Lung Cancer最新文献

Background

With the popularization of computed tomography, more and more pulmonary nodules (PNs) are being detected. Risk stratification of PNs is essential for detecting early-stage lung cancer while minimizing the overdiagnosis of benign nodules. This study aimed to develop a circulating tumor DNA (ctDNA) methylation-based, non-invasive model for the risk stratification of PNs.

Methods

A blood-based assay (“LUNG-TRAC”) was designed to include novel lung cancer ctDNA methylation markers identified from in-house reduced representative bisulfite sequencing data and known markers from the literature. A stratification model was trained based on 183 ctDNA samples derived from patients with benign or malignant PNs and validated in 62 patients. LUNG-TRAC was further single-blindly tested in a single- and multi-center cohort.

Results

The LUNG-TRAC model achieved an area under the curve (AUC) of 0.810 (sensitivity = 74.4 % and specificity = 73.7 %) in the validation set. Two test sets were used to evaluate the performance of LUNG-TRAC, with an AUC of 0.815 in the single-center test (N = 61; sensitivity = 67.5 % and specificity = 76.2 %) and 0.761 in the multi-center test (N = 95; sensitivity = 50.7 % and specificity = 80.8 %). The clinical utility of LUNG-TRAC was further assessed by comparing it to two established risk stratification models: the Mayo Clinic and Veteran Administration models. It outperformed both in the validation and the single-center test sets.

Conclusion

The LUNG-TRAC model demonstrated accuracy and consistency in stratifying PNs for the risk of malignancy, suggesting its utility as a non-invasive diagnostic aid for early-stage peripheral lung cancer.

Clinical trial registration

www.clinicaltrials.gov (NCT03989219).

Objectives

Limited data are available comparing the efficacy of osi versus earlier generation TKIs for mNSCLC with atypical EGFR mutations (AMs) such as L861Q, G719X, S768I and exon20.

Methods

We performed a single-institution retrospective analysis of patients with EGFR-mutated mNSCLC treated from 2007 to 2023 with 1L TKIs, comparing outcomes for AM patients treated with osi, afatinib, and erlotinib. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the electronic medical record and compared between TKIs using independent sample t-tests and chi-square analyses. Median progression free survival (mPFS) and overall survival (mOS) were compared via Kaplan-Meier log-rank analysis and Cox multivariable regression.

Results

Among 355 patients with EGFR-mutated mNSCLC, 36 (10 %) harbored AMs in G719X (N=21; 6 %), Exon 20 (N=11; 3 %), L861Q (N=7; 2 %), S768I (N=4; 1 %), C797S (N=1; 0.3 %); 6 patients had compound mutations. Patients with classical mutations (CMs) vs AMs had similar baseline demographic and disease characteristics and usage of TKIs (p = 0.124). Among AM patients, osi yielded superior mPFS (22 m) vs afatinib (12 m; p = 0.005) or erlotinib (9 m; p = 0.001). mOS was likewise superior for osi (32 m) vs afatinib (21 m; p = 0.032) or erlotinib (17 m; p = 0.011). Dose-reduction rates due to AEs were lower for osi (19 %) vs afatinib (24 %; p = 0.003) or erlotinib (23 %; p = 0.002). Discontinuation rates due to AEs were lower for osi vs afatinib (1 % vs 2 %; p < 0.001) or erlotinib (2 %; p = 0.004).

Conclusions

In a large real-world analysis, osi demonstrated superior progression-free and overall survival and improved tolerability compared to afatinib or erlotinib for atypical EGFR-mutated mNSCLC.

Objectives

IMbrella A is a Phase III extension study that allowed rollover from Roche/Genentech–sponsored atezolizumab trials, including IMpower133, a Phase I/III trial of first-line atezolizumab or placebo plus carboplatin/etoposide in extensive-stage small cell lung cancer. We report outcomes from an exploratory analysis of IMpower133 with extended time-to-event data for patients who rolled over to IMbrella A.

Materials and Methods

IMpower133 patients could roll over to IMbrella A to receive atezolizumab 1200 mg intravenously every three weeks if they continued to receive atezolizumab at IMpower133 closure or were in survival follow-up after atezolizumab discontinuation. Overall survival and safety were assessed; only serious adverse events and AEs of special interest were collected in IMbrella A.

Results

Eighteen of 26 eligible patients rolled over to IMbrella A. At clinical cutoff (March 16, 2023), median follow-up in the atezolizumab plus carboplatin/etoposide arm (IMpower133 and IMbrella A) was 59.4 months. The three-, four-, and five-year overall survival (95 % CI) estimates were 16 % (11 %–21 %), 13 % (8 %–18 %), and 12 % (7 %–17 %), respectively. In IMbrella A, serious adverse events occurred in three patients (16.7 %), and one adverse event of special interest was reported (grade two hypothyroidism).

Conclusion

This long-term analysis of patients from IMbrella A previously enrolled in IMpower133 provides the first report of five-year overall survival outcomes in patients with extensive-stage small cell lung cancer treated with first-line cancer immunotherapy and chemotherapy. While limited by small patient numbers and lack of long-term data for the IMpower133 control arm, exploratory overall survival analyses in patients treated with atezolizumab plus carboplatin/etoposide compared favorably with historical data with chemotherapy alone.

NCT03148418.

Objectives

Accurately predicting which patients diagnosed with non-small cell lung cancer (NSCLC) will respond to immunotherapy remains a clinical challenge. This study aims to determine the associations between MYC immunoreactivity, MYC copy number gain (CNG), driver mutations and survival following immunotherapy treatment, to provide insight into whether clinical MYC assessment may have predictive value.

Materials and Methods

MYC copy number status was determined in 82 patients with NSCLC treated with immunotherapy, and MYC immunohistochemistry (IHC) was performed on 80 of these cases. MYC staining in ≥ 40 % of tumor cells was considered positive. Driver gene alterations, PD-L1 status and survival outcomes were assessed through retrospective chart review. Overall survival (OS) and progression free survival (PFS) were calculated from the date of immunotherapy initiation.

Results

Nine (11 %) of 82 cases had MYC CNG and 56 (70 %) of the 80 immunostained cases were positive for MYC. MYC CNG was significantly associated with STK11 mutation (P=0.023), whereas positive MYC IHC was significantly associated with KRAS mutation (P=0.0076) and current/former smoking (P=0.0007). MYC CNG and positive MYC IHC were not significantly associated with each other (P=0.42), or with PD-L1 ≥ 1 % (MYC CNG: P=0.10; MYC IHC: P=0.09). Positive MYC IHC and PD-L1 ≥ 1 % were both significant predictors of OS (MYC: HR 2.7, 95 % CI 1.1–6.4, P=0.026; PD-L1: HR 0.33, 95 % CI 0.15–0.72, P=0.0055). MYC IHC positive/PD-L1 < 1 % cases had the shortest OS (median 230 versus 918 days, P=0.00069) and PFS (median 84 versus 254 days, P=0.0087). MYC CNG was not associated with OS or PFS.

Conclusion

We find that positive MYC IHC is an independent predictor of shorter OS after immunotherapy treatment, with MYC positive/PD-L1 < 1 % status predictive of particularly poor immunotherapy response. We identify positive MYC IHC as a feature of possible relevance to NSCLC treatment selection and of interest for future therapy development.

Objectives

Lung Cancer (LC) is a multifactorial disease for which the role of genetic susceptibility has become increasingly relevant. Our aim was to use artificial intelligence (AI) to analyze differences between patients with LC based on family history of cancer (FHC).

Materials and methods

From August 2016 to June 2020 clinical information was obtained from Thoracic Tumors Registry (TTR), a nationwide database sponsored by the Spanish Lung Cancer Group. In addition to descriptive statistical analysis, an AI-assisted analysis was performed. The German Technical Information Library supported the merging of data from the electronic medical records and database of the TTR. The results of the AI-assisted analysis were reported using Knowledge Graph, Unified Schema and descriptive and predictive analyses.

Results

Analyses were performed in two phases: first, conventional statistical analysis including 11,684 patients of those 5,806 had FHC. Median overall survival (OS) for the global population was 23 months (CI 95 %: 21.39–24.61) in patients with FHC versus 21 months (CI 95 %: 19.53–22.48) in patients without FHC (NFHC), p < 0.001. The second AI-assisted analysis included 5,788 patients of those 939 had FHC. 58.48 % of women with FHC had LC. 9.53 % of patients had an EGFR or HER2 mutation or ALK translocation and at least one relative with cancer. A family history of LC was associated with an increased risk of smoking-related LC. Non-smokers with a family history of LC were more likely to have an EGFR mutation in NSCLC. In Bayesian network analysis, 55 % of patients with a family history of LC and never-smokers had an EGFR mutation.

Conclusion

In our population, the incidence of LC in patients with a FHC is higher in women and younger patients. FHC is a risk factor and predictor of LC development, especially in people ≤ 50 years. These results were confirmed by conventional statistics and AI-assisted analysis.

Objective

The reported impact of age on the effectiveness of emerging immunotherapies in patients with advanced non-small cell lung cancer (NSCLC) has been inconsistent in clinical trials, largely due to an underrepresentation of older individuals. This meta-analysis aimed to evaluate the efficacy of immune checkpoint inhibitor (ICI) in older patients with NSCLC.

Materials and methods

The literature up to April 2024 was reviewed to identify articles meeting the criteria for inclusion. Hazard ratios (HRs) for overall survival (OS) across various age groups were examined. The ratio of HR (RHR) was computed and combined for each study.

Results

A preliminary search identified 118 articles, with 13 being phase II or III randomized clinical trials comparing the efficacy of nivolumab, avelumab, ipilimumab, pembrolizumab, atezolizumab, and chemotherapy with or without antiangiogenic therapy. The analysis revealed that the HR for OS was 0.75 (95 % CI: 0.70–0.80, P=0.080) in patients aged under 75 years and 0.87 (95 % CI: 0.74–1.01, P=0.913) in patients aged 75 years and older. The combined RHR for patients aged 75 years and above versus those aged under 75 years was 1.14 (95 % CI: 0.97–1.34, P=0.697). There was no significant difference in OS benefit between patients over 75 years and younger patients (P=0.105). Subgroup analyses indicated that the benefit of OS was consistent across all subgroups and age groups.

Conclusions

Our investigation found no significant differences in the efficacy of immunotherapy for patients with NSCLC aged 75 years and older compared to those under 75 years old. This suggests that the efficacy of immunotherapy against NSCLC is consistent across age groups.

Background

In the CodeBreaK 200 phase III, open-label trial, sotorasib significantly improved efficacy versus docetaxel in previously treated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). Patient-reported outcomes (PROs) for global health status, physical functioning, dyspnea, and cough favored sotorasib over docetaxel. Here, we report sotorasib’s additional impact on quality of life (QOL).

Methods

In CodeBreaK 200, 345 patients who had progressed after prior therapy received sotorasib (960 mg orally daily) or docetaxel (75 mg/m² intravenously every 3 weeks). Validated questionnaires captured patients’ perception of their QOL and symptom burden for key secondary and exploratory PRO endpoints, including the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and Quality-of-life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13), question GP5 from the Functional Assessment of Cancer Therapy Tool General Form (FACT-G GP5), PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE), and 5-level EuroQOL-5 dimensions (EQ-5D-5L) including visual analog scale (EQ-5D VAS). Change from baseline to week 12 was assessed with generalized estimating equations for ordinal outcomes.

Results

Patients receiving sotorasib were less bothered by treatment side effects than those receiving docetaxel (odds ratio [OR] 5.7) and experienced symptoms at lower severity (pain: OR 2.9; aching muscles: OR 4.4; aching joints: OR 4.2; mouth or throat sores: OR 4.3). Further, patients’ symptoms interfered less with usual/daily activities (pain: OR 3.2; aching muscles: OR 3.9; aching joints: OR 10.7). QOL remained stable with sotorasib but worsened with docetaxel (change from baseline in EQ-5D VAS score: 1.5 vs –8.4 at cycle 1 day 5 and 2.2 vs –5.8 at week 12).

Conclusions

Patients receiving sotorasib reported less severe symptoms than those receiving docetaxel. In addition to improving clinical efficacy outcomes, sotorasib maintained QOL versus docetaxel, suggesting sotorasib may be a more tolerable treatment option for patients with pretreated, KRAS G12C-mutated advanced NSCLC.

Objectives

Tigger transposable element-derived 1 (TIGD1) expression and its underlying functions and regulatory mechanisms in lung adenocarcinoma (LUAD) remain unknown. Therefore, we intended to explore the expression, potential functions, and regulatory mechanisms of TIGD1 in LUAD.

Materials and methods

TIGD1 expression in LUAD tissues was determined by immunohistochemistry analysis of a tissue microarray. Functional experiments were conducted to determine how TIGD1 affects LUAD tumorigenesis and metastasis. The molecular mechanisms by which TIGD1 induces LUAD progression were determined.

Results

TIGD1 was upregulated in LUAD tissues and was related to lymph node metastases. TIGD1 knockdown suppressed LUAD cell proliferation, migration, and invasion, while promoted cell apoptosis. Furthermore, decreased metastatic nodules were observed in the TIGD1 knockdown mouse metastasis model. Moreover, microarray analysis was performed to determine the potential downstream genes of TIGD1 in LUAD. Hallmark pathway analysis revealed that the downstream genes of TIGD1 were involved in epithelial-mesenchymal transition (EMT). Western blotting confirmed that vimentin and TWIST was downregulated in TIGD1 knockdown cells, while E-cadherin was upregulated. Ingenuity pathway and hallmark pathway analyses revealed that TIGD1 regulated the interleukin-6 signaling pathway and related gene members. Western blotting, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay indicated that downregulation of TIGD1 decreased interleukin-6 and CXCL1 expression. TIGD1 expression was negatively correlated with immune infiltration in LUAD. The upstream microRNA of TIGD1 was predicted, and subsequent luciferase reporter gene experiments confirmed the interactions between miR-137 and TIGD1. The expression of miR-137 was significantly downregulated in LUAD tissues and miR-137 suppressed the proliferation, migration, and invasion of LUAD cells, partially through negatively regulating the expression of TIGD1.

Conclusion

Our findings suggest that TIGD1, which was regulated by miR-137, contributed to LUAD progression by promoting cell proliferation, migration, invasion, and EMT and suppressing cell apoptosis.

Objective

Pulmonary blastoma is a rare, biphasic, adult-onset lung tumor. In this study, we investigate whether DICER1 pathogenic variants are a feature of pulmonary blastomas through in-depth analysis of the molecular events defining them.

Methods

We performed exome-wide sequencing and DNA methylation profiling of 8 pulmonary blastomas from 6 affected persons.

Results

We identified biallelic somatic DICER1 pathogenic variants in 7 of 8 cases. The remaining case had a solitary missense pathogenic variant in the RNase IIIb domain of DICER1. Six of 8 cases carried a CTNNB1 hotspot variant and 4 of 8 had a somatic pathogenic variant in TP53. Methylation analysis showed that the pulmonary blastomas clustered with other DICER1-mutated tumors and not with other more common types of lung cancer.

Conclusion

We conclude somatic DICER1 pathogenic variants are the major driver of pulmonary blastoma and are likely to act in conjunction with CTNNB1 hotspot variants that are often present.

Background

Several patients treated with osimertinib experience progressive disease. The aim was to clarify the mechanisms underlying resistance to osimertinib.

Methods

ELUCIDATOR: A multi-centre, prospective, observational study involved chemotherapy-naive patients with advanced non-small cell lung cancer receiving osimertinib. Mutations in cancer-associated genes, detected via ultrasensitive next-generation sequencing of circulating tumour deoxyribonucleic acid samples, were collected at baseline and after progressive disease detection. These paired plasma samples were compared.

Results

Of 188 patients enrolled (May 2019-January 2021), 178 (119 females [67 %]) median age 74 years, were included. Patients, n = 95 (53 %) had epidermal growth factor receptor exon 19 deletion mutations. Among 115 patients with progressive disease, circulating tumour deoxyribonucleic acid levels of 85 patients were analysed. MET amplification (n = 4), TP53 mutations (n = 4), PIK3CA mutations (n = 3), BRINP3 mutation (n = 2), BRAF mutation (n = 2), APC mutation (n = 1), RET mutation (n = 1) and epidermal growth factor receptor (EGFR) resistance mutation, and C797S (n = 1) were detected. Patients with baseline TP53 mutations, with MET or EGFR amplification had shorter progression-free (PFS) and overall survival. Patients with PIK3CA mutations tended to shorter PFS.

Conclusion

MET amplification and PIK3CA mutation mechanisms underly resistance to osimertinib in patients. Patients with coexisting mutations or amplifications at baseline had shorter PFS and overall survival.