Translational lung cancer research最新文献

Background and objective: The standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions is targeted therapy using tyrosine kinase inhibitors (TKIs). However, data are still lacking on the use of TKIs as a neoadjuvant or induction approach. Therefore, this narrative review aims to summarize the current knowledge on resectable EGFR-mutant and ALK-fused NSCLC regarding available perioperative treatment regimens and off-label neoadjuvant use of targeted therapy.

Methods: The relevant literature was identified by using PubMed and ClinicalTrials.gov (last search phase June 2024) and was restricted to English language. Peer-reviewed manuscripts but also conference abstracts that did not undergo peer-review were included.

Key content and findings: Patients with EGFR-mutations and ALK-fusions have typically been excluded from available phase III perioperative immunotherapy trials due to lower efficacy and higher toxicity of immunotherapy in those patients. In the adjuvant setting, recent evidence from the phase III ALINA and ADAURA trials demonstrated efficacy and safety of targeted therapy in resected ALK-fused and EGFR-mutant NSCLC. However, to date there is no approval for the use of TKIs as neoadjuvant or induction therapy in those patients. We have therefore identified a number of case series and phase II trials using targeted therapy in resectable EGFR-mutant and ALK-fused NSCLC.

Conclusions: Current evidence suggests that targeted therapies might be effective in patients with resectable EGFR-mutant and ALK-positive NSCLC, but ongoing trials will need to provide further evidence on the safety and efficacy of perioperative TKI therapy.

Background: Brain metastases (BM) are highly prevalent and associated with a poor prognosis in patients with small cell lung cancer (SCLC). However, the evidence regarding the efficacy of immune checkpoint inhibitors (ICIs) in combination with chemotherapy for patients with SCLC and BM remains limited. Therefore, the objective of this study is to evaluate whether the addition of ICIs confers survival benefits for patients with SCLC and BM.

Methods: This retrospective study enrolled patients with SCLC and BM at the Sun Yat-sen University Cancer Center between January 2018 and December 2022. Clinical characteristics were extracted from medical records. Depending on whether ICIs were added to the first-line treatment, the patients were categorized into the chemotherapy group and the chemoimmunotherapy group. The efficacy of these two treatment approaches was analyzed and compared.

Results: A total of 165 patients were enrolled, with 85 in the chemotherapy group and 80 in the chemoimmunotherapy group. The chemoimmunotherapy group showed a tendency towards prolonged intracranial [6.6 vs. 5.9 months, hazard ratio (HR) =0.77; P=0.14] and extracranial (6.9 vs. 6.5 months, HR =0.73; P=0.12) progression-free survival (PFS) and overall survival (OS) (15.6 vs. 14.5 months, HR =0.98; P=0.93) compared to the chemotherapy group. Cox regression analysis identified liver metastases and local treatment for BM as independent prognostic factors for OS in patients. Furthermore, the chemotherapy group and the chemoimmunotherapy group demonstrated similar patterns of initial disease progression.

Conclusions: Adding ICIs to chemotherapy confers modest survival benefits in patients with SCLC and BM.

Background: Antihistamines alleviate the side effects of antitumor drugs and exert antitumor effects. This study aimed to investigate the potential impact of short-term concomitant use of antihistamines with immune checkpoint inhibitor (ICI) therapy on the efficacy and immune-related adverse events (irAEs) of immunotherapy for patients with advanced lung cancer.

Methods: We retrospectively analyzed the medical records of 211 patients diagnosed with advanced primary lung cancer and treated with immunotherapy at Tianjin Medical University Cancer Institute and Hospital between January 1, 2018, and January 1, 2022. Among these patients, 109 who received H1 antihistamine during the infusion of anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies were assigned to the experimental group; meanwhile, the remaining 102 patients who did not receive H1 antihistamines were assigned to the control group. Balancing was achieved through inverse probability of treatment weight (IPTW) estimation. The data were analyzed using Kaplan-Meier curves and Cox regression analyses.

Results: The median progression-free survival (mPFS) was 12.7 months in the experimental group and 4.3 months in the control group, while the median overall survival (mOS) was 32.8 months in the experimental group and 18.1 months in the control group. In the experimental group, patients treated with only H1 antihistamines had longer mPFS and mOS compared with those who received H1 plus H2 antihistamines. Similarly, in the control group, patients who did not receive antihistamines had a longer mPFS and mOS than those who only received H2 antihistamines. After conducting multivariate analyses, we found that H1 and H2 antihistamines were respectively identified as good and poor independent prognostic factors for both progression-free survival (PFS) and overall survival (OS). The rates of irAEs in the experimental and control groups were 52.4% and 69.2%, respectively, and grade ≥3 irAEs occurred in 4.5% and 25.9% of patients, respectively.

Conclusions: Concomitant use of H1 antihistamines can improve immunotherapy efficacy and reduce irAEs. Meanwhile, concomitant use of H2 antihistamines is associated with reduced PFS and OS time.

Background: Spread through air spaces (STAS) is significantly associated with decreased overall survival (OS) and reduced recurrence-free survival. However, there are no reliable methods to confirm the presence of STAS before surgery. The sensitivity and specificity of the intraoperative frozen section diagnosis of STAS are not satisfactory. This study sought to determine the clinical, pathological, and computed tomography (CT) features of lung cancer with STAS before surgery to guide treatment decisions.

Methods: The data of 121 patients who were positive for STAS and 121 who were negative for STAS as confirmed by surgery and pathology were collected at Jiangsu Cancer Hospital from January 2020 to December 2022. The differences between the two groups in terms of the clinical, pathological, and CT characteristics were compared.

Results: STAS occurred not only in lung adenocarcinoma (LUAD) (106 of 121, 87.6%), but also in other pathological types of lung cancer (15 of 121, 12.4%). STAS was significantly correlated with pathological invasiveness [pathological differentiation, tumor, node, metastasis (TNM) staging, vascular invasion, and pleural invasion; all P<0.05]. STAS was most common in solid tumors (95 of 121, 78.51%). The receiver operating characteristic (ROC) curve showed that the optimal cut-off value for diagnosing STAS based on diameter is 1.55 cm with a sensitivity of 73.3% and a specificity of 47.9%. The percentage of solid components (PSC) is an independent influencing factor of lung cancer with STAS [odds ratio (OR) =111.27; P<0.05] with an optimal cut-off value of 63%, a sensitivity of 92.5%, and a specificity of 72.7%. In the part-solid nodules, the occurrence rate of STAS increased as the PSC increased. STAS was only observed in part-solid nodules with a PSC greater than 25%. Among the CT morphological features, lobulation was an independent influencing factor of lung cancer with STAS (OR =3.513; P<0.05), and persistent indistinct margin ground-glass opacity around the primary lesion of lung cancer (21 of 121, 17.36%) and satellite foci (9 of 121, 7.44%) strongly indicated the existence of STAS.

Conclusions: The clinical, pathological and CT features of STAS may guide clinicians to develop appropriate strategies and improve the survival rate of patients.

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: The intricate interplay between inflammation and lung cancer has long been recognized by large number of studies, yet a comprehensive understanding of this relationship remains elusive. There is a clinical need to elucidate the role of tertiary lymphoid structures (TLSs) in lung cancer, particularly their impact on prognosis and therapy. This study aims to address these gaps by conducting a bibliometric analysis to explore the correlations between lung cancer, inflammation, and TLS, highlighting collaborative networks, publication trends, and emerging research directions.

Methods: This study conducted a comprehensive bibliometric analysis of academic literature on lung cancer and inflammation from 2013 to 2023 using the Web of Science Core Collection database. The search strategy "topic (TS) = ('lung cancer') AND TS = (inflammation)" yielded 5,470 records, which were refined through exclusion criteria to 1,284 relevant studies. The inclusion process involved excluding non-English studies and non-original articles or reviews, followed by a relevance check based on titles and abstracts. The bibliometric indicators were calculated based on a transparent and repeatable methodology to ensure the integrity of the findings.

Results: The investigation encompassed 1,284 selected studies, revealing an escalating publication trend since 2013. The interdisciplinary scope of research is apparent, with contributions from 54 countries, with China at the forefront. In-depth author and journal analyses exposed key contributors like Zhang L and influential journals like "Lung Cancer". Co-citation networks illuminated crucial references, clusters, and evolving themes over time, underscoring the intricate relationship between inflammation, cancer, and TLS. TLS as a key component of immune response and inflammation, studying its mechanism of impact on cancer will be a potential research direction in the future.

Conclusions: This study underscores the pivotal role of inflammation in lung cancer progression, mediated by a delicate balance of immune responses. The emerging prominence of TLS as indicator of adaptive immune responses within the tumor microenvironment (TME) offers intriguing avenues for future research and therapeutic interventions. However, limitations in the current research, such as the need for more longitudinal studies and clinical trials, must be addressed. The insights gained from this bibliometric analysis can inform clinical practices and guide future investigations into novel strategies to improve patient outcomes.

Background: Platinum-based therapies for patients with advanced non-small-cell lung cancer (NSCLC) have classically provided overall survival (OS) rates of six to nine months and objective response rates (ORRs) of 20-30%. Whether prior immunotherapy determines a different response to platinum is currently unknown. This study aimed to analyse the current response characteristics to platinum as a second-line treatment for advanced NSCLC (PD-L1 ≥50%) after first-line immunotherapy.

Methods: This retrospective study was conducted at the University Hospital of Salamanca (CAUSA) between 2016 and 2023 with patients who had advanced NSCLC (PD-L1 ≥50%) treated with second-line platinum-based therapies after immunotherapy (without mutations in EGFR, ALK or ROS1 and with Eastern Cooperative Oncology Group (ECOG) ≤1 during the first- and second-line treatments). Survival and response correlation analyses (Kaplan-Meier and log rank tests in SPSS v. 25) were performed. Subsequently, the results were compared with historical cohorts (PubMed, COCHRANE, ScienceDirect, Embase, and the clinical trial registry) who had received platinum-based therapies for advanced NSCLC.

Results: Seventeen patients were analysed (11 male and 6 female). Their median age was 67 years (interquartile range, 50-77 years). Fifteen patients (88.2%) were smokers or former smokers. The patients' main histology was adenocarcinoma (9 patients, 52.9%). All first-line treatments applied pembrolizumab (median dose: 12 cycles). Second-line platinum-based therapy achieved OS of 25 months (95% CI: 7-45 months) and progression-free survival (PFS) of 6 months (95% CI: 2.5-95 months). The ORR was 47.1% [seven patients with a partial response (PR) and one patient with a complete response (CR)]. Of the patients with PRs or CRs, 75% were treated with platinum plus pemetrexed. The one-year survival rate was 58.8%. The historical OS for first-line platinum-based doublets is 7 to 12 months, with PFS of three to five months and an ORR of 17-30%.

Conclusions: The current response to second-line platinum-based therapies for patients with advanced NSCLC after immunotherapy appears to achieve favourable response rates and be an optimal treatment after progression to immunotherapy. Prior immunotherapy appears to enhance these patients' platinum response, though future confirmatory studies are necessary.

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: 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: 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.