© 2006 European Society for Medical Oncology
letters to the editor |
EGFR mutations in exons 18–21 in sporadic breast cancer
1 Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine
2 Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK
3 Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia
4 Mutation Detection Facility—CRUK, St James's University Hospital, Leeds, UK
* (E-mail: aharris.lab{at}cancer.org.uk)
The epidermal growth factor receptor (EGFR) is implicated in breast cancer (BC) progression and is associated with an aggressive phenotype. The presence of EGFR mutations in exons 18–21 in BC, as in non-small-cell lung cancer [1], might help predict patient response to EGFR inhibitors such as erlotinib and gefitinib. The EGFR mutation rate in patients with BC is still poorly defined. We analysed samples from 42 consecutive patients with invasive BC (T1–T3, N0–N1) used for estrogen receptor (ER) and EGFR expression, to detect mutations in exons 18–21 of EGFR gene. ER levels were measured with an enzyme-linked immunosorbent assay and tumours with levels >10 fmol/mg protein were considered positive. EGFR was determined using ligand binding of (125I)-EGF and a level of >20 fmol/mg of protein was considered positive. Tumour characteristics are summarised in Table 1. As previously reported, there was an inverse association between EGFR and ER, demonstrating the series to be representative (P <0.0001).
|
Exons 18–21 were screened using fluorescent single-strand conformational polymorphism and samples with DNA sequence variations were successively sequenced. Using this technique, the mutation 156891 G>A was detected in exon 18 in three EGFR-negative (cases 7, 8, and 11) and in two EGFR-positive tumours (cases 31 and 35). In exon 19 only a single mutation (157718 G>A) in one EGFR-positive tumour (case 31) was identified. In exon 20, the polymorphism 164200 G>A was detected in 16/18 EGFR-negative and in 22/23 EGFR-positive tumours. There was a double mutation (164200 G>A and 164102 C>T) in one EGFR-negative tumour (case 14). In exon 21 we identified the mutation 174590 C>T in four EGFR-negative patients (cases 8, 15, 16, and 17). Although most mutations were randomly distributed among all cases, 157718 G>A and 174590 C>T were confined to EGFR-positive and EGFR-negative subgroups, respectively. The detected mutations were silent variants.
Lynch et al. [1] and Bhargava et al. [2] did not find activating mutations of EGFR exons 19 and 21 in any of 15 and 11 primary BC samples, respectively, analysed. Weber et al. [3], detected a higher rate of EGFR missense mutations in BRCA1/2-positive tumours (11/24) compared with sporadic BC (7/48), indicating that EGFR mutations are more likely to be elevated in hereditary BC. These results in addition to ours indicate that the presence of activating mutations in EGFR exons is uncommon in sporadic BC.
There was no association between the level of EGFR and the presence of mutations. This may be reflected in the modest clinical benefits in anti-EGFR trials [4]. However, since 6% of BC showed EGFR amplification and protein overexpression in BC, these may be candidates for anti-EGFR therapies [5]. Besides, there is strong synergy of EGFR with HER2, so blocking both receptors may be critical. HER2 mutations were reported in BC recently, but at a much lower frequency (4% in similar exons) than amplification [6]. Thus, EGFR and/or HER2-targeted therapies should be selected according to the tumour gene mutation, amplification and protein expression, and coexpression with other partners which in association with other treatments may reverse chemo- and/or endocrine resistance.
 |
References |
|---|
 Top References |
|---|
1. Lynch TJ, Bell DW, Sordella R, et al. (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139.
2. Bhargava R, Gerald WL, Li AR, et al. (2005) EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations. Mod Pathol 18:1027–1033.[CrossRef][Web of Science][Medline]
3. Weber F, Fukino K, Sawada T, et al. (2005) Variability in organ-specific EGFR mutational spectra in tumour epithelium and stroma may be the biological basis for differential responses to tyrosine kinase inhibitors. Br J Cancer 92:1922–1926.[CrossRef][Web of Science][Medline]
4. Baselga J, Albanell J, Ruiz A, et al. (2005) Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol.
5. Polychronis A, Sinnett HD, Hadjiminas D, et al. (2005) Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: a double-blind placebo-controlled phase II randomised trial. Lancet Oncol 6:383–391.[CrossRef][Web of Science][Medline]
6. Lee JW, Soung YH, Seo SH, et al. (2006) Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res 12:57–61.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||