Translational lung cancer research最新文献

Background: Neuregulin 1 (NRG1) fusions are recognized oncogenic drivers in non-small cell lung cancer (NSCLC), yet, the clinical and genomic features of other types of NRG1 alterations are still rarely reported. This study aimed to characterize the associated clinicogenomic profiles for NRG1 fusions and single nucleotide variants (SNVs) in a Chinese NSCLC cohort.

Methods: We retrospectively analyzed next-generation sequencing (NGS) data from 3,132 Chinese NSCLC patients and investigated NRG1 alterations and their correlations with clinical characteristics, co-mutation landscapes, and treatment outcomes.

Results: NRG1 fusions and SNVs were detected in 0.2% (6/3,132) and 0.7% (22/3,132) of patients, respectively. Fusions were enriched in invasive mucinous adenocarcinoma (IMA) and associated with co-mutations in KRAS and EGFR. CD74 was the main fusion partner (50%). However, SNVs were significantly associated with male sex, smoking history, squamous cell histology, high tumor mutational burden, and mutations in epigenetic regulator genes, including SETD2, SMARCA4, KMT2A, and ARID1A. No hotspot mutation sites in NRG1 were found. The overall objective response rate of all NRG1-positive patients reached 73.9% after they received existing therapies. Operable patients achieved sustained remission for 6 to 29 months after surgery. Chemotherapy plus immunotherapy was highly effective for advanced-stage NRG1-positive patients.

Conclusions: This study revealed the distinct clinicogenomic landscapes of NRG1 fusions and SNVs in NSCLC. These findings emphasize the important role of molecular profiling for precision diagnosis and individualized treatment of NSCLC.

Background: There are many common gene mutations that occur in lung cancers, including KRAS. KRAS is an oncogene responsible for mediating cell growth through the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathway. ITPR2 is a calcium channel responsible for regulating intracellular calcium levels. This case report highlights the presence and detection of a previously unreported ITPR2::KRAS fusion in a large cell neuroendocrine carcinoma of the lung.

Case description: A 65-year-old patient with a history of smoking developed an aggressive large cell neuroendocrine carcinoma (LCNEC) of the lung. This rare tumor subtype (up to 3% incidence in lung cancer) has a particularly poor prognosis, with a median overall survival of 8-12 months. Additionally, the tumor possessed a previously unreported ITPR2::KRAS fusion, which was a unique event upon examining over 100,000 tumors in public databases. Comorbidities including chronic obstructive pulmonary disease (COPD) and neuropathy presented difficulties in the treatment of this patient due to an inability to undergo surgical resection. The patient was successfully treated with concurrent chemoradiotherapy with carboplatin and etoposide, a first-line chemoradiotherapy.

Conclusions: Upon applying relatively unused RNA-fusion tools, this fused ITPR2::KRAS was not projected to yield a functional protein. This supports that post hoc use of bioinformatics tools may support clinical decision-making for patients when encountering rare genomic alterations, captured by existing diagnostic tests, that would be perceived as highly oncogenic.

Background: A standard first-line regimen for patients with driver-gene-negative metastatic non-squamous non-small cell lung cancer (nsqNSCLC) is immune checkpoint inhibitors (ICIs) combined with pemetrexed and platinum, followed by maintenance therapy. However, the role of long-term pemetrexed maintenance remains controversial. This study evaluated the impact of pemetrexed maintenance discontinuation.

Methods: A total of 167 patients diagnosed with driver-gene-negative metastatic nsqNSCLC were treated with first-line ICIs plus pemetrexed and platinum as induction therapy between September 2020 and April 2024 at the Department of Medical Oncology, Fudan University Shanghai Cancer Center. The primary endpoint was progression-free survival (PFS). Patients who permanently discontinued pemetrexed at any time during maintenance for any reason were categorized as the ICIs maintenance group, while those who continued pemetrexed were categorized as the ICIs + pemetrexed maintenance group.

Results: Of the 167 patients, 141 received maintenance therapy, including 101 with ICIs plus pemetrexed maintenance, and 40 with ICIs maintenance. The median PFS was 26.9 months for ICIs maintenance group and 12.4 months for ICIs + pemetrexed maintenance group (P=0.052). No significant difference was observed in median PFS between ICIs and ICIs + pemetrexed maintenance group after propensity score matching. Biomarker analysis showed that in ICIs maintenance group, patients experiencing Grade 2 or higher lymphopenia before or during treatment and patients with low baseline plasma extracellular vesicle-derived EHF gene expression showed significantly prolonged survival.

Conclusions: This study demonstrated that discontinuation of pemetrexed maintenance did not compromise the efficacy of the first-line immunochemotherapy of metastatic driver-gene-negative nsqNSCLC, and identified potential biomarkers for decision making of pemetrexed discontinuation.

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have demonstrated superior efficacy compared with chemotherapy in ALK-positive non-small cell lung cancer (NSCLC) in both first-line and adjuvant settings; however, evidence supporting their use as neoadjuvant therapy in locally advanced disease remains limited. This retrospective study analyzed the clinicodemographic characteristics, treatment details, and toxicities of patients with locally advanced ALK-positive NSCLC who received neoadjuvant ALK-TKI monotherapy. The objective response rate (ORR), radical resection (R0) rate, and pathological response were evaluated, along with disease-free survival (DFS), overall survival, and the optimal duration of neoadjuvant treatment. A total of 25 patients were included, with a median age of 49 years; 48.0% were female, 68.0% were never-smokers, and 84.0% harbored EML4-ALK rearrangements. The median duration of neoadjuvant therapy was 5 months. The most common treatment-related adverse events were edema, nausea, and constipation, and grade 3 events occurred in 24% of patients. The ORR reached 92.0%, including 22 partial responses and 1 complete response (CR), and all patients underwent R0 resection. Pathological evaluation showed that 32.0% achieved a pathological CR and 36.0% achieved a major pathological response. The optimal neoadjuvant treatment duration was preliminarily defined as 4-6 months, based on a locally estimated scatterplot smoothing (LOESS) analysis of both pathological response and toxicity profiles. With postoperative follow-up ranging from 11 to 57 months, the 3-year DFS rate was 76.2%, and only one patient died due to intracranial hemorrhage secondary to brain metastasis. Overall, neoadjuvant ALK-TKI monotherapy showed promising efficacy and a manageable safety profile in locally advanced ALK-positive NSCLC, providing preliminary support for its further investigation in prospective trials.

Background: Immune checkpoint inhibitors (ICIs) have improved survival in non-small cell lung cancer (NSCLC), yet identifying who benefits from treatment remains difficult. Low skeletal muscle mass (SMM) is associated with poor cancer outcomes. We aim to examine the relationship between computed tomography (CT)-assessed sarcopenia and patient trajectories [death, immune-related adverse events (irAEs) and death after irAEs] following ICI initiation.

Methods: We conducted a retrospective cohort study of NSCLC patients treated with ICIs at the University Medical Center Groningen [2015-2021] with baseline low-dose computed tomography (LDCT) scans. Sarcopenia was defined using sex-specific SMM thresholds. Multi-state time-to-event models estimated transition probabilities between ICI initiation and three outcomes: direct mortality (without irAEs), development of irAEs, and mortality after irAEs. Models were adjusted for age, sex, performance status, cancer stage, treatment line, body mass index (BMI), and combination therapy. Separate models were built for severe and any-grade irAEs.

Results: Among 363 patients (96-month follow-up), 301 (82.9%) died and 166 (45.7%) developed irAEs, including 76 (20.9%) with severe irAEs. In the severe irAE model, sarcopenia was not associated with developing severe irAEs [hazard ratio (HR) =0.81, 95% confidence interval (CI): 0.42-1.58] or with mortality without severe irAEs (HR =1.19, 95% CI: 0.82-1.74). However, sarcopenia was associated with reduced mortality after severe irAEs (HR =0.39, 95% CI: 0.23-0.65). In the any-grade irAEs model, sarcopenic patients were less likely to develop irAEs (HR =0.63, 95% CI: 0.42-0.93). Sarcopenia was not linked to mortality without irAEs (HR =1.08, 95% CI: 0.70-1.67) or after any-grade irAEs (HR =0.81, 95% CI: 0.52-1.26).

Conclusions: In this NSCLC cohort, CT-assessed sarcopenia was not associated with direct mortality without irAEs but was linked to a lower likelihood of developing irAEs and reduced mortality after severe irAEs. These findings suggest that body composition may have prognostic value and influence responses to immunotherapy.

Background and objective: Mediastinal staging, whether through non-surgical or surgical approaches, plays a pivotal role in the management of non-small cell lung cancer (NSCLC) due to its impact on therapeutic decision-making and prognosis. This narrative review aims to provide a comprehensive overview of evidence-based strategies for mediastinal staging/restaging.

Methods: This review analyzes current evidence on the role of non-invasive methods [endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), cryobiopsy, robotic-assisted bronchoscopy] and surgical techniques in mediastinal staging/restaging. A literature search was conducted using the PubMed/Medline/Embase/CENTRAL/CINAHL databases for relevant English-language studies published since 1996. Studies were selected based on clinical relevance, diagnostic performance, and integration into staging algorithms. A critical appraisal of indications, advantages, limitations, and future developments is provided.

Key content and findings: The combination of EBUS and EUS offers high sensitivity and specificity for mediastinal lymph node assessment, with a favorable safety profile. Surgical staging remains crucial in selected cases, particularly when minimally invasive approaches yield inconclusive results or are negative in patients with high-risk features. Emerging technologies, including robotic-assisted platforms, may further enhance diagnostic accuracy.

Conclusions: EBUS and EUS have become first-line tools for mediastinal staging in NSCLC, while surgical techniques continue to serve a complementary role. Cryobiopsies and robotic-assisted biopsies may represent a useful diagnostic tool even if so far large prospective data are missing. Future research should aim to refine patient selection, improve diagnostic precision, and personalize staging strategies.

Background: Although neoadjuvant chemoimmunotherapy (NCIT) improves outcomes in resectable non-small cell lung cancer (NSCLC), traditional biomarkers like programmed death-ligand 1 (PD-L1) expression are insufficient for accurate patient selection. This study aimed to investigate the spatial interaction between specific T-cell subsets and PD-L1⁺ tumor cells using multiplex immunofluorescence (mIF), and to evaluate its value in predicting the efficacy of NCIT in NSCLC patients.

Methods: We retrospectively recruited 44 patients with stage IIA-IIIB NSCLC who had NCIT at Shandong Cancer Hospital and Institute from January 2021 to June 2023. Pre-treatment specimens were subjected to multicolor immunofluorescence staining (panel 1: CK/PD-L1/PD-1/CD8/CD103/CD4/FOXP3; panel 2: CK/CD8/CD4/α-SMA/CD31/HIF-1α) to quantify PD-L1⁺ tumor cells and specific target T cells (CD4/conventional CD4/regulatory CD4, CD8/CD8⁺ T_RM/bystander CD8) and to delineate their spatial distribution. The Mann-Whitney U test, receiver operating characteristic (ROC) curves, and logistic regression were employed to examine the correlation between these indicators and treatment response. Spearman correlation analysis assessed their relationship with tumor microvasculature, cancer-associated fibroblasts (CAFs), and hypoxia-inducible factor-1α (HIF-1α).

Results: Among the 44 patients, 52.3% showed a response. Compared with non-responders, responders had closer distances between PD-L1⁺ tumor cells and CD8⁺ T_RM, CD8, bystander CD8, conventional CD4, CD4, and regulatory CD4 prior to treatment, with decreasing area under the curve (AUC) values (0.728, 0.715, 0.680, 0.644, 0.643, 0.612). Further analysis of CD8⁺ T_RM expressing programmed cell death 1 (PD-1) revealed that PD-1⁺ CD8⁺ T_RM was the best predictor with an AUC of 0.743. Logistic regression analysis indicated that the closer PD-L1⁺ tumor cells were to CD8⁺ T_RM, the better the treatment response [odds ratio (OR) =10.43, 95% confidence interval (CI): 1.49-73.08, P=0.02], especially for PD-1⁺ CD8⁺ T_RM (OR =8.83, 95% CI: 1.81-43.13, P=0.007). Additionally, PD-L1⁺ tumor cell-CD8⁺ T_RM interactions and PD-L1⁺ tumor cell-PD-1⁺ CD8⁺ T_RM interactions were significantly positively correlated with HIF-1α+ CD8 (r=0.36 and 0.35, respectively, P<0.001 for both).

Conclusions: T cells interacting with PD-L1⁺ tumor cells may be characterized as PD-1⁺ CD8⁺ T_RM cells. A closer distance between the two enhances therapeutic efficacy and may be associated with density of hypoxic CD8 cells.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but are frequently accompanied by immune-related adverse events (irAEs) affecting multi-organ. Checkpoint inhibitor-associated pneumonitis (CIP) is a serious irAE whose mechanistic underpinnings remain poorly understood, limiting the clinical application of ICIs. The objective of this study was to investigate the role of the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome in the pathogenesis of CIP and to explore potential targeted therapies.

Methods: A CIP mouse model was established via regulatory T cell (Treg) depletion and anti-programmed cell death protein 1 (PD-1) antibody treatment. Lung tissue gene expression was analyzed using RNA-sequencing, quantitative polymerase chain reaction (qPCR), and Western blot. Therapeutic interventions with NLRP3 inflammasome inhibitors (MCC950 and dapansutrile) and a macrophage-depleting agent (clodronate liposomes) were evaluated by micro-computed tomography (CT), histopathology, and serum inflammatory cytokine assays. Validation was performed via single-cell transcriptomic analysis of bronchoalveolar lavage fluid from 13 non-small cell lung cancer patients with or without ICI-induced CIP.

Results: The findings revealed: (I) significant upregulation of NLRP3 inflammasome pathway-related genes and downstream factors (IL-1β, IL-18) in CIP mouse lungs, alongside increased macrophage infiltration; (II) pneumonitis injury was markedly alleviated and serum inflammatory cytokine levels were reduced by both NLRP3 inflammasome inhibition and macrophage depletion; (III) dapansutrile downregulated NLRP3 expression via inhibition of the NF-κB pathway; (IV) enriched macrophage subpopulations (Mac-IL1B) expressing high levels of NLRP3 were identified in CIP patients.

Conclusions: This study provides the first evidence that NLRP3 inflammasome activation constitutes a key upstream mechanism in CIP pathogenesis, offering novel therapeutic strategies for targeted intervention.