinib versus afatinib therapy, although the time to progression was comparable. We found that EGFR TKIs behave differently with respect to the development of the T790M resistance mutation, and this finding could have implications in the choice of second-line treatment.
Metabolic syndrome is associated with increased propensity for diabetes and cardiovascular disease. Low-grade inflammation is characteristic of metabolic syndrome. C-reactive protein, the best ...characterized biomarker of inflammation, is also an independent predictor of future cardiovascular events. This review outlines the role of high-sensitivity C-reactive protein in contributing to increased cardiovascular risk in metabolic syndrome by inducing endothelial cell dysfunction and activating monocytes.
Thymomas can benefit of cytoreductive surgery even if a complete resection is not feasible. The pleural cavity is the most common site of progression and the resection of pleural metastases can be ...performed in selected patients. We evaluated the results of stereotactic body radiation therapy for the treatment of pleural metastases in patients not eligible for surgery.
We retrospectively selected 22 patients treated with stereotactic body radiation therapy for pleural metastases between 2013 and 2019. According to RECIST criteria 1.1 modified for thymic epithelial tumors, time to local failure and progression free survival were calculated using Kaplan-Meier method.
The median age was 40 years (range, 29-73 years). There were 1 A, 3 AB, 3 B1, 3 B2, 3 B2/B3 and 9 B3 thymomas. Pleural metastases and primary tumor were synchronous in 8 patients. Five patients had a single pleural metastatic site and 17 presented multiple localizations. Sixteen patients received stereotactic body radiation therapy on multiple sites of pleural metastases. The median dose of radiation was 30 Gy (range, 24-40 Gy). With a median follow-up of 33.2 months (95% CI: 13.1-53.3 months), ten patients experienced disease progression with a median progression free survival was 20.4 months (95% CI: 10.7-30.0 months). The disease control rate was 79% and 41% after 1 and 2 years, respectively. Local disease control rate was 92% and 78% after 1 and 2 years, respectively. There were not significant differences in progression free survival between patients diagnosed with synchronous and metachronous metastases (P=0.477), across those treated or not with chemotherapy (P=0.189) and between those who received or not a previous surgical resection of the pleural metastases (P=0.871). There were not grade 3-4 toxicities related to the treatment.
Stereotactic body radiation therapy of pleural metastases is feasible and offers a promising local control of diseases. The impact of this treatment on patients' survival is hardly predictable because of the heterogeneous clinical behavior of thymomas.
C Reactive Protein (CRP) is an acute‐phase protein and a cardiovascular risk marker. CRP levels are inversely correlated with endothelial vasoreactivity. CRP decreases eNOS expression and activity in ...vitro and in vivo. We have shown that CRP mediates eNOS uncoupling. In this study, we tested the effect of CRP on eNOS interaction and association with docking proteins, a fundamental step in regulating eNOS activity. Human Aortic Endothelial cells were incubated in absence and presence of CRP (25ug/ml for 18hrs) followed by stimulation with VEGF (100ng/mL for 0–20 minutes). Association between eNOS and Caveolin‐1 (Cav1), Dynamin II (DynII), Porin and Heat Shock Protein 90 (Hsp90) was assessed by immunoprecipitating cell lysates with eNOS followed by blotting for Hsp90, DynII, Porin and Cav1, using eNOS as loading control (n=3–5 separate experiments). CRP treatment results in a 87% decrease in eNOS‐Hsp90 association, 26% decrease in eNOS‐Porin association and 33% increase in eNOS‐Cav1 association. No significant changes have been observed in eNOS‐DynII association. Thus, we provide further evidence for CRP inducing endothelial dysfunction in HAECs via changes in eNOS association with docking proteins such as Hsp90, Cav1 and Porin.
C-reactive protein (CRP) inhibits the activity of the endothelial isoform of nitric oxide synthase (eNOS) via uncoupling of the enzyme both in vitro and in vivo. eNOS activity appears to be related ...in part to its interaction with other cellular proteins, including heat shock protein 90 (Hsp90), caveolin-1, and porin. In this study, we examined the effect of CRP treatment of human aortic endothelial cells (HAECs) on eNOS interaction with caveolin-1, Hsp90, and porin.
We incubated HAECs with CRP (0, 12.5, and 25 mg/L) for 1, 6, or 24 h and assessed the interaction of these proteins with eNOS by immunoprecipitation and western blotting.
CRP treatment (12.5 and 25 mg/L) of HAECs for 24 h significantly increased eNOS binding to caveolin-1 (40% and 54% increase, respectively; P < 0.05) and decreased binding to Hsp90 (33% and 66% decrease, respectively; P < 0.05). CRP (25 mg/L) also significantly decreased the binding of porin to eNOS (11% decrease, P < 0.05). Similar results were seen when HAECs were treated with CRP for 6 h.
These negative protein-protein interactions of eNOS were able to partly explain the CRP-induced decreases in the activity of this critical enzyme, which caused endothelial dysfunction.
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