Baudo, Massimo

Mutti, Luciano

Rahouma, Mohamed

Zhang, Jun

Frontiers in Oncology

English

Lirias

Editorial: Prognostic factors in non-small cell lung cancer

IRIS Università degli Studi dell'Aquila

Frontiers in OncologyOPEN ACCESSEDITED AND REVIEWED BYLizza E.L. Hendriks,Maastricht University Medical Centre,Netherlands*CORRESPONDENCEMohamed RahoumaMmr2011@med.cornell.edumhmdrahouma@gmail.com†These authors have contributed equally tothis workSPECIALTY SECTIONThis article was submitted toThoracic Oncology,a section of the journalFrontiers in OncologyRECEIVED 26 February 2023ACCEPTED 06 March 2023PUBLISHED 14 March 2023CITATIONRahouma M, Baudo M, Zhang J and Mutti L(2023) Editorial: Prognostic factors in non-small cell lung cancer.Front. Oncol. 13:1174625.doi: 10.3389/fonc.2023.1174625COPYRIGHT© 2023 Rahouma, Baudo, Zhang and Mutti.This is an open-access article distributedunder the terms of the Creative CommonsAttribution License (CC BY). The use,distribution or reproduction in otherforums is permitted, provided the originalauthor(s) and the copyright owner(s) arecredited and that the original publication inthis journal is cited, in accordance withaccepted academic practice. No use,distribution or reproduction is permittedwhich does not comply with these terms.TYPE EditorialPUBLISHED 14 March 2023DOI 10.3389/fonc.2023.1174625Editorial: Prognostic factors innon-small cell lung cancerMohamed Rahouma1,2*†, Massimo Baudo1,3†, Jun Zhang4,5and Luciano Mutti6,71Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, United States,2Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt,3Department of Cardiac Surgery, Spedali Civili di Brescia, Brescia, Italy, 4Division of Medical Oncology,Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, United States,5Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, United States,6Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College ofScience and Technology, Temple University, Philadelphia, PA, United States, 7Department of AppliedClinical Sciences and Biotechnology, L’Aquila University, L’Aquila, ItalyKEYWORDSimmune checkpoint inhibitors, prognosis, survival, immunotherapy, lung cancer,noncoding RNAEditorial on the Research TopicPrognostic factors in non-small cell lung cancerLung cancer is the most frequent cause of cancer deaths, and non-small-cell lungcancer (NSCLC) accounts for 85% of all lung cancer cases (1). In 2023, 1,958,310 newcancer cases and 609,820 cancer deaths are projected to occur in the United States,including approximately 350 deaths per day from lung cancer (2). It is the second mostfrequently diagnosed cancer in both males and females, while the first for number of deathsin both sexes (2). Besides and in comparison to the most common cancers, malignancy-associated suicide risk is the highest among patients with lung cancer, particularly elderly,widowed, male patients and patients with unfavorable tumor characteristics (3). Currently,different cancer treatment options are available such as surgery, chemotherapy,radiotherapy, targeted therapy, immunotherapy, or combination of these. However,there are many patients who receive therapy from which the benefit is minimal or evenabsent, whilst they do experience treatment-related toxicity. This has raised the need toimprove the outcomes by selecting the best patient for an anticancer treatment throughprognostic and predictive biomarkers investigation especially in the current personalizedmedicine era. Prognostic factors provide information about the patients’ overall canceroutcome, regardless of therapy. On the other hand, a predictive biomarker givesinformation about the effect of a therapeutic intervention, i.e. the treatment benefit (4).This Research Topic in Frontiers in Oncology “Prognostic Factors in Non-Small CellLung Cancer” comes to shed light on potential treatment target for NSCLC through theidentification of the• prognostic value of tumor pathological characteristics,• prognostic gene signatures,• non-coding RNAs (ncRNA) as prognostic biomarkers, and• immune-related prognostic biomarkers.frontiersin.org01Rahouma et al. 10.3389/fonc.2023.1174625A total of 12 studies analyzed non-coding RNA as possibleprognostic biomarkers (Chen et al., Chen et al., Duan et al., Jianget al., Jiang et al., Li et al., Li et al., Li et al., Tang et al., Wang et al.,Weng et al., Yuan et al.). Long non-coding RNAs (lncRNAs) are aparticular type of RNA transcripts that don’t code for proteins butare involved in the regulation of critical biological processes andcellular behavior (5). Besides, lncRNAs influence gene expressionand have essential roles in carcinogenesis (6). MicroRNA (miRNA)refers to a class of short endogenously ncRNAs that negativelyregulate mRNA expression by binding the complementarysequences in the target genes’ 3′-untranslated region (7). Similarto lncRNA, miRNA was shown to be of paramount importance incancer development and progression. Both these forms of ncRNAinteract and compete with each other as competing endogenousRNA (ceRNA) to indirectly regulate downstream target mRNAexpression (8).Our current Research Topic identified various lncRNAs (Chenet al., Jiang et al., Li et al., Li et al., Weng et al.) and miRNA (Duanet al., Jiang et al.), whose up- or down-regulation in cancer tissuecompared to normal tissue were associated with adverse clinicaloutcomes and prognostic models were built upon. Interestingly, fivepapers (Chen et al., Li et al., Tang et al., Wang et al., Yuan et al.)were able to analyze the ceRNA network (lncRNA-miRNA-mRNA)demonstrating high performance in predicting the survival andchemotherapeutic responses of low- and high-risk patients.The focus of other 12 papers were the genes and related codedproteins. Elevated expression levels of phosphoenolpyruvatecarboxykinase 1 (Shao et al), ASPM, CCNB2, CDCA5, PRC1,KIAA0101, and UBE2T (Chen et al.), soluble Programmed DeathLigand 1 (PD-L1) (Liao et al.), HMMR (Jiang et al.), four particulargenes in the 7-methylguanosine-related gene signatures (Lu et al),eighteen endoplasmic reticulum stress-related genes (Shu et al.), twoM2 macrophage-related genes (GRIA1 and CLEC3B) (Xu et al.), andExtra Spindle Pole Bodies-Like 1 (Nie et al.) were associated withpoorer overall survival. On the other hand, lower expression levels ofTTN (Chen et al.) was also associated with worse survival. Of note,Prelaj et al. published the first case of a patient affected by metastaticNSCLC harboring an EGFR exon 20 insertion mutation who achieveda complete response under treatment with poziotinib. This affirms thatcertain mutations such as EGFR exon20ins has predictive value incertain targeted therapy.Two cell death paths were further investigated: ferroptosis andcuproptosis. Ferroptosis is a type of oxidative cell death presented inneurological disorders, blood diseases, and tumors that has beenproposed as a promising target for killing cancer cells that areresistant to conventional treatment. In their paper, Wang et al.constructed a predictive model of ferroptosis related gene showingthat the low-risk group in their model might profit more fromimmune checkpoint inhibitors. On the other hand, cuproptosis is anovel programmed cell death pathway different from apoptosis andcharacterized by mitochondrial copper-dependent functionaldestruction. Wu et al. were able to construct a nomogram forpredicting patients’ prognosis from cuproptosis-associated clusters.As far as pathological features, new insights on patients’subdivision were analyzed. Morphological changes in the bronchialepithelium (e.g. basal cell hyperplasia, squamous cell metaplasia, andFrontiers in Oncology 02dysplasia) away from tumor foci were associated with a high-risk ofdistant metastasis and less 5-year metastasis-free survival (Pankovaet al.). Besides, tumor-related atelectasis was associated with shorteroverall survival (Wang et al.), while adjuvant chemotherapy seems tobe beneficial in the survival of stage I lung adenocarcinoma patientswith tumor spread through air spaces after resection (Xie et al.).Patients with rib and parietal pleura invasion were also assessed.Patients with rib invasion had poorer survival than those with theinvasion of parietal pleura. In addition, in the cohort for parietalpleura invasion, patients were further classified by tumor size andpatients with tumor size >5cm had less satisfactory survival outcomesthan those with tumor size ≤5cm (Wu et al.). The development of anomogram of patients with stage I to IIIA NSCLC using machinelearning based on radiomic features extracted from computedtomography images and clinicopathological factors suggested thatstage IIB -IIIA patients didn’t show any statistically significantdifference in the survival rate, irrespective of administration ofadjuvant chemotherapy, while stage I-IIA patients displayed apoorer prognosis in patients who had received chemotherapy(Yang et al.). This is arguably not in line with most of theguidelines, and might be related to the technique of analysis usedby the authors therefore remains debatable. Of note, Meng et al.analyzed and developed a nomogram model in patients for lungadenocarcinoma (LUAD) with 1 to 5 bone-only metastases, reportingthat adding alkaline phosphatase, albumin and leukocyte wouldimprove the predictive accuracy of survival. The prognosis of non-small cell lung cancer patients with central nervous system (CNS)metastasis is poor and the study by Gao et al. deepened theknowledge of this subset of lung cancer patients. They observedthat patients with ≥5 CNS metastases or that were developed duringtreatment were independent risk factors for poor survival. However,radiotherapy for CNS metastasis showed a survival benefit in theentire group, and in patients with driver mutations that can be treatedby available targeted therapy such as EGFR, ALK, ROS-1, RET, andother mutations. Despite occurring mostly in the salivary glands,mucoepidermoid carcinoma may occur also in the lungs. Whenanalyzing pulmonary mucoepidermoid carcinoma, stage IV, degreeof differentiation (high grade), and lymph node metastasis wereassociated with worse survival (Li et al.).Finally, some papers in this Research Topic evaluated differenttherapeutic strategies or analyzed their outcomes. Luo et al. investigatedthe adjuvant use of Chinese herbal medicines preparations in thetreatment of primary NSCLC. Although Chinese herbal medicines arequite often used in China, such treatments are unlikely to begeneralized in other countries, therefore data interpretation has to becareful. PD-1/PD-L1 immune-checkpoint blockade is becoming widelyused for metastatic NSCLC. Nevertheless, the pathway inhibited bythese drugs is a biological mechanism that prevents autoimmunitywhen prolonged and/or repeated exposure to the same antigens occurs(9, 10). Fameli et al. reported in their single-cell cytometry study thatthere is an increase in antinuclear antibodies (ANAs) and extractablenuclear antigen (ENA) antibodies, and that the increased immune-related adverse events were associated with the deregulation of specificimmune subpopulations. Ma et al. constructed a nomogram based onpatients with metastatic LUAD undergoing primary surgery and threedifferent risk groups could be identified based on the risk score that wasfrontiersin.orgRahouma et al. 10.3389/fonc.2023.1174625constructed using age, gender, primary location, N stage, bonemetastasis, liver metastasis, radiotherapy, and chemotherapy.The brief overview of the articles included in this ResearchTopic provides important updates regarding prognostic factors inNSCLC from new ncRNAs and their interaction with the relatedgenes, possible subclassification of patients by pathological features,and new insights of current therapies. Eventually it results in aparticularly intriguing question regarding how to apply noveltechniques, e.g. machine learning and radiomics possesses toimprove the current clinical practice.Author contributionsAll Authors (MR, MB, JZ, LM) participated in writing, editingand reviewing the final manuscript.Frontiers in Oncology 03Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.References1. Duma N, Santana-Davila R, Molina JR. Non-small cell lung cancer:Epidemiology, screening, diagnosis, and treatment. Mayo Clin Proc (2019) 94:1623–40. doi: 10.1016/j.mayocp.2019.01.0132. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer JClin (2023) 73:17–48. doi: 10.3322/caac.217633. Rahouma M, Kamel M, Abouarab A, Eldessouki I, Nasar A, Harrison S, et al. Lungcancer patients have the highest malignancy-associated suicide rate in USA: A population-based analysis. Ecancermedicalscience (2018) 12:859. doi: 10.3332/ecancer.2018.8594. Oldenhuis CN a. M, Oosting SF, Gietema JA, de Vries EGE. Prognostic versuspredictive value of biomarkers in oncology. Eur J Cancer Oxf Engl 1990 (2008) 44:946–53. doi: 10.1016/j.ejca.2008.03.0065. Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis andfunction. Nat Rev Genet (2016) 17:47–62. doi: 10.1038/nrg.2015.106. Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology.Cancer Discovery (2011) 1:391–407. doi: 10.1158/2159-8290.CD-11-02097. Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell(2004) 116:281–97. doi: 10.1016/S0092-8674(04)00045-58. Yang C, Wu D, Gao L, Liu X, Jin Y, Wang D, et al. Competing endogenous RNAnetworks in human cancer: Hypothesis, validation, and perspectives. Oncotarget (2016)7:13479–90. doi: 10.18632/oncotarget.72669. He X, Xu C. Immune checkpoint signaling and cancer immunotherapy. Cell Res(2020) 30:660–9. doi: 10.1038/s41422-020-0343-410. Rahouma M, Baudo M, Kamel M, Abdel Karim N, Altorki N. Anti-PDL1 effectin squamous non-small cell lung cancer. Transl Lung Cancer Res (2020) 9:406–9.doi: 10.21037/tlcr.2020.02.06frontiersin.org

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Editorial: Prognostic factors in non-small cell lung cancer

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