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Journal of the Chinese Medical Association 76 (2013) 477e478 www.jcma-online.com
Editorial
Epidermal growth factor receptor mutation in adenosquamous carcinoma: A step forward Lung cancer is the most common cause of cancer death in the world. Before the millennium, physicians usually classified lung cancer into nonsmall-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) when newly diagnosed lung cancer patients were about to receive specific treatment. The World Health Organization (WHO) proposed a new schema of lung tumors that has been the foundation for lung cancer classification and treatment since 2004.1 This classification system included squamous cell carcinoma, small cell carcinoma, adenocarcinoma, large cell carcinoma, adenosquamous carcinoma, sarcomatoid carcinoma, carcinoid tumor, and salivary gland tumors. The most common histologic type is adenocarcinoma. Most of the remaining cases are squamous cell, small cell, or large cell carcinomas, followed by rare types of lung cancer that make up a small minority of cases. It was also during 2004 that tumor epidermal growth factor receptor (EGFR) activating mutations were found to be responsible for the responsiveness of NSCLC to EGFRtyrosine kinase inhibitor (TKI) treatment.2,3 Since both EGFR mutations and ALK rearrangements are found mainly in adenocarcinoma, a new proposal for pulmonary adenocarcinoma classification was put forth by a multidisciplinary expert panel in 2011 to improve classification, prognosis, and treatment evaluation.4 Thereafter, driver oncogene identification for targeted therapy against advanced stage NSCLC has become the most important issue in the modern era of pulmonary oncology, including both adenocarcinoma and squamous cell carcinoma.5 Among these oncogenes, the most frequently identified driver oncogene mutations in Asian populations are EGFR mutations, and in Caucasian populations, k-RAS mutation.5,6 A recent study by Bai et al revealed the genetic heterogeneity of EGFR mutations in intratumor tissue samples.7 A total of 1331 tumor foci were fractionated from 42 patients with tumor EGFR mutations. Samples from 26 patients consisted of cells with both wild-type and mutated EGFR, with the proportion of EGFR-mutant cells ranging from 30% to 90%. Another recent study of whole-genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 NSCLC patients identified 3726 point mutations and more than 90 indels in the coding sequence, with the average mutation frequency more than 10-fold higher
in smokers than in never-smokers. Deep digital sequencing revealed diverse clonality patterns in these tumors.8 Thus, tumor genetic heterogeneity is complex and frequently leads to treatment failure, even in patients with treatable activating driver oncogenes such as mutated EGFR. Adenosquamous carcinomas are defined as tumors comprised of more than 10% malignant glandular and squamous components. The mixed histology probably represents the well-recognized heterogeneity of lung cancers, rather than a prognostically distinct subset.9 The reported incidence of adenosquamous carcinoma ranges from 0.4% to 4% of all lung cancers. Song et al in this issue of the Journal of the Chinese Medical Association reported on the “Therapeutic efficacy of gefitinib and erlotinib in patients with advanced lung adenosquamous carcinoma”.10 They found 13 of 49 (26.5%) adenosquamous carcinoma patients responded to EGFR-TKI treatment, and seven of 21 patients who had adequate specimens for tumor EGFR DNA sequence analysis had EGFR activating mutations. This retrospective study found EGFRTKI is an effective treatment for adenosquamous carcinoma. They also reported that the frequency of EGFR mutations and the clinical characteristics of the EGFR mutants in adenosquamous carcinoma were similar to those of Asian patients with adenocarcinoma. With the exception of some case reports presented at medical meetings, this is the first report to focus on the frequency of EGFR mutations, the clinical characteristics, and the efficacy of EGFR-TKI in treating adenosquamous carcinoma. Two important messages emerge from this article. First, in terms of treatment benefits, it always necessary to check the tumor EGFR mutation status of patients with adenosquamous carcinoma, and EGFR-TKI treatment given when activating mutations are found. Second, patients with adenosquamous carcinoma who had tumor EGFR activating mutations benefitted from EGFR-TKI treatment similar to adenocarcinoma patients with EGFR activating mutations. Future work in the area of adenosquamous carcinoma should focus on the following: Do EGFR mutations occur purely in the adenocarcinoma component or in both the adenocarcinoma and squamous cell carcinoma components? Are the residual tumors after EGFR-TKI treatment purely of the squamous cell component or still of the adenosquamous component? Since the clinical characteristics and EGFR
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Editorial / Journal of the Chinese Medical Association 76 (2013) 477e478
mutation frequency are similar to those of adenocarcinoma patients, another issue is whether the acquired EGFR-TKI resistance mechanism is also similar to that of adenocarcinoma. As seen here, many questions remain unanswered, and further study is needed. References 1. Pathology and genetics of tumours of the lung, pleura, thymus and heart. In: Travis WD, Brambilla E, Muller-Hermlink HK, Harris CC, editors. World Health Organization classification of tumours. Lyon: IARC Press; 2004. 2. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497e500. 3. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129e39. 4. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. International Association for the Study of Lung Cancer/ American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244e85. 5. Chen YM. Update of epidermal growth factor receptor inhibitors in nonsmall cell lung cancer. J Chin Med Assoc 2013;76:249e57.
6. Goldberg SB, Schlessinger J, Boyer JL, Herbst RS. A step towards treating KRAS-mutant NSCLC. Lancet Oncol 2013;14:3e5. 7. Bai H, Wang Z, Chen K, Zhao J, Lee JJ, Wang S, et al. Influence of chemotherapy on EGFR mutation status among patients with non-smallcell lung cancer. J Clin Oncol 2012;30:3077e83. 8. Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 2012;150:1121e34. 9. Roggli VL, Vollmer RT, Greenberg SD, McGavran MH, Spjut HJ, Yesner R. Lung cancer heterogeneity: a blinded and randomized study of 100 consecutive cases. Hum Pathol 1985;16:569e79. 10. Song ZB, Lin BC, Shao L, Zhang YP. Therapeutic efficacy of gefitinib and erlotinib in patients with advanced lung adenosquamous carcinoma. J Chin Med Assoc 2013;76:481e5.
Yuh-Min Chen Department of Chest Medicine, Taipei Veterans General Hospital, National Yang-Ming Medical University School of Medicine, and Taipei Medical University, Taipei, Taiwan, ROC Dr. Yuh-Min Chen, Department of Chest Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan, ROC. E-mail address:
[email protected]
