bims-meluca 2022-07-31 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–07–31
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Association between Nutritional Status and Treatment Response and Survival in Patients Treated with Immunotherapy for Lung Cancer: A Retrospective French Study.
The Association between Muscle Quantity and Overall Survival Depends on Muscle Radiodensity: A Cohort Study in Non-Small-Cell Lung Cancer Patients.
Body mass index and serum markers associated with progression-free survival in lung cancer patients treated with immune checkpoint inhibitors.
Soluble Immune Checkpoint-Related Proteins in Blood Are Associated With Invasion and Progression in Non-Small Cell Lung Cancer.
Novel Diagnostic and Prognostic Tools for Lung Cancer Cachexia: Based on Nutritional and Inflammatory Status.
Efficacy of Combined Use of Everolimus and Second-Generation Pan-EGRF Inhibitors in KRAS Mutant Non-Small Cell Lung Cancer Cell Lines.
Interleukin-11: A Potential Biomarker and Molecular Therapeutic Target in Non-Small Cell Lung Cancer.
Blood-based tumour mutation index act as prognostic predictor for immunotherapy and chemotherapy in non-small cell lung cancer patients.

Cancers (Basel). 2022 Jul 15. pii: 3439. [Epub ahead of print]14(14):

Association between Nutritional Status and Treatment Response and Survival in Patients Treated with Immunotherapy for Lung Cancer: A Retrospective French Study.

Manon Gouez, Lidia Delrieu, Carole Bouleuc, Nicolas Girard, Bruno Raynard, Timothée Marchal.

  Malnutrition is associated with a greater risk of morbidity and mortality and lower tolerance to chemotherapy. Our purpose was to study the association between nutritional status and the efficiency and tolerance of immunotherapy in non-small cell lung cancer (NSCLC). Nutritional and oncological data were reported at 2 months (M2) and 4 months (M4) after the initiation of immunotherapy (M0). The influence of nutritional status at M0 was estimated with the efficacy and toxicity of immunotherapy at M2 to M4. In total, 127 patients were included in the study, and nutritional status was estimated at M0 for 120 patients: 67% were not malnourished, 20% presented with moderate malnutrition, and 13% presented with severe malnutrition. There was no significant link between the nutritional status at M0 and the toxicity of immunotherapy at M2 and M4. However, severe malnutrition was significantly associated with treatment efficacy at M2 (p = 0.04) and with a lower survival rate with an HR (Hazard Ratio) = 2.32-95% C.I: 1.13-4.75 (p = 0.02). Furthermore, a monthly decrease of 1% of the weight had an HR = 1.17-95% C.I: 1.13-1.21 (p = 0.0001). Severe malnutrition and weight loss are independent factors associated with lower survival. Studies integrating the systemic detection of sarcopenia with a closer nutritional follow-up could highlight an improvement in survival.

Keywords:  advanced cancer; immunotherapy; lung cancer; nutritional status; survival

DOI:  https://doi.org/10.3390/cancers14143439
J Pers Med. 2022 Jul 21. pii: 1191. [Epub ahead of print]12(7):

The Association between Muscle Quantity and Overall Survival Depends on Muscle Radiodensity: A Cohort Study in Non-Small-Cell Lung Cancer Patients.

Wouter A C van Amsterdam, Netanja I Harlianto, Joost J C Verhoeff, Pim Moeskops, Pim A de Jong, Tim Leiner.

  The prognostic value of CT-derived muscle quantity for overall survival (OS) in patients with non-small-cell lung cancer (NSCLC) is uncertain due to conflicting evidence. We hypothesize that increased muscle quantity is associated with better OS in patients with normal muscle radiodensity but not in patients with fatty degeneration of muscle tissue and low muscle radiodensity. We performed an observational cohort study in NSCLC patients treated with radiotherapy. A deep learning algorithm was used to measure muscle quantity as psoas muscle index (PMI) and psoas muscle radiodensity (PMD) on computed tomography. The potential interaction between PMI and PMD for OS was investigated using Cox proportional-hazards regression. Baseline adjustment variables were age, sex, histology, performance score and body mass index. We investigated non-linear effects of continuous variables and imputed missing values using multiple imputation. We included 2840 patients and observed 1975 deaths in 5903 patient years. The average age was 68.9 years (standard deviation 10.4, range 32 to 96) and 1692 patients (59.6%) were male. PMI was more positively associated with OS for higher values of PMD (hazard ratio for interaction 0.915; 95% confidence interval 0.861-0.972; p-value 0.004). We found evidence that high muscle quantity is associated with better OS when muscle radiodensity is higher, in a large cohort of NSCLC patients treated with radiotherapy. Future studies on the association between muscle status and OS should accommodate this interaction in their analysis for more accurate and more generalizable results.

Keywords:  cachexia; carcinoma; non-small-cell lung; prognosis; survival analysis

DOI:  https://doi.org/10.3390/jpm12071191
BMC Cancer. 2022 Jul 28. 22(1): 824

Body mass index and serum markers associated with progression-free survival in lung cancer patients treated with immune checkpoint inhibitors.

Zhenzhen Liu, Yuzhu Diao, Xiaoling Li.

BACKGROUND: ICIs have remarkably affected the treatment strategies for numerous malignancies, including lung cancer. However, only a fraction of patients experience durable responses to ICIs; thus, there is an urgent need to identify the parameters related to ICI therapeutic effects. In this study, we investigated nutritional status surrogates and several serum markers to estimate the efficacy of ICIs.
MATERIALS AND METHODS: The records of 66 patients with stage III/IV lung cancer who received ICIs were retrospectively analyzed. Features of patients' clinical pathology, including age, sex, histology, line of treatment, BMI, serum albumin, serum creatinine, and serum inflammatory markers such as LMR and PLR, were examined. Progression-free survival was the primary endpoint. Relationships among categorical variables were assessed by the chi-squared test. Survival analysis was performed using the Kaplan-Meier method followed by the log-rank test. Cox multivariate analysis was performed to analyze the association between each variable and the survival time of patients.
RESULTS: The patients with BMI ≥ 25 (kg/m2), serum ALB≥37 (g/dL), serum creatinine ≥61.8 (μmol/L), LMR ≥ 2.12 had a significantly prolonged PFS in comparison with BMI<25 (kg/m2), ALB<37 (g/dL), creatinine<61.8 (μmol/L), LMR<2.12 (p < 0.05). No statistically significant difference was detected between patients with PLR < 135 and PLR ≥ 135 (p = 0.612). Multivariate analysis revealed that ALB≥37 (g/dL) and creatinine ≥ 61.8 (μmol/L) were associated with prolonged PFS, while statistical significance was not achieved in the BMI groups.
CONCLUSIONS: The current results indicated that high BMI is related to longer PFS in lung cancer patients treated with ICIs, which may be correlated with high levels of serum albumin and creatinine.

DOI: https://doi.org/10.1186/s12885-022-09744-5
Front Immunol. 2022 ;13 887916

Soluble Immune Checkpoint-Related Proteins in Blood Are Associated With Invasion and Progression in Non-Small Cell Lung Cancer.

Qinchuan Wang, Yue He, Wanlu Li, Xiaohang Xu, Qingfeng Hu, Zilong Bian, Andi Xu, Huakang Tu, Ming Wu, Xifeng Wu.

   Background: Immune checkpoint inhibition therapy has been achieved significant success in the treatment of non-small cell lung cancer (NSCLC). However, the role of soluble immune checkpoint- related proteins in NSCLC remains obscure.
Methods: We evaluated the circulating levels of 14 immune checkpoint-related proteins panel (BTLA, LAG-3, GITR, IDO, PD-L2, PD-L1, PD-1, HVEM, Tim-3, CD28, CD27, CD80, CD137 and CTLA-4) and their associations with the risk of invasive disease and the risk of NSCLC in 43 pre-invasive (AIS), 81 invasive NSCLC (IAC) patients and matched 35 healthy donors using a multiplex Luminex assay. Gene expression in tumors from TCGA were analyzed to elucidate potential mechanisms. The multivariate logistic regression model was applied in the study. ROC(receiver operator characteristic) curve and calibration curve were used in the performance evaluation.
Results: We found that sCD27, sCD80, CD137 and sPDL2 levels were significantly increased in IAC cases compared to AIS cases (P= 1.05E-06, 4.44E-05, 2.30E-05 and 1.16E-06, respectively), whereas sPDL1 and sPDL2 levels were significantly increased in NSCLC cases compared to healthy controls (P=3.25E-05 and 1.49E-05, respectively). Unconditional univariate logistic regression analysis indicated that increased sCD27, sCD80, sCD137, and sPDL2 were significantly correlated with the risk of invasive diseases. The model with clinical variables, sCD27 and sPDL2 demonstrated the best performance (AUC=0.845) in predicting the risk of IAC. CD27 and PDCD1LG2 (PDL2) showed significant association with cancer invasion signature in TCGA dataset.
Conclusion: Our study provides evidence that soluble immune checkpoint-related proteins may associate with the risk of IAC, and we further established an optimized multivariate predictive model, which highlights their potential application in the treatment of NSCLC patients. Future studies may apply these biomarkers to test their predictive value of survival and treatment outcome during immunotherapy in NSCLC patients.

Keywords:  adenocarcinoma in situ; invasive adenocarcinoma; non-small cell lung cancer; prediction model; soluble immune checkpoint-related protein

DOI:  https://doi.org/10.3389/fimmu.2022.887916
Front Oncol. 2022 ;12 890745

Novel Diagnostic and Prognostic Tools for Lung Cancer Cachexia: Based on Nutritional and Inflammatory Status.

Chen-An Liu, Qi Zhang, Guo-Tian Ruan, Liu-Yi Shen, Hai-Lun Xie, Tong Liu, Meng Tang, Xi Zhang, Ming Yang, Chun-Lei Hu, Kang-Ping Zhang, Xiao-Yue Liu, Han-Ping Shi.

   Background: Cachexia is one of the most common complications affecting lung cancer patients that seriously affects their quality-of-life and survival time. This study aimed to analyze the predictors and prognostic factors of lung cancer cachexia as well as to develop a convenient and accurate clinical prediction tool for oncologists.
Methods: In this multicenter cohort study, 4022 patients with lung cancer were retrospectively analyzed. The patients were randomly categorized into training and verification sets (7:3 ratio). Univariate and multivariate logistic regression analyses were performed to determine the risk factors of cachexia in patients with lung cancer. Cox regression analysis was applied to determine independent prognostic factors in the patients with lung cancer cachexia. Meanwhile, two nomograms were established and evaluated by time-dependent receiver operating characteristic curve, calibration curve, and decision curve analysis (DCA).
Results: Stage, serum albumin, ALI, anemia, and surgery were independent risk factors for cachexia in patients with lung cancer. Patients with lung cancer cachexia have a shorter survival time. Sex, stage, serum albumin, ALI, KPS score, and surgery served as independent prognostic factors for patients with lung cancer cachexia. The area under the curves (AUCs) of diagnostic nomogram in the training and validation sets were 0.702 and 0.688, respectively, the AUCs of prognostic nomogram in the training set for 1-, 3-, and 5-year were 0.70, 0.72, and 0.75, respectively, while in the validation set the AUCs were 0.71, 0.75, and 0.79, respectively. The calibration curves and DCA of the two nomograms were consistent and the clinical benefit rate was high.
Conclusion: Cachexia brings an additional economic burden and worsens the prognosis of lung cancer patients. The two nomograms can accurately screen and predict the probability of occurrence of cachexia in lung cancer and the prognosis of patients with lung cancer cachexia, and guide clinical work.

Keywords:  Inflammation; cachexia; lung cancer; nomogram; nutrition; prognosis

DOI:  https://doi.org/10.3389/fonc.2022.890745
Int J Mol Sci. 2022 Jul 14. pii: 7774. [Epub ahead of print]23(14):

Efficacy of Combined Use of Everolimus and Second-Generation Pan-EGRF Inhibitors in KRAS Mutant Non-Small Cell Lung Cancer Cell Lines.

Renato José da Silva-Oliveira, Izabela Natalia Faria Gomes, Luciane Sussuchi da Silva, André van Helvoort Lengert, Ana Carolina Laus, Matias Eliseo Melendez, Carla Carolina Munari, Fernanda de Paula Cury, Giovanna Barbarini Longato, Rui Manuel Reis.

   BACKGROUND: EGFR mutations are present in approximately 15-50% of non-small cell lung cancer (NSCLC), which are predictive of anti-EGFR therapies. At variance, NSCLC patients harboring KRAS mutations are resistant to those anti-EGFR approaches. Afatinib and allitinib are second-generation pan-EGFR drugs, yet no predictive biomarkers are known in the NSCLC context. In the present study, we evaluated the efficacy of pan-EGFR inhibitors in a panel of 15 lung cancer cell lines associated with the KRAS mutations phenotype.
METHODS: KRAS wild-type sensitive NCI-H292 cell line was further transfected with KRAS mutations (p.G12D and p.G12S). The pan-EGFR inhibitors' activity and biologic effect of KRAS mutations were evaluated by cytotoxicity, MAPK phospho-protein array, colony formation, migration, invasion, and adhesion. In addition, in vivo chicken chorioallantoic membrane assay was performed in KRAS mutant cell lines. The gene expression profile was evaluated by NanoString. Lastly, everolimus and pan-EGFR combinations were performed to determine the combination index.
RESULTS: The GI50 score classified two cell lines treated with afatinib and seven treated with allitinib as high-sensitive phenotypes. All KRAS mutant cell lines demonstrated a resistant profile for both therapies (GI50 < 30%). The protein array of KRAS edited cells indicated a significant increase in AKT, CREB, HSP27, JNK, and, importantly, mTOR protein levels compared with KRAS wild-type cells. The colony formation, migration, invasion, adhesion, tumor perimeter, and mesenchymal phenotype were increased in the H292 KRAS mutated cells. Gene expression analysis showed 18 dysregulated genes associated with the focal adhesion-PI3K-Akt-mTOR-signaling correlated in KRAS mutant cell lines. Moreover, mTOR overexpression in KRAS mutant H292 cells was inhibited after everolimus exposure, and sensitivity to afatinib and allitinib was restored.
CONCLUSIONS: Our results indicate that allitinib was more effective than afatinib in NSCLC cell lines. KRAS mutations increased aggressive behavior through upregulation of the focal adhesion-PI3K-Akt-mTOR-signaling in NSCLC cells. Significantly, everolimus restored sensibility and improved cytotoxicity of EGFR inhibitors in the KRAS mutant NSCLC cell lines.

Keywords:  KRAS mutations; NSCLC; afatinib; allitinib; everolimus; mTOR; pan-EGFR

DOI:  https://doi.org/10.3390/ijms23147774
Cells. 2022 Jul 21. pii: 2257. [Epub ahead of print]11(14):

Interleukin-11: A Potential Biomarker and Molecular Therapeutic Target in Non-Small Cell Lung Cancer.

Jason Hongting Leung, Benjamin Ng, Wei-Wen Lim.

  Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer and is a fast progressive disease when left untreated. Identification of potential biomarkers in NSCLC is an ongoing area of research that aims to detect, diagnose, and prognosticate patients early to optimize treatment. We review the role of interleukin-11 (IL11), a stromal-cell derived pleiotropic cytokine with profibrotic and cellular remodeling properties, as a potential biomarker in NSCLC. This review identifies the need for biomarkers in NSCLC, the potential sources of IL11, and summarizes the available information leveraging upon published literature, publicly available datasets, and online tools. We identify accumulating evidence suggesting IL11 to be a potential biomarker in NSCLC patients. Further in-depth studies into the pathophysiological effects of IL11 on stromal-tumor interaction in NSCLC are warranted and current available literature highlights the potential value of IL11 detection as a diagnostic and prognostic biomarker in NSCLC.

Keywords:  biomarkers; cytokines; interleukin-11; non-small cell lung cancer

DOI:  https://doi.org/10.3390/cells11142257
Biomark Res. 2022 Jul 29. 10(1): 55

Blood-based tumour mutation index act as prognostic predictor for immunotherapy and chemotherapy in non-small cell lung cancer patients.

Jun Lu, Jun Wu, Yuqing Lou, Qin Shi, Jun Xu, Lele Zhang, Wei Nie, Jie Qian, Yanan Wang, Yanwei Zhang, Jing Jiao, Xueyan Zhang, Wei Zhang, Huimin Wang, Tianqing Chu, Hua Zhong, Baohui Han.

   BACKGROUND: Circulating tumour DNA (ctDNA)-based sequencing might provide a simple test for the stratified model of non-small cell lung cancer (NSCLC). Here, we aimed to assess the ctDNA sequencing-based tumour mutation index (TMI) model for screening responders (from non-responders) among NSCLC patients who received monotherapy with docetaxel or atezolizumab.
METHODS: We performed a retrospective analysis of the POPLAR (NCT01903993) and OAK (NCT02008227) trials. We identified three biomarkers, blood tumour mutation burden (bTMB), sensitive blood tumour mutation burden (sbTMB) and unfavourable mutation score (UMS), of the ctDNA profiles. After integrating the advantages and disadvantages of the three independent biomarkers, we developed the TMI model and identified NSCLC patients who may benefit from monotherapy with docetaxel or atezolizumab in terms of overall survival (OS).
RESULTS: The TMI model as a stratified biomarker for docetaxel responders provided a median OS duration of 5.55 months longer than non-responders in the OAK cohort, with a significantly decreased hazard ratio (HR). Moreover, atezolizumab responders had a 10.21-month OS advantage over atezolizumab non-responders in the OAK cohort via TMI stratification, and the HR was also decreased significantly. The TMI demonstrated effectiveness for stratifying responders in the POPLAR cohort. Importantly, we found that the TMI model could screen additional responders upon combining the cohorts from the POPLAR and OAK trials after adjustment.
CONCLUSION: In the present study, we provide a novel TMI model for screening responders (from non-responders) among NSCLC patients who received the 2nd-line monotherapy with docetaxel or atezolizumab. We believe that the biomarker TMI will potentially be effective for the clinical treatment of NSCLC in the future.

Keywords:  Circulating tumour DNA; Liquid biopsy; Non-small cell lung cancer; Precision therapy; Tumour mutation index

DOI:  https://doi.org/10.1186/s40364-022-00400-5