Subsequent treatments beyond progression on osimertinib in EGFR-mutated NSCLC and leptomeningeal metastases.

BACKGROUND: Despite the reported efficacy of osimertinib, central nervous system (CNS) progression is still frequent in EGFR-mutated NSCLC. This study aimed to reveal site-specific resistant mechanisms to osimertinib and investigate subsequent treatments for leptomeningeal metastases (LM). METHODS: EGFR-mutated NSCLC with LM who progressed on osimertinib were included. Molecular analysis of cerebrospinal fluid (CSF) at osimertinib progression was performed. Subsequent treatments of LM were collected and analyzed. RESULTS: A total of 246 patients were identified. Only those with LM as a progression site on osimertinib were included (n=81). In 58 CSF-plasma pairs, more alterations were uniquely detected in CSF (77%) than in plasma (7%). These mechanisms led to 22 patients receiving matched targeted therapy. Among them, 16 (72.7%) had a clinical response. The median overall survival was 7.2 months. For non-matched therapy (n=59), the osimertinib combination had a longer median overall survival than the regimen switch in CNS-only progression (15.3 vs. 7 months, p=0.03). Finally, serial monitoring by CSF revealed the potential evolution of LM. CONCLUSIONS: Private resistant mechanisms in CSF might match osimertinib-resistant LM for targeted therapy. Besides, continuing osimertinib with intensification strategy might prolong survival, especially for those with CNS-only progression. Prospective  exploration is needed.

Venous thromboembolism risk factors in Chinese non-small cell lung cancer patients.

PURPOSE: Certain clinicopathological factors contribute to the development of venous thromboembolism (VTE) in lung cancer. The aim of the current study was to assess the incidence of and the potential risk factors associated with the development of VTE in Chinese lung cancer patients. METHODS: Patients with lung cancer in our center were screened for VTE from January 2004 to July 2013. One VTE case was matched with two controls according to gender, pathology, clinical stage, and anticancer therapy. RESULTS: Among the 4,726 patient records screened, 61 (1.3 %) VTE cases with non-small cell lung cancer (NSCLC) were identified, including 58 (95.1 %) with adenocarcinoma and 59 (96.7 %) with advanced stage tumors (IIIb and IV). Serous effusion (OR 2.089, 95 % CI 1.022-4.270, P = 0.043), fever (OR 8.999, 95 % CI 1.688-47.968, P = 0.010), increased leukocytes (OR 4.136, 95 % CI 1.957-8.738, P < 0.001), hyponatremia (< 130 mmol/L, OR 5.335, 95 % CI 1.366-20.833, P = 0.016), and increased alanine aminotransferase (ALT) (OR 3.879, 95 % CI 1.514-9.936, P = 0.005) were associated with an increased risk of VTE. Patients with poor performance status (PS) (≥ 2 vs. < 1) (HR 1.574, 95 % CI 1.112-2.228, P = 0.010) and serous effusion (HR 1.571, 95% CI 1.114-2.215, P = 0.010) tended to have a poor prognosis. There was no difference in overall survival between VTE (median 15.2 months, 95 % CI 11.6-18.9) and control patients (median 16.3 months, 95 % CI 14.1-18.4, P = 0.184; HR 1.273, 95 % CI 0.890-1.820, P = 0.185). CONCLUSIONS: Clinical characteristics such as serous effusion, fever, increased leukocytes, hyponatremia, and increased ALT are potential risk factors for VTE in NSCLC. Poor PS and serous effusion imply poor prognosis for NSCLC patients, most of which have adenocarcinomas and advanced stage.

Combination of Cytologic Findings and Circulating Tumor DNA From Cerebrospinal Fluid Revealed SCLC Transformation in Patients With Leptomeningeal Metastases of Lung Adenocarcinoma.

Introduction: Transformation to SCLC is a resistance mechanism to tyrosine kinase inhibitor in EGFR-mutated lung adenocarcinoma (LUAD). Nevertheless, the clinical and molecular features of SCLC transformation in LUAD with leptomeningeal metastases (LM) are scarce. Methods: We retrospectively collected 237 patients with NSCLC who underwent lumbar puncture owing to suggestion of LM. All SCLC transformation in cerebrospinal fluid (CSF) was confirmed by two experienced pathologists using cytologic evaluation. CSF circulating tumor DNA (ctDNA) was tested by next-generation sequencing. Results: Tumor cells in CSF samples were found in 111 patients (111 of 237, 46.8%), and eight cases (eight of 111, 7.2%) were identified as having SCLC cells in CSF. Seven patients carried the EGFR mutation, including four patients with EGFR exon 19 deletion and three patients with EGFR exon 21 L858R mutation. Another patient harbored ERBB2 insertion. Seven of these patients were resistant to targeted therapy. CSF ctDNA analysis reported that TP53 and RB1 mutations were common. The median time from the diagnosis of advanced NSCLC to SCLC transformation found in CSF was 9.7 months (95% confidence interval [CI]: 4.0-17.5 mo). The median overall survival since the initial diagnosis of metastatic NSCLC was 15.3 months (95% CI: 1.2-29.4 mo). The median overall survival after SCLC transformation detected in CSF was 5.0 months (95% CI: 4.0-5.9 mo). Conclusions: SCLC transformation may be revealed in CSF by both cytologic evaluation and ctDNA, not just in tissue that underwent rebiopsy. SCLC transformation of CSF is informative for resistance mechanism in patients with LUAD with LM on tyrosine kinase inhibitor progression, which was associated with poor survival.

Impact of preoperative [18F]FDG PET/CT vs. contrast-enhanced CT in the staging and survival of patients with clinical stage I and II non-small cell lung cancer: a 10-year follow-up study.

OBJECTIVES: To elucidate the impact of [18F]FDG positron emission tomography/computed tomography (PET/CT) vs. CT workup on staging and prognostic evaluation of clinical stage (c) I-II NSCLC. METHODS: We retrospectively identified 659 cI-II NSCLC who underwent CT (267 patients) or preoperative CT followed by PET/CT (392 patients), followed by curative-intended complete resection in our hospital from January 2008 to December 2013. Differences were assessed between preoperative and postoperative stage. Five-year disease-free survival (DFS) and overall survival (OS) rates were calculated using the Kaplan-Meier approach and compared with log-rank test. Impact of preoperative PET/CT on survival was assessed by Cox regression analysis. RESULTS: The study included 659 patients [mean age, 59.5 years ± 10.8 (standard deviation); 379 men]. The PET/CT group was superior over CT group in DFS [12.6 vs. 6.9 years, HR 0.67 (95% CI 0.53-0.84), p < 0.001] and OS [13.9 vs. 10.5 years, HR 0.64 (95% CI 0.50-0.81), p < 0.001]. In CT group, more patients thought to have cN0 migrated to pN1/2 disease as compared with PET/CT group [26.4% (66/250) vs. 19.2% (67/349), p < 0.001], resulting in more stage cI cases being upstaged to pII-IV [24.7% (49/198) vs. 16.1% (47/292), p = 0.02], yet this was not found in cII NSCLC [27.5% (19/69) vs. 27.0% (27/100), p = 0.94]. Cox regression analysis identified preoperative PET/CT as an independent prognostic factor of OS and DFS (p = 0.002, HR = 0.69, 95% CI 0.54-0.88; p = 0.004, HR = 0.72, 95% CI 0.58-0.90). CONCLUSION: Addition of preoperative [18F]FDG PET/CT was associated with superior DFS and OS in resectable cI-II NSCLC, which may result from accurate staging and stage-appropriate therapy.

Neoadjuvant sintilimab plus chemotherapy in EGFR-mutant NSCLC: Phase 2 trial interim results (NEOTIDE/CTONG2104).

The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon's two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) in vitro. Infiltration and T cell receptor (TCR) clonal expansion of CCR8+ regulatory T (Treg)hi/CXCL13+ exhausted T (Tex)lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC.

Lipid-associated macrophages for osimertinib resistance and leptomeningeal metastases in NSCLC.

Leptomeningeal metastases (LMs) remain a devastating complication of non-small cell lung cancer (NSCLC), particularly following osimertinib resistance. We conducted single-cell RNA sequencing on cerebrospinal fluid (CSF) from EGFR-mutant NSCLC with central nervous system metastases. We found that macrophages of LMs displayed functional and phenotypic heterogeneity and enhanced immunosuppressive properties. A population of lipid-associated macrophages, namely RNASE1_M, were linked to osimertinib resistance and LM development, which was regulated by Midkine (MDK) from malignant epithelial cells. MDK exhibited significant elevation in both CSF and plasma among patients with LMs, with higher MDK levels correlating to poorer outcomes in an independent cohort. Moreover, MDK could promote macrophage M2 polarization with lipid metabolism and phagocytic function. Furthermore, malignant epithelial cells in CSF, particularly after resistance to osimertinib, potentially achieved immune evasion through CD47-SIRPA interactions with RNASE1_M. In conclusion, we revealed a specific subtype of macrophages linked to osimertinib resistance and LM development, providing a potential target to overcome LMs.

BCL11A overexpression predicts survival and relapse in non-small cell lung cancer and is modulated by microRNA-30a and gene amplification.

BACKGROUND: Aberrant activation of the proto-oncogene B-cell lymphoma/leukemia 11A (BCL11A) has been implicated in the pathogenesis of leukemia and lymphoma. However, the clinical significance of BCL11A in non-small cell lung cancer (NSCLC) remains unknown. RESULTS: We examined BCL11A expression at the protein and mRNA levels in a cohort (n=114) of NSCLC patients and assessed the relationship between BCL11A expression and clinicopathological parameters. Data from array-based Comparative Genomic Hybridization (aCGH) and microRNA transfection experiments were integrated to explore the potential mechanisms of abnormal BCL11A activation in NSCLC. Compared to adjacent non-cancerous lung tissues, BCL11A expression levels were specifically upregulated in NSCLC tissues at both the mRNA (t=9.81, P<0.001) and protein levels. BCL11A protein levels were higher in patients with squamous histology (χ2=15.81, P=0.001), smokers (χ2=8.92, P=0.004), patients with no lymph node involvement (χ2=5.14, P=0.029), and patients with early stage disease (χ2=3.91, P=0.048). A multivariate analysis demonstrated that in early stage NSCLC (IA-IIB), BCL11A was not only an independent prognostic factor for disease-free survival (hazards ratio [HR] 0.24, 95% confidence interval [CI] 0.12-0.50, P<0.001), but also for overall survival (HR=0.23, 95% CI 0.09-0.61, P=0.003). The average BCL11A expression level was much higher in SCC samples with amplifications than in those without amplifications (t=3.30, P=0.023). Assessing functionality via an in vitro luciferase reporter system and western blotting, we found that the BCL11A protein was a target of miR-30a. CONCLUSIONS: Our results demonstrated that proto-oncogene BCL11A activation induced by miR-30a and gene amplification may be a potential diagnostic and prognostic biomarker for effective management of this disease.

The regularity of anatomical variations of dominant pulmonary segments in the right upper lobe.

BACKGROUND: Anatomical variations often pose challenges to pulmonary surgery. Previous studies have mainly described the frequencies of bronchovascular anatomical variations in pulmonary segments, but did not determine the differences between pulmonary segments and the regularity behind these anatomical variations. Here, we attempted to investigate the regularity of bronchovascular anatomical variations in different pulmonary segments. METHODS: Thin-slice enhanced computed tomography data of 800 cases from our center were included in this study. Digitalized three-dimensional virtual lung segmentation was done, the dominant and inferior lung segments of the right upper lobe were defined, and the regularity of anatomical variations was explored. RESULTS: The mean volume ratio of the anterior segment of the right upper lobe (39.6 ± 8.6%) was highest, and that of the posterior segment (28.6 ± 7.9%) was lowest. Therefore, the dominant-type segment (DS + SDS) was dominant in the anterior segment, accounting for 74.6% (597/800), and the inferior-type segment (SIS + IS) was dominant in the posterior segment of the right upper lobe, accounting for 71.5% of cases (573/800). During the transformation of dominant and inferior lung segments, the corresponding regularity of anatomical variations could be displayed. For example, with an increase in the volume of the anterior segment of the right upper lobe, the occurrence rate of the bifurcated type of bronchus (B1 + 2, B3), the "central vein type" and the involvement of the trunk inferior and ascending artery in the blood supply of anterior segment gradually increased. CONCLUSIONS: The existence of dominant segments will increase the diversity of anatomical variations and the complexity of pulmonary segmentectomy.

Spatial downregulation of CD74 signatures may drive invasive component development in part-solid lung adenocarcinoma.

Pulmonary nodules with part-solid imaging features manifest during the progression from preinvasive to invasive lung adenocarcinoma. To define the spatial composition and evolutionary trajectories of early-stage lung adenocarcinoma, we combined spatial transcriptomics (ST) and pathological annotations from 20 part-solid nodules (PSNs), four of which were matched with single-cell RNA sequencing. Two malignant cell populations (MC1 and MC2) were identified, and a linear evolutionary relationship was observed. Compared to MC2, the pre-existing malignant MC1 exhibited a lower metastatic signature, corresponding to the preinvasive component (lepidic) on pathology and the ground glass component on PSN imaging. Higher immune infiltration was observed among MC1 regions in ST profiles, and further analysis revealed that macrophages may be involved in this process through the CD74 axis. This work provides deeper insights into the evolutionary process and spatial immune cell composition behind PSNs and highlights the mechanisms of immune escape behind this adenocarcinoma trajectory.

Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC (CTONG1804): a multicenter open-label phase II study.

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive (N) and nivolumab-chemotherapy (N/C) combinations based on PD-L1 expression. Eligible patients exhibited resectable clinical stage IIA-IIIB (AJCC 8th edition) NSCLC without EGFR/ALK alterations. Patients received either mono-nivolumab (N) or nivolumab + nab-paclitaxel+ carboplatin (N/C) for three cycles based on PD-L1 expression. The primary endpoint was the major pathological response (MPR). Key secondary endpoints included the pathologic complete response (pCR), objective response rate (ORR), and event-free survival (EFS). Baseline PD-L1 expression and perioperative circulating tumor DNA (ctDNA) status were correlated with pCR and EFS. Fifty-two patients were enrolled, with 46 undergoing surgeries. The MPR was 50.0% (26/52), with 25.0% (13/52) achieving pCR, and 16.7% and 66.7% for patients with PD-L1 ≥ 50% in N and N/C groups, respectively. Thirteen (25.0%) patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment. Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR (39.1%) compared with those remained positive (6.7%, odds ratio = 6.14, 95% CI 0.84-Inf, p = 0.077). With a median follow-up of 25.1 months, the 18-month EFS rate was 64.8% (95% CI 51.9-81.0%). For patients with ctDNA- vs. ctDNA + , the 18m-EFS rate was 93.8% vs 47.3% (HR, 0.15; 95% CI 0.04, 0.94; p = 0.005). Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression ≥ 50%. ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits, which requires further confirmation in a prospective clinical trial (NCT04015778).

EGFR mutation heterogeneity and the mixed response to EGFR tyrosine kinase inhibitors of lung adenocarcinomas.

BACKGROUND: Non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations have mixed responses to tyrosine kinase inhibitors (TKIs). Intertumor heterogeneity in EGFR mutations is one potential explanation for this phenomenon. METHODS: We performed direct sequencing to identify EGFR mutations in 180 pairs of lung adenocarcinoma samples (from 3,071 patients). The high-resolution melting method was used in discordant cases to confirm EGFR mutation status. Matching samples were divided into four groups: primary lesions detected at different times, primary tumors with matched metastatic lymph nodes, multiple pulmonary nodules, and primary tumors with matched distant metastases. Multivariate analyses were performed to evaluate correlations between heterogeneity and patient characteristics. RESULTS: In the study population, the discordance rate was 13.9% (25 of 180). The multiple pulmonary nodules group had the highest discordance rate of 24.4% (10 of 41; odds ratio for heterogeneity in primary lesions detected at different times, 6.37; 95% confidence interval, 1.71-23.72; p = .006). Discordance rates in the metachronous and synchronous settings were 15.7% (22 of 140) and 7.5% (three of 40), respectively. In the 34 patients who developed EGFR TKI resistance, 10 (29.4%) cases exhibited heterogeneity and five (14.7%) patients exhibited a mixed response to the drug. Three (8.8%) of the patients with a mixed response also exhibited discordant EGFR mutations. CONCLUSIONS: The overall discordance rate of EGFR mutation heterogeneity in Asian patients with pulmonary adenocarcinoma is relatively low, but the rate in patients with multiple pulmonary nodules is significantly higher. This observation may explain the mixed tumor response to EGFR TKIs.

Dynamic 18 F-FDG PET/CT can predict the major pathological response to neoadjuvant immunotherapy in non-small cell lung cancer.

Major pathological response (MPR) is a potential surrogate for overall survival. We determined whether the dynamic changes in 18 F-labeled fluoro-2-deoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) were associated with MPR in patients receiving neoadjuvant immunotherapy. Forty-four patients with stage II-III non-small cell lung cancer (NSCLC) who received neoadjuvant immunotherapy and radical surgery were enrolled. Moreover, 18 F-FDG PET/CT scans were performed at baseline and within 1 week before surgery to evaluate the disease. All histological sections were reviewed to assess MPR. The detailed clinical features of the patients were analyzed. The reliability of the clinical variables was assessed in differentiating between MPR and non-MPR using logistic regression. Receiver-operating characteristic (ROC) curve analysis identified the SUVmax changes threshold most associated with MPR. Most of the patients were pathologically diagnosed with squamous cell carcinoma and received anti-PD-1 antibodies plus chemotherapy. The immunotherapy regimens included nivolumab, pembrolizumab, and camrelizumab. MPR was observed in more than half of lesions. Tumors with MPR had a higher decrease in the longest dimension on dynamic PET/CT than those without MPR. Furthermore, the decline in SUVmax was significantly different between MPR and non-MPR diseases, and MPR lesions had a prominent mean reduction in SUVmax. SUVmax reduction was independently associated with MPR in the multivariate regression. On ROC analysis, the threshold of SUVmax decrease in 60% was associated with MPR. Dynamic changes in SUVmax were associated with MPR. The tumors with MPR showed a greater PET/CT response than those without MPR. A SUVmax decrease of more than 60% is more likely to result in an MPR after receiving neoadjuvant immunotherapy.

Investigation on the incidence and risk factors of lung cancer among Chinese hospital employees.

OBJECTIVE: In recent years, the lung cancer incidence has grown and the population is younger. We intend to find out the true detection rate of pulmonary nodules and the incidence of lung cancer in the population and search for the risk factors. METHOD: Hospital employees ≥40 years old who underwent low-dose computed tomography (CT) lung cancer screening from January 2019 to March 2022 were selected to record CT-imaging characteristics, pathology, staging, and questionnaires to investigate past history, smoking history, diet, mental health, etc. PM2.5 and radiation intake in radiation-related occupation received monitoring in hospital. RESULT: The detection rate of suspicious pulmonary nodules was 9.1% (233/2552), and the incidence rate of lung cancer (including adenocarcinoma in situ) was 4.0% (103/2552). Morbidity among doctors, nurses, technicians, administers, and logistics was no difference (p = 0.184), but higher in women than in men (4.7% vs 2.4% p = 0.002). The invasiveness increased with age and CT density of nodules (p = 0.018). The relationship between lung cancer morbidity and PM2.5 was not clear (p = 0.543); and no lung cancer has been found in employees related ionizing radiation. CONCLUSION: The high screening rate has brought about a high incidence of lung cancer. At present, the risk factor analysis of lung cancer based on small samples cannot find the direct cause. Most of the ground glass opacity (GGO)s detected by LDCT screening are indolent, but there are also rapidly progressive lung cancer. A predictive model to identify active and indolent GGO is necessary.

Induction immune-checkpoint inhibitors for resectable oncogene-mutant NSCLC: A multicenter pooled analysis.

Despite limited efficacy of immunotherapy for advanced non-small-cell lung cancer (NSCLC) with driver mutations, whether neoadjuvant immunotherapy could be clinically valuable in those patients warrants further investigation. We utilized 40 oncogene-mutant NSCLC treated with induction immunotherapy from a large consecutive multicenter cohort. Overall response rate was 62.5% while 2 patients had disease progression. Of 39 patients that received surgery, R0 resection rate was 97.4%. The major pathological response (MPR) rate was 37.5% and the pathological complete response (pCR) rate was 12.5%. Pre-treatment PD-L1 expression was not a predictive biomarker in these patients. Median disease-free survival for all oncogenic mutation and EGFR mutation was 28.5 months. Indirect comparison through integrating CTONG1103 cohort showed neoadjuvant immunotherapy plus chemotherapy yielded the most superior efficacy among erlotinib and chemotherapy for resectable EGFR-mutant NSCLC. No MPR patients were identified with neoadjuvant immunotherapy plus chemotherapy for uncommon EGFR insertion or point mutations. Our results indicated the potential clinical feasibility of neoadjuvant immunotherapy for resectable localized oncogene-mutant NSCLC especially for EGFR-mutant NSCLC.

Deep learning-based growth prediction for sub-solid pulmonary nodules on CT images.

Background: Estimating the growth of pulmonary sub-solid nodules (SSNs) is crucial to the successful management of them during follow-up periods. The purpose of this study is to (1) investigate the measurement sensitivity of diameter, volume, and mass of SSNs for identifying growth and (2) seek to establish a deep learning-based model to predict the growth of SSNs. Methods: A total of 2,523 patients underwent at least 2-year examination records retrospectively collected with sub-solid nodules. A total of 2,358 patients with 3,120 SSNs from the NLST dataset were randomly divided into training and validation sets. Patients from the Yibicom Health Management Center and Guangdong Provincial People's Hospital were collected as an external test set (165 patients with 213 SSN). Trained models based on LUNA16 and Lndb19 datasets were employed to automatically obtain the diameter, volume, and mass of SSNs. Then, the increase rate in measurements between cancer and non-cancer groups was studied to evaluate the most appropriate way to identify growth-associated lung cancer. Further, according to the selected measurement, all SSNs were classified into two groups: growth and non-growth. Based on the data, the deep learning-based model (SiamModel) and radiomics model were developed and verified. Results: The double time of diameter, volume, and mass were 711 vs. 963 days (P = 0.20), 552 vs. 621 days (P = 0.04) and 488 vs. 623 days (P< 0.001) in the cancer and non-cancer groups, respectively. Our proposed SiamModel performed better than the radiomics model in both the NLST validation set and external test set, with an AUC of 0.858 (95% CI 0.786-0.921) and 0.760 (95% CI 0.646-0.857) in the validation set and 0.862 (95% CI 0.789-0.927) and 0.681 (95% CI 0.506-0.841) in the external test set, respectively. Furthermore, our SiamModel could use the data from first-time CT to predict the growth of SSNs, with an AUC of 0.855 (95% CI 0.793-0.908) in the NLST validation set and 0.821 (95% CI 0.725-0.904) in the external test set. Conclusion: Mass increase rate can reflect more sensitively the growth of SSNs associated with lung cancer than diameter and volume increase rates. A deep learning-based model has a great potential to predict the growth of SSNs.

Genetic Profiling of Cell-Free DNA From Pleural Effusion in Advanced Lung Cancer as a Surrogate for Tumor Tissue and Revealed Additional Clinical Actionable Targets.

BACKGROUND: Pleural effusion (PE) has been one of the promising sources of liquid biopsy in advanced lung cancer patients. However, its clinical utility is not widely accepted due to the lack of full estimation of its potential versus routine clinical samples. METHOD: A total of 164 advanced lung cancer patients were enrolled with 164 matched tumor tissue and PE-cfDNA, 153 accompanied plasma and 63 1PE-sDNA. RESULT: PE-cfDNA displayed significantly higher median mutant allele frequency and an overall mutation concordance rate of 65% to tissue, which was higher than PE-sDNA (43%) and plasma-cfDNA (43%). The discrepancies between PE-cfDNA and tumor tissue were high in several genes, including SMARCA4, PIK3CA, ERBB2, KM T2A, ALK and NF1. For clinically actionable mutations, the concordance rate between PE-cfDNA and tumor tissue is 87%. Eleven patients were identified with actionable mutations in PE-cfDNA and four patients benefited from PE-cfDNA-guided targeted. Meanwhile, PE-cfDNA recapitulated mutations of diverse tissue origins and provided more mutational information under the circumstance that tumor tissue or tumor tissue of different origins were unavailable. The combination of tumor tissue and PE-cfDNA profiling increased positive detection rates of patients compared to tumor tissue alone. Our finding highlighted the importance of PE-cfDNA in the optimal selection of patients for targeted therapy. CONCLUSION: The PE-cfDNA-based liquid biopsy displays better performance in the characterization of gene alterations than PE-sDNA and plasma-cfDNA. PE-cfDNA together with tumor tissue profiling optimizes comprehensively genomic profiling of lung cancer patients, which might be important for selecting patients for better treatment management.

Longitudinal Undetectable Molecular Residual Disease Defines Potentially Cured Population in Localized Non-Small Cell Lung Cancer.

The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non-small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC. SIGNIFICANCE: This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection. This article is highlighted in the In This Issue feature, p. 1599.

Genotyping of Cerebrospinal Fluid Associated With Osimertinib Response and Resistance for Leptomeningeal Metastases in EGFR-Mutated NSCLC.

INTRODUCTION: Patients with NSCLC with leptomeningeal metastases (LM) presented dismal prognosis. Cerebrospinal fluid (CSF) is suggested as a medium of liquid biopsy of LM. However, the clinical implications of CSF genotyping on treatment outcomes remained elusive. METHODS: Patients with EGFR-mutated advanced NSCLC with LM were included: cohort 1, patients with LM who were treated with osimertinib with CSF and plasma genotyping performed before the first dosing of osimertinib (baseline, n = 45); cohort 2, CSF genotyping on progression on osimertinib and development of LM (the progression event on osimertinib is the diagnosis of LM, n = 35). Circulating tumor DNA in CSF underwent next-generation sequencing. RESULTS: Sensitivity of CSF genotyping for EGFR-sensitizing mutations was 93.3% (42 of 45) and 97.1% (34 of 35) in cohorts 1 and 2, respectively. In cohort 1, patients with EGFR exon 19 deletion had higher median intracranial progression free survival (iPFS) than those with EGFR exon 21 L858R mutation (11.9 versus 2.8 mo; p = 0.02). Median iPFS was significantly longer in patients with T790M-positive CSF genotyping (15.6 mo) than T790M-negative CSF (7.0 mo, p = 0.04). Concurrent CDK4 (2.8 versus 11.6 mo, p = 0.002) and CDKN2A (2.5 versus 9.6 mo, p = 0.04) mutation with EGFR-sensitizing mutations indicated lower median iPFS. Patients with T790M-negative CSF, EGFR exon 21 L858R mutation, concurrent FGF3 alteration, and over first-line osimertinib had shortened iPFS. In cohort 2, possible EGFR-related and EGFR-independent resistance mechanisms were found including C797S mutation, MET dysregulation, and TP53 plus RB1 co-occurrence. Patients with loss of T790M in CSF had a shorter median iPFS (7.4 mo) compared with those with reserved T790M (13.6 mo, p = 0.01). CONCLUSIONS: Genotyping of CSF indicated heterogeneous response to osimertinib and revealed the genetic characteristic of LM on osimertinib failure in patients with EGFR-mutated NSCLC diagnosed with LM.

Clinical outcomes of non-small cell lung cancer patients with leptomeningeal metastases after immune checkpoint inhibitor treatments.

OBJECTIVE: Leptomeningeal metastases (LM) occur in up to 5% of non-small cell lung cancer (NSCLC) patients and often develop after previous systemic treatments. In this article, we explored whether immune checkpoint inhibitors (ICIs) enhanced the dismal survival of patients with LM. MATERIALS AND METHODS: Data on NSCLC patients with LM prescribed ICIs were collected at the Guangdong Lung Cancer Institute. Furthermore, relevant literature was reviewed. RESULTS: A total of 255 NSCLC patients diagnosed with LM were screened from January 2015 to March 2020 at our institute. Cases reported by literature were also included. Finally, 32 NSCLC patients received ICIs after LM diagnosis; their median age was 55 years. Druggable genes were detected in 37.5% of all patients. The ICI regimens included nivolumab (n = 21), pembrolizumab (n = 9), and atezolizumab (n = 2). Ultimately, 62.5% of patients evidenced neurological symptom controlled. Two patients exhibited both intracranial and extracranial complete tumour response; one patient showed both intracranial and extracranial partial response (PR), one patient indicated intracranial PR and a systemic PR, and one patient showed central nervous system PR without extracranial response reported. The median progression-free survival (PFS) in the single-agent subgroup was 2.1 months (95% confidence interval [CI]: 1.4-2.9 months), and the median overall survival (OS) was 4.0 months (95% CI: 0.1-13.3 months). In the combined subgroup, the median PFS and OS were 3.0 months (95% CI: 1.1-4.9 months) and 5.4 months (95% CI: 0.5-10.3 months), respectively. Three patients exhibited remarkable PFS of over 20 months: all patients had ICI single agent, received cranial radiotherapy before ICI prescription, and took ICIs as second-line therapy, and two patients were EGFR/ALK wild type. Multivariate analysis showed that a better Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score was associated with prolonged PFS (P = 0.04). No difference in survival was seen between monotherapy and combination therapy groups. CONCLUSION: NSCLC patients with LM may benefit from ICIs of both monotherapy and combination with other therapies, especially those with good ECOG-PS scores. Further work in this regard is required.

Value of interim 18F-FDG PET/CT for predicting progression-free survival in stage â ¢B/IV EGFR-mutant non-small-cell lung cancer patients with EGFR-TKI therapy.

OBJECTIVES: We retrospectively investigated the prognostic value of FDG-PET performed for patients with Stage ⅢB/IV EGFR-mutant non-small-cell lung cancer (NSCLC) receiving EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS: A total of 78 patients newly diagnosed with Stage ⅢB/IV EGFR-mutant NSCLC who received baseline and interim PET/CT examination and were treated with EGFR-TKI therapy were included. Interim PET was performed after 4-6 weeks of treatment. Cox proportional hazards regression analysis was used to assess the association between quantitative 18F-FDG PET/CT parameters, other clinicopathological factors and progression-free survival (PFS), non-durable clinical benefit (non-DCB). Five interim PET variables were analyzed in this study in the prediction of non-DCB. RESULTS: The one-year and two-year progression-free survival rates of the patients were 33.9% (28.6-39.2%) and 20.7% (16.1-25.3%), respectively. Multivariable analysis indicated that interim PET relevant factors ΔSUVmax (p = 0.002, p = 0.014) and ΔSUVmean (p = 0.000, p = 0.030) were independent risk factors for predicting the PFS or non-DCB of patients receiving EGFR-TKI treatment. The optimal cutoff values of the parameters in the tumor survival analyses were 56.74% for ΔSUVmax (p = 0.002) and 36.48% for ΔSUVmean (p = 0.001). ΔSUVmax had the highest diagnostic value in the prediction of non-DCB. The one-year progression-free survival rates (95% confidence intervals) of patients with ΔSUVmax ≥ 56.74% and ΔSUVmax <56.74% were 59.5% (44.2-74.8%) and 5.7% (0.0-13.3%), respectively (p = 0.000). CONCLUSION: An early PET scan after 4-6 weeks can effectively predict the PFS and non-DCB of patients with Stage ⅢB/IV EGFR-mutant NSCLC receiving EGFR-TKI therapy.