bims-meluca 2023-04-16 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–04–16
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Prognostic effect of cachexia in patients with non-small cell lung cancer receiving immune checkpoint inhibitors.
NMR-Metabolomics Reveals a Metabolic Shift after Surgical Resection of Non-Small Cell Lung Cancer.
Expression and clinical significance of tumor necrosis factor receptor-associated factor 1 in peripheral blood of patients with advanced lung cancer.
A novel zinc metabolism-related gene signature to predict prognosis and immunotherapy response in lung adenocarcinoma.
Body composition and lung cancer-associated cachexia in TRACERx.
Efficacy of immunotherapy as second-line or later-line therapy and prognostic significance of KRAS and/or TP53 mutations in advanced non-small cell lung cancer patients.
Soluble interleukin-2 receptor as a predictive biomarker for poor efficacy of combination treatment with anti-PD-1/PD-L1 antibodies and chemotherapy in non-small cell lung cancer patients.

Thorac Cancer. 2023 Apr 10.

Prognostic effect of cachexia in patients with non-small cell lung cancer receiving immune checkpoint inhibitors.

Norikazu Matsuo, Koichi Azuma, Kenta Murotani, Daiki Murata, Goushi Matama, Akihiko Kawahara, Takashi Kojima, Takaaki Tokito, Tomoaki Hoshino.

   BACKGROUND: The presence of cachexia in cancer patients negatively affects the quality of life and survival. However, the impact of cachexia on immunotherapy, such as PD-1/L1 inhibitors, is not fully understood. Therefore, we examined whether cancer cachexia affects the prognosis of patients with non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors.
METHODS: We retrospectively screened patients with pathologically confirmed advanced or recurrent NSCLC who were treated with PD-1/PD-L1 monotherapy at Kurume University Hospital. We defined cancer cachexia as weight loss of at least 5% during the past 6 months or any degree of weight loss more than 2% and BMI <20.
RESULTS: Among 182 patients, 74 had cancer cachexia. The presence of cachexia was significantly associated with females, poor performance status (PS), never-smokers, and driver mutations. Multivariate analysis revealed that poor PS and being a smoker were associated with the presence of cachexia. Patients with cancer cachexia had significantly shorter progression-free survival (PFS) and overall survival (OS). In the multivariate analysis, PS and sex were significantly correlated with PFS, whereas PS and cachexia were significantly correlated with OS. Subanalysis revealed that patients in the PS0/without cachexia group had longer PFS and OS than those in the cachexia or PS1-3 group.
CONCLUSIONS: In NSCLC patients, cachexia was associated with a worse prognosis, irrespective of tumor PD-L1 expression, indicating that cachexia is a predictive factor for NSCLC patients receiving immune checkpoint inhibitors.

Keywords:  NSCLC; PD-1 inhibitor; cachexia

DOI:  https://doi.org/10.1111/1759-7714.14881
Cancers (Basel). 2023 Apr 03. pii: 2127. [Epub ahead of print]15(7):

NMR-Metabolomics Reveals a Metabolic Shift after Surgical Resection of Non-Small Cell Lung Cancer.

Elien Derveaux, Melvin Geubbelmans, Maarten Criel, Ingel Demedts, Ulrike Himpe, Kurt Tournoy, Piet Vercauter, Erik Johansson, Dirk Valkenborg, Karolien Vanhove, Liesbet Mesotten, Peter Adriaensens, Michiel Thomeer.

   BACKGROUND: Lung cancer can be detected by measuring the patient's plasma metabolomic profile using nuclear magnetic resonance (NMR) spectroscopy. This NMR-based plasma metabolomic profile is patient-specific and represents a snapshot of the patient's metabolite concentrations. The onset of non-small cell lung cancer (NSCLC) causes a change in the metabolite profile. However, the level of metabolic changes after complete NSCLC removal is currently unknown.
PATIENTS AND METHODS: Fasted pre- and postoperative plasma samples of 74 patients diagnosed with resectable stage I-IIIA NSCLC were analyzed using 1H-NMR spectroscopy. NMR spectra (s = 222) representing two preoperative and one postoperative plasma metabolite profile at three months after surgical resection were obtained for all patients. In total, 228 predictors, i.e., 228 variables representing plasma metabolite concentrations, were extracted from each NMR spectrum. Two types of supervised multivariate discriminant analyses were used to train classifiers presenting a strong differentiation between the pre- and postoperative plasma metabolite profiles. The validation of these trained classification models was obtained by using an independent dataset.
RESULTS: A trained multivariate discriminant classification model shows a strong differentiation between the pre- and postoperative NSCLC profiles with a specificity of 96% (95% CI [86-100]) and a sensitivity of 92% (95% CI [81-98]). Validation of this model results in an excellent predictive accuracy of 90% (95% CI [77-97]) and an AUC value of 0.97 (95% CI [0.93-1]). The validation of a second trained model using an additional preoperative control sample dataset confirms the separation of the pre- and postoperative profiles with a predictive accuracy of 93% (95% CI [82-99]) and an AUC value of 0.97 (95% CI [0.93-1]). Metabolite analysis reveals significantly increased lactate, cysteine, asparagine and decreased acetate levels in the postoperative plasma metabolite profile.
CONCLUSIONS: The results of this paper demonstrate that surgical removal of NSCLC generates a detectable metabolic shift in blood plasma. The observed metabolic shift indicates that the NSCLC metabolite profile is determined by the tumor's presence rather than donor-specific features. Furthermore, the ability to detect the metabolic difference before and after surgical tumor resection strongly supports the prospect that NMR-generated metabolite profiles via blood samples advance towards early detection of NSCLC recurrence.

Keywords:  NMR spectroscopy; metabolomics; non-small cell lung cancer

DOI:  https://doi.org/10.3390/cancers15072127
Am J Transl Res. 2023 ;15(3): 1871-1879

Expression and clinical significance of tumor necrosis factor receptor-associated factor 1 in peripheral blood of patients with advanced lung cancer.

Guojing Li, Tiejun Wu, Ming Yang.

BACKGROUND: To assess the serum level of tumor necrosis factor receptor related factor 1 (TRAF1) in advanced lung cancer patients and its clinical significance.
METHODS: In this retrospective study, the serum level of TRAF1 in 50 patients with stage III-IV lung cancer and 50 healthy people who received physical examination during the same period were detected and compared. The differences in serum TRAF1 level in patients with lung cancer in terms of gender, age, smoking status, pathological type, tumor location, TNM stage and other clinicopathological features were analyzed. The 50 patients with lung cancer were treated with conventional chemotherapy for 2 cycles, and serum TRAF1 level was tested. The area under the curve (AUC) was calculated to evaluate the diagnostic value of serum TRAF1 for advanced lung cancer.
RESULTS: The serum level of TRAF1 in lung cancer patients was significantly higher than that of healthy controls (P < 0.05). The serum level of TRAF1 in patients with stage IV lung cancer was significantly higher than that in patients with stage III lung cancer (P < 0.05). Serum level of TRAF1 in lung adenocarcinoma and lung squamous cell carcinoma group after chemotherapy was significantly lower than that before chemotherapy (P < 0.05); However, the serum level of TRAF1 in small cell lung cancer group after chemotherapy had no significant change compared with that before chemotherapy (P > 0.05). The AUC of serum TRAF1 for the diagnosis of lung cancer was 0.903, and the yoden index was 0.668. The best cut-off value of serum TRAF1 for the diagnosis of lung cancer was 113.87 pg/ml, with a sensitivity of 90.6% and a specificity of 78.57%.
CONCLUSION: Serum level of TRAF1 has potential diagnostic value for advanced lung cancer. TRAF1 could assist clinicians to diagnose lung cancer patient and assess patient's condition.

Keywords: Tumor necrosis factor receptor related factor 1; advanced lung cancer; clinical significance
Front Immunol. 2023 ;14 1147528

A novel zinc metabolism-related gene signature to predict prognosis and immunotherapy response in lung adenocarcinoma.

Wuguang Chang, Hongmu Li, Wei Ou, Si-Yu Wang.

   Background: Zinc is a key mineral element in regulating cell growth, development, and immune system. We constructed the zinc metabolism-related gene signature to predict prognosis and immunotherapy response for lung adenocarcinoma (LUAD).
Methods: Zinc metabolism-associated gene sets were obtained from Molecular Signature Database. Then, the zinc metabolism-related gene signature (ZMRGS) was constructed and validated. After combining with clinical characteristics, the nomogram for practical application was constructed. The differences in biological pathways, immune molecules, and tumor microenvironment (TME) between the different groups were analyzed. Tumor Immune Dysfunction and Exclusion algorithm (TIDE) and two immunotherapy datasets were used to evaluate the immunotherapy response.
Results: The signature was constructed according to six key zinc metabolism-related genes, which can well predict the prognosis of LUAD patients. The nomogram also showed excellent prediction performance. Functional analysis showed that the low-risk group was in the status of immune activation. More importantly, the lower risk score of LUAD patients showed a higher response rate to immunotherapy.
Conclusion: The state of zinc metabolism is closely connected to prognosis, tumor microenvironment, and response to immunotherapy. The zinc metabolism-related signature can well evaluate the prognosis and immunotherapy response for LUAD patients.

Keywords:  biomarker; immunotherapy; lung adenocarcinoma; prognosis; zinc; zinc metabolism

DOI:  https://doi.org/10.3389/fimmu.2023.1147528
Nat Med. 2023 Apr 12.

Body composition and lung cancer-associated cachexia in TRACERx.

TRACERx Consortium

Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.

DOI: https://doi.org/10.1038/s41591-023-02232-8
Eur J Cancer Prev. 2023 Apr 05.

Efficacy of immunotherapy as second-line or later-line therapy and prognostic significance of KRAS and/or TP53 mutations in advanced non-small cell lung cancer patients.

Jingya Liu, Jianing Gao.

OBJECTIVE: In this retrospective study, we aimed to assess the relationship between mutations in the Kirsten rats sarcoma viral oncogene (KRAS)/ tumor protein p53 (TP53) genes and the efficacy of immune checkpoint inhibitors (ICIs) therapy as a second-line or later-line treatment for patients with stage IIIB/IV non-small cell lung cancer (NSCLC).
METHODS: We retrospectively analyzed the clinical data of 143 patients with stage IIIB/IV NSCLC who were admitted to the Cancer Hospital of Harbin Medical University between January 2019 and September 2022. Kaplan-Meier survival curve analysis was performed to analyze the survival outcomes. Univariate and multivariate Cox proportional risk models were used to analyze the factors associated with the progression-free survival (PFS) and overall survival (OS) of advanced-stage NSCLC patients who received ICIs as second-line or later-line therapy.
RESULTS: NSCLC patients with KRAS and/or TP53 mutations treated with ICIs showed significantly higher objective response rate, disease control rate, PFS, and OS compared to NSCLC patients with wild-type KRAS/TP53 (P < 0.05). Multivariate Cox regression analysis showed that a combined treatment regimen of ICIs plus chemotherapy was significantly associated with prolonged PFS [hazard ratio = 0.192; 95% confidence interval (CI), 0.094-0.392; P < 0.001] and OS (hazard ratio = 0.414; 95% CI, 0.281-0.612; P < 0.001).
CONCLUSION: KRAS and/or TP53 mutations were associated with improved PFS of advanced NSCLC patients treated with ICIs as second-line or later-line therapy. KRAS and/or TP53 mutations show great potential as clinical biomarkers to predict the efficacy of ICIs therapy.

DOI: https://doi.org/10.1097/CEJ.0000000000000799
Invest New Drugs. 2023 Apr 14.

Soluble interleukin-2 receptor as a predictive biomarker for poor efficacy of combination treatment with anti-PD-1/PD-L1 antibodies and chemotherapy in non-small cell lung cancer patients.

Takehiro Tozuka, Noriko Yanagitani, Hiroshi Yoshida, Ryo Manabe, Shinsuke Ogusu, Ryosuke Tsugitomi, Hiroaki Sakamoto, Yoshiaki Amino, Ryo Ariyasu, Ken Uchibori, Satoru Kitazono, Masahiro Seike, Akihiko Gemma, Makoto Nishio.

  Soluble interleukin-2 receptor (sIL-2R) suppresses effector T-cells. Few studies have assessed serum sIL-2R in patients receiving immunotherapy. We evaluated the association between serum sIL-2R levels and the efficacy of anti-programmed cell death 1/ programmed death-ligand 1 (anti-PD-1/PD-L1) antibody combined with chemotherapy in non-small cell lung cancer (NSCLC) patients. We prospectively enrolled NSCLC patients who received anti-PD-1/PD-L1 antibody combined with platinum-based chemotherapy between 8/2019 and 8/2020 and measured their serum sIL-2R. The patients were divided into high and low sIL-2R groups based on the median of sIL-2R levels at pretreatment. Progression-free survival (PFS) and overall survival (OS) of patients in the high and low sIL-2R groups were compared. The Kaplan-Meier curves of PFS and OS were evaluated using the log-rank test. The multivariate analysis of PFS and OS was performed using the Cox proportional hazard models. Among 54 patients (median age 65, range 34-84), 39 were male and 43 had non-squamous cell carcinoma. The sIL-2R cut-off value was 533 U/mL. Median PFS was 5.1 months (95% CI, 1.8-7.5 months) and 10.1 months (95% CI, 8.3-not reached [NR] months) in the high and low sIL-2R groups (P = 0.007), respectively. Median OS was 10.3 months (95% CI, 4.0-NR months) and NR (95% CI, 10.3-NR months) in the high and low sIL-2R groups (P = 0.005), respectively. Multivariate Cox regression analysis showed that high sIL-2R was significantly associated with shorter PFS and OS. SIL-2R may be a biomarker for the poor efficacy of anti-PD-1/PD-L1 antibody combined with chemotherapy.

Keywords:  Anti PD-1/PD-L1 antibody; Chemotherapy; Immunotherapy; Non-small cell lung cancer; Soluble IL-2 receptor

DOI:  https://doi.org/10.1007/s10637-023-01358-3