Clinical Advancement of Biomarkers for Precise Lung Cancer Therapy: Challenges and Strategies

Snur Rasool Abdullah; Roshna Hiwa Hady; Kamaran Younis Mohammadamin; Hazha Jamal Hidayat; Zanko Hassan Jawhar

doi:10.21271/ZJPAS.38.2.1

Authors

Snur Rasool Abdullah 1Department of Medical Laboratory Science, College of Health Sciences, Lebanese French University, Kurdistan Region, Erbil, Iraq 2Department of Biology, College of Education, Salahaddin University-Erbil,Erbil, Kurdistan Region, Iraq
Roshna Hiwa Hady Department of Pharmacy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
Kamaran Younis Mohammadamin Department of Chemistry, College of Education, Salahaddin University-Erbil, Erbil, Kurdistan Region,Iraq.
Hazha Jamal Hidayat Department of Biology, College of Education, Salahaddin University-Erbil,Erbil, Kurdistan Region, Iraq
Zanko Hassan Jawhar Department of Medical Laboratory Science, College of Health Sciences, Lebanese French University, Kurdistan Region, Erbil, Iraq

DOI:

https://doi.org/10.21271/ZJPAS.38.2.1

Keywords:

Lung Cancer, Biomarkers, Challenges, Strategies, Therapeutic Target

Abstract

Lung cancer (LC) remains one of the key factors contributing to cancer-related deaths globally, necessitating precise and personalized therapeutic approaches. The clinical management of LC has been markedly advanced with the identification and incorporation of biomarkers, facilitating more accurate and individualized treatment strategies. Biomarkers are essential for directing targeted therapeutic approaches, selecting immunotherapy, and predicting prognosis. The usage of genetic-based biomarkers, including the identification of driver mutations, has incredibly generated genotype-directed therapy and constructed altering LC treatment from cytotoxic chemotherapy into targeted and individualized therapy. They have become essential tools for managing LC, enabling focused treatments, and bettering patient outcomes. Despite the considerable promise of biomarker-driven precision medicine, substantial challenges remain to be addressed. These challenges include the genetic heterogeneity of LC, the variability in the sensitivity and specificity of biomarker assays, and the complexity of incorporating biomarker data into clinical decision-making. However, many biomarkers lack the necessary sensitivity and specificity for early-stage LC detection, and the emergence of these biomarkers remains poorly understood. Thus, in this study, in order to fully exploit the capabilities of these advancements, continuous research efforts should prioritize addressing the constraints of existing methods, creating reliable techniques that involve several biomarkers, and guaranteeing the widespread availability of advanced diagnostic tools.

References

ABDULLAH-ZAWAWI, M.-R., MOHAMAD-MOKHTAR, M.-F., SYAFRUDDIN, S. E., IBRAHIM, F. F., ROSE, I. M., HARUN, R. & MURAD, N. A. A. 2023. miR-99a-5p and miR-148a-3p as Candidate Molecular Biomarkers for the Survival of Lung Cancer Patients. Malaysian Applied Biology, 52, 87-100.

AHMED, N. 2023. Harnessing the power of genomic sequencing in cancer research. The Cancer Research Review, 1, 41-50.

ALREHAILI, A. A., GHARIB, A. F., ALGHAMDI, S. A., ALHAZMI, A., AL-SHEHRI, S. S., HAGAG, H. M., ALSAEEDI, F. A., ALHUTHALI, H. M., RAAFAT, N. & ETEWA, R. L. 2023. Evaluation of TET Family Gene Expression and 5-Hydroxymethylcytosine as Potential Epigenetic Markers in Non-small Cell Lung Cancer. in vivo, 37, 445-453.

BABAYEV, M. & SILVEYRA, P. 2022. Role of Non-Coding RNAs in Lung Cancer.

BALGKOURANIDOU, I., LILOGLOU, T. & LIANIDOU, E. S. 2013. Lung cancer epigenetics: emerging biomarkers. Biomarkers in medicine, 7, 49-58.

BARAN, K. & BRZEZIAŃSKA-LASOTA, E. 2021. Proteomic biomarkers of non-small cell lung cancer patients. Advances in Respiratory Medicine, 89, 419-426.

BARDONI, C., SPAGGIARI, L. & BERTOLACCINI, L. 2024. Artificial intelligence in lung cancer. Annals of Translational Medicine.

BARIONI, C. T. S., DE BARROS WANDRESEN, R. P., PEREIRA, L. F., COIMBRA, A. F., KUBO, B. B. D. A. O. & DA CUNHA, R. C. 2024. Artificial Intelligence for the Identification of Biomarkers in Cancer Prevention and Diagnosis: Advances and Perspectives. Revista Brasileira de Cancerologia, 70.

BASRA, J. K., GUPTA, E., SAINI, M. & CHHABRA, A. Lung Cancer Diagnosis Using Deep Convolutional Neural Network. Proceedings of the International Health Informatics Conference: IHIC 2022, 2023. Springer, 365-380.

BERLAND, L., HEEKE, S., HUMBERT, O., MACOCCO, A., LONG-MIRA, E., LASSALLE, S., LESPINET-FABRE, V., LALVÉE, S., BORDONE, O. & COHEN, C. 2019. Current views on tumor mutational burden in patients with non-small cell lung cancer treated by immune checkpoint inhibitors. Journal of thoracic disease, 11, S71.

BIERNACKA, A., TSONGALIS, P. D., PETERSON, J. D., DE ABREU, F. B., BLACK, C. C., GUTMANN, E. J., LIU, X., TAFE, L. J., AMOS, C. I. & TSONGALIS, G. J. 2016. The potential utility of re-mining results of somatic mutation testing: KRAS status in lung adenocarcinoma. Cancer genetics, 209, 195-198.

BLANDIN KNIGHT, S., CROSBIE, P. A., BALATA, H., CHUDZIAK, J., HUSSELL, T. & DIVE, C. 2017. Progress and prospects of early detection in lung cancer. Open biology, 7, 170070.

BOYLE, P., CHAPMAN, C., HOLDENRIEDER, S., MURRAY, A., ROBERTSON, C., WOOD, W., MADDISON, P., HEALEY, G., FAIRLEY, G. & BARNES, A. 2011. Clinical validation of an autoantibody test for lung cancer. Annals of Oncology, 22, 383-389.

CALLES, A., LIAO, X., SHOLL, L. M., RODIG, S. J., FREEMAN, G. J., BUTANEY, M., LYDON, C., DAHLBERG, S. E., HODI, F. S. & OXNARD, G. R. 2015. Expression of PD-1 and its ligands, PD-L1 and PD-L2, in smokers and never smokers with KRAS-mutant lung cancer. Journal of thoracic oncology, 10, 1726-1735.

CAMMARATA, G., DE MIGUEL-PEREZ, D., RUSSO, A., PELEG, A., DOLO, V., ROLFO, C. & TAVERNA, S. 2022. Emerging noncoding RNAs contained in extracellular vesicles: rising stars as biomarkers in lung cancer liquid biopsy. Therapeutic Advances in Medical Oncology, 14, 17588359221131229.

CASAGRANDE, G. M. S., SILVA, M. D. O., REIS, R. M. & LEAL, L. F. 2023. Liquid biopsy for lung cancer: up-to-date and perspectives for screening programs. International Journal of Molecular Sciences, 24, 2505.

CASTIGLIONI, I., GALLIVANONE, F., SODA, P., AVANZO, M., STANCANELLO, J., AIELLO, M., INTERLENGHI, M. & SALVATORE, M. 2019. AI-based applications in hybrid imaging: how to build smart and truly multi-parametric decision models for radiomics. European Journal of Nuclear Medicine and Molecular Imaging, 46, 2673-2699.

CHARKIEWICZ, R., SULEWSKA, A., MROZ, R., CHARKIEWICZ, A., NAUMNIK, W., KRASKA, M., GYENESEI, A., GALIK, B., JUNTTILA, S. & MISKIEWICZ, B. 2023. Serum Insights: Leveraging the Power of miRNA Profiling as an Early Diagnostic Tool for Non-Small Cell Lung Cancer. Cancers, 15, 4910.

CHEN, D., MA, W., KE, Z. & XIE, F. 2018. CircRNA hsa_circ_100395 regulates miR-1228/TCF21 pathway to inhibit lung cancer progression. Cell Cycle, 17, 2080-2090.

CHEN, K., HE, Y., WANG, W., YUAN, X., CARBONE, D. P. & YANG, F. 2024. Development of new techniques and clinical applications of liquid biopsy in lung cancer management. Science Bulletin.

CHEN, N., FANG, W., LIN, Z., PENG, P., WANG, J., ZHAN, J., HONG, S., HUANG, J., LIU, L. & SHENG, J. 2017. KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma. Cancer Immunology, Immunotherapy, 66, 1175-1187.

CHEN, S., LI, C., QIN, Z., SONG, L., ZHANG, S., SUN, C., ZHUANG, P., WANG, Y., YANG, B. & NING, L. 2023. Serum metabolomic profiles for distinguishing lung cancer from pulmonary tuberculosis: identification of rapid and noninvasive biomarker. The Journal of Infectious Diseases, jiad175.

CHIMBANGU, C. T., YA, Z., XI, L., JIAYUE, Z., XIAO, M., YING, W., XINGXU, Y. & LIU, X. 2023. Promising response of dabrafenib, trametinib, and osimertinib combination therapy for concomitant BRAF and EGFR-TKI resistance mutations. Anti-Cancer Drugs, 10.1097.

CHMIELEWSKA, I., KRAWCZYK, P., GRENDA, A., WÓJCIK-SUPERCZYŃSKA, M., KRZYŻANOWSKA, N., GIL, M. & MILANOWSKI, J. 2023. Breaking the ‘Undruggable’Barrier: Anti-PD-1/PD-L1 Immunotherapy for Non-Small Cell Lung Cancer Patients with KRAS Mutations—A Comprehensive Review and Description of Single Site Experience. Cancers, 15, 3732.

CHO, W. C., WONG, C. F., LI, K. P., FONG, A. H., FUNG, K. Y. & AU, J. S. 2023. miR-145 as a Potential Biomarker and Therapeutic Target in Patients with Non-Small Cell Lung Cancer. International Journal of Molecular Sciences, 24, 10022.

COHEN, R., COLLE, R., PUDLARZ, T., HERAN, M., DUVAL, A., SVRCEK, M. & ANDRÉ, T. 2021. Immune checkpoint inhibition in metastatic colorectal cancer harboring microsatellite instability or mismatch repair deficiency. Cancers, 13, 1149.

DAHABREH, I. J., LINARDOU, H., SIANNIS, F., KOSMIDIS, P., BAFALOUKOS, D. & MURRAY, S. 2010. Somatic EGFR mutation and gene copy gain as predictive biomarkers for response to tyrosine kinase inhibitors in non–small cell lung cancer. Clinical Cancer Research, 16, 291-303.

DAJAC, J., KAMDAR, J., MOATS, A. & NGUYEN, B. 2016. To screen or not to screen: low dose computed tomography in comparison to chest radiography or usual care in reducing morbidity and mortality from lung cancer. Cureus, 8.

DARVISH, M., TRASK, R., TALLON, P., KHANSARI, M., REN, L., HERSHMAN, M. & YOUSEFI, B. 2024. AI-Enabled Lung Cancer Prognosis. arXiv preprint arXiv:2402.09476.

DE GRAMONT, A., WATSON, S., ELLIS, L. M., RODÓN, J., TABERNERO, J., DE GRAMONT, A. & HAMILTON, S. R. 2015. Pragmatic issues in biomarker evaluation for targeted therapies in cancer. Nature reviews Clinical oncology, 12, 197-212.

DEMIRCI, N. Y. 2023. Diagnostic Workup for Lung Cancer. Airway diseases. Springer.

DESCOURT, R., GREILLIER, L., PEROL, M., RICORDEL, C., AULIAC, J.-B., FALCHERO, L., GERVAIS, R., VEILLON, R., VIEILLOT, S. & GUISIER, F. 2023. First-line single-agent pembrolizumab for PD-L1-positive (tumor proportion score≥ 50%) advanced non-small cell lung cancer in the real world: impact in brain metastasis: a national French multicentric cohort (ESCKEYP GFPC study). Cancer Immunology, Immunotherapy, 72, 91-99.

DONG, A., ZHAO, Y., LI, Z. & HU, H. 2021. PD‐L1 versus tumor mutation burden: Which is the better immunotherapy biomarker in advanced non‐small cell lung cancer? The Journal of Gene Medicine, 23, e3294.

DOVAL, D., DESAI, C. & SAHOO, T. 2019. Molecularly targeted therapies in non-small cell lung cancer: The evolving role of tyrosine kinase inhibitors. Indian journal of cancer, 56, S23-S30.

DU, Y., ZHANG, S., LIANG, T., SHANG, J., GUO, C., LIAN, J., GONG, H., YANG, J. & NIU, G. 2023. Dynamic contrast-enhanced MRI perfusion parameters are imaging biomarkers for angiogenesis in lung cancer. Acta Radiologica, 64, 572-580.

DUFFY, M. J. 2024. Circulating tumor DNA (ctDNA) as a biomarker for lung cancer: Early detection, monitoring and therapy prediction. Tumor Biology, 46, S283-S295.

FAN, W.-B., LI, M., MIAO, H., LI, K.-B., DING, F., ZHANG, Y.-Q., JIN, S. & CHENG, W. 2023. Altered Piwi-RNA Profiles of Peripheral Blood in Bone Metastasis of Non-Small Cell Lung Cancer.

FAROOQ, M. & HERMAN, J. G. 2020. Noninvasive diagnostics for early detection of lung cancer: challenges and potential with a focus on changes in DNA methylation. Cancer Epidemiology, Biomarkers & Prevention, 29, 2416-2422.

FENG, L., FENG, Z., HU, J., GAO, J., LI, A., HE, X., LIU, L. & SHEN, Z. 2023a. Identification of hsa-miR-619-5p and hsa-miR-4454 in plasma-derived exosomes as a potential biomarker for lung adenocarcinoma. Frontiers in Genetics, 14, 1138230.

FENG, Y., ZHANG, T., ZHANG, Z., LIANG, Y., WANG, H., CHEN, Y., YU, X., SONG, X., MAO, Q. & XIA, W. 2023b. The super-enhancer-driven lncRNA LINC00880 acts as a scaffold between CDK1 and PRDX1 to sustain the malignance of lung adenocarcinoma. Cell Death & Disease, 14, 551.

FILIPSKA, M. & ROSELL, R. 2021. Mutated circulating tumor DNA as a liquid biopsy in lung cancer detection and treatment. Molecular Oncology, 15, 1667-1682.

FISTE, O., GKIOZOS, I., CHARPIDOU, A. & SYRIGOS, N. K. 2024. Artificial Intelligence-Based Treatment Decisions: A New Era for NSCLC. Cancers, 16, 831.

GANDARA, D. R., PAUL, S. M., KOWANETZ, M., SCHLEIFMAN, E., ZOU, W., LI, Y., RITTMEYER, A., FEHRENBACHER, L., OTTO, G. & MALBOEUF, C. 2018. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nature medicine, 24, 1441-1448.

GAO, Y., YANG, J., CAI, Y., FU, S., ZHANG, N., FU, X. & LI, L. 2018. IFN‐γ‐mediated inhibition of lung cancer correlates with PD‐L1 expression and is regulated by PI3K‐AKT signaling. International journal of cancer, 143, 931-943.

GHAFOURI-FARD, S., SHOOREI, H., OSKUEI, S. D., HUSSEN, B. M., ABDULLAH, S. R., TAHERI, M. & JAMALI, E. 2023. The interaction between miRNAs and hazardous materials. Non-coding RNA Research.

GHOSSEIN, J., GINGRAS, S. & ZENG, W. 2023. Differentiating primary from secondary lung cancer with FDG PET/CT and extra-pulmonary tumor grade. Journal of Medical Imaging and Radiation Sciences.

GOYETTE, M.-A., LIPSYC-SHARF, M. & POLYAK, K. 2023. Clinical and translational relevance of intratumor heterogeneity. Trends in Cancer, 9, 726-737.

HANSSEN, A., WAGNER, J., GORGES, T. M., TAENZER, A., UZUNOGLU, F. G., DRIEMEL, C., STOECKLEIN, N. H., KNOEFEL, W. T., ANGENENDT, S. & HAUCH, S. 2016. Characterization of different CTC subpopulations in non-small cell lung cancer. Scientific reports, 6, 28010.

HONG, S., CHEN, N., FANG, W., ZHAN, J., LIU, Q., KANG, S., HE, X., LIU, L., ZHOU, T. & HUANG, J. 2016. Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: Implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients. Oncoimmunology, 5, e1094598.

HU, H., JIANG, L., KANG, X., ZHANG, L. & ZENG, S. 2023. Extracellular vesicles derived from lung cancer cells promote the progression of lung cancer by delivering miR-151a-5p. Experimental Cell Research, 425, 113526.

HUSSEN, B. M., ABDULLAH, S. R., RASUL, M. F., JAWHAR, Z. H., FARAJ, G. S. H., KIANI, A. & TAHERI, M. 2023a. MiRNA-93: a novel signature in human disorders and drug resistance. Cell Communication and Signaling, 21, 79.

HUSSEN, B. M., ABDULLAH, S. T., ABDULLAH, S. R., YOUNIS, Y. M., HIDAYAT, H. J., RASUL, M. F. & MOHAMADTAHR, S. 2023b. Exosomal non-coding RNAs: Blueprint in colorectal cancer metastasis and therapeutic targets. Non-coding RNA Research.

HUSSEN, B. M., SALEEM, S. J., ABDULLAH, S. R., MOHAMADTAHR, S., HIDAYAT, H. J., RASUL, M. F., TAHERI, M. & KIANI, A. 2023c. Current landscape of miRNAs and TGF‐β signaling in lung cancer progression and therapeutic targets. Molecular and Cellular Probes, 72, 101929.

IKEDA, Y., MORIKAWA, S., NAKASHIMA, M., YOSHIKAWA, S., TANIGUCHI, K., SAWAMURA, H., SUGA, N., TSUJI, A. & MATSUDA, S. 2023. CircRNAs and RNA-Binding Proteins Involved in the Pathogenesis of Cancers or Central Nervous System Disorders. Non-coding RNA, 9, 23.

IYER, S., PRAJAPATI, R., RAMESH, A., BASAVALINGEGOWDA, M., TODUR, S., KAVISHVAR, S., VIJAYKUMAR, R., NAIK, R., KULKARNI, P. & BHATT, A. D. 2019. The future of lung cancer therapy: Striding beyond conventional EGFR and ALK treatments. Molecular and Clinical Oncology, 10, 469-475.

JAMAL-HANJANI, M., WILSON, G. A., MCGRANAHAN, N., BIRKBAK, N. J., WATKINS, T. B., VEERIAH, S., SHAFI, S., JOHNSON, D. H., MITTER, R. & ROSENTHAL, R. 2017. Tracking the evolution of non–small-cell lung cancer. New England Journal of Medicine, 376, 2109-2121.

JIANG, F., HUANG, X., LING, L., TANG, S., ZHOU, H., CAI, X. & WANG, Y. 2023. Long Noncoding RNA ZBED5-AS1 Facilitates Tumor Progression and Metastasis in Lung Adenocarcinoma via ZNF146/ATR/Chk1 Axis. International Journal of Molecular Sciences, 24, 13925.

KHODADOUST, A., NASIRIZADEH, N., SEYFATI, S. M., TAHERI, R. A., GHANEI, M. & BAGHERI, H. 2023. High-performance strategy for the construction of electrochemical biosensor for simultaneous detection of miRNA-141 and miRNA-21 as lung cancer biomarkers. Talanta, 252, 123863.

KOH, Y., YAGI, S., AKAMATSU, H., KANAI, K., HAYATA, A., TOKUDOME, N., AKAMATSU, K., HIGUCHI, M., KANBARA, H. & NAKANISHI, M. 2019. Heterogeneous expression of programmed death receptor-ligand 1 on circulating tumor cells in patients with lung cancer. Clinical Lung Cancer, 20, 270-277. e1.

KUMAR, K. R., COWLEY, M. J. & DAVIS, R. L. Next-generation sequencing and emerging technologies. Seminars in thrombosis and hemostasis, 2024. Thieme Medical Publishers.

KUMAR, S., GAUR, V., MIR, I. A., SAIKIA, J. & KUMAR, S. 2023. MicroRNA-3692-3p is overexpressed in lung tumors but may not serve as a prognostic biomarker in lung cancer patients. Molecular Biology Reports, 50, 1147-1156.

LAFON, M., COUSIN, S., ALAMÉ, M., NOUGARET, S., ITALIANO, A. & CROMBÉ, A. 2024. Metastatic Lung Adenocarcinomas: Development and Evaluation of Radiomic-Based Methods to Measure Baseline Intra-Patient Inter-Tumor Lesion Heterogeneity. Journal of Imaging Informatics in Medicine, 1-17.

LAI, I.-L., YANG, C.-A., LIN, P.-C., CHAN, W.-L., LEE, Y.-T., YEN, J.-C., CHANG, Y.-S. & CHANG, J.-G. 2017. Long noncoding RNA MIAT promotes non-small cell lung cancer proliferation and metastasis through MMP9 activation. Oncotarget, 8, 98148.

LAN, Y., MOUSTAFA, M., KNOLL, M., XU, C., FURKEL, J., LAZORCHAK, A., YEUNG, T.-L., HASHEMINASAB, S.-M., JENKINS, M. H. & MEISTER, S. 2021. Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion. Cancer Cell, 39, 1388-1403. e10.

LANGEVIN, S. M., KRATZKE, R. A. & KELSEY, K. T. 2015. Epigenetics of lung cancer. Translational Research, 165, 74-90.

LEIGHL, N. B., PAGE, R. D., RAYMOND, V. M., DANIEL, D. B., DIVERS, S. G., RECKAMP, K. L., VILLALONA-CALERO, M. A., DIX, D., ODEGAARD, J. I. & LANMAN, R. B. 2019. Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non–small cell lung cancer. Clinical cancer research, 25, 4691-4700.

LI, J., WANG, N., ZHANG, F., JIN, S., DONG, Y., DONG, X., CHEN, Y., KONG, X., TONG, Y. & MI, Q. 2021. PIWI‐interacting RNAs are aberrantly expressed and may serve as novel biomarkers for diagnosis of lung adenocarcinoma. Thoracic cancer, 12, 2468-2477.

LI, W., LIU, J.-B., HOU, L.-K., YU, F., ZHANG, J., WU, W., TANG, X.-M., SUN, F., LU, H.-M. & DENG, J. 2022. Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring. Molecular cancer, 21, 25.

LIAO, Y., WU, X., WU, M., FANG, Y., LI, J. & TANG, W. 2022. Non-coding RNAs in lung cancer: emerging regulators of angiogenesis. Journal of Translational Medicine, 20, 1-11.

LINDEMAN, N. I., CAGLE, P. T., AISNER, D. L., ARCILA, M. E., BEASLEY, M. B., BERNICKER, E. H., COLASACCO, C., DACIC, S., HIRSCH, F. R. & KERR, K. 2018. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Archives of pathology & laboratory medicine, 142, 321-346.

LIU, Y., FAN, X., JIANG, C. & XU, S. 2023. SPOCK2 and SPRED1 function downstream of EZH2 to impede the malignant progression of lung adenocarcinoma in vitro and in vivo. Human Cell, 36, 812-821.

LOK, B. H., GARDNER, E. E., SCHNEEBERGER, V. E., NI, A., DESMEULES, P., REKHTMAN, N., DE STANCHINA, E., TEICHER, B. A., RIAZ, N. & POWELL, S. N. 2017. PARP inhibitor activity correlates with SLFN11 expression and demonstrates synergy with temozolomide in small cell lung cancer. Clinical Cancer Research, 23, 523-535.

LU, S., WU, L., JIAN, H., CHENG, Y., WANG, Q., FANG, J., WANG, Z., HU, Y., HAN, L. & SUN, M. 2023. Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial. The Lancet Respiratory Medicine.

LUCÀ, S., ZANNINI, G., MORGILLO, F., DELLA CORTE, C. M., FIORELLI, A., ZITO MARINO, F., CAMPIONE, S., VICIDOMINI, G., GUGGINO, G. & RONCHI, A. 2023. The prognostic value of histopathology in invasive lung adenocarcinoma: a comparative review of the main proposed grading systems. Expert review of anticancer therapy, 23, 265-277.

MANOLAKOS, P. & WARD, L. D. 2023. A Critical Review of the Prognostic and Predictive Implications of KRAS and STK11 Mutations and Co-Mutations in Metastatic Non-Small Lung Cancer. Journal of Personalized Medicine, 13, 1010.

MARIÑO-ENRÍQUEZ, A. & DAL CIN, P. 2013. ALK as a paradigm of oncogenic promiscuity: different mechanisms of activation and different fusion partners drive tumors of different lineages. Cancer genetics, 206, 357-373.

MARTINS, T. S., VAZ, M. & HENRIQUES, A. G. 2023. A review on comparative studies addressing exosome isolation methods from body fluids. Anal Bioanal Chem, 415, 1239-1263.

MESSNER, C. B., DEMICHEV, V., WANG, Z., HARTL, J., KUSTATSCHER, G., MÜLLEDER, M. & RALSER, M. 2023. Mass spectrometry‐based high‐throughput proteomics and its role in biomedical studies and systems biology. Proteomics, 23, 2200013.

MOURKSI, N.-E.-H., MORIN, C., FENOUIL, T., DIAZ, J.-J. & MARCEL, V. 2020. snoRNAs offer novel insight and promising perspectives for lung cancer understanding and management. Cells, 9, 541.

NKOSI, D., GEORGE, G. V., LIU, H., BULDO, M., VELEZ, M. J. & OLTVAI, Z. N. 2023. Efficient Lung Cancer Molecular Diagnostics by Combining Next Generation Sequencing with Reflex Idylla Genefusion Assay Testing. Genes, 14, 1551.

NOGUEIRA JORGE, N. A., WAJNBERG, G., FERREIRA, C. G., DE SA CARVALHO, B. & PASSETTI, F. 2017. snoRNA and piRNA expression levels modified by tobacco use in women with lung adenocarcinoma. PLoS One, 12, e0183410.

OBEID, J. & DAMAGHI, M. 2024. Metabolic adaptation and epigenetic modulations: Unraveling tumor plasticity under variable tumor microenvironment. Cancer Epigenetics and Nanomedicine. Elsevier.

OSHIMA, Y., HARUKI, T., MATSUI, S., MAKISHIMA, K., SAKABE, T., UMEKITA, Y. & NAKAMURA, H. 2023. Clinical significance of MYC family protein expression in surgically resected high‐grade neuroendocrine carcinoma of the lung. Thoracic Cancer, 14, 758-765.

PACHIKA, P., VALASAPALLI, S., NGO, P. & KLOECKER, G. 2024. The Use of Artificial Intelligence in Lung Cancer Management. AI in Precision Oncology, 1, 33-42.

PAHUJA, K. B., NGUYEN, T. T., JAISWAL, B. S., PRABHASH, K., THAKER, T. M., SENGER, K., CHAUDHURI, S., KLJAVIN, N. M., ANTONY, A. & PHALKE, S. 2018. Actionable activating oncogenic ERBB2/HER2 transmembrane and juxtamembrane domain mutations. Cancer cell, 34, 792-806. e5.

PANTEL, K. & ALIX-PANABIÈRES, C. 2010. Circulating tumour cells in cancer patients: challenges and perspectives. Trends in molecular medicine, 16, 398-406.

PANTEL, K. & ALIX-PANABIÈRES, C. 2017. Circulating tumour cells and cell-free DNA in gastrointestinal cancer. Nature Reviews Gastroenterology & Hepatology, 14, 73-74.

PARRA-MEDINA, R., CASTAÑEDA-GONZÁLEZ, J. P., MONTOYA, L., GÓMEZ-GÓMEZ, M. P., CABEZAS, D. C. & VARGAS, M. P. 2023. Prevalence Of Oncogenic Driver Mutations in Hispanics/Latin Patients With Lung Cancer. A Systematic Review and Meta-Analysis. Lung Cancer, 107378.

PASSARO, A., AL BAKIR, M., HAMILTON, E. G., DIEHN, M., ANDRÉ, F., ROY-CHOWDHURI, S., MOUNTZIOS, G., WISTUBA, I. I., SWANTON, C. & PETERS, S. 2024. Cancer biomarkers: Emerging trends and clinical implications for personalized treatment. Cell, 187, 1617-1635.

PEI, X., CHEN, S.-W., LONG, X., ZHU, S.-Q., QIU, B.-Q., LIN, K., LU, F., XU, J.-J., ZHANG, P.-F. & WU, Y.-B. 2020. circMET promotes NSCLC cell proliferation, metastasis, and immune evasion by regulating the miR-145-5p/CXCL3 axis. Aging (Albany NY), 12, 13038.

PENNELL, N. A., ARCILA, M. E., GANDARA, D. R. & WEST, H. 2019. Biomarker testing for patients with advanced non–small cell lung cancer: real-world issues and tough choices. American Society of Clinical Oncology Educational Book, 39, 531-542.

PISHKO, G. L., MULDOON, L. L., PAGEL, M. A., SCHWARTZ, D. L. & NEUWELT, E. A. 2015. Vascular endothelial growth factor blockade alters magnetic resonance imaging biomarkers of vascular function and decreases barrier permeability in a rat model of lung cancer brain metastasis. Fluids and Barriers of the CNS, 12, 1-10.

PROIETTO, M., CRIPPA, M., DAMIANI, C., PASQUALE, V., SACCO, E., VANONI, M. & GILARDI, M. 2023. Tumor heterogeneity: preclinical models, emerging technologies, and future applications. Frontiers in Oncology, 13, 1164535.

RAJURKAR, S., MAMBETSARIEV, I., PHARAON, R., LEACH, B., TAN, T., KULKARNI, P. & SALGIA, R. 2020. Non-small cell lung cancer from genomics to therapeutics: A framework for community practice integration to arrive at personalized therapy strategies. Journal of Clinical Medicine, 9, 1870.

RASTOGI, A., YADAV, K., MISHRA, A., SINGH, M. S., CHAUDHARY, S., MANOHAR, R. & PARMAR, A. S. 2022. Early diagnosis of lung cancer using magnetic nanoparticles-integrated systems. Nanotechnology Reviews, 11, 544-574.

REINA, C., ŠABANOVIĆ, B., LAZZARI, C., GREGORC, V. & HEESCHEN, C. 2024. Unlocking the future of cancer diagnosis–promises and challenges of ctDNA-based liquid biopsies in non-small cell lung cancer. Translational Research.

REN, M., HONG, M., LIU, G., WANG, H., PATEL, V., BIDDINGER, P., SILVA, J., COWELL, J. & HAO, Z. 2013. Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1. Oncology Reports, 29, 2181-2190.

RENAUT, S., SAAVEDRA ARMERO, V., BOUDREAU, D. K., GAUDREAULT, N., DESMEULES, P., THÉRIAULT, S., MATHIEU, P., JOUBERT, P. & BOSSÉ, Y. 2024. Single-cell and single-nucleus RNA-sequencing from paired normal-adenocarcinoma lung samples provide both common and discordant biological insights. PLoS Genetics, 20, e1011301.

RODRÍGUEZ, M., AJONA, D., SEIJO, L. M., SANZ, J., VALENCIA, K., CORRAL, J., MESA-GUZMÁN, M., PÍO, R., CALVO, A. & LOZANO, M. D. 2021. Molecular biomarkers in early stage lung cancer. Translational lung cancer research, 10, 1165.

RUSSANO, M., LA CAVA, G., CORTELLINI, A., CITARELLA, F., GALLETTI, A., DI FAZIO, G. R., SANTO, V., BRUNETTI, L., VENDITTELLI, A. & FIORONI, I. 2023. Immunotherapy for Metastatic Non-Small Cell Lung Cancer: Therapeutic Advances and Biomarkers. Current Oncology, 30, 2366-2387.

SAKAI, H., TAKEDA, M., SAKAI, K., NAKAMURA, Y., ITO, A., HAYASHI, H., TANAKA, K., NISHIO, K. & NAKAGAWA, K. 2019. Impact of cytotoxic chemotherapy on PD-L1 expression in patients with non–small cell lung cancer negative for EGFR mutation and ALK fusion. Lung Cancer, 127, 59-65.

SAMAN, H., RAZA, A., PATIL, K., UDDIN, S. & CRNOGORAC-JURCEVIC, T. 2022. Non-invasive biomarkers for early lung cancer detection. Cancers, 14, 5782.

SANTARPIA, M., LIGUORI, A., D’AVENI, A., KARACHALIOU, N., GONZALEZ-CAO, M., DAFFINÀ, M. G., LAZZARI, C., ALTAVILLA, G. & ROSELL, R. 2018. Liquid biopsy for lung cancer early detection. Journal of thoracic disease, 10, S882.

SATAM, H., JOSHI, K., MANGROLIA, U., WAGHOO, S., ZAIDI, G., RAWOOL, S., THAKARE, R. P., BANDAY, S., MISHRA, A. K. & DAS, G. 2023. Next-generation sequencing technology: current trends and advancements. Biology, 12, 997.

SCHROEDER, K. E., ACHARYA, L., MANI, H., FURQAN, M. & SIEREN, J. C. 2023. Radiomic biomarkers from chest computed tomography are assistive in immunotherapy response prediction for non-small cell lung cancer. Translational lung cancer research, 12, 1023.

SEIJO, L. M., PELED, N., AJONA, D., BOERI, M., FIELD, J. K., SOZZI, G., PIO, R., ZULUETA, J. J., SPIRA, A. & MASSION, P. P. 2019. Biomarkers in lung cancer screening: achievements, promises, and challenges. Journal of Thoracic Oncology, 14, 343-357.

SEN, T., TONG, P., STEWART, C. A., CRISTEA, S., VALLIANI, A., SHAMES, D. S., REDWOOD, A. B., FAN, Y. H., LI, L. & GLISSON, B. S. 2017. CHK1 inhibition in small-cell lung cancer produces single-agent activity in biomarker-defined disease subsets and combination activity with cisplatin or olaparib. Cancer research, 77, 3870-3884.

SHARMA, P., KUMAR, N., KHANDELWAL, K., CHAND, S. & DHAKA, S. 2024. Biomarkers for disease identification and drug development. Biomarkers in Environmental and Human Health Biomonitoring. Elsevier.

SINGH, A., RAMAKRISHNA, G., KAILA, T., SAXENA, S., SHARMA, S., GAIKWAD, A. B., ABDIN, M. & GAIKWAD, K. 2022. Next-generation sequencing technologies: Approaches and applications for crop improvement. Genomics of Cereal Crops. Springer.

STRANSKY, N., CERAMI, E., SCHALM, S., KIM, J. L. & LENGAUER, C. 2014. The landscape of kinase fusions in cancer. Nature communications, 5, 4846.

SULEWSKA, A., PILZ, L., MANEGOLD, C., RAMLAU, R., CHARKIEWICZ, R. & NIKLINSKI, J. 2023. A Systematic Review of Progress toward Unlocking the Power of Epigenetics in NSCLC: Latest Updates and Perspectives. Cells, 12, 905.

SUNG, H.-J., AHN, J.-M., YOON, Y.-H., RHIM, T.-Y., PARK, C.-S., PARK, J.-Y., LEE, S.-Y., KIM, J.-W. & CHO, J.-Y. 2011. Identification and validation of SAA as a potential lung cancer biomarker and its involvement in metastatic pathogenesis of lung cancer. Journal of proteome research, 10, 1383-1395.

TAKEDA, M., OKAMOTO, I. & NAKAGAWA, K. 2015. Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer, 88, 74-79.

TALWELKAR, S. S., MÄYRÄNPÄÄ, M. I., SCHÜLER, J., LINNAVIRTA, N., HEMMES, A., ADINOLFI, S., KANKAINEN, M., SOMMERGRUBER, W., LEVONEN, A. L. & RÄSÄNEN, J. 2023. PI3Kβ inhibition enhances ALK‐inhibitor sensitivity in ALK‐rearranged lung cancer. Molecular oncology, 17, 747-764.

TIAN, Y., XU, J., CHU, Q., DUAN, J., ZHANG, J., BAI, H., YANG, Z., FANG, W., CAI, L. & WAN, R. 2020. A novel tumor mutational burden estimation model as a predictive and prognostic biomarker in NSCLC patients. BMC medicine, 18, 1-11.

TIJHUIS, A. E. & FOIJER, F. 2024. Characterizing chromosomal instability-driven cancer evolution and cell fitness at a glance. Journal of Cell Science, 137, jcs260199.

TREICHLER, G., HOELLER, S., RUESCHOFF, J., RECHSTEINER, M., BRITSCHGI, C., ARNOLD, F., ZOCHE, M., HILTBRUNNER, S., MOCH, H. & AKHOUNDOVA, D. 2023. Improving the turnaround time of molecular profiling for advanced non-small cell lung cancer: Outcome of a new algorithm integrating multiple approaches. Pathology-Research and Practice, 248, 154660.

TROTTER, J., PANTEL, A. R., TEO, B.-K. K., ESCORCIA, F. E., LI, T., PRYMA, D. A. & TAUNK, N. K. 2023. Positron Emission Tomography (PET)/Computed Tomography (CT) Imaging in Radiation Therapy Treatment Planning: A Review of PET Imaging Tracers and Methods to Incorporate PET/CT. Advances in Radiation Oncology, 8.

VITALE, I., SHEMA, E., LOI, S. & GALLUZZI, L. 2021. Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nature medicine, 27, 212-224.

WANG, C., TAN, S., LI, J., LIU, W.-R., PENG, Y. & LI, W. 2020a. CircRNAs in lung cancer-Biogenesis, function and clinical implication. Cancer letters, 492, 106-115.

WANG, H.-L., WANG, H.-R., LIANG, Y., HU, A.-N., ENGUITA, F. J., ZHOU, X.-G. & DONG, J. 2020b. Hsa_circ_0006571 promotes spinal metastasis through sponging microRNA-138 to regulate sirtuin 1 expression in lung adenocarcinoma. Translational Lung Cancer Research, 9, 2411.

WANG, J., HE, X., YAO, Q., WANG, C., LU, X., WANG, R. & MIAO, D. 2023. LncRNA PTTG3P promotes tumorigenesis and metastasis of NSCLC by binding with ILF3 to maintain mRNA stability and form a positive feedback loop with E2F1. International Journal of Biological Sciences, 19, 4291.

WANG, M. 2021. Next-generation sequencing (NGS). Clinical Molecular Diagnostics, 305-327.

WANG, Y., LI, Y., HE, H. & WANG, F. 2019. Circular RNA circ-PRMT5 facilitates non-small cell lung cancer proliferation through upregulating EZH2 via sponging miR-377/382/498. Gene, 720, 144099.

WU, Y., LIU, H., SHI, X., YAO, Y., YANG, W. & SONG, Y. 2015. The long non-coding RNA HNF1A-AS1 regulates proliferation and metastasis in lung adenocarcinoma. Oncotarget, 6, 9160.

XIAO, H., SHI, Z., ZOU, Y., XU, K., YU, X., WEN, L., LIU, Y., CHEN, H., LONG, H. & CHEN, J. 2023. One-off low-dose CT screening of positive nodules in lung cancer: A prospective community-based cohort study. Lung Cancer, 177, 1-10.

XIAO, L., WANG, J., JU, S., CUI, M. & JING, R. 2022. Disorders and roles of tsRNA, snoRNA, snRNA and piRNA in cancer. Journal of Medical Genetics, 59, 623-631.

XIN, L., YUE, Y., ZIHAN, R., YOUBIN, C., TIANYU, L. & RUI, W. 2023. Clinical application of liquid biopsy based on circulating tumor DNA in non-small cell lung cancer. Frontiers in Physiology, 14, 1200124.

XU, Y., DONG, X., QIN, C., WANG, F., CAO, W., LI, J., YU, Y., ZHAO, L., TAN, F. & CHEN, W. 2023. Metabolic biomarkers in lung cancer screening and early diagnosis. Oncology Letters, 25, 1-11.

YAN, E., GOYAL, G., YILDIZ, U. H., BOEHM, B. O. & PALANIAPPAN, A. 2023. Colorimetric assaying of exosomal metabolic biomarkers. Molecules, 28, 1909.

YAN, X. & LIU, C. 2023. Clinical application and prospect of MRD evaluation in lung cancer based on ctDNA level: A review. Tumori Journal, 109, 356-362.

YANG, B., ZHAO, F., YAO, L., ZONG, Z. & XIAO, L. 2021a. CircRNA circ_0006677 inhibits the progression and glycolysis in non–small-cell lung cancer by sponging miR-578 and regulating SOCS2 expression. Frontiers in Pharmacology, 12, 657053.

YANG, L., WANG, J., FAN, Y., YU, K., JIAO, B. & SU, X. 2018. Hsa_circ_0046264 up-regulated BRCA2 to suppress lung cancer through targeting hsa-miR-1245. Respiratory research, 19, 1-13.

YANG, M., SHI, L., HUANG, T., LI, G., SHAO, H., SHEN, Y., ZHU, J. & NI, B. 2023. Value of contrast-enhanced magnetic resonance imaging-T2WI-based radiomic features in distinguishing lung adenocarcinoma from lung squamous cell carcinoma with solid components> 8 mm. Journal of Thoracic Disease, 15, 635.

YANG, S., BÖGELS, B. W., WANG, F., XU, C., DOU, H., MANN, S., FAN, C. & DE GREEF, T. F. 2024. DNA as a universal chemical substrate for computing and data storage. Nature Reviews Chemistry, 8, 179-194.

YANG, S., TALBI, A., WANG, X., SONG, H. & CHEN, X. 2014. Pharmacokinetics study of calf thymus DNA in rats and beagle dogs with 3H-labeling and tracing method. Journal of Pharmaceutical and Biomedical Analysis, 88, 60-65.

YANG, X., ZHANG, Y., ZHANG, Y., ZHANG, S., QIU, L., ZHUANG, Z., WEI, M., DENG, X., WANG, Z. & HAN, J. 2021b. The Key Role of Exosomes on the Pre-metastatic Niche Formation in Tumors. Front Mol Biosci, 8, 703640.

YE, Z. & GUO, J. 2023. Acquired ALK G1202R-, ALK I1171N-, or EML4-ALK-mediated resistance to ensartinib in lung adenocarcinoma but responded to lorlatinib: A case report. Frontiers in Oncology, 13, 1082115.

YONESHIMA, Y., IJICHI, K., ANAI, S., OTA, K., OTSUBO, K., IWAMA, E., TANAKA, K., ODA, Y., NAKANISHI, Y. & OKAMOTO, I. 2018. PD-L1 expression in lung adenocarcinoma harboring EGFR mutations or ALK rearrangements. Lung Cancer, 118, 36-40.

YU, L., SHEN, J., MANNOOR, K., GUARNERA, M. & JIANG, F. 2014. Identification of ENO1 as a potential sputum biomarker for early-stage lung cancer by shotgun proteomics. Clinical lung cancer, 15, 372-378. e1.

YUAN, D.-F., WANG, H.-R., WANG, Z.-F., LIANG, G.-H., XING, W.-Q. & QIN, J.-J. 2021. CircRNA CircZMYM4 inhibits the growth and metastasis of lung adenocarcinoma via the miR-587/ODAM pathway. Biochemical and biophysical research communications, 580, 100-106.

ZHANG, B., LIU, Y., ZHOU, S., JIANG, H., ZHU, K. & WANG, R. 2020. Predictive effect of PD-L1 expression for immune checkpoint inhibitor (PD-1/PD-L1 inhibitors) treatment for non-small cell lung cancer: A meta-analysis. International immunopharmacology, 80, 106214.

ZHANG, C., LENG, W., SUN, C., LU, T., CHEN, Z., MEN, X., WANG, Y., WANG, G., ZHEN, B. & QIN, J. 2018. Urine proteome profiling predicts lung cancer from control cases and other tumors. EBioMedicine, 30, 120-128.

ZHANG, F., CHENG, R., LI, P., LU, C. & ZHANG, G. 2021. Hsa_circ_0010235 functions as an oncogenic drive in non-small cell lung cancer by modulating miR-433-3p/TIPRL axis. Cancer Cell International, 21, 1-14.

ZHANG, P.-F., PEI, X., LI, K.-S., JIN, L.-N., WANG, F., WU, J. & ZHANG, X.-M. 2019. Circular RNA circFGFR1 promotes progression and anti-PD-1 resistance by sponging miR-381-3p in non-small cell lung cancer cells. Molecular Cancer, 18, 1-13.

ZHENG, B., PENG, M., GONG, J., LI, C., CHENG, H., LI, Y. & TANG, Y. 2023. Circulating exosomal microRNA-4497 as a potential biomarker for metastasis and prognosis in non-small-cell lung cancer. Experimental Biology and Medicine, 248, 1403-1413.

ZHONG, Y., CAI, C., CHEN, T., GUI, H., CHEN, C., DENG, J., YANG, M., YU, B., SONG, Y. & WANG, T. 2023. PET/CT-based deep learning grading signature to optimize surgical decisions for clinical stage I invasive lung adenocarcinoma and biologic basis under its prediction: a multicenter study. European Journal of Nuclear Medicine and Molecular Imaging, 1-14.

ZHOU, Y., SHI, H., DU, Y., ZHAO, G., WANG, X., LI, Q., LIU, J., YE, L., SHEN, Z. & GUO, Y. 2019. lncRNA DLEU2 modulates cell proliferation and invasion of non-small cell lung cancer by regulating miR-30c-5p/SOX9 axis. Aging (Albany NY), 11, 7386.

ZHU, L., SUN, L., XU, G., SONG, J., HU, B., FANG, Z., DAN, Y., LI, N. & SHAO, G. 2022. The diagnostic value of has_circ_0006423 in non-small cell lung cancer and its role as a tumor suppressor gene that sponges miR-492. Scientific Reports, 12, 13722.

ZHUO, T., WU, Z., YANG, C., LI, Z., HUANG, H., GAN, J., LI, N., LI, X., LYU, J. & WU, Y. 2023. lncRNA CERS6-AS1 promotes cell proliferation, migration, invasion, and epithelial-mesenchymal transformation of lung adenocarcinoma by sponging miR-424-5p upregulates ANLN expression.