Non-small-cell lung cancer

Nature Reviews Disease Primers

Volumn 1, Issue , 2015, Pages

  Gridelli, Cesare ^a   Rossi, Antonio ^a   Carbone, David P ^b   Guarize, Juliana ^c   Karachaliou, Niki ^d   Mok, Tony ^e   Petrella, Francesco ^c   Spaggiari, Lorenzo ^c   Rosell, Rafael ^d  

^a SG Moscati Hospital   (Italy)

^b THE OHIO STATE UNIVERSITY WEXNER MEDICAL CENTER   (United States)

^c EUROPEAN INSTITUTE OF ONCOLOGY   (Italy)

^d HOSPITAL UNIVERSITARI GERMANS TRIAS I PUJOL   (Spain)

^e CHINESE UNIVERSITY OF HONG KONG   (Hong Kong)

Author keywords

[No Author keywords available]

Indexed keywords

ANAPLASTIC LYMPHOMA KINASE INHIBITOR; ANTINEOPLASTIC AGENT; CRIZOTINIB; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; IMMUNOMODULATING AGENT; PROTEIN TYROSINE KINASE; ANAPLASTIC LYMPHOMA KINASE; EGFR PROTEIN, HUMAN;

ADVANCED CANCER; BRONCHOSCOPY; CANCER CHEMOTHERAPY; CANCER DIAGNOSIS; CANCER EPIDEMIOLOGY; CANCER GENETICS; CANCER IMMUNOTHERAPY; CANCER INCIDENCE; CANCER PATIENT; CANCER PREVENTION; CANCER RADIOTHERAPY; CANCER RISK; CANCER SCREENING; CANCER STAGING; CANCER SURGERY; CLINICAL FEATURE; DIAGNOSTIC IMAGING; DIAGNOSTIC PROCEDURE; GENE MUTATION; GENE REARRANGEMENT; GENETIC HETEROGENEITY; HUMAN; LUNG CARCINOGENESIS; LUNG EXAMINATION; LUNG LOBECTOMY; LUNG SURGERY; MEDIASTINUM; NON SMALL CELL LUNG CANCER; ONCOGENE; PLEURA; PRIORITY JOURNAL; QUALITY OF LIFE; REVIEW; SIGNAL TRANSDUCTION; SPUTUM CYTODIAGNOSIS; STROMA CELL; TRANSTHORACIC ASPIRATION; TUMOR IMMUNITY; GENETICS; LUNG TUMOR; MUTATION; PROGNOSIS; SMOKING;

CARCINOMA, NON-SMALL-CELL LUNG; HUMANS; LUNG NEOPLASMS; MUTATION; NEOPLASM STAGING; PROGNOSIS; RECEPTOR PROTEIN-TYROSINE KINASES; RECEPTOR, EPIDERMAL GROWTH FACTOR; TOBACCO SMOKING;

EID: 85017264829     PISSN: None     EISSN: 2056676X     Source Type: Journal    
DOI: 10.1038/nrdp.2015.9     Document Type: Review

References (168)

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).
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).
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).
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).
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).
6. Giroux, D. J. et al. The IASLC Lung Cancer Staging Project. J. Thorac. Oncol. 4, 679-683 (2009).
7. Siegel, R., Ma, J., Zou, Z. & Jemal, A. Cancer statistics, 2014. CA. Cancer J. Clin. 64, 9-29 (2014).
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).
9. American Cancer Society. Global cancer facts & figures 2nd edition. [online], http://www.cancer.org/acs/ groups/content/@epidemiologysurveilance/documents/ document/acspc-027766.pdf (2011).
10. Gabrielson, E. Worldwide trends in lung cancer pathology. Respirology 11, 533-538 (2006).
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).
12. Weibel, E. R. What makes a good lung? Swiss Med. Wkly 139, 375-386 (2009).
13. Colby, T. V., Wistuba, I. I. & Gazdar, A. Precursors to pulmonary neoplasia. Adv. Anat. Pathol. 5, 205-215 (1998).
14. Subramanian, J. & Govindan, R. Lung cancer in never smokers: a review. J. Clin. Oncol. 25, 561-570 (2007).
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).
16. Thunnissen, E. et al. Reproducibility of histopathological diagnosis in poorly differentiated NSCLC. J. Thorac. Oncol. 9, 1354-1362 (2014).
17. Shaw, A. T. & Engelman, J. A. ALK in lung cancer: past, present, and future. J. Clin. Oncol. 31, 1105-1111 (2013).
18. Collisson, E. A. et al. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543-550 (2014).
19. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519-525 (2012).
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).
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).
22. Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).
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).
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).
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).
26. Carbone, D. P. An era of lung cancer iconoclasts. J. Thorac. Oncol. 9, 436-437 (2014).
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).
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).
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).
30. De Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346, 251-256 (2014).
31. Zhang, J. et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 346, 256-259 (2014).
32. Govindan, R. Cancer. Attack of the clones. Science 346, 169-170 (2014).
33. Roberts, S. A. et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat. Genet. 45, 970-976 (2013).
34. Marusyk, A. et al. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature 514, 54-58 (2014).
35. Polyak, K. & Marusyk, A. Cancer: clonal cooperation. Nature 508, 52-53 (2014).
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).
37. Malanchi, I. et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481, 85-89 (2012).
38. Weis, S. M. & Cheresh, D. A. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat. Med. 17, 1359-1370 (2011).
39. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392-401 (2006).
40. Madar, S. Goldstein, I. & Rotter, V. "Cancer associated fibroblasts" - more than meets the eye. Trends Mol. Med. 19, 447-453 (2013).
41. Trimboli, A. J. et al. Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature 461, 1084-1091 (2009).
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).
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).
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).
45. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252-264 (2012).
46. Harvey, R. D. Immunologic and clinical effects of targeting PD-1 in lung cancer. Clin. Pharmacol. Ther. 96, 214-223 (2014).
47. Di Maio, M. et al. in ESTS Textbook of Thoracic Surgery Ch. 41.1, 679-687 (European Society of Thoracic Surgeons, 2014).
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).
49. National Institutes of Health. National Cancer Institute Smoking and Tobacco Control. Monograph 10: health effect of exposure to environmental tobacco smoke [online], http://cancercontrol.cancer.gov/brp/tcrb/ monographs/10/ (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).
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).
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).
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).
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).
55. Rami-Porta, R. et al. in ESTS Textbook of Thoracic Surgery Ch.44.1, 745-773 (European Society of Thoracic Surgeons, 2014).
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).
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).
58. Antoch, G. et al. Non-small cell lung cancer: dual-modality PET/CT in preoperative staging 1. Radiology 229, 526-533 (2003).
59. Thunnissen, F. B. J. M. Sputum examination for early detection of lung cancer. J. Clin. Pathol. 56, 805-810 (2003).
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).
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).
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).
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).
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).
65. Kurimoto, N. Endobronchial ultrasonography using a guide sheath increases the ability to diagnose peripheral pulmonary lesions endoscopically. Chest 126, 959-965 (2004).
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).
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).
68. Ruano-Ravina, A., Heleno, B. & Fernadez-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).
69. Aberle, D. R. et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365, 395-409 (2011).
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).
71. Patz, E. F. et al. Overdiagnosis in low-dose computed tomography screening for lung cancer. JAMA Intern. Med. 174, 269-274 (2014).
72. Moyer, V. A. Screening for lung cancer: U. S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 160, 330-338 (2014).
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).
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).
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).
76. Sardari Nia, P. et al. Prognostic value of smoking status in operated non-small cell lung cancer. Lung Cancer 47, 351-359 (2005).
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).
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).
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).
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).
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).
84. Aupin, 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).
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).
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).
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).
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).
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).
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).
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).
92. Chong, C. R. & Jne, P. A. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat. Med. 19, 1389-1400 (2013).
93. Li, D. et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27, 4702-4711 (2008).
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).
95. Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561-566 (2007).
96. Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693-1703 (2010).
97. Shaw, A. T. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385-2394 (2013).
98. Solomon, B. J. et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl. J. Med. 371, 2167-2177 (2014).
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).
100. Shaw, A. T. & Engelman, J. A. Ceritinib in ALK-rearranged non-small-cell lung cancer. N. Engl. J. Med. 370, 2537-2539 (2014).
101. US National Library of Medicine. LDK378 versus chemotherapy in previously untreated patients with ALK rearranged non-small cell lung cancer. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/ show/NCT01828099?term=NCT01828099&rank=1 (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], https:// clinicaltrials.gov/ct2/show/NCT01828112?term= NCT01828112&rank=1 (2015).
103. Shaw, A. T. et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N. Engl. J. Med. 371, 140927034510006 (2014).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
118. Rabin, R. & de Charro, F. EQ-5D: a measure of health status from the EuroQol Group. Ann. Med. 33, 337-343 (2001).
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).
120. Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947-957 (2009).
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).
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).
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).
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).
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).
126. Berger, A. H. et al. Oncogenic RIT1 mutations in lung adenocarcinoma. Oncogene 33, 4418-4423 (2014).
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).
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).
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).
130. De Bruin, E. C. et al. Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov. 4, 606-619 (2014).
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).
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).
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).
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).
135. Zhou, W. et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462, 1070-1074 (2009).
136. Akkermans, R. Third-generation EGFR-TKIs - a new hope for NSCLC. Lancet. Respir. Med. 2, 520 (2014).
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], https:// www.clinicaltrials.gov/ct2/show/NCT02094261?term =NCT02094261&rank=1 (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], https://www.clinicaltrials.gov/ct2/show/ NCT02147990?term=NCT02147990&rank=1 (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], https:// www.clinicaltrials.gov/ct2/show/NCT02151981?term =NCT02151981&rank=1 (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], https://www.clinicaltrials.gov/ct2/show/ NCT02322281?term=NCT02322281&rank=1 (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).
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).
143. Lee, H.-J. et al. Noncovalent wild-type-sparing inhibitors of EGFR T790M. Cancer Discov. 3, 168-181 (2013).
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).
145. Young, R. M. & Staudt, L. M. Ibrutinib treatment of CLL: the cancer fights back. Cancer Cell 26, 11-13 (2014).
146. Puissant, A. et al. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell 25, 226-242 (2014).
147. Hahn, C. K. et al. Proteomic and genetic approaches identify Syk as an AML target. Cancer Cell 16, 281-294 (2009).
148. Stegmaier, K. et al. Gefitinib induces myeloid differentiation of acute myeloid leukemia. Blood 106, 2841-2848 (2005).
149. Boehrer, S. et al. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study. Blood 111, 2170-2180 (2008).
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).
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).
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).
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).
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).
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).
156. Rosell, R., Bivona, T. G. & Karachaliou, N. Genetics and biomarkers in personalisation of lung cancer treatment. Lancet 382, 720-731 (2013).
157. Friboulet, L. et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 4, 662-673 (2014).
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).
159. Sos, M. L. & Thomas, R. K. Genetic insight and therapeutic targets in squamous-cell lung cancer. Oncogene 31, 4811-4814 (2012).
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).
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).
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).
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).
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).
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).
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).
167. Casaluce, F. et al. Emerging drugs targeting PD-1 and PD-L1: reality or hope? Expert Opin. Emerg. Drugs 19, 557-569 (2014).
168. Bender, E. Epidemiology: the dominant malignancy. Nature 513, S2-S3 (2014).