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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
adenocarcinomas.
20
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.
21
Recent meta-analyses
22–25
showed treatment groups.
29
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.
36
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
type tumours.
26,27
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,
37,38
possibly
than in non-invasive lesions.
28
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.
29
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
mutations;
29,30
no significant differences were found in patients undergoing detachment, migration, invasiveness, tubule formation and branching, in
resections of NSCLC
31
or lung adenocarcinomas.
11
In contrast, there is no addition to proliferative and anti-apoptotic activities.
39
MET appears to be
doubt about the predictive value of EGFR mutations in tumour response, implicated especially in adenocarcinomas.
40
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.
32
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.
25
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.
41
MET amplification showed a trend
13 and rarely in codon 61.
33
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
recent meta-analysis.
33
Mutations of KRAS may be predictive of resistance TKI resistance.
42
to chemotherapy. Adjuvant chemotherapy did not confer survival
advantage in patients whose tumours had RAS mutations.
34
The Conclusion
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).
35
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.
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