bims-meluca 2024-08-11 papers

BMC Cancer. 2024 Aug 05. 24(1): 954

The impact of the expression level of growth differentiation factor 15 in tumor tissue on the response to immunotherapy in non-small cell lung cancer.

Orhun Akdogan, Betul Ogut, Osman Sutcuoglu, Aysenur Sert, Fatih Gurler, Nalan Akyurek, Nuriye Ozdemir, Ahmet Ozet, Ozan Yazici.

BACKGROUND: Growth differentiation factor-15 (GDF-15), a member of the TGF-β superfamily, is overexpressed in various cancers and facilitates immune evasion by inhibiting T-cell activation. GDFATHER-TRIAL's phase 2a results demonstrated promising outcomes when combining the GDF-15 neutralizing antibody visugromab (CTL002) with nivolumab, enhancing the response to immunotherapy. This study evaluated the prognostic significance of GDF-15 expression in non-small cell lung cancer (NSCLC) tumor tissues in terms of immunotherapy response.
METHODS: This retrospective study included 50 patients with metastatic NSCLC treated with nivolumab at Gazi University Hospital between January 2021 and July 2023. GDF-15 expression was evaluated using immunochemistry staining and categorized based on the intensity of cytoplasmic or membranous staining. Samples were divided into a low expression group (scores 0 and 1) and a high expression group (scores 2 and 3). The primary outcomes were progression-free survival (PFS) and overall survival (OS), which were analyzed using Kaplan‒Meier and Cox proportional hazards models. Objective response rates were assessed in secondary outcomes.
RESULTS: Of the 50 patients, 43 were men (86%), with a median age of 63.9 years. Half of the patients exhibited low GDF-15 expression. High GDF-15 expression correlated with shorter PFS and OS. The median PFS was 7.8 months for the low-expression group versus 4.4 months for the high-expression group (HR, 0.41; 95% CI, 0.20-0.83; p = 0.013). The median OS was 18.1 months for the low-expression group compared to 11.8 months for the high-expression group (HR, 0.36; 95% CI, 0.16-0.78; p = 0.007). The objective response rate was significantly greater in the low GDF-15 group (52%) than in the high GDF-15 group (24%) (p = 0.040).
CONCLUSION: Elevated GDF-15 expression in NSCLC tumor tissues is associated with poorer response to nivolumab, suggesting that GDF-15 is a potential prognostic biomarker for immunotherapy efficacy. These findings warrant further validation through prospective studies to optimize treatment strategies for NSCLC patients.

Keywords: Biomarker; Chemotherapy; GDF-15; Immunotherapy; NSCLC

DOI: https://doi.org/10.1186/s12885-024-12727-3

Cancer Res Commun. 2024 Aug 08.

Loss of STK11 Suppresses Lipid Metabolism and Attenuates KRAS-Induced Immunogenicity in Patients with Non-Small Cell Lung Cancer.

Daniel R Principe, Mary M Pasquinelli, Ryan H Nguyen, Hidayatullah G Munshi, Alicia Hulbert, Alexandre F Aissa, Frank Weinberg.

As many as 30% of non-small cell lung cancer (NSCLC) patients harbor oncogenic KRAS mutations, which lead to extensive remodeling of the tumor immune microenvironment. Though co-mutations in several genes have prognostic relevance in KRAS-mutated patients, their effect on tumor immunogenicity are poorly understood. In the present study, a total of 189 NSCLC patients underwent a standardized analysis including immunohistochemistry, whole exome DNA sequencing, and whole transcriptome RNA sequencing. Patients with activating KRAS mutations demonstrated a significant increase in PD-L1 expression and CD8+ T-cell infiltration. Both were increased in the presence of a co-occurring TP53 mutation and lost with STK11 co-mutation. Subsequent genomic analysis demonstrated that KRAS/TP53 co-mutated tumors had a significant decrease in the expression of glycolysis-associated genes, and increase in several genes involved in lipid metabolism, notably Lipoprotein Lipase (LPL), Low Density Lipoprotein Receptor (LDLR), and LDLRAD4. Conversely, in the immune-excluded KRAS/STK11 co-mutated group, we observed diminished lipid metabolism and no change in anaerobic glycolysis. Interestingly, in patients with low expression of LPL, LDLR, or LDLRAD4, KRAS mutations had no effect on tumor immunogenicity. However, in patients with robust expression of these genes, KRAS mutations were associated with increased immunogenicity and associated with improved overall survival. Our data further suggest that the loss of STK11 may function as a metabolic switch, suppressing lipid metabolism in favor of glycolysis, thereby negating KRAS-induced immunogenicity. Hence, this concept warrants continued exploration, both as a predictive biomarker and potential target for therapy in patients receiving ICI-based immunotherapy.

DOI: https://doi.org/10.1158/2767-9764.CRC-24-0153

Transl Lung Cancer Res. 2024 Jul 30. 13(7): 1481-1494

Differential impact of intratumor heterogeneity (ITH) on survival outcomes in early-stage lung squamous and adenocarcinoma based on tumor mutational burden (TMB).

Stanislav Fridland, Hye Sung Kim, Young Kwang Chae.

Background: Molecular biomarkers are reshaping patient stratification and treatment decisions, yet their precise use and best implementation remain uncertain. Intratumor heterogeneity (ITH), an area of increasing research interest with prognostic value across various conditions, lacks defined clinical relevance in certain non-small cell lung cancer (NSCLC) subtypes. Exploring the relationship between ITH and tumor mutational burden (TMB) is crucial, as their interplay might reveal distinct patient subgroups. This study evaluates how the ITH-TMB dynamic affects prognosis across the two main histological subtypes of NSCLC, squamous cell and adenocarcinoma, with a specific focus on early-stage cases to address their highly unmet clinical needs.
Methods: We stratify a cohort of 741 early-stage NSCLC patients from The Cancer Genome Atlas (TCGA) based on ITH and TMB and evaluate differences in clinical outcomes. Additionally, we compare driver mutations and the tumor microenvironment (TME) between high and low ITH groups.
Results: In lung squamous cell carcinoma (LUSC), high ITH predicts an extended progression-free survival (PFS) (median: 21 vs. 14 months, P=0.01), while in lung adenocarcinoma (LUAD), high ITH predicts a reduced PFS (median: 15 vs. 20 months, P=0.04). This relationship is driven by the low TMB subset of patients. Additionally, we found that CD8 T cells were enriched in better-performing subgroups, regardless of histologic subtype or ITH status.
Conclusions: There are significant differences in clinical outcomes, driver mutations, and the TME between high and low ITH groups among early-stage NSCLC patients. These differences may have treatment implications, necessitating further validation in other NSCLC datasets.

Keywords: Non-small cell lung cancer (NSCLC); intratumor heterogeneity (ITH); molecular biomarkers; tumor mutational burden (TMB)

DOI: https://doi.org/10.21037/tlcr-24-226

Ther Adv Med Oncol. 2024 ;16 17588359241266188

Pretreatment pulmonary tumor necrosis is a promising prognostic imaging biomarker for first-line anti-PD-1/PD-L1 therapy in advanced lung squamous cell carcinoma: a multi-institutional, propensity score-matching cohort analysis.

Background: Tumor necrosis (TN) is a common feature in lung squamous cell carcinoma (LSCC), which could provide useful predictive and prognostic information.
Objectives: This study aimed to investigate the effect of pretreatment pulmonary TN (PTN) on the prognosis of first-line anti-programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) inhibitor in advanced LSCC.
Design: We conducted a retrospective study to analyze the association between the presence of PTN and clinical outcomes in advanced LSCC patients treated with anti-PD-1/PD-L1 inhibitors.
Methods: Data from 240 eligible patients were collected from 27 hospitals across China between 2016 and 2020. The presence of PTN was assessed using contrast-enhanced chest computed tomography (CT) imaging at baseline. We utilized the Cox proportional-hazards regression model to analyze the association between PTN and clinical outcomes. In addition, to account for potential confounding factors and ensure comparability between groups, we employed propensity score-matching (PSM) analysis.
Results: In the overall patient cohort, the presence of PTN was 39.6%. The median follow-up duration was 20.3 months. The positive PTN group exhibited a notably inferior median progression-free survival (PFS; 6.5 months vs 8.6 months, p = 0.012) compared to the negative PTN group. Within the Cox proportional-hazards regression model, PTN emerged as an independent predictor of unfavorable PFS (hazard ratio (HR) = 1.354, 95% confidence interval (CI): 1.002-1.830, p = 0.049). After PSM, the median PFS for the positive PTN group (6.5 months vs 8.0 months, p = 0.027) remained worse than that of the negative PTN group. Multivariate analyses also further underscored that the presence of PTN independently posed a risk for shorter PFS (HR = 1.494, 95% CI: 1.056-2.112, p = 0.023). However, no statistically significant difference in overall survival was observed between the two groups.
Conclusion: Our study suggests that the presence of PTN on baseline contrast-enhanced chest CT is a potential negative prognostic imaging biomarker for the outcome of anti-PD-1/PD-L1 inhibitor therapy in advanced LSCC. Further studies are warranted to validate these findings and explore the underlying mechanisms.

Keywords: anti-PD-1/PD-L1 inhibitor; lung squamous cell carcinoma; prognostic biomarker; propensity score-matching; pulmonary tumor necrosis

DOI: https://doi.org/10.1177/17588359241266188

Transl Lung Cancer Res. 2024 Jul 30. 13(7): 1672-1684

Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer patients with rare KRAS mutations: a real-world retrospective study.

Haohua Jiang, Yujing Li, Yanan Wang, Benkun Zou, Ya Chen, Yanwei Zhang, Hatim Husain, Fabien Forest, Fangfei Qian, Lele Zhang, Chao Zhou, Hongyu Liu, Danni Wang, Wei Zhang, Jun Lu, Baohui Han.

Background: Kirsten rat sarcoma homolog (KRAS) mutations are one of the key drivers in non-small cell lung cancer (NSCLC) and FDA-approved specific inhibitors of KRAS-G12C mutation are available clinically. However, inhibitors of certain KRAS mutation subtypes remain unavailable, especially rare KRAS mutations including G13C, G13D, and Q61H. In this study, we retrospectively investigated the outcomes of NSCLC patients with rare KRAS-mutation to determine if they may benefit from immune checkpoint inhibitors (ICIs).
Methods: Our retrospective study involved 240 advanced NSCLC patients with KRAS mutations, who visited Shanghai Chest Hospital from July 2018 to July 2021. Complete clinical and pathological data were recorded and progression-free survival (PFS) and overall survival (OS) were adopted as primary endpoints.
Results: The median follow-up time was 36.5 months (range, 30.8-42.1 months) and the median OS was 9.7 months (range, 7.6-11.8 months). Of the 240 patients evaluated, 130 (54.2%) received chemotherapy and 110 (45.8%) received ICI-based treatment. Among the patients who received chemotherapy, patients with rare KRAS-mutations presented worse survival outcomes (median PFS, 3.4 vs. 4.1 months, P=0.047; median OS, 5.2 vs. 7.1 months, P=0.02) than conventional KRAS-mutant patients. PFS and OS of rare KRAS-mutation patients were prolonged after immunotherapy (median PFS 7.3 vs. 3.4 months, P<0.001; median OS, 13.3 vs. 5.2 months, P<0.001) and had no significant difference compared with conventional KRAS-mutant patients, in part of them whose programmed death-ligand 1 (PD-L1) expression data before immunotherapy were available (n=72), patients with a higher rate of PD-L1 positive tumor cells (≥50%) presented elevated PFS and OS.
Conclusions: Despite having potential survival disadvantage compared with other NSCLC patients, rare KRAS-mutant patients (other than G12A, C, D, V) could benefit specifically from ICI-based therapy and survival outcomes are correlated with PD-L1 expression.

Keywords: Advanced non-small cell lung cancer (advanced NSCLC); Kirsten rat sarcoma homolog mutations (KRAS mutations); immune checkpoint inhibitor (ICI); rare KRAS mutations; survival benefit

DOI: https://doi.org/10.21037/tlcr-24-372