bims-meluca 2023-08-27 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–08–27
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Real world prognostic utility of platelet lymphocyte ratio and nutritional status in first-line immunotherapy response in stage IV non-small cell lung cancer.
Prognostic Potential of the Prognostic Nutritional Index in Non-Small Cell Lung Cancer Patients Receiving Pembrolizumab Combination Therapy with Carboplatin and Paclitaxel/Nab-Paclitaxel.
Integration of metabolomics and machine learning revealed tryptophan metabolites are sensitive biomarkers of pemetrexed efficacy in non-small cell lung cancer.
TRIM11 promotes cell proliferation of non-small cell lung cancer through the inhibition of ferroptosis by AMPK.
Exploratory analysis to predict pneumonitis during durvalumab consolidation therapy for patients with locally advanced non-small cell lung cancer from proteomic profiling of circulating extracellular vesicles.
Diagnostic and Prognostic Significance of Serum Biomarkers - Serum Amyloid A and CYFRA 21-1 in Lung Cancer.
DARS2 overexpression is associated with PET/CT metabolic parameters and affects glycolytic activity in lung adenocarcinoma.
The benefit and risk of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small-cell lung cancer: a systematic review and single-arm meta-analysis of prospective clinical trials.
Bintrafusp alfa versus pembrolizumab in patients with treatment-naive, PD-L1-high advanced non-small cell lung cancer: a randomized, open-label, phase 3 trial.

Cancer Treat Res Commun. 2023 Aug 18. pii: S2468-2942(23)00074-6. [Epub ahead of print]36 100752

Real world prognostic utility of platelet lymphocyte ratio and nutritional status in first-line immunotherapy response in stage IV non-small cell lung cancer.

Madeline MacDonald, Darin Poei, Alexis Leyba, Raymond Diep, Krithika Chennapan, Christopher Leon, Bing Xia, Jorge J Nieva, Robert Hsu.

   BACKGROUND: Elevated platelet lymphocyte ratio (PLR) and low body mass index (BMI) are associated with inferior survival in non-small cell lung cancer (NSCLC) patients receiving immunotherapy (IO). We evaluated real-world prognostic utility of PLR, BMI, and albumin level in stage IV NSCLC patients receiving first line (1L) IO.
METHODS: We identified 75 stage IV patients who received 1L IO therapy at USC Norris Comprehensive Cancer Center and Los Angeles General Medical Center from 2015 to 2022. The primary outcome was overall survival (OS) from time of IO with attention to pre-treatment BMI < 22, albumin < 3.5 g/dL, and PLR > 180.
RESULTS: Median age was 66.5 years with 49 (65.3%) males. 25 (33.3%) had BMI < 22. 45/75 (60%) had PLR > 180. Patients with BMI < 22 had inferior OS (13.1 months (m) vs. 37.4 m in BMI > 28, p-value = 0.042) along with patients with albumin<3.5 g/dL (OS: 2.8 m vs. 14.6 m, p-value = 0.0027), and patients with PLR>180 (OS: 8.7 m vs. 23.0 m, p = 0.028). Composite BMI < 22, PLR > 180 had the worst OS, p-value = 0.0331. Multivariate analysis controlling for age, smoking, gender, PD-L1 tumor proportion score (TPS), and histology (adenocarcinoma, squamous, adenosquamous, and large cell) showed that BMI (HR: 0.8726, 95% CI: 0.7892-0.954) and PLR > 180 (HR: 2.48, 95% CI: 1.076-6.055) were significant in OS mortality risk.
CONCLUSION: Patients with a composite of BMI < 22, albumin < 3.5 g/dL, and PLR > 180 had significantly worse OS. This highlights the importance of screening for poor nutritional status and high PLR to better inform stage IV NSCLC patients receiving IO therapy of their prognosis and supportive care.
MICROABSTRACT: We evaluated real-world prognostic utility of platelet lymphocyte ratio (PLR), body mass index (BMI), and albumin level in 75 Stage IV NSCLC patients receiving first line IO. Patients with a composite of BMI < 22, albumin < 3.5 g/dL, and PLR > 180 had significantly worse OS. This highlights the importance of screening for poor nutritional status and high PLR to better inform stage IV NSCLC patients of their prognosis and to emphasize supportive care needs.

Keywords:  BMI; Cachexia; NSCLC; Platelet lymphocyte ratio; Real world

DOI:  https://doi.org/10.1016/j.ctarc.2023.100752
Oncology. 2023 Aug 18.

Prognostic Potential of the Prognostic Nutritional Index in Non-Small Cell Lung Cancer Patients Receiving Pembrolizumab Combination Therapy with Carboplatin and Paclitaxel/Nab-Paclitaxel.

Fuyumi Nishihara-Kato, Hisao Imai, Takeshi Tsuda, Satoshi Wasamoto, Yoshiaki Nagai, Takayuki Kishikawa, Yosuke Miura, Akihiro Ono, Yutaka Yamada, Ken Masubuchi, Takashi Osaki, Junichi Nakagawa, Yukihiro Umeda, Hiroyuki Minemura, Yuki Kozu, Hirokazu Taniguchi, Hiromitsu Ohta, Kyoichi Kaira, Hiroshi Kagamu.

INTRODUCTION: Pembrolizumab (Pemb) therapy in conjunction with carboplatin and paclitaxel (PTX)/nab-PTX has been efficacious in treating non-small-cell lung cancer (NSCLC). However, the response predictors of this combination therapy (Pemb-combination) remain undetermined. We aimed to evaluate whether Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), body mass index (BMI), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI) are potential factors in prognosticating the response to Pemb-combination therapy in advanced NSCLC patients.
METHODS: We retrospectively recruited 144 NSCLC patients receiving first-line treatment with Pemb-combination therapy from 13 institutions between December 1, 2018, and December 31, 2020. GPS, NLR, BMI, PLR, and PNI were assessed for their efficacy as prognostic indicators. Cox proportional hazard models and the Kaplan-Meier method were used to compare the progression-free survival (PFS) and overall survival (OS) of the patients.
RESULTS: The treatment exhibited a response rate of 63.1% (95% confidence interval [CI]: 55.0-70.6%). Following Pemb-combination administration, the median PFS and OS were 7.3 (95% CI: 5.3-9.4) and 16.5 (95% CI: 13.9-22.1) months, respectively. Contrary to PNI, NLR, GPS, BMI, and PLR did not display substantially different PFS in univariate analysis. However, multivariate analysis did not identify PNI as an independent prognostic factor for PFS. Furthermore, univariate analysis revealed that GPS, BMI, and PLR exhibited similar values for OS but not NLR and PNI. Patients with PNI ≥45 were predicted to have better OS than those with PNI <45 (OS: 23.4 and 13.9 months, respectively, p=0.0028). Multivariate analysis did not establish NLR as an independent prognostic factor for OS.
DISCUSSION/CONCLUSION: The PNI evidently predicted OS in NSCLC patients treated with Pemb-combination as first-line therapy, thereby validating its efficiency as a prognostic indicator of NSCLC.

DOI: https://doi.org/10.1159/000533604
Cancer Med. 2023 Aug 21.

Integration of metabolomics and machine learning revealed tryptophan metabolites are sensitive biomarkers of pemetrexed efficacy in non-small cell lung cancer.

Runbin Sun, Fei Fei, Min Wang, Junyi Jiang, Guangyu Yang, Na Yang, Dandan Jin, Zhi Xu, Bei Cao, Juan Li.

   BACKGROUND: Anti-folate drug pemetrexed is a vital chemotherapy medication for non-small cell lung cancer (NSCLC). Its response varies widely and often develops resistance to the treatment. Therefore, it is urgent to identify biomarkers and establish models for drug efficacy evaluation and prediction for rational drug use.
METHODS: A total of 360 subjects were screened and 323 subjects were recruited. Using metabolomics in combination with machine learning methods, we are trying to select potential biomarkers to diagnose NSCLC and evaluate the efficacy of pemetrexed in treating NSCLC. Furtherly, we measured the concentration of eight metabolites in the tryptophan metabolism pathway in the validation set containing 201 subjects using a targeted metabolomics method with UPLC-MS/MS.
RESULTS: In the discovery set containing 122 subjects, the metabolic profile of healthy controls (H), newly diagnosed NSCLC patients (ND), patients who responded well to pemetrexed treatment (S) and pemetrexed-resistant patients (R) differed significantly on the PLS-DA scores plot. Pathway analysis showed that glycine, serine and threonine metabolism occurred in every two group comparisons. TCA cycle, pyruvate metabolism and glycerolipid metabolism are the most significantly changed pathways between ND and H group, pyruvate metabolism was the most altered pathway between S and ND group, and tryptophan metabolism was the most changed pathway between S and R group. We found Random forest method had the maximum area under the curve (AUC) and can be easily interpreted. The AUC is 0.981 for diagnosing patients with NSCLC and 0.954 for evaluating pemetrexed efficiency.
CONCLUSION: We compared eight mathematical models to evaluate pemetrexed efficiency for treating NSCLC. The Random forest model established with metabolic markers tryptophan, kynurenine and xanthurenic acidcan accurately diagnose NSCLC and evaluate the response of pemetrexed.

Keywords:  NSCLC; drug resistance; machine learning; pemetrexed; pharmacometabolomics

DOI:  https://doi.org/10.1002/cam4.6446
Clin Respir J. 2023 Aug 21.

TRIM11 promotes cell proliferation of non-small cell lung cancer through the inhibition of ferroptosis by AMPK.

Zheng Liang, Jian Li, Guoliang Zhang, Menghui Chen.

  Lung cancer is one of the leading causes of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent type. This study investigates the role of TRIM11 gene in NSCLC and its underlying mechanism. NSCLC patients were recruited from our hospital and showed upregulated TRIM11 mRNA and protein expressions. Patients with high TRIM11 expression had lower survival rates. TRIM11 gene was found to promote cell proliferation and reduce ROS-induced ferroptosis in NSCLC. Additionally, TRIM11 gene induced AMPK expression and its regulation affected TRIM11's effects on cell proliferation and ferroptosis in NSCLC. IP analysis revealed that TRIM11 protein interacted with AMPK protein in NSCLC. These data confirmed that TRIM11 promotes cell proliferation and reduces ROS-induced ferroptosis in NSCLC through AMPK. Hence, TRIM11 is a potential target for the treatment of NSCLC and other cancers.

Keywords:  AMPK; TRIM11; ferroptosis; non-small cell lung cancer

DOI:  https://doi.org/10.1111/crj.13675
Thorac Cancer. 2023 Aug 24.

Exploratory analysis to predict pneumonitis during durvalumab consolidation therapy for patients with locally advanced non-small cell lung cancer from proteomic profiling of circulating extracellular vesicles.

Masahiro Torasawa, Hidehito Horinouchi, Shigehiro Yagishita, Hirofumi Utsumi, Keitaro Okuda, Daisuke Takekoshi, Saburo Ito, Hiroshi Wakui, Saori Murata, Sawako Kaku, Kae Okuma, Yuji Matsumoto, Yuki Shinno, Yusuke Okuma, Tatsuya Yoshida, Yasushi Goto, Noboru Yamamoto, Jun Araya, Yuichiro Ohe, Yu Fujita.

   BACKGROUND: Risk factors for predicting pneumonitis during durvalumab consolidation after chemoradiotherapy (CRT) in locally advanced non-small cell lung cancer (LA-NSCLC) are still lacking. Extracellular vesicles (EVs) play a crucial role in intercellular communication and are potential diagnostic tools for various diseases.
METHODS: We retrospectively collected predurvalumab treatment serum samples from patients treated with durvalumab for LA-NSCLC, isolated EVs using anti-CD9 and anti-CD63 antibodies, and performed proteomic analyses. We examined EV proteins that could predict the development of symptomatic pneumonitis (SP) during durvalumab treatment. Potential EV-protein biomarkers were validated in an independent cohort.
RESULTS: In the discovery cohort, 73 patients were included, 49 with asymptomatic pneumonitis (AP) and 24 with SP. Of the 5797 proteins detected in circulating EVs, 33 were significantly elevated (fold change [FC] > 1.5, p < 0.05) in the SP group, indicating enrichment of the nuclear factor kappa B (NF-κB) pathway. Patients with high levels of EV-RELA, an NF-κB subunit, had a higher incidence of SP than those with low levels of EV-RELA (53.8% vs. 13.4%, p = 0.0017). In the receiver operating characteristic analysis, EV-RELA demonstrated a higher area under the curve (AUC) than lung V20 (0.76 vs. 0.62) and was identified as an independent risk factor in the multivariate logistic regression analysis (p = 0.008, odds ratio 7.72). Moreover, high EV-RELA was also a predictor of SP in the validation cohort comprising 43 patients (AUC of 0.80).
CONCLUSIONS: Circulating EV-RELA may be a predictive marker for symptomatic pneumonitis in patients with LA-NSCLC treated with durvalumab.

Keywords:  chemoradiotherapy; durvalumab; extracellular vesicles; pneumonitis

DOI:  https://doi.org/10.1111/1759-7714.15077
Int J Appl Basic Med Res. 2023 Apr-Jun;13(2):13(2): 89-94

Diagnostic and Prognostic Significance of Serum Biomarkers - Serum Amyloid A and CYFRA 21-1 in Lung Cancer.

Yera Dhanurdhar, Suman Kumar Jagaty, Saswat Subhankar, Debasis Behera.

   Introduction: Bronchogenic carcinoma is a leading cause of cancer-related death in men and women. Early diagnosis and treatment in these cases are essential for a better prognosis. Serum biomarkers such as serum amyloid A (SAA) and CYFRA 21-1 have generated encouraging results regarding their use in the diagnosis of these cases but data on their role in the Indian scenario are still lacking.
Aim: The study aims to measure the levels of SAA and CYFRA 21-1 in various types of lung cancer and compare them with patients without lung cancer. It also aims to compare the values of these biomarkers before and after chemotherapy and correlate them with response to treatment.
Materials and Methods: It was a prospective, case-control study conducted in the Department of Pulmonary Medicine, Government Medical College, Chandigarh. All histologically and/or cytologically proven lung cancer cases were included in the study group while patients with diseases other than lung cancer formed the control group. All patients were evaluated through a complete history and thorough clinical examination. Measurement of SAA and CYFRA 21-1 in blood was done by sandwich ELISA method. The patients in the study group were followed up regularly and the biomarkers were measured again after four cycles of chemotherapy. The response of tumors to chemotherapy was evaluated as per modified Response Evaluation Criteria in Solid Tumors criteria. The statistical analysis was carried out using SPSS version 19.0.
Results: The study group and control group included 20 patients each. Hoarseness of voice and hemoptysis were significantly associated with lung cancer patients (P = 0.001 and P = 0.025, respectively). Serum levels above 8745 ng/ml for SAA and 2.55 ng/ml for serum CYFRA 21-1 were used as diagnostic biomarker in lung cancer. The serum levels of CYFRA 21-1 were found to be significantly raised in nonsmall cell carcinoma (NSCLC) in comparison to SCLC of lung. There was a statistically significant decrease in the serum levels of CYFRA 21-1 in lung cancer patients on C4 cycle of chemotherapy in comparison to C1 cycle (P = 0.014).
Conclusion: SAA and CYFRA 21-1 could be valuable diagnostic biomarkers in lung cancer. CYFRA 21-1, in addition, could also be used as prognostic biomarker in lung cancer patients undergoing chemotherapy as it showed significant decrease after C4-cycle of chemotherapy. It can also be a potential biomarker to differentiate small cell and NSCLC.

Keywords:  Biomarkers; Cyfra 21-1; bronchogenic carcinoma; serum amyloid A

DOI:  https://doi.org/10.4103/ijabmr.ijabmr_639_22
J Transl Med. 2023 Aug 26. 21(1): 574

DARS2 overexpression is associated with PET/CT metabolic parameters and affects glycolytic activity in lung adenocarcinoma.

Xu-Sheng Liu, Ling-Ling Yuan, Yan Gao, Xing Ming, Yao-Hua Zhang, Yu Zhang, Zi-Yue Liu, Yi Yang, Zhi-Jun Pei.

   BACKGROUND: This study investigated the correlation between the expression of DARS2 and metabolic parameters of 18F-FDG PET/CT, and explored the potential mechanisms of DARS2 affecting the proliferation and glycolysis of lung adenocarcinoma (LUAD) cells.
METHODS: This study used genomics and proteomics to analyze the difference in DARS2 expression between LUAD samples and control samples. An analysis of 62 patients with LUAD who underwent 18F-FDG PET/CT examinations before surgery was conducted retrospectively. The correlation between DARS2 expression and PET/CT metabolic parameters, including SUVmax, SUVmean, MTV, and TLG, was examined by Spearman correlation analysis. In addition, the molecular mechanism of interfering with DARS2 expression in inhibiting LUAD cell proliferation and glycolysis was analyzed through in vitro cell experiments.
RESULTS: DARS2 expression was significantly higher in LUAD samples than in control samples (p < 0.001). DARS2 has high specificity (98.4%) and sensitivity (95.2%) in the diagnosis of LUAD. DARS2 expression was positively correlated with SUVmax, SUVmean, and TLG (p < 0.001). At the same time, the sensitivity and specificity of SUVmax in predicting DARS2 overexpression in LUAD were 88.9% and 65.9%, respectively. In vitro cell experiments have shown that interfering with DARS2 expression can inhibit the proliferation and migration of LUAD cells, promote cell apoptosis, and inhibit the glycolytic activity of tumor cells by inhibiting the expression of glycolytic related genes SLC2A1, GPI, ALDOA, and PGAM1.
CONCLUSIONS: Overexpression of DARS2 is associated with metabolic parameters on 18F-FDG PET/CT, which can improve LUAD diagnosis accuracy. DARS2 may be a useful biomarker to diagnose, prognosis, and target treatment of LUAD patients.

Keywords:  DARS2; Glycolysis; Lung adenocarcinoma; PET/CT; SUVmax

DOI:  https://doi.org/10.1186/s12967-023-04454-3
Front Immunol. 2023 ;14 1218258

The benefit and risk of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small-cell lung cancer: a systematic review and single-arm meta-analysis of prospective clinical trials.

Shubin Chen, Wanying Mo, Wei Jiang, Shaozhang Zhou, Haijie Gan, Qitao Yu.

   Background: Previous studies revealed that Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus anti-angiogenic agents had extensive anti-tumor activities. However, almost all studies on the efficacy and safety of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small cell lung cancer are non-randomized controlled trials with small sample sizes, which might lead to a lack of effective metrics to assess the effectiveness and safety of the therapeutic regimen. Here, this meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small cell lung cancer.
Methods: A single-arm meta-analysis was performed, and published literature from PubMed, Web of Science and Embase databases as of January 13, 2023, was systematically retrieved. We used the Cochrane risk of bias tool and methodological index for non-randomized studies (MINORS) Methodological items to evaluate the quality of eligible clinical trials. Outcomes including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were extracted for further analysis. The random effect model is used to calculate the pooled parameters.
Results: 19 studies (16 were non-comparative single-arm clinical trials and 3 were randomized controlled trials) were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 22.4% (95% CI, 16.6-28.1%) and 76.8% (95% CI, 72.6-81.1%), respectively. With regard to survival analysis, the pooled PFS and OS were 5.20 (95% CI, 4.46-5.93) months and 14.09 (95% CI, 13.20-14.97) months, respectively. The pooled grade ≥3 adverse effect (AE) rate was 47.6% (95% CI, 33.1-62.0%).
Conclusion: PD-1/PD-L1 inhibitors plus anti-angiogenic agents has promising efficacy and safety as second or later-line treatment in patients with advanced non-small cell lung cancer.
Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023407559.

Keywords:  PD-1/PD-L1 inhibitors; advanced non-small cell lung cancer; anti-angiogenic agents; meta-analysis; second or later-line therapy

DOI:  https://doi.org/10.3389/fimmu.2023.1218258
J Thorac Oncol. 2023 Aug 17. pii: S1556-0864(23)00738-4. [Epub ahead of print]

Bintrafusp alfa versus pembrolizumab in patients with treatment-naive, PD-L1-high advanced non-small cell lung cancer: a randomized, open-label, phase 3 trial.

Byoung Chul Cho, Jong Seok Lee, Yi-Long Wu, Irfan Cicin, Manuel Cobo Dols, Myung-Ju Ahn, Kristof Cuppens, Rémi Veillon, Ernest Nadal, Josiane Mourão Dias, Claudio Martin, Martin Reck, Edward B Garon, Enriqueta Felip, Luis Paz-Ares, Francoise Mornex, Everett E Vokes, Alex A Adjei, Clifford Robinson, Masashi Sato, Yulia Vugmeyster, Andreas Machl, Francois Audhuy, Surendra Chaudhary, Fabrice Barlesi.

   INTRODUCTION: Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking PD-L1, has shown clinical activity in a phase 1 expansion cohort of patients with PD-L1-high, advanced non-small cell lung cancer (NSCLC).
METHODS: This adaptive phase 3 trial (NCT03631706) compared the efficacy and safety of bintrafusp alfa versus pembrolizumab as first-line treatment in patients with PD-L1-high advanced NSCLC. Primary endpoints were progression-free survival (PFS) according to RECIST 1.1 per independent review committee (IRC) and overall survival (OS).
RESULTS: Patients (N=304) were randomized 1:1 to receive either bintrafusp alfa or pembrolizumab (n=152 each). The median follow-up was 14.3 months (95% CI 13.1-16.0 months) for bintrafusp alfa and 14.5 months (95% CI 13.1-15.9 months) for pembrolizumab. PFS by IRC was not significantly different between bintrafusp alfa and pembrolizumab arms (median 7.0 months [95% CI 4.2 months-not reached (NR)] versus 11.1 months [95% CI 8.1 months-NR]; HR=1.232 [95% CI, 0.885-1.714]). Median OS was 21.1 months (95% CI 21.1 months-NR) for bintrafusp alfa and 22.1 months (95% CI: 20.4 months-NR) for pembrolizumab (HR=1.201 [95% CI, 0.796-1.811]). Treatment-related adverse events (TRAEs) were higher with bintrafusp alfa versus pembrolizumab; grade 3/4 TRAEs occurred in 42.4% versus 13.2% of patients, respectively. The study was discontinued at an interim analysis as it was unlikely to meet the primary endpoint.
CONCLUSIONS: First-line treatment with bintrafusp alfa did not demonstrate superior efficacy compared with pembrolizumab in patients with PD-L1-high, advanced NSCLC.

Keywords:  PD-L1; bintrafusp alfa; non-small cell lung cancer; phase 3

DOI:  https://doi.org/10.1016/j.jtho.2023.08.018