EGFR Mutations in Lung Cancer: Different Frequencies for Different Folks

Abstract

On the basis of its important role in cellular growth and its almost ubiquitous expression, epidermal growth factor receptor (EGFR) became a priority target for the development of anti-non–small-cell lung cancer (NSCLC) treatments, and tyrosine kinase inhibitors were introduced for the therapy of NSCLC in the early 2000s.1Sequist LV Lynch TJ EGFR tyrosine kinase inhibitors in lung cancer: an evolving story.Annu Rev Med. 2008; 59: 429-442Crossref PubMed Scopus (132) Google Scholar Early results indicated survival benefits for highly selected subgroups. The discovery of activating mutations in the kinase domain of the EGFR gene in 2004 identified the basis for the response to TKI therapies. Mutations corresponded to the responsive subgroups, namely never-smoking status, adenocarcinoma histology, East Asian ethnicity, and female sex.1Sequist LV Lynch TJ EGFR tyrosine kinase inhibitors in lung cancer: an evolving story.Annu Rev Med. 2008; 59: 429-442Crossref PubMed Scopus (132) Google Scholar,2Shigematsu H Lin L Takahashi T et al.Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers.J Natl Cancer Inst. 2005; 97: 339-346Crossref PubMed Scopus (2086) Google Scholar The reasons for these highly selective mutational subgroups are not fully understood, and in this editorial we focus on the relationship between ethnicity and mutation frequency. We know from a modest-sized study,3Tsao AS Tang XM Sabloff B et al.Clinicopathologic characteristics of the EGFR gene mutation in non-small cell lung cancer.J Thorac Oncol. 2006; 1: 231-239Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar that East Asians born or domiciled in the United States have similar high EGFR mutation frequency rates. This finding suggests that genetics ( ethnicity) along with lifestyle (smoke-exposure history) may be more important in determining mutation frequency than geographic location or local environmental factors. Of interest, polymorphisms that predispose to lung cancer also demonstrate histology type, ethnic and smoke-exposure–related differences.4VanderWeele TJ Asomaning K Tchetgen Tchetgen EJ et al.Genetic variants on 15q25.1, smoking, and lung cancer: an assessment of mediation and interaction.Am J Epidemiol. 2012; 175: 1013-1020Crossref PubMed Scopus (115) Google Scholar, 5Shiraishi K Kunitoh H Daigo Y et al.A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population.Nat Genet. 2012; 44: 900-903Crossref PubMed Scopus (142) Google Scholar, 6Lan Q Hsiung CA Matsuo K et al.Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia.Nat Genet. 2012; 44: 1330-1335Crossref PubMed Scopus (243) Google Scholar Polymorphism frequencies within the EGFR gene are also influenced by ethnicity.7Nomura M Shigematsu H Li L et al.Polymorphisms, mutations, and amplification of the EGFR gene in non-small cell lung cancers.PLoS Med. 2007; 4: e125Crossref PubMed Scopus (125) Google Scholar Although we have known of the higher rates of mutation frequency in East Asians for nearly a decade, our knowledge was derived largely from studies on Japanese patients, with data available from only modest numbers of other Asians. In this issue of the journal Shi et al.9Shi Y Au J Thongprasert S et al.A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small cell lung cancer of adenocarcinomas histology (PIONEER).J Thorac Oncol. 2014; 9: 154Abstract Full Text Full Text PDF PubMed Scopus (922) Google Scholar report a molecular epidemiology study of EGFR mutations in Asian patients with advanced lung adenocarcinomas (Patients With Advanced Non-small Cell Lung Cancer of Adenocarcinoma Histology [PIONEER]). They studied nearly 1500 patients from seven Asian regions. Although many multi-institutional studies from Asia have low tissue acquisition rates, remarkably, nearly 98% of the tumors were available for evaluation. Another strength of the study was that a single, proven test method was used, and that the vast majority of the specimens were successfully tested. The authors deserve a great deal of credit both for their organizational abilities as well as their technical skills. As with previous studies, there was a strong positive relationship with female sex and a negative relationship with the degree of tobacco exposure. There was also a relationship between mutation frequency and disease state (advanced stage and invasive tumors compared with earlier stages and noninvasive carcinomas). Multivariate analyses indicated that sex was not a significant factor when it was stratified by smoking status. The reason for this finding probably lies in the fact that the vast majority of Asian women with lung cancer are lifetime never-smokers. The most interesting and novel finding was the wide differences in mutation frequency by country/ethnicity. With the exception of India (22.2%), high (although variable) rates were noted in the other six Asian countries, including Vietnam and the Philippines (not considered part of East Asia). In these six regions, the frequency rates varied from 64.2% (Vietnam) to 47.2% (Hong Kong). Although the frequencies in Hong Kong and China were similar, the frequency was higher in Taiwan (62.1%). The senior author of this study, P.-C. Yang, had previous reported a similar frequency in Taiwan.8Wu JY Shih JY Chen KY Yang CH Yu CJ Yang PC Gefitinib therapy in patients with advanced non-small cell lung cancer with or without testing for epidermal growth factor receptor (EGFR) mutations.Medicine (Baltimore). 2011; 90: 159-167Crossref PubMed Scopus (31) Google Scholar One shortcoming of the study was lack of Japanese or Korean participation. Although prior data exist regarding these countries, differences in methodologies and approach may make comparisons with the results of the present study less reliable. We still know little or nothing about mutation frequencies in Mongolia in East Asia as well as about several other important Asiatic regions. In the medical literature, East Asia, and Asia itself, are often referred to as single entities. Asia, the world’s largest and most populous continent, was artificially created when the ancient Greeks divided the Euro-Asian land mass into two. This arbitrary division results in some modern-day countries such as Russia and Turkey spanning both continents. According to the United Nations, East (or Eastern) Asia is a subregion of Asia, which encompasses China (including Taiwan, Hong Kong, and Macau), Japan, the Koreas, and Mongolia (http://esa.un.org/unpd/wup/cdrom_2009/wpp2009_definition_of_major_areas_and_regions.pdfEast). It covers nearly 30% of the Asian continent, is bigger than the area of Europe and is home to over one fifth of all the people in the world. Within East Asia are numerous cultural or linguistic groups, dominated by the Han Chinese. Although the Han Chinese constitute over 90% of China’s population, the Chinese government recognizes over 50 other ethnic groups, some of whom feature prominently in large geographic areas of the country (http://en.wikipedia.org/wiki/List_of_ethnic_groups_in_China). The purpose of this geographic/cultural lesson in a medical journal is to point out that neither Asians nor East Asians (nor even the Chinese) can be regarded (or treated) as a single, homogenous ethnic population. For instance, we have no data about the mutation frequency rates among important Chinese ethnic minorities such as the Uyghurs or Tibetans. In the world of EGFR testing, the vast Indian subcontinent and its teeming population of about two million, was until recently, terra incognita, with no information available about mutation frequency. While examining only a modest number of Indian tumors, Shi et al.9Shi Y Au J Thongprasert S et al.A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small cell lung cancer of adenocarcinomas histology (PIONEER).J Thorac Oncol. 2014; 9: 154Abstract Full Text Full Text PDF PubMed Scopus (922) Google Scholar found a mutation rate of 22.2% in adenocarcinomas. Other recent studies from India have reported higher frequencies,10Sahoo R Harini VV Babu VC et al.Screening for EGFR mutations in lung cancer, a report from India.Lung Cancer. 2011; 73: 316-319Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar,11Moorjani P Thangaraj K Patterson N et al.Genetic evidence for recent population mixture in India.Am J Hum Genet. 2013; 93: 422-438Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar but the cases were preselected, and therefore are not comparable with the present study. Although larger confirmatory studies are needed, we need to know why the EGFR mutation rate in India is lower than those of the other Asian countries studied. Most Indians descend from a mixture of two very divergent ancestral North Indian and South Indian populations, the former containing a considerable admixture of other European ancestry.11Moorjani P Thangaraj K Patterson N et al.Genetic evidence for recent population mixture in India.Am J Hum Genet. 2013; 93: 422-438Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar This fact may help explain why the reported EGFR mutation rate in India may be similar to those of white populations. How can we put these facts and findings into context? A detailed knowledge of the EGFR mutation patterns and frequencies and their relationship to clinical, pathological, genetic, geographic, ethnic, and cultural features, as well as to lifestyles and environmental exposures will help us understand lung cancer biology and the origin of EGFR mutations. In a perfect world, all NSCLC cancers of nonsquamous histologies would undergo mutation testing. However, in parts of Asia (and elsewhere) a substantial percentage of physicians treating lung cancer cases do not use or do not have access to EGFR mutation testing, and rely on patient and tumor characteristics to guide selection of tyrosine kinase inhibitor therapy.12Gazdar AF Tyrosine kinase inhibitors and epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer: to test or not to test?.Medicine (Baltimore). 2011; 90: 168-170Crossref PubMed Scopus (7) Google Scholar Of interest, P.-C. Yang, the senior author of the report by Shi et al.,9Shi Y Au J Thongprasert S et al.A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small cell lung cancer of adenocarcinomas histology (PIONEER).J Thorac Oncol. 2014; 9: 154Abstract Full Text Full Text PDF PubMed Scopus (922) Google Scholar performed a large study in Taiwan to investigate the influence of clinical factors on the treatment outcomes.8Wu JY Shih JY Chen KY Yang CH Yu CJ Yang PC Gefitinib therapy in patients with advanced non-small cell lung cancer with or without testing for epidermal growth factor receptor (EGFR) mutations.Medicine (Baltimore). 2011; 90: 159-167Crossref PubMed Scopus (31) Google Scholar Positive EGFR mutation status was an important factor for objective response to gefitinib. However, in the patients who did not receive EGFR testing, never-smoker status, female sex, and adenocarcinoma histology were predictors for improved gefitinib response. The authors advocated mutation testing when possible, and for those with unknown EGFR mutation status, they recommended using the other characteristics to guide therapy decisions. Although this may be appropriate, the lesson we are learning is that optimal use of patient and tumor characteristics to select therapy should be influenced by both knowledge of the cultural and ethnic background of the local population in general as well as by that of the individual patient.