Kosmidis_edit.qxp 10/9/08 12:22 pm Page 61
Predicting Metastatic Behaviour in Lung Adenocarcinoma
Epidermal Growth Factor Receptor cautiously, especially since survival results were not overwhelming, the
Epidermal growth factor receptor (EGFR) is a receptor protein tyrosine study involved multiple subsets and was retrospective. Moreover, the
kinase (RTK) deeply involved in the carcinogenesis of NSCLC, mainly relatively small number of patients with KRAS-mutant tumours increases
The EGFR induces cancer via at least three major the likelihood of an imbalance in baseline characteristics that could have
mechanisms: overexpression of EGFR ligands, amplification of EGFR and been responsible for some or all of the observed difference between
activating mutations in the EGFR gene.
showed treatment groups.
that EGFR mutations, especially deletions in exon 19 and L858R point
mutations in exon 21, are more frequent in East-Asian ethnicity, never- HER2
smokers, adenocarcinoma histology and female gender. Increased copy HER2 amplifications have been observed in lung carcinomas, while HER2
number of EGFR, as assessed by fluorescence in situ hybridisation (FISH) mutations were found to be restricted to the adenocarcinoma
assay, was associated with lymph node metastasis, more advanced histotype.
The frequency of HER2 mutations was slightly higher in
pathological stage and poor prognosis. This alteration has been described females (4.1%) than in males (1.8%) and in never-smokers (3.1%) than
in NSCLC, especially adenocarcinomas, and may occur in mutant or wild- in smokers (1.9%). The mutations show a similar positioning when
A recent study revealed that increased copy number of compared with those found in the EGFR gene. Increased copy number of
the EGFR gene seems to be a progression event independent of the initial the HER2 gene and overexpression of HER2 are associated with tyrosine
alterations, being more than four times more frequent in invasive lesions kinase inhibitor (TKI) sensitivity in EGFR-positive patients,
than in non-invasive lesions.
Lung adenocarcinomas that harbour somatic because TKIs induce sequestration of HER2 and HER3 receptors in an
mutations in the EGFR are highly likely to respond to the EGFR RTK inactive heterodimer configuration with the EGFR.
inhibitors gefitinib and erlotinib.
One possible explanation for this
phenomenon is that the cancer cells are ‘addicted’ to signalling via the MET
mutant EGFRs and die when the mutant oncoprotein is inactivated. The MET gene encodes a transmembrane tyrosine kinase receptor for
Available data on the prognostic value of EGFR mutations are conflicting. human growth factor/scatter factor (HGF/SF). Binding of HGF/SF to MET
The molecular analysis of patients treated in the TRIBUTE (erlotinib) and leads to the activation of a number of signalling pathways. MET elicits
INTACT (gefinitib) trials suggested a prolonged survival in patients with unique mitogenic and morphogenic effects by stimulating cell–cell
no significant differences were found in patients undergoing detachment, migration, invasiveness, tubule formation and branching, in
resections of NSCLC
or lung adenocarcinomas.
In contrast, there is no addition to proliferative and anti-apoptotic activities.
MET appears to be
doubt about the predictive value of EGFR mutations in tumour response, implicated especially in adenocarcinomas.
Cigarette smoking induces
which ranged between 65 and 92% in patients with mutations and was overexpression of HGF in type II alveolar pneumocytes and lung cancer
9–13% in patients without mutations.
cells. Overexpression of HGF in lung cancer cells induces alveolar
differentiation/proliferation and MET activation may play special roles in
RAS well-differentiated lung adenocarcinomas. Furthermore, HGF seems to
The RAS proteins are pivotal regulators of cellular proliferation, have a particular role in the bronchioloalveolar carcinoma (BAC) subtype
differentiation, motility and apoptosis, with mutations in KRAS occurring of pulmonary adenocarcinomas, in which a high level of HGF in
in 30–50% of lung adenocarcinomas, predominantly in smokers.
In bronchoalveolar lavage (BAL) fluid is associated with poorer outcome and
total, 80% of KRAS mutations occur in codon 12, occasionally in codon is an independent prognostic factor.
MET amplification showed a trend
13 and rarely in codon 61.
The negative prognostic impact of KRAS towards poor prognosis in adenocarcinoma, suggesting that anti-MET
mutations has been demonstrated in several studies and confirmed in a could be an alternative therapeutic in this subtype, particularly for EGFR
Mutations of KRAS may be predictive of resistance TKI resistance.
to chemotherapy. Adjuvant chemotherapy did not confer survival
advantage in patients whose tumours had RAS mutations.
correlation of KRAS status to clinical outcomes in the TRIBUTE study Several layers of evidence indicate that multiple genetic disturbances
showed that patients with KRAS-mutant tumours not only fail to benefit found in lung adenocarcinomas can be incorporated as predictive markers
from erlotinib plus chemotherapy, but may experience decreased survival for metastatic behaviour in lung adenocarcinomas. These predictive
and time to progression (TTP).
Despite demonstrating statistical markers can also be used to identify subgroups of patients who can have
significance, the erlotinib–KRAS interaction results must be viewed a dramatic response when treated with novel targeted therapies. ■
1. Miller YE, Am J Respir Cell Mol Biol, 2005;33:216–2323. 14. Reed C, et al., J Thorac Cardiovasc Surg, 2008;135:627–34. 29. Eberhard DA, et al., J Clin Oncol, 2005;23(25):5900–9.
2. Travis WD, et al., WHO classification of tumours, pathology and 15. Calin GA, Nat Rev Cancer, 2006;6:857–66. 30. Bell DW, et al., J Clin Oncol, 2005;23:8081–92.
genetics: tumours of the lung, pleura, thymus and heart, Lyon: 16. Yanaihara N, et al., Cancer Cell, 2006;9:189–98. 31. Shigematsu H, et al., J Natl Cancer Inst, 2005;97:339–46.
IARC Press, 2004:9–124. 17. Johnson SM, et al., Cell, 2005;120:635–47. 32. Janne PA, Johnson BE, Clin Cancer Res, 2006;12:4416s–4420s.
3. Garber M, et al., Proc Natl Acad Sci U S A, 2001;98:13784–9. 18. Takamizawa J, et al., Cancer Res, 2004 ;64:3753–6. 33. Mascaux C, et al., Br J Cancer, 2005;92:131–9.
4. Chen HY, et al., N Eng J Med, 2007;356:11–20. 19. Yu S-L, et al., Cancer Cell, 2008;13:48–57. 34. Winton T, et al., N Engl J Med, 2005;352:2589–97.
5. Poti A, et al., N Eng J Med, 2006;355:570–80. 20. Tomida S, et al., Cancer Sci, 2005;96:63–8. 35. Herbst RS, et al., J Clin Oncol, 2005;23(25):5892–9.
6. Raponi M, et al., Cancer Res, 2006;66:(15):7466–72. 21. Scagliotti GV, et al., Clin Cancer Res, 2004;10:4227–34. 36. Buttitta F, et al., Int J Cancer, 2006;119:2586–91.
7. Beer DG, et al., Nat Med, 2002;8:816–24. 22. Shigematsu H, Gazdar AF, Int J Cancer, 2006;118(2):257–62. 37. Cappuzzo F, et al., J Clin Oncol, 2005;23:5007–18.
8. Ramaswamy S, et al., Nat Genet, 2003;3:49–54. 23. Ji H, et al., Cancer Cell, 2006;9:485–95. 38. Hirata A, et al., Cancer Res, 2005;65:4253–60.
9. Xi L, et al., Clin Cancer Res, 2005;11(11):4128–35. 24. Toyooka S, et al., Cancer Res, 2006;66(3):1371–5. 39. Nakamura Y, et al., Cancer Sci, 2007;98:1006–13.
10. Guo L, et al., Clin Cancer Res, 2006;12(11):3344–54. 25. Janakiraman S, Ramaswamy G, J Clin Oncol, 2007;25:561–70. 40. Tsao MS, et al., Lung Cancer, 1998;20:1–16.
11. Takeuchi T, et al., J Clin Oncol, 2006;24:1679–88. 26. Brabender J, et al., Clin Cancer Res, 2001;7:1850–55. 41. Wislez M, et al., Cancer Res, 2003;63:1405–12.
12. Larsen J, et al., Clin Cancer Res, 2007;13(10):2946–54. 27. Suzuki S, et al., Cancer, 2005;103:1265–73. 42. Engelman JA, et al., Science, 2007;316:1039–43.
13. Ehdoh H, et al., J Clin Oncol, 2004;22:811–19. 28. Soh J, et al., J Thorac Oncol, 2008;3:340–47.
EUROPEAN ONCOLOGY 61
| Page 2
| Page 3
| Page 4
| Page 5
| Page 6
| Page 7
| Page 8
| Page 9
| Page 10
| Page 11
| Page 12
| Page 13
| Page 14
| Page 15
| Page 16
| Page 17
| Page 18
| Page 19
| Page 20
| Page 21
| Page 22
| Page 23
| Page 24
| Page 25
| Page 26
| Page 27
| Page 28
| Page 29
| Page 30
| Page 31
| Page 32
| Page 33
| Page 34
| Page 35
| Page 36
| Page 37
| Page 38
| Page 39
| Page 40
| Page 41
| Page 42
| Page 43
| Page 44
| Page 45
| Page 46
| Page 47
| Page 48
| Page 49
| Page 50
| Page 51
| Page 52
| Page 53
| Page 54
| Page 55
| Page 56
| Page 57
| Page 58
| Page 59
| Page 60
| Page 61
| Page 62
| Page 63
| Page 64
| Page 65
| Page 66
| Page 67
| Page 68
| Page 69
| Page 70
| Page 71
| Page 72
| Page 73
| Page 74
| Page 75
| Page 76
| Page 77
| Page 78
| Page 79
| Page 80
| Page 81
| Page 82
| Page 83
| Page 84
| Page 85
| Page 86
| Page 87
| Page 88
| Page 89
| Page 90
| Page 91
| Page 92
| Page 93
| Page 94
| Page 95
| Page 96
| Page 97
| Page 98
| Page 99