Systemic Inflammation Index and Tumor Glycolytic Heterogeneity Help Risk Stratify Patients with Advanced Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma Treated with Tyrosine Kinase Inhibitor Therapy

Tyrosine kinase inhibitors (TKIs) are the first-line treatment for patients with advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma. Over half of patients failed to achieve prolonged survival benefits from TKI therapy. Awareness of a reliable prognostic tool may provide a valuable direction for tailoring individual treatments. We explored the prognostic power of the combination of systemic inflammation markers and tumor glycolytic heterogeneity to stratify patients in this clinical setting. One hundred and five patients with advanced EGFR-mutated lung adenocarcinoma treated with TKIs were retrospectively analyzed. Hematological variables as inflammation-induced biomarkers were collected, including the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation index (SII). First-order entropy, as a marker of heterogeneity within the primary lung tumor, was obtained by analyzing 18F-fluorodeoxyglucose positron emission tomography images. In a univariate Cox regression analysis, sex, smoking status, NLR, LMR, PLR, SII, and entropy were associated with progression-free survival (PFS) and overall survival (OS). After adjusting for confounders in the multivariate analysis, smoking status, SII, and entropy, remained independent prognostic factors for PFS and OS. Integrating SII and entropy with smoking status represented a valuable prognostic scoring tool for improving the risk stratification of patients. The integrative model achieved a Harrell’s C-index of 0.687 and 0.721 in predicting PFS and OS, respectively, outperforming the traditional TNM staging system (0.527 for PFS and 0.539 for OS, both p < 0.001). This risk-scoring model may be clinically helpful in tailoring treatment strategies for patients with advanced EGFR-mutated lung adenocarcinoma.

High Circulating Sonic Hedgehog Protein Is Associated With Poor Outcome in EGFR-Mutated Advanced NSCLC Treated With Tyrosine Kinase Inhibitors

IntroductionGrowing preclinical evidence has suggested that the Sonic hedgehog (Shh) pathway is involved in resistance to tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). However, little is known concerning the prognostic value of this pathway in this context.Materials and MethodsWe investigated the relationship between plasma levels of Shh and EGFRm NSCLC patients’ outcome with EGFR TKIs. We included 74 consecutive patients from two institutions with EGFRm advanced NSCLC treated by EGFR TKI as first-line therapy. Plasma samples were collected longitudinally for each patient and were analyzed for the expression of Shh using an ELISA assay. The activation of the Shh–Gli1 pathway was assessed through immunohistochemistry (IHC) of Gli1 and RT-qPCR analysis of the transcripts of Gli1 target genes in 14 available tumor biopsies collected at diagnosis (baseline).ResultsAmong the 74 patients, only 61 had baseline (diagnosis) plasma samples, while only 49 patients had plasma samples at the first evaluation. Shh protein was detectable in all samples at diagnosis (n = 61, mean = 1,041.2 ± 252.5 pg/ml). Among the 14 available tumor biopsies, nuclear expression of Gli1 was observed in 57.1% (8/14) of patients’ biopsies. Shh was significantly (p &lt; 0.05) enriched in youth (age &lt; 68), male, nonsmokers, patients with a PS &gt; 1, and patients presenting more than 2 metastatic sites and L858R mutation. Higher levels of Shh correlated with poor objective response to TKI, shorter progression-free survival (PFS), and T790M-independent mechanism of resistance. In addition, the rise of plasma Shh levels along the treatment was associated with the emergence of drug resistance in patients presenting an initial good therapy response.ConclusionThese data support that higher levels of plasma Shh at diagnosis and increased levels of Shh along the course of the disease are related to the emergence of TKI resistance and poor outcome for EGFR-TKI therapy, suggesting that Shh levels could stand both as a prognostic and as a resistance biomarker for the management of EGFR-mutated NSCLC patients treated with EGFR-TKI.

Cytoreductive Stereotactic Body Radiotherapy with Tyrosine Kinase Inhibitors for Intrathoracic Oligoprogressive EGFR-mutated Lung Cancer

Background: Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) shows an impressive initial response to EGFR tyrosine kinase inhibitors (EGFR-TKI). However, resistance invariably develops, commonly involving the site of initial gross disease. Cytoreductive stereotactic body radiotherapy (SBRT) for thoracic oligoprogressive disease (OPD) may effectively delay progression through EGFR-TKI therapy.Methods: From a prospectively maintained IRB-approved institutional registry, we identified 23 patients consecutively treated between 2011-2019 with thoracic SBRT and received EGFR-TKI within 6-months of SBRT. Radiographic progression-free (PFS) and overall survival (OS) were estimated using Kaplan-Meier analysis. Toxicity and patient-reported Edmonton Symptom Assessment Scale (ESAS) scores were reviewed.Results: Median follow-up after SBRT was 20-months (range, 4-100), and the median age was 68-years (range, 33-89). Most patients were females (n=21;91.3%). RT dose was 50-60 Gy in 5-10 fractions. EGFR-TKI administered were erlotinib, osimertinib and gefitinib in 15, 5, and 3 patients, respectively. Median PFS and OS following SBRT were 8-months and 31-months, respectively. 1-year PFS and OS were 34.8% and 78.3%. The median duration of EGFR-TKI therapy was 26-months (1-91). Most patients progressed in new distant sites, most commonly bones (n=5;21.7%) and distant lung (n=4;17.4%), with only 2/23 patients having initial progression within the SBRT field. Grade-2 pneumonitis (n=2) and rib fracture (n=1) were noted radiation-related toxicities. Dominant ESAS symptoms were fatigue (21.7%), pain (8.7%), and loss of appetite (8.7%).Conclusions: For EGFR-mutated NSCLC patients with thoracic OPD on EGFR-TKI, SBRT was well tolerated, resulted in changes in subsequent patterns of failure, lengthened PFS, and prolongs the duration of initial TKI therapy.