Predictive Biomarkers in Lung Cancer

  • Reinhard BuettnerEmail author


Lung cancer is traditionally classified as small cell carcinoma (SCLC) and non-small cell carcinoma (NSCLC). Although advances in SCLC have been limited, NSCLC has become a paradigm for personalized oncology as practically all treatment decisions depend on biomarkers selecting patients for enhanced response to targeted therapies by tyrosine kinase or immune checkpoint inhibitors. As such, targeted therapies are usually more effective and less toxic than conventional combined chemotherapies as they target specific vulnerabilities of lung cancers. As a consequence survival of patients with advanced lung cancers is increasing for the first time in history.

In principle, tumors driven by single activated oncogenes, such as mutated EGFR, BRAF, or gene fusions of ALK or ROS kinases, are highly sensitive to kinase-specific inhibitors. As they typically reveal flat genomes (i.e., tumors without large number of mutations), they lack presentation of manifold tumor (neo)antigens, and hence they do not benefit from therapies with immune checkpoint inhibitors. Rather, these tumors need surveillance under therapy, and once acquired resistance emerges, second- or third-line TKIs overcoming resistance are being administered.

In contrast, tumors harboring high mutational load (referred as high TMB, tumor mutational burden) in their genomes, such as smoking-related NSCLC, frequently present many tumor (neo)antigens and require masking from immune surveillance by presentation of PD-L1 to the adaptive immune system or by other mechanisms. Therapies with immune checkpoint inhibitors have reached clinical practice, and tumors presenting high levels of PD-L1 on their surface are now been treated by PD1 monoclonal antibodies in first line. In comparison with conventional chemotherapy, these therapies revealed enhanced overall survival (OS), enhanced overall response rates (ORR), prolonged progression-free survival (PFS), and better quality of life (QoL). Thus, all therapeutic decisions in lung cancer from first line to second line depend critically on the measurement of biomarkers from tumor tissue or from circulating tumor cell DNA.


Lung cancer therapy EGFR mutation ALK fusion ROS1 fusion PD-L1 score in lung cancer 


  1. 1.
    American Cancer Society. (2016). Cancer facts & figures 2016. Accessed 13 Dec 2016.
  2. 2.
    Reck M, Rodríguez-Abreu D, Robinson AG et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016. Scholar
  3. 3. Identifier: NCT02477826.
  4. 4.
    Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013;24:2371–6. Scholar
  5. 5.
    Postmus PE, Kerr KM, Oudkerk M, Senan S, Waller DA, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv1–21. Scholar
  6. 6.
    Lindeman NI, Cagle PT, Aisner DL, Arcila ME, Beasley MB, Bernicker E, Colasacco C, Dacic S, Hirsch FR, Kerr K, Kwiatkowski DJ, Ladanyi M, Nowak JA, Sholl L, Temple-Smolkin R, Solomon B, Souter LH, Thunnissen E, Tsao MS, Ventura CB, Wynes MW, Yatabe Y. 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. Arch Pathol Lab Med. 2018, in press. 2018 Jan 22. [Epub ahead of print].CrossRefGoogle Scholar
  7. 7.
    Seidel D, et al. A genomics-based classification of human lung tumors. Sci Transl Med. 2013;5(209):209ra153. Scholar
  8. 8.
    Pasi A, Jänne MD, Yang JC-H, Kim D-W, Planchard D, Ohe Y, et al. AZD9291 in EGFR inhibitor–resistant non–small-cell lung cancer. N Engl J Med. 2015;372:1689–99. Scholar
  9. 9.
    Crino L, Ahn MJ, De Marinis F, Groen HJM, Wakelee H, Hida T, et al. Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non–small-cell lung cancer previously treated with chemotherapy and crizotinib: results from ASCEND-2. J Clin Oncol. 2016;34:2866–73. Scholar
  10. 10.
    Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Presented at: ESMO Congress. Madrid. 2017. 9–12 September 2017. Abstract LBA2_PR.Google Scholar
  11. 11.
    Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer. N Engl J Med. 2017;377:829–38. Scholar
  12. 12.
    Büttner R, Gosney JR, Skov BG, Adam J, Motoi N, Bloom KJ, Dietel M, Longshore JW, López-Ríos F, Penault-Llorca F, Viale G, Wotherspoon AC, Kerr KM, Tsao MS. Programmed death-ligand 1 immunohistochemistry testing: a review of analytical assays and clinical implementation in non-small-cell lung cancer. JCO. 2017. PMID: 29053400.CrossRefPubMedGoogle Scholar
  13. 13.
    Schallenberg S, Merkelbach-Bruse S Buettner R. Lung cancer as a paradigm for precision oncology in lung cancer. Virchows Arch. 2017 (in press).Google Scholar
  14. 14.
    Nogova L, Sequist LV, Perez Garcia JM, Andre F, Delord JP, Hidalgo M, Schellens JH, Cassier PA, Camidge DR, Schuler M, Vaishampayan U, Burris H, Tian GG, Campone M, Wainberg ZA, Lim WT, LoRusso P, Shapiro GI, Parker K, Chen X, Choudhury S, Ringeisen F, Graus-Porta D, Porter D, Isaacs R, Buettner R, Wolf J. Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol: JCO. 2016. 2016672048. [Epub ahead of print]. PMID:27870574.
  15. 15.
    Meder L, König K, Fassunke J, Ozretić L, Wolf J, Merkelbach-Bruse S, et al. Implementing amplicon-based next generation sequencing in the diagnosis of small cell lung carcinoma metastases. Exp Mol Pathol. 2015;99(3):6826. PMID:26546837CrossRefGoogle Scholar
  16. 16.
    Scheel AH, Dietel M, Heukamp LC, et al. Harmonized PD-L1 immunohistochemistry for pulmonary squamous-cell and adenocarcinomas. Mod Pathol. 2016;29(10):1165–72. Scholar
  17. 17.
    Rudin CM, Pietanza MC, Bauer TM, Ready N, Morgensztern D, Glisson BS, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study.; SCRX16-001 investigators. Lancet Oncol. 2017;18(1):42–51. Epub 2016 Dec 5.CrossRefPubMedGoogle Scholar
  18. 18.
    Sharma P, Callahan MK, Bono P, Kim J, Spiliopoulou P, Calvo E, et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol. 2016;17(11):1590–8. Epub 2016 Oct 9.CrossRefPubMedCentralPubMedGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of PathologyUniversity Hospital CologneCologneGermany

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