Translational lung cancer research最新文献

Background: Lung cancer remains the primary cause of cancer-related mortality globally, treated using immune checkpoint inhibitors (ICIs), which are introducing new therapeutic potential and complexities, including severe immune-related adverse events (irAEs) and rare fistula formation. The interaction between coronavirus disease 2019 (COVID-19) and ICIs further complicates treatment outcomes, occasionally leading to spontaneous tumor regression, suggesting potential immune response modulation by COVID-19. This report elucidates a unique case of non-small cell lung cancer (NSCLC) managed with these challenges, highlighting the delicate balance required for modern oncological care.

Case description: A 44-year-old male patient with stage IIIC NSCLC, no driver mutations such as those in epidermal growth-factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genes, and a tumor proportion score of <1% experienced multiple complications after ICI plus chemotherapy. The treatment regimen comprised durvalumab, tremelimumab, carboplatin, and nab-paclitaxel. The patient experienced multiple complications including: (I) esophageal mediastinal fistula; (II) severe irAEs such as grade 3 colitis; (III) COVID-19 and Candida albicans infections; (IV) cytokine release syndrome; and (V) myocarditis. Treatment interventions included high-dose steroids, antifungal therapy, mechanical support in the intensive care unit, and hemodialysis. The patient showed remarkable tumor regression and recovery from acute adverse events with eventual tumor resolution and closure of the esophageal mediastinal fistula. Tumor cells were positive for angiotensin-converting enzyme 2, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have infected tumor cells and caused an antitumor effect as an oncolytic virus.

Conclusions: Clinicians should be aware that COVID-19 might be associated with the development of severe irAEs and unexpectedly enhanced antitumor effects. The findings also suggest new fields of study regarding the interaction between viral infection and tumor immune response, which may inform future therapeutic approaches.

Background: While the resident microbiome of tumors has been shown to be associated with the occurrence and progression of non-small cell lung cancer, there remains a significant knowledge gap in understanding the correlation between the microbial spectrum and immunity response to cancer therapy. In the case of lung adenocarcinoma (LUAD), the tumor microenvironment, encompassing a diverse array of microbes and immune cells, plays a crucial role in modulating therapeutic response. Towards comprehending the underlying mechanism, we present the microbe-immunity interactive networks to delineate the microbiota and immunity repertoires for two distinct molecular subtypes in LUAD.

Methods: We obtained multi-omics data of LUAD patients from the publicly available database. In this study, we conducted a systematic exploration of the microbial and immunological etiology of cancer prognosis, by integrating the microbiome, genome, transcriptome, and clinic data. The mutational signature analysis, transcriptome analysis, gene set enrichment analysis, and microbiota-immunity network analysis were performed.

Results: Based on the transcriptome repertories, we classified the patients into two molecular subtypes and observed that the overall survival of molecular subtype 2 (MS2) was notably shortened. We identified the microbial biomarkers in patients that distinguished between these molecular subtypes. The significant up-regulation of γδT and neutrophil in MS2, suggesting the inflammation augmentation and stimulation of γδT activation. What is more, the MS2 are characterized by a correlation network between microbiota biomarkers and γδT cell, which may contribute to suppression of anti-tumor immunity and poor overall survival.

Conclusions: Our findings not only display the repertoires of tumor microbiota and immune cells, but also elucidate the potential contribution of the microbiota-immunity correlation network to unfavorable overall survival and therapeutic resistance, thereby exerting profound implications on future LUAD therapy.

Background: The SWItch/Sucrose Nonfermentable (SWI/SNF) complex, a multi-subunit chromatin remodeler, is linked to aggressive tumors when deficient. Accurate identification of SWI/SNF expression status is crucial for tailoring targeted therapies. Previous studies on the efficacy of immunotherapy for SWI/SNF-deficient (SWI/SNF-d) pulmonary tumors primarily focus on non-small cell lung cancer (NSCLC), with limited data on other modalities like radiotherapy. This study aims to analyze the clinicopathological characteristics and prognostic factors of SWI/SNF-d pulmonary neoplasms, including NSCLC and undifferentiated tumors, and to evaluate the effectiveness of radiotherapy and immunotherapy, providing a foundation for improved treatment strategies and prognostic assessments.

Methods: Patient data on SWI/SNF-d pulmonary neoplasms were collected from Fudan University Shanghai Cancer Center, assessing ARID1A, SMARCA2, SMARCA4, and SMARCB1 subunit expression via immunohistochemistry, with retrospective analysis of survival and treatment results.

Results: The study analyzed 101 SWI/SNF-d pulmonary neoplasms from 675 SWI/SNF-d cancer patients (January 2017 to August 2023), mostly male smokers, showing high malignancy. Clinicopathologic features were consistent across patients with various SWI/SNF subunit deficiencies. TP53 was the most common co-mutated gene (71%), followed by STK11, CDKN2A, KRAS, APC, and EGFR. Key prognostic factors for overall survival (OS) were distant metastasis, radiotherapy, and immunotherapy. Immunotherapy improved 3-year OS rates from 20.8% to 68.4% (P<0.001). KRAS-mutated patients on immunotherapy showed a lower 1-year survival rate (60.0% vs. 83.1%, P=0.08). Radiotherapy increased 3-year OS rates to 61.7% from 30.7% (P=0.012). Of 38 patients treated with immunotherapy, 16 benefited from radiotherapy [median OS: 31.4 months vs. not estimable (NE), P=0.045], with an average 17.2 days between radiotherapy and immunotherapy.

Conclusions: SWI/SNF-d pulmonary neoplasms, whether with multiple or single subunit losses, exhibit similar clinicopathological characteristics. Radiotherapy and immunotherapy are effective treatments for these patients, and the combination of radiotherapy with immunotherapy may offer synergistic effects.

Background: The use of immunotherapy in treatment of non-small cell lung cancer (NSCLC) patients with the BRAF gene mutations is an area of active research and is an item of clinical trials. While BRAF mutations are relatively infrequent in NSCLC patients, comprising approximately 1-3% of cases, the V600E substitution stands out as the most prevalent subtype of BRAF mutations. The presence of this mutation in cancer cells qualifies the patients for first-line therapy with BRAF and MEK inhibitors. This study aims to evaluate the efficacy of immunotherapy in NSCLC patients with BRAF mutations. We presented a series of seven NSCLC cases with BRAF mutations, four of whom received immunotherapy or chemoimmunotherapy.

Methods: We observed benefit from immunotherapy in all patients, but its duration depended on comorbidities and the presence of brain metastases. Utilization of the next generation sequencing (NGS) technique causes high detection frequency of BRAF mutations (4.7% of patients), although mutations other than V600E may predominate (4 out of 7 patients).

Results: In patients receiving immune checkpoint inhibitors (ICIs)-based therapy, the median progression-free survival (PFS) was 17 months from the start of immunotherapy, the overall objective response rate (ORR) was 50%, and disease control was achieved in all patients.

Conclusions: Immunotherapy can benefit NSCLC patients with BRAF mutations, though its efficacy is affected by comorbidities and brain metastases. The use of NGS enhances mutation detection, highlighting the need for personalized treatment approaches in NSCLC management. The varying responses to treatments among the patients emphasize the complexity of NSCLC management and the necessity for a personalized approach.

Background: The B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation is responsible for approximately 3% of acquired resistance mechanisms to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in advanced EGFR-mutant non-small cell lung cancer (NSCLC). This study investigated the efficacy and safety of a triple-targeted therapy combining EGFR/BRAF/mitogen-activated protein kinase kinase (MEK) inhibitors of dabrafenib, trametinib, and osimertinib in NSCLC patients with acquired BRAF V600E mutation after EGFR-TKI treatment.

Methods: A multi-center retrospective review of medical records was performed to analyze EGFR-mutated advanced Chinese NSCLC patients who acquired the BRAF V600E mutation following EGFR-TKI treatment. All patients subsequently received dabrafenib, trametinib, and osimertinib. The clinical characteristics, progression-free survival (PFS), and adverse events (AEs) were documented. The in-vivo drug response of patient-derived organoids (PDOs) was observed. Next-generation sequencing (NGS) was performed upon progression to triple-targeted therapy.

Results: Thirteen patients with BRAF V600E mutations were included. Following triple-targeted therapy, the corresponding objective response rate and disease control rate were 61.5% and 92.3%, respectively. The median PFS was 13.5 months (95% confidence interval: 6.6-20.4). PDOs derived from one patient's tumor sample were established, revealing that the triple-targeted therapy had a significantly lower half-maximal inhibitory concentration (IC₅₀) value compared to other regimens. The tumor growth inhibitory rate was 99.36% for dabrafenib, trametinib, and osimertinib; 99.25% for osimertinib plus vemurafenib; 98.92% for osimertinib, encorafenib, and cetuximab; and 62.83% for pemetrexed plus carboplatin. NGS analysis identified major resistance mechanisms following the triple-targeted therapy, including the EGFR-dependent pathway, EGFR and BRAF V600E-dependent pathway, and an off-target mechanism.

Conclusions: EGFR/BRAF/MEK triple-targeted therapy is an effective and safe approach for treating EGFR-mutated NSCLC patients resistant to EGFR-TKIs with acquired BRAF V600E mutations.

Background: Lung adenocarcinoma (LUAD) is one of the most prevalent types of lung cancer (LC), accounting for 50% of all LC cases. Despite therapeutic advancements, patients suffer from adverse drug reactions. Furthermore, the prognosis of LC patients remains poor. Necroptosis is a novel mode of cell death and is critically involved in regulating immunotherapy in patients. However, the correlation between the necroptosis-related long non-coding RNA (lncRNA) (necro-related lnc) signature (NecroLncSig) and the response of patients with LUAD to immunotherapy is unclear. This study developed a model using lncRNAs to predict the prognosis of patients with LUAD.

Methods: We obtained the transcriptomic and clinical data of LUAD patients from The Cancer Genome Atlas (TCGA) database. Next, we conducted a co-expression analysis to identify the necro-related lnc. In addition, we constructed the NecroLncSig using univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. Then we evaluated and validated the NecroLncSig using a Kaplan-Meier (KM) survival analysis, receiver operating characteristic (ROC) curves, principal component analysis (PCA), Gene Ontology (GO) enrichment analysis, a nomogram, and calibration curves. Finally, we used the NecroLncSig to predict the responses of patients to immunotherapy.

Results: We constructed the NecroLncSig based on seven necro-related lnc. The patients were classified into a high-risk group (HRG) and a low-risk group (LRG). The overall survival (OS) of patients in the HRG was significantly poorer in the training, testing, and entire sets (P<0.05) than that of the patients in the LRG. Univariate and multivariate Cox regression analyses demonstrated that the risk score could predict the OS of patients in an independent manner (P<0.001). Time-dependent ROC analysis demonstrated that the area under the curve values of the NecroLncSig for 1-, 2-, and 3-year OS were 0.689, 0.700, and 0.685, respectively, for the entire set. Furthermore, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm showed that the response of patients in the HRG to immunotherapy was better than that of patients in the LRG.

Conclusions: Necro-related lnc can affect disease progression and patient prognosis. In addition, these lncRNAs can be used to design therapeutic strategies, such as immunotherapy, to treat patients with LUAD.

Background: The appreciation of sex differences is substantial for precise cancer management. Surgery is the main treatment for non-small cell lung cancer (NSCLC). We aimed to identify sex differences on perioperative outcomes in NSCLC patients and to uncover the origins of sex effect in outcomes using a Chinese cohort.

Methods: We retrospectively enrolled patients undergoing NSCLC surgery in the Western China Lung Cancer Database from January 2014 to April 2021. We compared baseline characteristics and perioperative outcomes between male and female. Multivariable analyses were performed. We conducted causal mediation analysis to identify drivers to sex differences in perioperative outcomes.

Results: Altogether, data of 10,181 patients (5,738 women and 4,443 men) were analyzed. Women had lower incidence of complications (5.05% vs. 12.15%), shorter postoperative length of stays (4.92 vs. 6.41 days), and less hospitalization cost (50,713.69 vs. 54,580.85, Chinese Yuan). Multivariable regression analysis identified sex as an independent factor of perioperative complications [odds ratio (OR), 1.843, 95% confidence interval (CI): 1.476-2.294], as well as of postoperative length of hospital stays (beta 0.123, 95% CI: 0.099-0.148), and hospitalization cost (beta 0.026, 95% CI: 0.026-0.026). Mediation analysis revealed that age, body mass index, prevalence of chronic obstructive pulmonary disease, predicted diffusion capacity for carbon monoxide, tumor size, pleural adhesion, and surgery duration were identified as mediators for sex differences in outcomes, while smoking status, surgery type, and resection extent were not.

Conclusions: Female NSCLC patients demonstrated lower incidence of complications, shorter postoperative length of stays, and less hospitalization cost after surgery. Those differences between men and women could be explained by their inherent biological differences and baseline health status. Perioperative management strategies for NSCLC should prioritize recognizing the potentially poorer outcomes among male patients and implementing tailored precautions accordingly.

Background: Chronic obstructive pulmonary disease (COPD) is associated with frequent complications after transthoracic biopsy. Radial probe endobronchial ultrasound-guided transbronchial lung biopsy (RP-EBUS-TBLB) is widely used to diagnose peripheral pulmonary lesions (PPLs). However, the efficacy and safety of this procedure for the diagnosis of PPLs in patients with COPD remain poorly understood. We investigated the usefulness of RP-EBUS-TBLB for diagnosing PPLs in patients with COPD.

Methods: This retrospective observational study aimed to identify clinical outcomes of RP-EBUS-TBLB in patients with COPD. A total of 175 patients with COPD and 439 patients without COPD were included in this study. RP-EBUS-TBLB was performed without fluoroscopy using a guide sheath.

Results: The overall diagnostic accuracies in patients with COPD and without COPD were 80.6% (141/175) and 78.8% (346/439), respectively. There was no significant difference in the diagnostic yield based on the severity of airflow limitation (80.0%, 81.4%, and 79.2% for mild, moderate, and severe to very airflow limitations, respectively; P=0.97). In patients with COPD, diagnostic yields for malignant and benign lesions were 85.6% (95/111) and 71.9% (46/64). In multivariable analyses, larger lesion size [≥30 mm; odds ratio (OR), 2.86; 95% confidence interval (CI): 1.10-7.45; P=0.03] and within the lesion on EBUS image (OR 9.29; 95% CI: 3.79-22.79; P<0.001) were associated with diagnostic success in patients with COPD, whereas lesion location of upper lobe (OR, 0.36; 95% CI: 0.14-0.92; P=0.03) were associated with diagnostic failure. The overall complication rate in our study was 7.4% (13/175) in patients with COPD. Pneumothorax occurred in 4.6% (8/175), and chest tube insertion was needed in 1.7% (3/175) of the patients.

Conclusions: RP-EBUS-TBLB can be used as an appropriate method to diagnose PPLs in patients with COPD. The size of the lesion (≥30 mm) and having the probe within the lesion were important for successful diagnosis. The location of the lesion in the upper lobe is associated with diagnostic failure. No difference was observed in the diagnostic yield based on the severity of airflow limitation. The complication rates were acceptable.

Background: Few studies have examined the safety and efficacy of docetaxel/ramucirumab (DOC/RAM) therapy in advanced non-small cell lung cancer (NSCLC) complicated by interstitial lung disease (ILD). Given the potential of vascular endothelial growth factor inhibitors to prevent drug-induced pneumonia, we aimed to clarify the role of this therapy in NSCLC with ILD.

Methods: This retrospective observational study evaluated the incidence of ILD in stage IV NSCLC patients receiving DOC/RAM therapy at our institution, stratified by ILD status. We also assessed the efficacy of this treatment. The primary objective was to investigate the incidence of ILD, while secondary objectives included evaluating the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), stratified by ILD status.

Results: Among patients with pre-existing ILD, 7 out of 28 (25%) developed DOC/RAM-induced interstitial pneumonia, while none of the 40 patients without pre-existing ILD developed this condition (P<0.001). Comparing historical controls (DOC only) with the DOC/RAM group, RAM did not significantly alter the incidence of interstitial pneumonia (P=0.33). There were no significant differences in ORR, PFS, or OS between patients with and without ILD. Subgroup analysis of smokers showed a non-significant trend toward worse survival in those with pre-existing ILD (P=0.20).

Conclusions: DOC/RAM therapy significantly increased the incidence of interstitial pneumonia in NSCLC patients with pre-existing ILD but did not significantly affect efficacy outcomes such as ORR, PFS, or OS.

Background: The time to surgery (TTS) after the completion of the final cycle of neoadjuvant chemoimmunotherapy in patients with non-small cell lung cancer (NSCLC) is inconsistent. Pathological complete response (pCR) and major pathological response (MPR) are associated with enhanced survival in those with NSCLC. The optimal TTS interval remains to be determined, some studies indicated that TTS ≤6 weeks has a vital role in NSCLC prognosis. Therefore, this study aimed to determine whether TTS is correlated with pathological outcomes and to identify the factors associated with TTS.

Methods: We retrospectively analyzed 82 individuals who had surgery after neoadjuvant chemoimmunotherapy for NSCLC between January 2020 and December 2023. Fifty participants were included in this study after inclusion and exclusion criteria. Participants were categorized into two groups: TTS ≤4 weeks and TTS >4 to 6 weeks. Univariate and multivariate regression analyses were employed to determine the impact of TTS on pathological response and to identify the variables associated with TTS. Variables that showed their P value <0.2 in univariate analyses were included in the multivariate analysis. Kaplan-Meier analysis was used to analyze disease-free survival (DFS).

Results: Our study evaluating 50 patients revealed that patients in the TTS ≤4 weeks group achieved pCR or MPR compared to patients in the >4 to 6 weeks group (P=0.01). In univariate analyses, TTS ≤4 weeks was more correlated with achieving pCR or MPR than TTS >4 to 6 weeks [odds ratio (OR) =0.211; 95% confidence interval (CI): 0.062-0.711; P=0.01] The multivariate analysis showed that cT1 stage (compared to cT4), and cN1 stage (compared to cN0) showed statistical correlation with achieving pCR or MPR. cN1 stage was independent predictor of achieving pCR or MPR (OR =27.817; 95% CI: 1.536-503.88; P=0.02). Concerning to the DFS, TTS ≤4 weeks group and TTS >4 to 6 weeks group showed no statistical differences (2-year DFS rate were 70.6% and 72.6%, respectively). Regarding the tendency of being patients' TTS ≤4 weeks, patients with ventilatory impairment (OR =0.203; 95% CI: 0.04-0.98; P=0.047) were more tending to prolong the TTS to >4 to 6 weeks.

Conclusions: TTS ≤4 weeks was associated with a significant improvement of pathological response. Therefore, patients with NSCLC should undergo surgery within 4 weeks after the last cycle of neoadjuvant chemoimmunotherapy.