Translational lung cancer research最新文献

Background: In 2021, the US Preventive Services Task Force expanded the initial age for lung cancer screening from 55 to 50 years, which other associations have not followed. The objective of this study was to evaluate the beneficiary age range for lung cancer screening and assess the potential heterogeneity in tumor histology and patient sex.

Methods: Using the Surveillance, Epidemiology, and End Results database, patients with non-small cell lung cancer (NSCLC) between 2011 and 2016 were included. The estimation of overall survival (OS) and lung cancer-specific survival (LCSS) was conducted for survival analysis among three different age groups: 45-49 (n=4,203), 50-54 (n=10,126), and 55-59 years (n=17,122), adjusting for other clinicopathological characteristics.

Results: Significant differences were observed in OS {hazard ratio (HR) [95% confidence interval (CI)]: 0.94 (0.92-0.96)} and LCSS [HR (95% CI): 0.94 (0.91-0.97)] for patients aged 50-54 compared to those aged 55-59. However, no survival advantage was observed for patients aged 45-49 [HR (95% CI) for OS: 0.97 (0.93-1.01), HR (95% CI) for LCSS: 0.98 (0.93-1.02)]. Similar survival trends were observed in patients with adenocarcinoma whereas no difference among those with squamous cell carcinoma across all age groups. Among patients aged 40-45, we observed a significant survival advantage for males, with no corresponding advantage in females.

Conclusions: Patients aged 50 to 54 can benefit from lung cancer screening, in accordance with the recommendations of the US Preventive Services Task Force (USPSTF). The benefits are probably more apparent in adenocarcinoma cases. Younger male patients may benefit more than female patients, which may reflect the need for sex differences in cancer screening.

Background: Lung mucinous adenocarcinoma has various genetic alterations, but there are no reported cases with MET exon 14 skipping mutations. Multiplex genetic testing is commonly assessed in non-small cell lung cancer (NSCLC) and treatment usually comprises molecular targeted drugs. However, the efficacy of molecular targeted drugs in lung mucinous adenocarcinoma is not reported. Here, we report on the clinical features of tepotinib in invasive mucinous adenocarcinoma (IMA) harboring MET exon 14 skipping mutation.

Case description: A 68-year-old Japanese woman was diagnosed with IMA that harbored MET exon 14 skipping mutation. Initial treatment targeting community-acquired pneumonia or cryptogenic organizing pneumonia was ineffective. Blood carcinoembryonic antigen had increased, and positron emission tomography showed uptake of ¹⁸F-fluorodeoxyglucose on the infiltration. A second trans-bronchial lung biopsy allowed diagnosis of IMA that harbored MET exon 14 skipping mutation. Tepotinib 500 mg once daily was initiated as the patient's first-line treatment and she showed a durable response with mild adverse events during treatment.

Conclusions: Molecular targeted drugs (tepotinib) showed similar efficacy for IMA harboring MET exon 14 skipping mutation to their use for NSCLC. This case suggests the benefit of aggressive multiplex genetic testing in patients with IMA and subsequent treatment with molecular targeted drugs.

Background: In the treatment of central-type non-small cell lung cancer (NSCLC), sleeve lobectomy (SL) has emerged as the surgical treatment of choice over pneumonectomy (PN). This retrospective study evaluates the clinical profiles and prognostic elements impacting survival and recurrence rates in patients who underwent SL.

Methods: We retrospectively analyzed 288 patients who underwent SL from January 2010 to December 2023. Survival analysis was performed using the Kaplan-Meier method, and survival curves were subsequently drawn. Factors predicting SL outcomes were investigated through univariate and multivariable Cox regression analyses.

Results: Univariate and multivariable analyses consistently demonstrated significant variations in overall survival (OS) and disease-free survival (DFS) among subgroups receiving neoadjuvant therapy (NT), which also stood out as independent prognostic factors. Patients undergoing NT showed enhanced OS [hazard ratio (HR) =0.4652, 95% confidence interval (CI): 0.3042-0.7116, P=0.004] and DFS (HR =0.5182, 95% CI: 0.3243-0.8279, P=0.01). Earlier pT stages were associated with better prognosis (P<0.05). Significant differences in both OS and DFS were noted across pN stages, with earlier stages indicating improved prognosis; this was a significant independent factor for DFS (P<0.001). Similar significant trends were observed across pathological Tumor-Node-Metastasis (pTNM) stages, with earlier stages linked to better outcomes. Additionally, body mass index (BMI) was identified as an independent prognostic factor for both OS and DFS. Clinical T stage independently influenced DFS. No significant prognostic disparities were observed in other clinical characteristics (P>0.05).

Conclusions: NT significantly improves the prognosis for NSCLC patients undergoing SL. Pathological staging is proven to be more indicative of prognosis than clinical staging. Understanding the staging of lymph nodes (LNs) is crucial for predicting the long-term recurrence risk in patients with NSCLC who undergo SL treatment. Mediastinal and hilar LN dissection is especially important in minimizing this risk and improving prognosis.

Background: Epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) gene mutations are well established in the pathogenesis of non-small cell lung cancer (NSCLC). However, there is limited understanding about the impact of rare variants, such as EGFR exon 20 insertion mutation (EGFRex20ins) and MET exon 14 skipping mutation (METex14) in the Chinese population even though targeted therapies have been approved in China. We conducted a scoping review to assess the current available evidence of these two mutations in NSCLC in the Chinese population.

Methods: Electronic searches were performed before November 2023. Two investigators independently collected data. Any discrepancies were resolved through discussion with a senior investigator.

Results: We identified 111 studies, involving a total of 159,993 NSCLC Chinese patients. Of the 111 studies, 76 studies reported on EGFRex20ins and 45 reported on METex14. When we evaluated the frequency from studies with at least 1,000 patients, the frequency of EGFRex20ins ranged from 0.02-2.85% of all NSCLC patients and 0.56-6.90% of all EGFR mutations. The frequency of METex14 ranged from 0.08-1.38% of all NSCLC patients and 8.33-56.60% of all MET mutations. The treatments for NSCLC with EGFRex20ins varied depending on the study, and all available treatments have limited therapeutic efficacy and a relatively poor prognosis, and fewer studies have examined the efficacy and effectiveness of treatments for NSCLC with METex14 mutation in the Chinese population.

Conclusions: Despite the recent approval of three targeted therapies in China, there is still insufficient evidence regarding their optimal treatment and therapeutic efficacy for Chinese patients. Further large-scale studies are needed to establish links between these mutations and clinical features at baseline and following treatment. Furthermore, moving forward, the development of novel drugs will be essential to fulfill the clinical unmet needs.

Background: Early-stage non-small cell lung cancer (NSCLC) has a high recurrence rate despite proper management, including curative surgery. Circulating tumor cells (CTCs) are believed to play a key role in the distant metastasis of lung cancer. Immunofluorescence imaging studies of CTCs have revealed that they are associated with the prognosis of NSCLC. However, the mutational profiling of CTCs from early-stage NSCLC has not been extensively explored. We hypothesized that CTCs could be detected by mutational analysis using panel sequencing and would have distinct mutations associated with distant metastasis compared to those of primary cancer tissue in early-stage NSCLC. Thus, this study examined the DNA from CTCs using targeted panel sequencing to identify mutations and compared them with mutations found in primary cancer tissue in patients with resectable early-stage NSCLC.

Methods: Overall, 45 patients with resectable NSCLC were prospectively enrolled from September to December 2023. Matched whole blood samples and primary cancer tissues were collected during curative surgery. Then, 405-gene targeted panel sequencing was performed on DNA from primary cancer tissues and CTCs.

Results: In this study, 37 patients (82%) had adenocarcinoma, and 30 (67%) were classified as having pathologic stage 1 disease. Mutated genes were detected in all (100%) and 31 patients (69%) for primary cancer tissue and CTCs from panel sequencing, respectively. The partial concordance rate of mutations between primary cancer tissue and CTCs was 17.8%, with the top 10 mutated genes differing significantly. Among primary cancer tissue samples, mutated genes differed by stage and histologic type; these findings were not observed in CTCs. CTCs predominantly displayed mutations in tumor suppressor genes, whereas primary cancer tissues exhibited mutations in both oncogenes and tumor suppressor genes.

Conclusions: CTCs exhibited unique mutations, showing low concordance with mutations found in primary cancer tissue. CTCs may possess specific mutations independent from those of primary cancer tissue in early-stage NSCLC.

Background: Rearrangement in anaplastic lymphoma kinase (ALK) occurs in 4-7% of non-small cell lung cancer (NSCLC) cases. Despite improved survival with tyrosine kinase inhibitors (TKIs), treatment resistance remains challenging. This retrospective study analyzed advanced ALK-positive NSCLC patients, focusing on clinical aspects, treatments, resistance, and outcomes.

Methods: Patients diagnosed between January 2009 and December 2021 who received at least one ALK-TKI line at the Karolinska University Hospital, were included. We evaluated crizotinib or 2^nd generation ALK-TKI effectiveness in first-line treatment and lorlatinib in subsequent lines. Overall survival (OS) was defined as from the date of advanced lung cancer diagnosis until the date of last follow-up (April 22, 2022) or the date of death from any cause. Progression-free survival (PFS), from the date of starting ALK-TKI until the date of progression, death, or last follow-up. Resistance mechanisms were assessed through re-biopsies utilizing next-generation sequencing (NGS).

Results: Out of 160 eligible patients, 10 were excluded. Median follow-up was 54.0 months from diagnosis and 45.0 months from initial ALK-TKI treatment. Crizotinib showed a median PFS of 8.0 months and a median OS of 35.0 months. Second generation ALK-TKIs demonstrated a median PFS of 52.0 months [OS was not reached (NR)]. Overall, the median OS was 65.0 months. Poor prognostic factors included male sex, thromboembolism, crizotinib treatment, and chronic obstructive pulmonary disease (COPD)/asthma. Rebiopsies in 18 cases revealed secondary ALK mutations in 8 patients, correlating with a shorter median PFS in subsequent ALK-TKI treatment (1.0 vs. 7.0 months).

Conclusions: This comprehensive study, spanning over a decade, provides crucial insights into the clinical characteristics, treatment patterns, and resistance mechanisms of advanced ALK-positive NSCLC, where median OS exceeds 5 years. Re-biopsies during treatment are essential for advancing our understanding of resistance mechanisms and the tumor dynamics evolving during ALK-TKI therapy.

Background: Therapeutic strategies to engage anti-tumor innate immunity are still underdeveloped. Imprime PGG (imprime), a pathogen-associated molecular pattern (PAMP), through pattern recognition receptors, successfully illicit a broad-based innate immune response in preclinical models against various cancers. We aimed to study safety and efficacy of imprime in combination with pembrolizumab in advanced stage non-small cell lung cancer (NSCLC).

Methods: We conducted an investigator-initiated, multi-institutional, single-arm, phase Ib/II trial in previously treated, advanced stage NSCLC patients. Primary endpoints were maximum-tolerated dose (MTD) of imprime for the phase Ib, and progression-free survival (PFS) for the phase II study (NCT03003468).

Results: All 33 eligible patients were included in the safety analysis. No dose-limiting toxicity was observed and the imprime dose of 4 mg/kg was determined as the MTD. Thirty patients treated at the MTD (phase Ib, 6; phase II, 24) were included in the efficacy analysis. Median length of follow-up was 10.8 months. Confirmed objective response rate was 10% [95% confidence interval (CI): 2-27%], with one complete and two partial responses. Median PFS was 2.6 months (95% CI: 1.4-7.0), and 6- and 12-month PFS rates were 37% and 17%, respectively. Median overall survival (OS) was 11.1 months, and 6- and 12-month OS rates were 75% and 46%. Univariate analysis was performed to assess the impact of age, sex, race, disease-stage, programmed death-ligand 1 (PD-L1) expression levels, and prior immunotherapy on PFS and OS. Of these, prior immunotherapy negatively influenced OS [hazard ratio (HR): 2.95, 95% CI: 1.21-7.24]. Overall, the combination was safe and tolerable.

Conclusions: The combination of imprime and pembrolizumab is tolerable but did not improve the outcome of advanced stage NSCLC patients who previously progressed on anti-programmed death 1 (PD-1)/PD-L1 immunotherapies. Further investigation is needed to understand the effects of therapeutic PAMPs to mount a strong innate immune response against cancer.

Background: Identifying biomarkers to predict responses for neoadjuvant immunotherapy in resectable non-small cell lung cancer (NSCLC) is under intensive study. Considering the interplay between cancer, inflammation, and immunosuppression, we hypothesized that circulating and imaging inflammatory markers could serve as indicators of anti-tumor immune responses, and thus conducting an exploratory study to reveal the predictive value of combining longitudinal systemic inflammatory markers in stratifying pathologic response to neoadjuvant sintilimab.

Methods: We retrospectively reviewed 36 patients (29 male and seven female) with NSCLC (stage IA-IIIB) who underwent pre- and post-treatment peripheral blood tests and ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) scans before and after two cycles of neoadjuvant sintilimab (registration number: ChiCTR-OIC-17013726). The neutrophil-to-lymphocyte ratio (NLR), immune-related adverse events (irAEs) on imaging, and lymphoid organ metabolism [spleen-to-liver ratio (SLR) and bone marrow-to-liver ratio (BLR)] were evaluated to examine their predictive value for the major pathologic response (MPR). Significant variables were used to classify patients into low, intermediate, and high inflammatory burden groups for stratifying pathologic regression and tumor-infiltrating immune cells abundance in the tumor microenvironment. Spearman's correlation analysis was performed to explore the correlation between systemic inflammatory markers, primary tumor metabolism, and tumor-infiltrating immune cells abundance at various time points.

Results: Of the 36 enrolled patients, 13 (36.1%) exhibited MPR. ΔNLR% was a significant negative predictor of MPR (P=0.047) and negatively correlated with pathologic regression (r=-0.34, P=0.045). Pre- and post-treatment SLRs were potential negative predictors of MPR (P=0.06; P=0.055) and negatively correlated with pathologic regression (r=-0.30, P=0.07; r=-0.31, P=0.06). The high inflammatory burden group (pre-treatment SLR >0.83 and ΔNLR% >-17%) had the lowest pathologic regression (P=0.01) and the highest infiltration abundance of pre-treatment CD68⁺ macrophage (P=0.01-0.04). irAEs on imaging did not have significant effects on MPR and pathologic regression in overall and per-organ analyses.

Conclusions: The combination of pre-treatment SLR and ΔNLR% demonstrates predictive value in stratifying pathologic response to neoadjuvant immunotherapy in resectable NSCLC. The high inflammatory burden group had the lowest pathologic regression and the pre-treatment immunosuppressive microenvironment with macrophage enrichment.