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  • Primer
  • Published:

Non-small-cell lung cancer

Abstract

Lung cancer is one of the most frequently diagnosed cancers and is the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC), a heterogeneous class of tumours, represents approximately 85% of all new lung cancer diagnoses. Tobacco smoking remains the main risk factor for developing this disease, but radon exposure and air pollution also have a role. Most patients are diagnosed with advanced-stage disease owing to inadequate screening programmes and late onset of clinical symptoms; consequently, patients have a very poor prognosis. Several diagnostic approaches can be used for NSCLC, including X-ray, CT and PET imaging, and histological examination of tumour biopsies. Accurate staging of the cancer is required to determine the optimal management strategy, which includes surgery, radiochemotherapy, immunotherapy and targeted approaches with anti-angiogenic monoclonal antibodies or tyrosine kinase inhibitors if tumours harbour oncogene mutations. Several of these driver mutations have been identified (for example, in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)), and therapy continues to advance to tackle acquired resistance problems. Also, palliative care has a central role in patient management and greatly improves quality of life. For an illustrated summary of this Primer, visit: http://go.nature.com/rWYFgg

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Figure 1: Lung cancer classification.
Figure 2: Annual incidence of lung cancer per 100,000 people in 2012.
Figure 3: Genetic adaptation in non-small-cell lung cancer.
Figure 4: Implications of EGFR and HER2 mutations.
Figure 5: Illustration of intratumour heterogeneity in non-small-cell lung cancer development.
Figure 6: Diagnosis of lung cancer.
Figure 7: Strategy for invasive mediastinal staging.
Figure 8: Management of non-small-cell lung cancer.
Figure 9: Intersection of the FLT3, SYK and EGFR pathways.

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References

  1. Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2014). This paper provides up-to-date incidence and mortality rates of cancer worldwide.

    Article  CAS  PubMed  Google Scholar 

  2. Goldstraw, P. et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J. Thorac. Oncol. 2, 706–714 (2007).

    Article  PubMed  Google Scholar 

  3. Shepherd, F. A. et al. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J. Thorac. Oncol. 2, 1067–1077 (2007).

    Article  PubMed  Google Scholar 

  4. Govindan, R. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J. Clin. Oncol. 24, 4539–4544 (2006).

    Article  PubMed  Google Scholar 

  5. Travis, W. D., Brambilla, E. & Riely, G. J. New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. J. Clin. Oncol. 31, 992–1001 (2013). This paper presents an up-to-date pathological classification system of lung cancer.

    Article  CAS  PubMed  Google Scholar 

  6. Giroux, D. J. et al. The IASLC Lung Cancer Staging Project. J. Thorac. Oncol. 4, 679–683 (2009).

    Article  PubMed  Google Scholar 

  7. Siegel, R., Ma, J., Zou, Z. & Jemal, A. Cancer statistics, 2014. CA. Cancer J. Clin. 64, 9–29 (2014).

    Article  PubMed  Google Scholar 

  8. Ferlay, J. et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur. J. Cancer 49, 1374–1403 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. American Cancer Society. Global cancer facts & figures 2nd edition. [online], (2011).

  10. Gabrielson, E. Worldwide trends in lung cancer pathology. Respirology 11, 533–538 (2006).

    Article  PubMed  Google Scholar 

  11. Wahbah, M., Boroumand, N., Castro, C., El-Zeky, F. & Eltorky, M. Changing trends in the distribution of the histologic types of lung cancer: a review of 4,439 cases. Ann. Diagn. Pathol. 11, 89–96 (2007).

    Article  PubMed  Google Scholar 

  12. Weibel, E. R. What makes a good lung? Swiss Med. Wkly 139, 375–386 (2009).

    PubMed  Google Scholar 

  13. Colby, T. V., Wistuba, I. I. & Gazdar, A. Precursors to pulmonary neoplasia. Adv. Anat. Pathol. 5, 205–215 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Subramanian, J. & Govindan, R. Lung cancer in never smokers: a review. J. Clin. Oncol. 25, 561–570 (2007).

    Article  PubMed  Google Scholar 

  15. Travis, W. D. et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: international multidisciplinary classification of lung adenocarcinoma. J. Thorac. Oncol. 6, 244–285 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Thunnissen, E. et al. Reproducibility of histopathological diagnosis in poorly differentiated NSCLC. J. Thorac. Oncol. 9, 1354–1362 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Shaw, A. T. & Engelman, J. A. ALK in lung cancer: past, present, and future. J. Clin. Oncol. 31, 1105–1111 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Collisson, E. A. et al. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). An important paper describing lung adenocarcinoma molecular profiling.

    Article  CAS  Google Scholar 

  19. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012). An important paper describing squamous cell lung carcinoma molecular profiling.

    Article  CAS  PubMed Central  Google Scholar 

  20. Rudin, C. M. et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat. Genet. 44, 1111–1116 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012). This article presents an open-access resource of cancer genomics data sets.

    Article  PubMed  Google Scholar 

  22. Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013). This article provides an analysis of clinical profiles based on cancer genomics.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pao, W. & Miller, V. A. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J. Clin. Oncol. 23, 2556–2568 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Oxnard, G. R. et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J. Thorac. Oncol. 8, 179–184 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gazdar, A. F. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 28 (Suppl. 1), 24–31 (2009).

    Article  CAS  Google Scholar 

  26. Carbone, D. P. An era of lung cancer iconoclasts. J. Thorac. Oncol. 9, 436–437 (2014).

    Article  PubMed  Google Scholar 

  27. Gazdar, A. et al. Hereditary lung cancer syndrome targets never smokers with germline EGFR gene T790M mutations. J. Thorac. Oncol. 9, 456–463 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yu, H. A. et al. Germline EGFR T790M mutation found in multiple members of a familial cohort. J. Thorac. Oncol. 9, 554–558 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. De Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346, 251–256 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhang, J. et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 346, 256–259 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Govindan, R. Cancer. Attack of the clones. Science 346, 169–170 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Roberts, S. A. et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat. Genet. 45, 970–976 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Marusyk, A. et al. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature 514, 54–58 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Polyak, K. & Marusyk, A. Cancer: clonal cooperation. Nature 508, 52–53 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Bremnes, R. M. et al. The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. J. Thorac. Oncol. 6, 209–217 (2011).

    Article  PubMed  Google Scholar 

  37. Malanchi, I. et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481, 85–89 (2012).

    Article  CAS  Google Scholar 

  38. Weis, S. M. & Cheresh, D. A. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat. Med. 17, 1359–1370 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392–401 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Madar, S. Goldstein, I. & Rotter, V. “Cancer associated fibroblasts”— more than meets the eye. Trends Mol. Med. 19, 447–453 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Trimboli, A. J. et al. Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature 461, 1084–1091 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chen, H. L. et al. Structural and functional analysis of β2 microglobulin abnormalities in human lung and breast cancer. Int. J. Cancer 67, 756–763 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Chen, H. L. et al. A functionally defective allele of TAP1 results in loss of MHC class I antigen presentation in a human lung cancer. Nat. Genet. 13, 210–213 (1996).

    Article  CAS  PubMed  Google Scholar 

  44. Wiedenfeld, E. A., Fernandez-Viña, M., Berzofsky, J. A. & Carbone, D. P. Evidence for selection against human lung cancers bearing p53 missense mutations which occur within the HLA A*0201 peptide consensus motif. Cancer Res. 54, 1175–1177 (1994).

    CAS  PubMed  Google Scholar 

  45. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Harvey, R. D. Immunologic and clinical effects of targeting PD-1 in lung cancer. Clin. Pharmacol. Ther. 96, 214–223 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Di Maio, M. et al. in ESTS Textbook of Thoracic Surgery Ch. 41.1, 679–687 (European Society of Thoracic Surgeons, 2014).

    Google Scholar 

  48. Couraud, S., Zalcman, G., Milleron, B., Morin, F. & Souquet, P.-J. Lung cancer in never smokers — a review. Eur. J. Cancer 48, 1299–1311 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. National Institutes of Health. National Cancer Institute Smoking and Tobacco Control. Monograph 10: health effect of exposure to environmental tobacco smoke [online], (1999).

  50. Raaschou-Nielsen, O. et al. Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE). Lancet. Oncol. 14, 813–822 (2013). This paper provides the first evidence of a correlation between air pollution and lung cancer.

    Article  PubMed  Google Scholar 

  51. Darby, S. Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case–control studies. BMJ 330, 223 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Matakidou, A., Eisen, T. & Houlston, R. S. Systematic review of the relationship between family history and lung cancer risk. Br. J. Cancer 93, 825–833 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Coté, M. L. et al. Increased risk of lung cancer in individuals with a family history of the disease: a pooled analysis from the International Lung Cancer Consortium. Eur. J. Cancer 48, 1957–1968 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Yamamoto, H. et al. Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas. J. Natl Cancer Inst. 106, djt338 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Rami-Porta, R. et al. in ESTS Textbook of Thoracic Surgery Ch.44.1, 745–773 (European Society of Thoracic Surgeons, 2014).

    Google Scholar 

  56. Spiro, S. G., Gould, M. K. & Colice, G. L. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 132, 149S–160S (2007).

    Article  PubMed  Google Scholar 

  57. Silvestri, G. A., Tanoue, L. T., Margolis, M. L., Barker, J. & Detterbeck, F. The noninvasive staging of non-small cell lung cancer: the guidelines. Chest 123, 147S–156S (2003).

    Article  PubMed  Google Scholar 

  58. Antoch, G. et al. Non–small cell lung cancer: dual-modality PET/CT in preoperative staging 1. Radiology 229, 526–533 (2003).

    Article  PubMed  Google Scholar 

  59. Thunnissen, F. B. J. M. Sputum examination for early detection of lung cancer. J. Clin. Pathol. 56, 805–810 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hubers, A. J., Prinsen, C. F. M., Sozzi, G., Witte, B. I. & Thunnissen, E. Molecular sputum analysis for the diagnosis of lung cancer. Br. J. Cancer 109, 530–537 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rivera, M. P. & Mehta, A. C. Initial diagnosis of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132, 131S–148S (2007).

    Article  PubMed  Google Scholar 

  62. Schreiber, G. & McCrory, D. C. Performance characteristics of different modalities for diagnosis of suspected lung cancer: summary of published evidence. Chest 123, 115S–128S (2003).

    Article  PubMed  Google Scholar 

  63. Varela-Lema, L., Fernández-Villar, A. & Ruano-Ravina, A. Effectiveness and safety of endobronchial ultrasound-transbronchial needle aspiration: a systematic review. Eur. Respir. J. 33, 1156–1164 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Nakajima, T. & Yasufuku, K. How I do it — optimal methodology for multidirectional analysis of endobronchial ultrasound-guided transbronchial needle aspiration samples. J. Thorac. Oncol. 6, 203–206 (2011).

    Article  PubMed  Google Scholar 

  65. Kurimoto, N. Endobronchial ultrasonography using a guide sheath increases the ability to diagnose peripheral pulmonary lesions endoscopically. Chest 126, 959–965 (2004).

    Article  PubMed  Google Scholar 

  66. Detterbeck, F. C., Lewis, S. Z., Diekemper, R., Addrizzo-Harris, D. & Alberts, W. M. Executive summary: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143, 7S–37S (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Kinsey, C. M. & Arenberg, D. A. Endobronchial ultrasound-guided transbronchial needle aspiration for non-small cell lung cancer staging. Am. J. Respir. Crit. Care Med. 189, 640–649 (2014).

    Article  PubMed  Google Scholar 

  68. Ruano-Ravina, A., Heleno, B. & Fernández-Villar, A. Lung cancer screening with low-dose CT (LDCT), or when a public health intervention is beyond the patient's benefit. J. Epidemiol. Commun. Health 69, 99–100 (2015).

    Article  Google Scholar 

  69. Aberle, D. R. et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365, 395–409 (2011). This article provides the first evidence of reduction of lung cancer mortality through the use of low-dose CT as a screening tool.

    Article  PubMed  Google Scholar 

  70. Kramer, B. S., Berg, C. D., Aberle, D. R. & Prorok, P. C. Lung cancer screening with low-dose helical CT: results from the National Lung Screening Trial (NLST). J. Med. Screen. 18, 109–111 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Patz, E. F. et al. Overdiagnosis in low-dose computed tomography screening for lung cancer. JAMA Intern. Med. 174, 269–274 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Moyer, V. A. Screening for lung cancer: U. S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 160, 330–338 (2014).

    PubMed  Google Scholar 

  73. Sozzi, G. et al. Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD trial study. J. Clin. Oncol. 32, 768–773 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Videtic, G. M. M. et al. Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival. J. Clin. Oncol. 21, 1544–1549 (2003).

    Article  PubMed  Google Scholar 

  75. Tammemagi, C. M., Neslund-Dudas, C., Simoff, M. & Kvale, P. Smoking and lung cancer survival: the role of comorbidity and treatment. Chest 125, 27–37 (2004).

    Article  PubMed  Google Scholar 

  76. Sardari Nia, P. et al. Prognostic value of smoking status in operated non-small cell lung cancer. Lung Cancer 47, 351–359 (2005).

    Article  PubMed  Google Scholar 

  77. Liu, Y. et al. Curcumin and resveratrol in combination modulate drug-metabolizing enzymes as well as antioxidant indices during lung carcinogenesis in mice. Hum. Exp. Toxicol. http://dx.doi.org/10.1177/0960327114551396 (2015).

  78. Gray, A., Read, S., McGale, P. & Darby, S. Lung cancer deaths from indoor radon and the cost effectiveness and potential of policies to reduce them. BMJ 338, a3110 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Farjah, F. et al. Safety and efficacy of video-assisted versus conventional lung resection for lung cancer. J. Thorac. Cardiovasc. Surg. 137, 1415–1421 (2009).

    Article  PubMed  Google Scholar 

  80. Haasbeek, C. J. A. et al. Early-stage lung cancer in elderly patients: a population-based study of changes in treatment patterns and survival in the Netherlands. Ann. Oncol. 23, 2743–2747 (2012).

    Article  CAS  PubMed  Google Scholar 

  81. Arriagada, R. et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 375, 1267–1277 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. [No authors listed.] Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 352, 257–263 (1998).

  83. Le Pechoux, C. et al. Need for a new trial to evaluate adjuvant postoperative radiotherapy in non-small-cell lung cancer patients with N2 mediastinal involvement. J. Clin. Oncol. 25, e10–e11 (2007).

    Article  PubMed  Google Scholar 

  84. Aupérin, A. et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J. Clin. Oncol. 28, 2181–2190 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Vokes, E. E. et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B. J. Clin. Oncol. 25, 1698–1704 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Hanna, N. et al. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U. S. Oncology. J. Clin. Oncol. 26, 5755–5760 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Butts, C. et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet. Oncol. 15, 59–68 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Lindeman, N. I. et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J. Thorac. Oncol. 8, 823–859 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Mok, T., Yang, J.-J. & Lam, K.-C. Treating patients with EGFR-sensitizing mutations: first line or second line — is there a difference? J. Clin. Oncol. 31, 1081–1088 (2013). This review discusses the most appropriate approach to treating patients with advanced NSCLC harbouring activating EGFR mutations.

    Article  CAS  PubMed  Google Scholar 

  90. Park, K. et al. ASPIRATION: first-line erlotinib (E) until and beyond RECIST progression (PD) in Asian patients (pts) with EGFR mutation-positive (mut+) NSCLC. Ann. Oncol. 25 (Suppl. 4), 1223O (2014).

    Google Scholar 

  91. Mok, T. S. et al. Gefitinib/chemotherapy vs chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) after progression on first-line gefitinib: the Phase III, randomised IMPRESS study. Ann. Oncol. 25 (Suppl. 5), LBA2_PR (2014).

    Google Scholar 

  92. Chong, C. R. & Jänne, P. A. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat. Med. 19, 1389–1400 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Li, D. et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27, 4702–4711 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Janne, P. A. et al. Clinical activity of the mutant selective EGFR inhibitor AZD9291 in patients with EGFR inhibitor resistant non-small cell lung cancer (NSCLC). J. Clin. Oncol. 32, (Suppl. 6) 8009 (2014).

    Article  Google Scholar 

  95. Soda, M. et al. Identification of the transforming EML4ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Shaw, A. T. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385–2394 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. Solomon, B. J. et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl. J. Med. 371, 2167–2177 (2014). This is the first paper to provide clinical evidence that crizotinib is superior to chemotherapy as a first-line treatment for patients with ALK-positive advanced-stage NSCLC.

    Article  CAS  PubMed  Google Scholar 

  99. McDermott, U. et al. Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res. 68, 3389–3395 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Shaw, A. T. & Engelman, J. A. Ceritinib in ALK-rearranged non-small-cell lung cancer. N. Engl. J. Med. 370, 2537–2539 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. US National Library of Medicine. LDK378 versus chemotherapy in previously untreated patients with ALK rearranged non-small cell lung cancer. ClinicalTrials.gov[online], (2014).

  102. US National Library of Medicine. LDK378 versus chemotherapy in ALK rearranged (ALK positive) patients previously treated with chemotherapy (platinum doublet) and crizotinib. ClinicalTrials.gov[online], (2015).

  103. Shaw, A. T. et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N. Engl. J. Med. 371, 140927034510006 (2014). This article provides the first clinical evidence of crizotinib activity in patients with ROS1-positive advanced NSCLC.

    Article  CAS  Google Scholar 

  104. Azzoli, C. G. et al. 2011 Focused update of 2009 American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J. Clin. Oncol. 29, 3825–3831 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Scagliotti, G. V. et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J. Clin. Oncol. 26, 3543–3551 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Sandler, A. et al. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355, 2542–2550 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Paz-Ares, L. G. et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J. Clin. Oncol. 31, 2895–2902 (2013). This clinical study defines the continuation maintenance approach with pemetrexed in advanced-stage NSCLC.

    Article  CAS  PubMed  Google Scholar 

  108. Ciuleanu, T. et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 374, 1432–1440 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Coudert, B. et al. Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) according to response to first-line chemotherapy. Ann. Oncol. 23, 388–394 (2011).

    Article  PubMed  Google Scholar 

  110. Hanna, N. et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J. Clin. Oncol. 22, 1589–1597 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Reck, M. et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet. Oncol. 15, 143–155 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Garon, E. B. et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 384, 665–673 (2014).

    Article  CAS  PubMed  Google Scholar 

  113. Socinski, M. A. et al. Treatment of stage IV non-small cell lung cancer. Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143, e341S–e368S (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J. Natl Cancer Inst. 91, 66–72 (1999). This is the first Phase III study exploring chemotherapy in elderly patients with advanced NSCLC with quality of life as the primary end-point.

    Article  Google Scholar 

  115. Mannion, E., Gilmartin, J. J., Donnellan, P., Keane, M. & Waldron, D. Effect of chemotherapy on quality of life in patients with non-small cell lung cancer. Support. Care Cancer 22, 1417–1428 (2014).

    Article  PubMed  Google Scholar 

  116. Cella, D., Peterman, A., Hudgens, S., Webster, K. & Socinski, M. A. Measuring the side effects of taxane therapy in oncology. Cancer 98, 822–831 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Bergman, B., Aaronson, N. K., Ahmedzai, S., Kaasa, S. & Sullivan, M. The EORTC QLQ-LC13: a modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur. J. Cancer 30A, 635–642 (1994).

    Article  CAS  PubMed  Google Scholar 

  118. Rabin, R. & de Charro, F. EQ-5D: a measure of health status from the EuroQol Group. Ann. Med. 33, 337–343 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Cella, D. F. et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J. Clin. Oncol. 11, 570–579 (1993).

    Article  CAS  PubMed  Google Scholar 

  120. Mok, T. S. et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009).

    Article  CAS  PubMed  Google Scholar 

  121. Oizumi, S. et al. Quality of life with gefitinib in patients with EGFR-mutated non-small cell lung cancer: quality of life analysis of North East Japan Study Group 002 Trial. Oncologist 17, 863–870 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Chen, G. et al. Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). Ann. Oncol. 24, 1615–1622 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Geater, S. et al. LUX-lung 6: patient reported outcomes (PROs) from a randomized open-label, phase III study in 1st-line advanced NSCLC patients (pts) harboring epidermal growth factor receptor (EGFR) mutations. J. Clin. Oncol. 31, (Suppl.) 8061 (2013).

    Google Scholar 

  124. Yang, J. C.-H. et al. Symptom control and quality of life in LUX-Lung 3: a Phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 31, 3342–3350 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Temel, J. S. et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N. Engl. J. Med. 363, 733–742 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Berger, A. H. et al. Oncogenic RIT1 mutations in lung adenocarcinoma. Oncogene 33, 4418–4423 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Takezawa, K. et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov. 2, 922–933 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Bean, J. et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl Acad. Sci. USA 104, 20932–20937 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Ohashi, K. et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc. Natl Acad. Sci. USA 109, E2127–E2133 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. De Bruin, E. C. et al. Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov. 4, 606–619 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zhang, Z. et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat. Genet. 44, 852–860 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Walter, A. O. et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 3, 1404–1415 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Janjigian, Y. Y. et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 4, 1036–1045 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Cross, D. A. E. et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 4, 1046–1061 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zhou, W. et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462, 1070–1074 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Akkermans, R. Third-generation EGFR-TKIs — a new hope for NSCLC. Lancet. Respir. Med. 2, 520 (2014).

    Article  PubMed  Google Scholar 

  137. US National Library of Medicine. Phase II AZD9291 Open Label Study in NSCLC After Previous EGFR TKI Therapy in EGFR and T790M Mutation Positive Tumours (AURA2). ClinicalTrials.gov[online], (2015).

  138. US National Library of Medicine. TIGER-2: Open Label Safety and Efficacy Study of Rociletinib (CO-1686) in Patients With T790M Positive NSCLC Who Have Failed One Previous EGFR-Directed TKI. ClinicalTrials.gov[online], (2015).

  139. US National Library of Medicine. AZD9291 Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (AURA3). ClinicalTrials.gov[online], (2015).

  140. US National Library of Medicine. TIGER-3: Open Label, Multicenter Study of Rociletinib (CO-1686) Mono Therapy Versus Single-agent Cytotoxic Chemotherapy in Patients With Mutant EGFR NSCLC Who Have Failed at Least One Previous EGFR-Directed TKI and Platinum-doublet Chemotherapy. ClinicalTrials.gov[online], (2015).

  141. Costa, C. et al. The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin. Cancer Res. 20, 2001–2010 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. Ma, H. S. et al. FLT3 kinase Inhibitor TTT-3002 overcomes both activating and drug resistance mutations in FLT3 in acute myeloid leukemia. Cancer Res. 74, 5206–5217 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Lee, H.-J. et al. Noncovalent wild-type-sparing inhibitors of EGFR T790M. Cancer Discov. 3, 168–181 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. Gao, W. et al. Selective antitumor activity of ibrutinib in EGFR-mutant non-small cell lung cancer cells. J. Natl Cancer Inst. 106, dju204 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Young, R. M. & Staudt, L. M. Ibrutinib treatment of CLL: the cancer fights back. Cancer Cell 26, 11–13 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Puissant, A. et al. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell 25, 226–242 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Hahn, C. K. et al. Proteomic and genetic approaches identify Syk as an AML target. Cancer Cell 16, 281–294 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Stegmaier, K. et al. Gefitinib induces myeloid differentiation of acute myeloid leukemia. Blood 106, 2841–2848 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Boehrer, S. et al. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study. Blood 111, 2170–2180 (2008).

    Article  CAS  PubMed  Google Scholar 

  150. Hong, J. et al. Expression of variant isoforms of the tyrosine kinase SYK determines the prognosis of hepatocellular carcinoma. Cancer Res. 74, 1845–1856 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Sethi, G., Ahn, K. S., Chaturvedi, M. M. & Aggarwal, B. B. Epidermal growth factor (EGF) activates nuclear factor-κB through IBα kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IκBα. Oncogene 26, 7324–7332 (2007).

    Article  CAS  PubMed  Google Scholar 

  152. Gao, S. P. et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J. Clin. Invest. 117, 3846–3856 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Fan, W. et al. MET-independent lung cancer cells evading EGFR kinase inhibitors are therapeutically susceptible to BH3 mimetic agents. Cancer Res. 71, 4494–4505 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Li, R. et al. Niclosamide overcomes acquired resistance to erlotinib through suppression of STAT3 in non-small cell lung cancer. Mol. Cancer Ther. 12, 2200–2212 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Nan, J. et al. TPCA-1 Is a direct dual inhibitor of STAT3 and NF-κB and regresses mutant EGFR-associated human non-small cell lung cancers. Mol. Cancer Ther. 13, 617–629 (2014).

    Article  CAS  PubMed  Google Scholar 

  156. Rosell, R., Bivona, T. G. & Karachaliou, N. Genetics and biomarkers in personalisation of lung cancer treatment. Lancet 382, 720–731 (2013). This review describes personalized therapy in patients with advanced-stage NSCLC.

    Article  CAS  PubMed  Google Scholar 

  157. Friboulet, L. et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 4, 662–673 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Awad, M. M., Engelman, J. A. & Shaw, A. T. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N. Engl. J. Med. 369, 1173 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Sos, M. L. & Thomas, R. K. Genetic insight and therapeutic targets in squamous-cell lung cancer. Oncogene 31, 4811–4814 (2012).

    Article  CAS  PubMed  Google Scholar 

  160. Hammerman, P. S. et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 1, 78–89 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Beauchamp, E. M. et al. Acquired resistance to dasatinib in lung cancer cell lines conferred by DDR2 gatekeeper mutation and NF1 loss. Mol. Cancer Ther. 13, 475–482 (2014).

    Article  CAS  PubMed  Google Scholar 

  162. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Fife, B. T. & Bluestone, J. A. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol. Rev. 224, 166–182 (2008).

    Article  CAS  PubMed  Google Scholar 

  165. Lynch, T. J. et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage iiib/iv non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J. Clin. Oncol. 30, 2046–2054 (2012).

    Article  CAS  PubMed  Google Scholar 

  166. Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Casaluce, F. et al. Emerging drugs targeting PD-1 and PD-L1: reality or hope? Expert Opin. Emerg. Drugs 19, 557–569 (2014).

    Article  CAS  PubMed  Google Scholar 

  168. Bender, E. Epidemiology: the dominant malignancy. Nature 513, S2–S3 (2014).

    Article  CAS  PubMed  Google Scholar 

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Contributions

Introduction (C.G. and A.R.); Epidemiology (C.G. and A.R.); Mechanisms/pathophysiology (D.P.C.); Diagnosis, screening and prevention (J.G., F.P. and L.S.); Management (T.M.); Quality of life (C.G. and A.R.); Outlook (N.K.); overview of Primer (C.G. and R.R.).

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Correspondence to Cesare Gridelli.

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Competing interests

C.G. has received honoraria, speaker's fees, research funding and/or has served as an advisor to Eli Lilly, Roche, Novartis, Bristol-Meyers Squibb, Pfizer, and Boehringer Ingelheim. A.R. has received honoraria, speaker's fees and/or has served as an advisor to Eli Lilly, AstraZeneca and Boehringer Ingelheim. D.P.C. has been a paid consultant for Roche/Genentech, Pfizer, Novartis, BioDesix, Merck, EMD Serono, GlaxoSmithKline, Boehringer Ingelheim and Amgen. T.M. has received honoraria, speaker's fees, research funding and/or has served as an advisor to: AstraZeneca, Roche/Genentech, Eli Lilly, EMD Serono, Eisai, Bristol-Meyers Squibb, AVEO, Pfizer, Taiho, Boehringer Ingelheim, Novartis, GlaxoSmithKline Biologicals, Clovis Oncology, Amgen, Janssen and BioMarin Pharmaceuticals. J.G., N.K., F.P., L.S. and R.R. declare no competing interests.

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Gridelli, C., Rossi, A., Carbone, D. et al. Non-small-cell lung cancer. Nat Rev Dis Primers 1, 15009 (2015). https://doi.org/10.1038/nrdp.2015.9

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