© The Author 2006. Published by Oxford University Press.
CORRESPONDENCE |
RESPONSE: Re: Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers
Affiliation of authors: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas
Correspondence to: Adi F. Gazdar, MD, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Bldg. NB8-206, Dallas, TX 75390-8593 (e-mail: adi.gazdar{at}utsouthwestern.edu).
We wish to comment on several points raised by Pardinas et al. concerning our findings regarding EGFR gene mutations in lung cancers (1). First, they suggest that two of the complex mutations we described, D8 and 
9, may not be due to combinations of deletions or insertions and nucleotide substitutions as we indicated. Instead, they suggest that D8 may have resulted from a single duplication and that 9 may have resulted from two distinct deletions. One of the arguments they propose is that "it is reasonable to assume that a sequence variant results from a single mutation rather than from a concatenation of multiple events." We have no difficulty in accepting this proposal, but we note that they also suggest that the 9 mutation arose as a result of two deletions. It is not possible to know precisely how these complex mutations arose, and we can foresee a single genetic event simultaneously resulting in two distinct forms of mutations. Although the hypothesis advanced by Pardinas et al. is plausible, we do not believe it negates our original interpretation of how these mutations arose but offers instead an alternative mechanism.
Second, Pardinas et al. suggest that because treatment of non–small-cell lung cancers (NSCLCs) with tyrosine kinase inhibitors (TKIs) such as gefitinib or erlotinib was not associated with clinical remission in one study (2), EGFR mutations may not be the primary cause of lung carcinogenesis. The study they cite did not perform mutation analysis. Multiple studies have demonstrated high (albeit variable) rates of clinical response for EGFR gene mutation containing NSCLC tumors following therapy with TKIs. However, only some studies have demonstrated improved survival following TKI therapy (3), whereas others have not (4). Activation of EGFR signaling in solid tumors is a highly complex multifactorial process, and increased gene copy number (of EGFR or its family members), autocrine loops, the presence of specific mutations associated with resistance to TKIs, and other factors may play a role in tumorigenesis as well as in responses to targeted therapies. Also, not all activating mutations are created equal (5,6). Although the common activating EGFR mutations have been shown to have oncogenic activity in vitro, not all impart sensitivity to TKIs (6). EGFR gene mutations occur early during lung cancer pathogenesis and they exhibit a limited field effect, and can be detected in histologically normal small airways adjacent to mutant tumors (7). They have also been described in atypical adenomatous hyperplasias, which are putative precursor lesions of peripheral adenocarcinomas. Thus, although many genetic changes contribute to lung carcinogenesis, EGFR gene mutations probably represent mutations that drive the cell toward tumor rather than acting as incidental changes.
The final point raised by Pardinas et al. involves a report that concludes that one of the actions of TKIs is inhibition of angiogenesis. We presume that they raise this point to suggest that the tumor action of TKIs may occur via actions unrelated to inhibition of kinase activity. It is well known that EGFR activation has effects on multiple downstream signaling pathways, including promotion of angiogenesis, and clinical trials targeting both tyrosine kinase activity and angiogenesis have been proposed. Thus, angiogenesis may be a downstream result of tyrosine kinase activation, and it is not surprising that TKIs inhibit angiogenesis.
REFERENCES
(1) Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339–46.
(2) Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527–37.[CrossRef][Web of Science][Medline]
(3) Kim KS, Jeong JY, Kim YC, Na KJ, Kim YH, Ahn SJ, et al. Predictors of the response to gefitinib in refractory non-small cell lung cancer. Clin Cancer Res 2005;11:2244–51.
(4) Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non–small-cell lung cancer. J Natl Cancer Inst 2005;97:643–55.
(5) Gazdar AF, Minna JD. Inhibition of EGFR signaling: all mutations are not created equal. PLoS Med 2005;2:e377.[Medline]
(6) Greulich H, Chen TH, Feng W, Janne PA, Alvarez JV, Zappaterra M, et al. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2005;2:e313.[CrossRef][Medline]
(7) Tang X, Shigematsu H, Bekele BN, Roth JA, Minna JD, Hong WK, et al. EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients. Cancer Res 2005;65:7568–72.
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J Natl Cancer Inst 2006 98: 362-363.
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