bims-meluca 2024-11-17 papers

Radiat Oncol. 2024 Nov 07. 19(1): 155

Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected locally advanced non-small cell lung cancer treated with chemoradiotherapy.

INTRODUCTION: Growth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard of care concurrent chemoradiotherapy (cCRT). OCOG-ALMERA was not able to demonstrate benefit in the metformin arm. Therefore, biomarker studies are needed to better define stratification parameters for future trials.
METHODS: Patients were randomized to treatment with platinum-based chemotherapy and concurrent chest radiotherapy (60-66 Gy), with or without metformin (2000 mg/d). The trial collected tumor volume parameters, survival outcomes, and patient blood plasma at baseline, during (weeks 1 and 6) and 6 months after cCRT. Plasma GDF15 levels were assayed with the ELISA method. Statistical analyses explored associations between GDF15, survival outcomes, and radiotherapy tumor volumes.
RESULTS: Baseline plasma levels of GDF15 were elevated in study patients, they increased during cCRT (p < 0.001), and the addition of metformin was associated with a further increase (week 6, p = 0.033). Baseline GDF15 levels correlated with the radiotherapy gross target volume (GTV, p < 0.01), while week 1 of radiotherapy levels correlated with radiotherapy planned target volume (PTV, p < 0.006). In multivariate analysis, baseline plasma GDF15 was prognostic for poor relapse-free (RFS) and overall survival (OS) (p = 0.005 and p = 0.002, respectively).
CONCLUSIONS: GDF15 is a plasma marker that responds to the treatment of unresected LA-NSCLC with cCRT and metformin. GDF15 levels correspond with tumor volume and increased GDF15 levels predict for poor RFS and OS. These results require validation in larger clinical trial datasets.

Keywords: Concurrent chemoradiotherapy; GDF15; Lung cancer biomarker; Metformin

DOI: https://doi.org/10.1186/s13014-024-02546-y

Discov Oncol. 2024 Nov 14. 15(1): 655

Correlation between glucose metabolism and body mass index in tumor lesions of patients with lung cancer.

Zhengqin Zhao, Xiaona Wang, Dong Wang, Jiahui Zhang, Hongjie Yang.

OBJECTIVE: Lung cancer, along with various other cancers, is characterized by increased glucose metabolism. The maximum standardized uptake value (SUVmax), derived from positron emission tomography-computed tomography (PET-CT), serves as an indicator of glucose metabolic activity in tumor lesions. This study aimed to evaluate the correlation between body mass index (BMI) and SUVmax in individuals with lung cancer.
METHODS: This study included 41 patients with lung cancer, who were divided into two groups: Group 1 (n = 21), with a BMI greater than 22.4, and Group 2 (n = 20), with a BMI less than 22.4. All participants underwent 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) imaging. The SUVmax was calculated by manually delineating the regions of interest. A t-test was performed to assess whether the differences in SUVmax between the two groups were statistically significant.
RESULTS: The mean SUVmax for Group 1 was 11.20 ± 5.45, while for Group 2 it was 10.65 ± 5.96. Although the mean SUVmax was higher in Group 1 compared to Group 2, the difference between the groups was not statistically significant (P = 0.757).
CONCLUSION: The findings indicate a non-significant difference in glucose metabolism in lung cancer lesions between patients with different BMI levels. These results offer valuable insights into the metabolic characteristics of lung cancer and contribute to a deeper understanding of its pathophysiology.

Keywords: Body mass index; Glucose metabolism; PET-CT; SUVmax

DOI: https://doi.org/10.1007/s12672-024-01539-3

Cancers (Basel). 2024 Nov 04. pii: 3712. [Epub ahead of print]16(21):

Serum CYFRA 21-1 as a Prognostic Marker in Non-Small-Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors.

Keiki Miyadera, Sho Kakuto, Mayu Sugai, Ryosuke Tsugitomi, Yoshiaki Amino, Ken Uchibori, Noriko Yanagitani, Hisatoshi Sugiura, Masahiro Seike, Makoto Nishio, Ryo Ariyasu.

Background: A prognostic marker in patients with non-small-cell lung cancer (NSCLC) treated with anti-PD-1/PD-L1 antibodies must be established. This study explored serum cytokeratin fraction 21-1 (CYFRA 21-1), which represents a squamous cell histology, as a prognostic factor in anti-PD-1/PD-L1 antibody treatment, stratifying by histology and treatment regimen. Methods: This study retrospectively evaluated patients with advanced NSCLC without driver mutations receiving anti-PD-1/PD-L1 antibodies between November 2015 and March 2023. Cutoff values for CYFRA 21-1 and carcinoembryonic antigen (CEA) were 3.5 and 5.0 ng/mL, respectively. The Kaplan-Meier method and a log-rank test were conducted. The Cox proportional hazards model was utilized for univariate and multivariate analyses. Results: This study included 258 patients. The squamous NSCLC group demonstrated a shorter overall survival (OS) than the non-squamous NSCLC group (median, 17.8 vs. 23.7 months, p = 0.141). Patients with high serum CYFRA 21-1 and CEA levels exhibited a significantly shorter OS than those with normal levels (median, 11.7 vs. 32.7 months, p < 0.005; 15.8 vs. 29.7 months, p < 0.005). The multivariate analysis identified a performance status (PS) of ≥2, a PD-L1 expression of ≥50%, and a serum CYFRA 21-1 of >3.5 ng/mL as independent prognostic factors. Patients with high serum CYFRA 21-1 levels exhibited a significantly shorter OS even focusing on non-squamous NSCLC, anti-PD-1/PD-L1 antibody and chemotherapy combination therapy, or anti-CTLA-4 antibody combination therapy. Conclusion: Serum CYFRA 21-1 is a poor prognostic marker for patients with NSCLC receiving anti-PD-1/PD-L1 antibody treatment even when stratifying by histology or treatment regimen.

Keywords: CYFRA 21-1; immune checkpoint inhibitor; non-small-cell lung cancer; serum tumor marker

DOI: https://doi.org/10.3390/cancers16213712

Mol Cancer. 2024 Nov 12. 23(1): 253

The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer.

W J McDaid, L Wilson, H Adderley, A Martinez-Lopez, M J Baker, J Searle, L Ginn, T Budden, M Aldea, A Marinello, J V Aredo, A Viros, B Besse, H A Wakelee, F Blackhall, S Castillo-Lluva, C R Lindsay, A Malliri.

INTRODUCTION: KRASG12C and KRASG12D inhibitors represent a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general by directly targeting its most mutated oncoprotein. However, resistance to these small molecules has highlighted the need for rational combination partners necessitating a critical understanding of signaling downstream of KRAS mutant isoforms.
METHODS: We contrasted tumor development between KrasG12C and KrasG12D genetically engineered mouse models (GEMMs). To corroborate findings and determine mutant subtype-specific dependencies, isogenic models of KrasG12C and KrasG12D initiation and adaptation were profiled by RNA sequencing. We also employed cell line models of established KRAS mutant NSCLC and determined therapeutic vulnerabilities through pharmacological inhibition. We analysed differences in survival outcomes for patients affected by advanced KRASG12C or KRASG12D-mutant NSCLC.
RESULTS: KRASG12D exhibited higher potency in vivo, manifesting as more rapid lung tumor formation and reduced survival of KRASG12D GEMMs compared to KRASG12C. This increased potency, recapitulated in an isogenic initiation model, was associated with enhanced PI3K-AKT-mTOR signaling. However, KRASG12C oncogenicity and downstream pathway activation were comparable with KRASG12D at later stages of tumorigenesis in vitro and in vivo, consistent with similar clinical outcomes in patients. Despite this, established KRASG12D NSCLC models depended more on the PI3K-AKT-mTOR pathway, while KRASG12C models on the MAPK pathway. Specifically, KRASG12D inhibition was enhanced by AKT inhibition in vitro and in vivo.
CONCLUSIONS: Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling.

Keywords: KRAS; KRASG12D inhibition; NSCLC; PI3K-AKT-mTOR pathway

DOI: https://doi.org/10.1186/s12943-024-02157-x

Diabetes Res Clin Pract. 2024 Nov 11. pii: S0168-8227(24)00840-4. [Epub ahead of print] 111930

The prognostic significance of diabetes in non-small cell lung cancer patients treated with immune checkpoint inhibitors: A meta-analysis.

Nam Nhat Nguyen, Thu Huynh Ha Nguyen, Kinh Dinh Hoang, Thai Kien Vo, Quan Hoang Minh Pham, Yang Ching Chen.

AIMS: Studies on the prognosis of patients with diabetes and non-small-cell lung cancer (NSCLC) in the era of immune checkpoint inhibitors (ICIs) are limited, and existing findings remain inconsistent. This meta-analysis explored the association between diabetes and survival outcomes in this population.
METHODS: A total of 10 non-randomized studies comparing overall survival between patients with NSCLC receiving ICIs with and without diabetes were included. A meta-analysis was performed to estimate the hazard of death or disease progression between the two groups. Another analysis was employed to explore the difference in median survival between the groups. Additionally, subgroup, meta-regression, and sensitivity analyses were conducted.
RESULTS: Patients with diabetes exhibited a significantly higher risk of death than those without diabetes (HR = 1.28, 95 % CI = 1.14-1.44; P < 0.01). Moreover, individuals with diabetes had a median life expectancy that was 6.04 months shorter (95 % CI = -10.53 to - 1.54 months, P = 0.009) than that of individuals without diabetes. Moreover, for every 1 % increase in the proportion of patients with diabetes using metformin, a corresponding 2.2 % decrease in the HR of progression-free survival was observed (95 % CI = 1.2-3.1 %).
CONCLUSION: Diabetes compromises the effectiveness of ICI treatment in patients with NSCLC.

Keywords: Diabetes; Immune checkpoint inhibitors; Non-small cell lung cancer

DOI: https://doi.org/10.1016/j.diabres.2024.111930