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Lack of epidermal growth factor receptor (EGFR)-activating mutations in triple-negative breast cancer in China
Breast Cancer Research volume 17, Article number: 115 (2015)
We read with interest the study by Teng and colleagues reporting a high frequency (11.4 %) of epidermal growth factor receptor (EGFR)-activating mutations in triple-negative breast cancer (TNBC) in a Singapore cohort . In a separate study, EGFR-activating mutations were detected in 7.7 % (1 out of 13) of Chinese basal-like breast cancers . Interestingly, this frequency ranged from 0 to 3 % of other Asian and Caucasian patients [3, 4]. These results indicate that the frequency of these mutations may vary according to geographic and ethnic differences, as reported in non-small cell lung cancer, and these mutations appear to be limited mostly to Chinese patients with TNBC. In this study, in-depth characterization of these mutations in Chinese TNBC was attempted on retrospective archival tissues.
Fifty freshly frozen specimens of TNBC from patients without neoadjuvant chemotherapy were randomly selected from Zhejiang Cancer Hospital, China, from 2010 to 2011. The specimens were confirmed to be estrogen receptor- and progesterone receptor-negative, and less than 1 % of tumor cells showed positive nuclear staining by an immunohistochemistry (IHC) assay. HER-2 negativity was defined as a score of 0 or 1+ by IHC assay or a HER-2/chromosome 17 ratio of less than 2 and fewer than 4 HER-2 copies per nucleus by a fluorescence in situ hybridization assay. Written consent was obtained from all participants. This study was approved by the Research and Ethics Committee of Zhejiang Cancer Hospital.
Twenty-five EGFR-activating mutations (G719S, G719A, G719C, S768I, L858R, and L861Q and 19 mutations of exon 19-Del) were analyzed by an Amplification Refractory Mutation System (ARMS) assay by using an ADx EGFR29 Mutation Kit (Amoy Diagnostics, Xiamen, China). The ARMS assay is able to detect mutations with allele frequencies as low as 1 % . Exons 18, 19, 20, and 21 were amplified by polymerase chain reaction assay, and all fragments were bidirectionally sequenced to screen for other mutations.
None of the EGFR-activating mutations was found by these two assays, but four single-nucleotide polymorphisms (SNPs) were identified by the sequencing assay (Table 1).
In silico prediction was performed to investigate the effect of the SNPs on gene splicing by using two programs: NNSplice 0.9 version (http://www.fruitfly.org/seq_tools/splice.html) and Human Splicing Finder (http://www.umd.be/HSF3/). All four SNPs, particularly the c.2457G > A SNP, were predicted to alter splicing by one or both programs.
In summary, none of the well-known EGFR-activating mutations was identified in our cohort. This suggests that TNBCs form a group of cancers with marked heterogeneity. Targetable mutations may be present and clinically helpful in only a limited number of Chinese patients with TNBC.
Amplification Refractory Mutation System
Epidermal growth factor receptor
Triple-negative breast cancer
Teng YH, Tan WJ, Thike AA, Cheok PY, Tse GM, Wong NS, et al. Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative breast cancer: possible implications for targeted therapy. Breast Cancer Res. 2011;13:R35.
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This study was supported by grants from the Science and Technology Program offered by the Health Bureau of Zhejiang Province, China (grants 2012RCB006 and 2014KYA006) and the Zhejiang Province Traditional Medical Science Fund Project of China (grant 2012ZB019). ARMS assay and sequencing were performed by the Innovation Center China, AstraZeneca Global R&D, Shanghai, China.
The authors declare that they have no competing interests.
WMC designed the study, performed in silico prediction of SNPs, and drafted the manuscript. YG prepared specimens for mutation analysis, collected the clinical data, and analyzed the sequencing data. XJW conceived and designed the study and revised the manuscript. All authors read and approved the final manuscript.
XJW is the director of the Department of Breast Medical Oncology and the Department of Science and Education at Zhejiang Cancer Hospital in Hangzhou, China. His research interests include breast cancer, translational medicine, and breast cancer genetics. XJW has served as the principal investigator of several phase III breast cancer trials, such as those for Afinitor, Pertuzumab, and Lapatinib. XJW serves as a Chinese Anti-cancer Society Breast Cancer committee member and chairman designate of the Zhejiang Province Anti-cancer Society Breast Cancer Committee.
See related research by Teng et al., http://www.breast-cancer-research.com/content/13/2/R35
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Cao, WM., Gao, Y. & Wang, XJ. Lack of epidermal growth factor receptor (EGFR)-activating mutations in triple-negative breast cancer in China. Breast Cancer Res 17, 115 (2015). https://doi.org/10.1186/s13058-015-0628-6
- Epidermal Growth Factor Receptor
- Polymerase Chain Reaction Assay
- Chinese Patient
- EGFR29 Mutation
- Archival Tissue