Non-invasive approaches for lung cancer diagnosis

  • Aditi MehtaEmail author
  • Guillermo BarretoEmail author
Review Article


Lung cancer is the leading cause of cancer-related deaths worldwide. The case-fatality rate of lung cancer remains exceptionally high at 95% despite numerous medical advancements in therapeutic strategies in the last decades. However, patients diagnosed at Stage I are commonly curable and have a 5-year survival rate of 50–80%. Unfortunately, delayed diagnosis of lung cancer has been unavoidable and is an important factor in the overall outcome of treatment. Accordingly, screening of high-risk individuals is likely to have hugely beneficial outcomes for patient survival. Current screening approaches include low-dose computed tomography and chest X-ray. Recently, alternative approaches for lung cancer screening have been developed including analysis of biomarkers, including DNA, RNA, proteins, and antibodies in blood, sputum, bronchoalveolar lavage (BAL), and breath. Biomarker analysis would also provide critical information regarding tumor growth pattern, cells of origin of tumor, subtype of lung cancer, and/or drug metabolism as well as monitor patient prognosis. Novel non-invasive lung cancer diagnostic strategies could improve and complement the success of CT-scan and chest X-ray.


Lung cancer Diagnosis Non-invasive 



Guillermo Barreto is funded by the “LOEWE-Initiative der Landesförderung” (Wiesbaden Germany) (III L 4–518/15.004 2009) and the “Deutsche Forschungsgemeinschaft” (DFG, Bonn, Germany) (BA 4036/1-2). This work was done according to the program of competitive growth of the Kazan Federal University and the Russian Government.

Compliance with ethical standards

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67:7–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Giangreco A, Groot KR, Janes SM. Lung cancer and lung stem cells: strange bedfellows? Am J Respir Crit Care Med. 2007;175:547–53.CrossRefPubMedGoogle Scholar
  3. 3.
    Viswanathan R, Sen G, Iyer PV. Incidence of primary lung cancer in India. Thorax. 1962;17:73–6.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Noronha V, Pinninti R, Patil VM, Joshi A, Prabhash K. Lung cancer in the Indian subcontinent. South Asian J Cancer. 2016;5:95–103.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon: International Agency for Research on Cancer; 2013. Available from: Scholar
  6. 6.
    Program NCR. Annual Reports accessed from on 05.06.2017.
  7. 7.
    Mehta A, Dobersch S, Romero-Olmedo AJ, Barreto G. Epigenetics in lung cancer diagnosis and therapy. Cancer Metastasis Rev. 2015;34:229–41.CrossRefPubMedGoogle Scholar
  8. 8.
    Bender E. Epidemiology: The dominant malignancy. Nature. 2014;513:S2–3.CrossRefPubMedGoogle Scholar
  9. 9.
    Pass HI CD JD, Minna JD, Scagliotti GV, Turrisi AT Principles and Practice of Lung Cancer . The Official Reference Text of the International Association for the Study of Lung Cancer (IASLC) Lippincott Williams and Wilkins, a Wolters Kluwer business: Alphen aan den Rijn, The Netherlands . 2010.Google Scholar
  10. 10.
    Howington JA, Blum MG, Chang AC, Balekian AA, Murthy SC. Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143:e278S–313S.CrossRefPubMedGoogle Scholar
  11. 11.
    Peters GJ, Avan A, Ruiz MG, et al. Predictive role of repair enzymes in the efficacy of Cisplatin combinations in pancreatic and lung cancer. Anticancer Res. 2014;34:435–42.PubMedGoogle Scholar
  12. 12.
    Chu Q, Vincent M, Logan D, Mackay JA, Evans WK. Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-based Care. Taxanes as first-line therapy for advanced non-small cell lung cancer: a systematic review and practice guideline. Lung cancer. 2005;50:355–74.CrossRefPubMedGoogle Scholar
  13. 13.
    Clegg A, Scott DA, Sidhu M, Hewitson P, Waugh N. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer. Health Technol Assess. 2001;5:1–195.CrossRefGoogle Scholar
  14. 14.
    Herbst RS, Heymach JV, Lippman SM. Lung cancer. New Eng J Med. 2008;359:1367–80.CrossRefPubMedGoogle Scholar
  15. 15.
    Burdett SS, Stewart LA, Rydzewska L. Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Cochrane Database Syst Rev. 2007;3:CD006157.Google Scholar
  16. 16.
    Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83:584–94.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Corner J, Hopkinson J, Fitzsimmons D, Barclay S, Muers M. Is late diagnosis of lung cancer inevitable? Interview study of patients' recollections of symptoms before diagnosis. Thorax. 2005;60:314–9.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. New Eng J Med. 2011;365:395–409.CrossRefPubMedGoogle Scholar
  19. 19.
    Subbaraman N. Public health: A burning issue. Nature. 2014;513:S16–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Brett GZ. The value of lung cancer detection by six-monthly chest radiographs. Thorax. 1968;23:414–20.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Brett GZ. Earlier diagnosis and survival in lung cancer. Br Med J. 1969;4:260–2.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Yousaf-Khan U, van der Aalst C, de Jong PA, et al. Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval. Thorax. 2017;72:48–56.CrossRefPubMedGoogle Scholar
  23. 23.
    Horeweg N, van der Aalst CM, Vliegenthart R, et al. Volumetric computed tomography screening for lung cancer: three rounds of the NELSON trial. Eur Respir J. 2013;42:1659–67.CrossRefPubMedGoogle Scholar
  24. 24.
    Bhatt M, Kant S, Bhaskar R. Pulmonary tuberculosis as differential diagnosis of lung cancer. South Asian J Cancer. 2012;1:36–42.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hammen I. Tuberculosis mimicking lung cancer. Respir Med Case Rep. 2015;16:45–7.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Eramo A, Haas TL, De Maria R. Lung cancer stem cells: tools and targets to fight lung cancer. Oncogene. 2010;29:4625–35.CrossRefPubMedGoogle Scholar
  27. 27.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefPubMedGoogle Scholar
  28. 28.
    Hong B, Zu Y. Detecting circulating tumor cells: current challenges and new trends. Theranostics. 2013;3:377–94.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Pantel K. Blood-based analysis of circulating cell-free DNA and tumor cells for early cancer detection. PLoS Med. 2016;13:e1002205.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Nurwidya F, Zaini J, Putra AC, et al. Circulating tumor cell and cell-free circulating tumor DNA in lung cancer. Chonnam Med J. 2016;52:151–8.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Reclusa P, Sirera R, Araujo A, et al. Exosomes genetic cargo in lung cancer: a truly Pandora's box. Transl Lung Cancer Res. 2016;5:483–91.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Alama A, Truini A, Coco S, Genova C, Grossi F. Prognostic and predictive relevance of circulating tumor cells in patients with non-small-cell lung cancer. Drug Discov Today. 2014;19:1671–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Calabuig-Farinas S, Jantus-Lewintre E, Herreros-Pomares A, Camps C. Circulating tumor cells versus circulating tumor DNA in lung cancer-which one will win? Transl Lung Cancer Res. 2016;5:466–82.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Elshimali YI, Khaddour H, Sarkissyan M, Wu Y, Vadgama JV. The clinical utilization of circulating cell free DNA (CCFDNA) in blood of cancer patients. Int J Mol Sci. 2013;14:18925–58.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Nadal E, Truini A, Nakata A, et al. A Novel serum 4-microRNA signature for lung cancer detection. Sci Rep. 2015;5:12464.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Birse CE, Lagier RJ, FitzHugh W, et al. Blood-based lung cancer biomarkers identified through proteomic discovery in cancer tissues, cell lines and conditioned medium. Clin Proteomics. 2015;12:18.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Nolen BM, Langmead CJ, Choi S, et al. Serum biomarker profiles as diagnostic tools in lung cancer. Cancer Biomark. 2011;10:3–12.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Oshita F, Nomura I, Yamada F, Kato F, Tanaka F, Noda F. Detection of K-ras mutations of bronchoalveolar lavage fluid cells aids the diagnosis of lung cancer in small pulmonary lesions. Clinical cancer research : an official journal of the American Association for Cancer Research. 1999;5:617–20.Google Scholar
  39. 39.
    Risse EK, van't Hof MA, Laurini RN, Vooijs PG. Sputum cytology by the Saccomanno method in diagnosing lung malignancy. Diagn Cytopathol. 1985;1:286–91.CrossRefPubMedGoogle Scholar
  40. 40.
    Roby TJ, Swan GE, Sorensen KW, Hubbard GA, Schumann GB. Discriminant analysis of lower respiratory tract components associated with cigarette smoking, based on quantitative sputum cytology. Acta Cytol. 1990;34:147–54.PubMedGoogle Scholar
  41. 41.
    Mehta AC, Marty JJ, Lee FY. Sputum cytology. Clin Chest Med. 1993;14:69–85.PubMedGoogle Scholar
  42. 42.
    Baryshnikova E, Destro A, Infante MV, et al. Molecular alterations in spontaneous sputum of cancer-free heavy smokers: results from a large screening program. Clin Cancer Res. 2008;14:1913–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Destro A, Bianchi P, Alloisio M, et al. K-ras and p16(INK4A)alterations in sputum of NSCLC patients and in heavy asymptomatic chronic smokers. Lung cancer. 2004;44:23–32.CrossRefPubMedGoogle Scholar
  44. 44.
    Keohavong P, Gao WM, Zheng KC, et al. Detection of K-ras and p53 mutations in sputum samples of lung cancer patients using laser capture microdissection microscope and mutation analysis. Anal Biochem. 2004;324:92–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Minh Tdo C, Blake DR, Galassetti PR. The clinical potential of exhaled breath analysis for diabetes mellitus. Diabetes Res Clin Pract. 2012;97:195–205.CrossRefPubMedGoogle Scholar
  46. 46.
    Krisher S, Riley A, Mehta K. Designing breathalyser technology for the developing world: how a single breath can fight the double disease burden. J Med Eng Technol. 2014;38:156–63.CrossRefPubMedGoogle Scholar
  47. 47.
    Boedeker E, Friedel G, Walles T. Sniffer dogs as part of a bimodal bionic research approach to develop a lung cancer screening. Interact Cardiovasc Thorac Surg. 2012;14:511–5.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lippi G, Cervellin G. Canine olfactory detection of cancer versus laboratory testing: myth or opportunity? Clin Chem Lab Med. 2012;50:435–9.PubMedGoogle Scholar
  49. 49.
    Davis MD, Montpetit A, Hunt J. Exhaled breath condensate: an overview. Immunol Allergy Clin North Am. 2012;32:363–75.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Di Natale C, Macagnano A, Martinelli E, et al. Lung cancer identification by the analysis of breath by means of an array of non-selective gas sensors. Biosens Bioelectron. 2003;18:1209–18.CrossRefPubMedGoogle Scholar
  51. 51.
    Dragonieri S, Annema JT, Schot R, et al. An electronic nose in the discrimination of patients with non-small cell lung cancer and COPD. Lung cancer. 2009;64:166–70.CrossRefPubMedGoogle Scholar
  52. 52.
    Barash O, Peled N, Tisch U, Bunn PA Jr, Hirsch FR, Haick H. Classification of lung cancer histology by gold nanoparticle sensors. Nanomedicine. 2012;8:580–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Peled N, Barash O, Tisch U, et al. Volatile fingerprints of cancer specific genetic mutations. Nanomedicine. 2013;9:758–66.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Nardi-Agmon I, Abud-Hawa M, Liran O, et al. Exhaled breath analysis for monitoring response to treatment in advanced lung cancer. J Thorac Oncol. 2016;11:827–37.CrossRefPubMedGoogle Scholar
  55. 55.
    Chen JL, Chen JR, Huang FF, Tao GH, Zhou F, Tao YJ. Analysis of p16 gene mutations and their expression using exhaled breath condensate in non-small-cell lung cancer. Oncol Lett. 2015;10:1477–80.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Xiao P, Chen JR, Zhou F, et al. Methylation of P16 in exhaled breath condensate for diagnosis of non-small cell lung cancer. Lung cancer. 2014;83:56–60.CrossRefPubMedGoogle Scholar
  57. 57.
    Mozzoni P, Banda I, Goldoni M, et al. Plasma and EBC microRNAs as early biomarkers of non-small-cell lung cancer. Biomarkers. 2013;18:679–86.CrossRefPubMedGoogle Scholar
  58. 58.
    Mehta A, Cordero J, Dobersch S, et al. Non-invasive lung cancer diagnosis by detection of GATA6 and NKX2-1 isoforms in exhaled breath condensate. EMBO Mol Med. 2016;8:1380–9.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Singh I, Mehta A, Contreras A, et al. Hmga2 is required for canonical WNT signaling during lung development. BMC Biol. 2014;12:21.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Bach PB, Silvestri GA, Hanger M, Jett JR. American College of Chest Physicians. Screening for lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132:69S–77S.CrossRefPubMedGoogle Scholar

Copyright information

© Indian Association of Cardiovascular-Thoracic Surgeons 2017

Authors and Affiliations

  1. 1.Pharmaceutical Technology and Biopharmaceutics, Department of PharmacyLudwig-Maximilians UniversityMünchenGermany
  2. 2.German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL)Bad NauheimGermany
  3. 3.LOEWE Research Group Lung Cancer EpigeneticMax Planck Institute for Heart and Lung ResearchBad NauheimGermany
  4. 4.Institute of Fundamental Medicine and BiologyKazan (Volga Region) Federal UniversityKazanRussian Federation
  5. 5.Member of the Universities of Giessen and Marburg Lung Center (UGMLC)Bad NauheimGermany

Personalised recommendations