Oncotarget, Vol. 7, No. 48
www.impactjournals.com/oncotarget/
Research Paper
The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis Yue-Lun Zhang1,2, Jin-Qiu Yuan1,2, Kai-Feng Wang3, Xiao-Hong Fu1,2, Xiao-Ran Han1,2, Diane Threapleton1, Zu-Yao Yang1,2, Chen Mao1,2, Jin-Ling Tang1,2 1
Division of Epidemiology, The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China
2
Shenzhen Municipal Key Laboratory for Health Risk Analysis, Shenzhen Research Institute of The Chinese University of Hong Kong, Shenzhen, Guangdong Province, China
3
Division of Epidemiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong Province, China
Correspondence to: Chen Mao, email: [email protected] Jin-Ling Tang, email: [email protected] Keywords: non-small cell lung cancer, epidermal growth factor receptor, prevalence, systematic review, meta-analysis Received: May 17, 2016 Accepted: September 25, 2016 Published: October 12, 2016
ABSTRACT Objectives: Estimate the epidermal growth factor receptor (EGFR) mutation prevalence in all non-small cell lung cancer (NSCLC) patients and patient subgroups. Results: A total of 456 studies were included, reporting 30,466 patients with EGFR mutation among 115,815 NSCLC patients. The overall pooled prevalence for EGFR mutations was 32.3% (95% CI 30.9% to 33.7%), ranging from 38.4% (95% CI: 36.5% to 40.3%) in China to 14.1% (95% CI: 12.7% to 15.5%) in Europe. The pooled prevalence of EGFR mutation was higher in females (females vs. males: 43.7% vs. 24.0%; OR: 2.7, 95% CI: 2.5 to 2.9), non-smokers (non-smokers vs. past or current smokers: 49.3% vs. 21.5%; OR: 3.7, 95% CI: 3.4 to 4.0), and patients with adenocarcinoma (adenocarcinoma vs. non-adenocarcinoma: 38.0% vs. 11.7%; OR: 4.1, 95% CI: 3.6 to 4.8). Materials and Methods: PubMed, EMBASE, and the Cochrane Library were searched to June 2013. Eligible studies reported EGFR mutation prevalence and the association with at least one of the following factors: gender, smoking status and histology. Random-effects models were used to pool EGFR mutation prevalence data. Conclusion: This study provides the exact prevalence of EGFR mutations in different countries and NSCLC patient subgroups.
45 and 40% of patients, respectively) which activate the tyrosine kinase domain in epidermal growth factor receptors (EGFR). The discovery of EGFR tyrosine kinase inhibitors (TKI) was regarded as a landmark finding in the treatment of lung cancer [5–8]. Targeted EGFR-TKI first-line treatment of sensitizing EGFR mutations results in longer PFS, improved health-related quality of life and decreased treatment-related severe side effects when compared with those who received standard chemotherapy [6, 7, 9–13]. Many clinical guidelines therefore recommend that all patients with sensitizing EGFR mutations receive first-line treatment with these drugs [14–19], in addition to all patients with advanced or metastatic NSCLC [2, 20]. Despite benefits in using EGFR-TKIs for first-line therapy in all sensitizing mutations, in resource limited
INTRODUCTION Lung cancer is the most common cause of cancer death, claiming 1.59 million lives in 2012 worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and chemotherapy is one of the key components in the treatment protocol [2]. Although there is strong evidence to show that standard chemotherapy in addition to best supportive care can prolong overall survival and improve the quality of life [3], prognosis remains poor, especially in patients with advanced NSCLC. The median overall survival and the 5-year survival rate is only 1 year and 3.5%, respectively [4]. A large proportion of NSCLC patients have sensitizing mutations in exon 19 or 21 (approximately www.impactjournals.com/oncotarget
78985
Oncotarget
situations, targeted screening may be appropriate [21]. Knowledge on the prevalence of EGFR mutations in different patient subgroups could therefore inform policy and testing strategies. Existing individual studies may not be informative for estimating prevalence because of small sample sizes in case-series or non-representative sample selection. The mutation prevalence reported in whole study or sub-group populations also varies dramatically in published studies [22–30] and the reported prevalence rates are therefore currently inappropriate for applying to other populations. In order to obtain a more precise estimate of EGFR mutation prevalence in NSCLC patients and patient subgroups, we conducted this systematic review and meta-analysis.
tumor histology in Caucasian and Asian populations. Overall, prevalence was higher in females (females vs. males: 43.7% vs. 24.0%; OR: 2.7, 95% CI: 2.5 to 2.9) and the ORs did not differ significantly by ethnicity: Caucasian females vs. males OR 2.7, 95% CI 2.3 to 3.3; Asian females vs. males OR 2.8, 95% CI 2.6 to 3.1. The prevalence was also higher overall in non-smokers (nonsmoker vs. past or current smoker: 49.3% vs. 21.5%; OR: 3.7, 95% CI: 3.4 to 4.0). Among non-smokers, as compared to past or current smokers, the mutation prevalence in Caucasians was greater than in Asians: Caucasian nonsmokers vs. past or current smokers 39.8% vs. 10.8%; OR: 5.2, 95% CI: 4.4 to 6.3; Asian non-smokers vs. past or current smokers 52.2% vs. 26.3%; OR: 3.3, 95% CI: 2.9 to 3.6. NSCLC patients with adenocarcinoma were also far more likely to carry the EGFR mutation (adenocarcinoma vs. non-adenocarcinoma: 38.0% vs. 11.7%; OR: 4.1, 95% CI: 3.6 to 4.8) in overall participants. This observation was more striking in the Asian population (adenocarcinoma vs. non-adenocarcinoma: 44.7% vs. 12.5%; OR: 5.3, 95% CI: 4.4 to 6.4) than the Caucasian population (adenocarcinoma vs. non-adenocarcinoma: 19.7% vs. 9.6%; OR: 2.2, 95% CI: 1.7 to 2.7). The prevalence of EGFR mutation was not different in patients diagnosed at different NSCLC stages and by chemotherapy use history. The prevalence trends in different patient groups remained when countries with at least of 50 studies were assessed separately (China, Japan, Korea and U.S) (Table A.3 to A.6). Notable exceptions included a very low prevalence (3.3%, 95% CI: 2.4% to 4.1%) among patients with non-adenocarcinoma patients in Japan (Table A.4) and the higher prevalence for those who previously received chemotherapy in Japan (45.3%, 95% CI: 37.7% to 52.8%) and Korea (34.8%, 95% CI: 18.4% to 51.2%) (Tables A.4 and A.5).
RESULTS We identified 6,221 potentially eligible citations, of which 456 studies were finally included (Figure 1). The majority of included studies were case series (56.6%) and cohort studies (33.2%). Sixty-six percent of the studies were conducted in Asian countries. The median sample size was 103, ranging from 11 to 18,246. Median participant age was 63 years, 56.1% were males and 57.0% were past or current smokers. Histology was reported in 45.0% of studies and 73.3% of patients had adenocarcinoma. EGFR exon 19 or 21 mutation was assessed in 89.3% of the studies (see Table A.1 for study characteristics). In total, 30,466 patients with an EGFR mutation were reported among 115,815 patients with NSCLC. The overall pooled prevalence of all EGFR mutations and EGFR exon 19 or 21 mutations was 32.3% (95% CI: 30.9% to 33.7%) and 32.2% (95% CI: 29.6% to 34.8%), respectively (Table 1). EGFR mutation prevalence varied by study location and ethnicity: Asia had the highest prevalence (38.4%, 95% CI: 36.5% to 40.3%) [China: 38.4% (95% CI: 35.7% to 41.1%); Japan: 36.6% (95% CI: 33.2% to 40.0%); Korea 32.4% (95% CI: 28.0% to 36.8%)], followed by North and South America (24.4%, 95% CI: 22.1% to 26.8%) and Europe (14.1%, 95% CI: 12.7% to 15.5%). The prevalence among different ethnicities were similar to study locations, with the prevalence of 38.8% (95% CI: 36.8% to 40.8%) in Asian populations, 17.4% (95% CI: 15.8% to 18.9%) in Caucasians, 17.2% (95% CI: 5.7% to 28.8%) in AfricanAmericans, and 27.0% (95% CI: 22.6% to 31.4%) in mixed populations. Many study or patient characteristics had little influence on EGFR mutation prevalence rates, including the disease stage at diagnosis, history of chemotherapy, mutation detection methods (post-hoc analysis of methods reported in 10+ studies) or year of study publication (posthoc analysis) (Table A.2 for post-hoc analysis). Table 2 provides associations between of EGFR mutation prevalence and gender, smoking status, and www.impactjournals.com/oncotarget
DISCUSSION In this study, we found that approximately onethird of NSCLC patients harbor an EGFR mutation. Patients who are Asian, female, non-smokers, and have adenocarcinoma are more likely to harbor an EGFR mutation, which is consistent with previous studies [23, 29, 31–33]. Some previous systematic reviews were published reporting the prevalence of EGFR mutation in patients with non-small cell lung cancer [34–38]. These previously published work focused on patient subgroups such as smokers, adenocarcinomas or studies only in Chinese population. Moreover, all these previous reviews did not employ meta-analysis method to pool the prevalence from original studies. Despite of these difference, the pooled prevalence estimates we generated were similar to these smaller systematic reviews. The overall pooled prevalence in our study is similar to some existing large individual studies, though there is considerable variation among 78986
Oncotarget
countries and individual studies may not be relied upon for accurate prevalence rates [39–41]. Individual study divergence from the pooled estimates likely reflects the patient characteristics within studies. EGFR mutation prevalence is clearly influenced by these characteristics and thus, this large review of whole populations and subgroups provides the best evidence for EGFR mutation prevalence [42, 43].
Recent clinical guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) recommend all patients with advanced or metastatic non-squamous NSCLC to receive EGFR mutation testing [2, 44]. A costeffectiveness analysis also supports mutation testing vs. no testing for eligibility of second-line gefitinib treatment, after the failure of platinum-containing doublet [45]. However,
Figure 1: The flow chart of study selection. This figure provides detailed information for the study inclusion and exclusion. www.impactjournals.com/oncotarget
78987
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Table 1: The pooled prevalence of EGFR mutation in different NSCLC patient subgroups Group variables
Tests of heterogeneity P I2(%)
No. of studies
Mutation prevalence, % (95%CI)
456
32.3(30.9 to 33.7)
www.impactjournals.com/oncotarget/
Research Paper
The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis Yue-Lun Zhang1,2, Jin-Qiu Yuan1,2, Kai-Feng Wang3, Xiao-Hong Fu1,2, Xiao-Ran Han1,2, Diane Threapleton1, Zu-Yao Yang1,2, Chen Mao1,2, Jin-Ling Tang1,2 1
Division of Epidemiology, The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China
2
Shenzhen Municipal Key Laboratory for Health Risk Analysis, Shenzhen Research Institute of The Chinese University of Hong Kong, Shenzhen, Guangdong Province, China
3
Division of Epidemiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong Province, China
Correspondence to: Chen Mao, email: [email protected] Jin-Ling Tang, email: [email protected] Keywords: non-small cell lung cancer, epidermal growth factor receptor, prevalence, systematic review, meta-analysis Received: May 17, 2016 Accepted: September 25, 2016 Published: October 12, 2016
ABSTRACT Objectives: Estimate the epidermal growth factor receptor (EGFR) mutation prevalence in all non-small cell lung cancer (NSCLC) patients and patient subgroups. Results: A total of 456 studies were included, reporting 30,466 patients with EGFR mutation among 115,815 NSCLC patients. The overall pooled prevalence for EGFR mutations was 32.3% (95% CI 30.9% to 33.7%), ranging from 38.4% (95% CI: 36.5% to 40.3%) in China to 14.1% (95% CI: 12.7% to 15.5%) in Europe. The pooled prevalence of EGFR mutation was higher in females (females vs. males: 43.7% vs. 24.0%; OR: 2.7, 95% CI: 2.5 to 2.9), non-smokers (non-smokers vs. past or current smokers: 49.3% vs. 21.5%; OR: 3.7, 95% CI: 3.4 to 4.0), and patients with adenocarcinoma (adenocarcinoma vs. non-adenocarcinoma: 38.0% vs. 11.7%; OR: 4.1, 95% CI: 3.6 to 4.8). Materials and Methods: PubMed, EMBASE, and the Cochrane Library were searched to June 2013. Eligible studies reported EGFR mutation prevalence and the association with at least one of the following factors: gender, smoking status and histology. Random-effects models were used to pool EGFR mutation prevalence data. Conclusion: This study provides the exact prevalence of EGFR mutations in different countries and NSCLC patient subgroups.
45 and 40% of patients, respectively) which activate the tyrosine kinase domain in epidermal growth factor receptors (EGFR). The discovery of EGFR tyrosine kinase inhibitors (TKI) was regarded as a landmark finding in the treatment of lung cancer [5–8]. Targeted EGFR-TKI first-line treatment of sensitizing EGFR mutations results in longer PFS, improved health-related quality of life and decreased treatment-related severe side effects when compared with those who received standard chemotherapy [6, 7, 9–13]. Many clinical guidelines therefore recommend that all patients with sensitizing EGFR mutations receive first-line treatment with these drugs [14–19], in addition to all patients with advanced or metastatic NSCLC [2, 20]. Despite benefits in using EGFR-TKIs for first-line therapy in all sensitizing mutations, in resource limited
INTRODUCTION Lung cancer is the most common cause of cancer death, claiming 1.59 million lives in 2012 worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and chemotherapy is one of the key components in the treatment protocol [2]. Although there is strong evidence to show that standard chemotherapy in addition to best supportive care can prolong overall survival and improve the quality of life [3], prognosis remains poor, especially in patients with advanced NSCLC. The median overall survival and the 5-year survival rate is only 1 year and 3.5%, respectively [4]. A large proportion of NSCLC patients have sensitizing mutations in exon 19 or 21 (approximately www.impactjournals.com/oncotarget
78985
Oncotarget
situations, targeted screening may be appropriate [21]. Knowledge on the prevalence of EGFR mutations in different patient subgroups could therefore inform policy and testing strategies. Existing individual studies may not be informative for estimating prevalence because of small sample sizes in case-series or non-representative sample selection. The mutation prevalence reported in whole study or sub-group populations also varies dramatically in published studies [22–30] and the reported prevalence rates are therefore currently inappropriate for applying to other populations. In order to obtain a more precise estimate of EGFR mutation prevalence in NSCLC patients and patient subgroups, we conducted this systematic review and meta-analysis.
tumor histology in Caucasian and Asian populations. Overall, prevalence was higher in females (females vs. males: 43.7% vs. 24.0%; OR: 2.7, 95% CI: 2.5 to 2.9) and the ORs did not differ significantly by ethnicity: Caucasian females vs. males OR 2.7, 95% CI 2.3 to 3.3; Asian females vs. males OR 2.8, 95% CI 2.6 to 3.1. The prevalence was also higher overall in non-smokers (nonsmoker vs. past or current smoker: 49.3% vs. 21.5%; OR: 3.7, 95% CI: 3.4 to 4.0). Among non-smokers, as compared to past or current smokers, the mutation prevalence in Caucasians was greater than in Asians: Caucasian nonsmokers vs. past or current smokers 39.8% vs. 10.8%; OR: 5.2, 95% CI: 4.4 to 6.3; Asian non-smokers vs. past or current smokers 52.2% vs. 26.3%; OR: 3.3, 95% CI: 2.9 to 3.6. NSCLC patients with adenocarcinoma were also far more likely to carry the EGFR mutation (adenocarcinoma vs. non-adenocarcinoma: 38.0% vs. 11.7%; OR: 4.1, 95% CI: 3.6 to 4.8) in overall participants. This observation was more striking in the Asian population (adenocarcinoma vs. non-adenocarcinoma: 44.7% vs. 12.5%; OR: 5.3, 95% CI: 4.4 to 6.4) than the Caucasian population (adenocarcinoma vs. non-adenocarcinoma: 19.7% vs. 9.6%; OR: 2.2, 95% CI: 1.7 to 2.7). The prevalence of EGFR mutation was not different in patients diagnosed at different NSCLC stages and by chemotherapy use history. The prevalence trends in different patient groups remained when countries with at least of 50 studies were assessed separately (China, Japan, Korea and U.S) (Table A.3 to A.6). Notable exceptions included a very low prevalence (3.3%, 95% CI: 2.4% to 4.1%) among patients with non-adenocarcinoma patients in Japan (Table A.4) and the higher prevalence for those who previously received chemotherapy in Japan (45.3%, 95% CI: 37.7% to 52.8%) and Korea (34.8%, 95% CI: 18.4% to 51.2%) (Tables A.4 and A.5).
RESULTS We identified 6,221 potentially eligible citations, of which 456 studies were finally included (Figure 1). The majority of included studies were case series (56.6%) and cohort studies (33.2%). Sixty-six percent of the studies were conducted in Asian countries. The median sample size was 103, ranging from 11 to 18,246. Median participant age was 63 years, 56.1% were males and 57.0% were past or current smokers. Histology was reported in 45.0% of studies and 73.3% of patients had adenocarcinoma. EGFR exon 19 or 21 mutation was assessed in 89.3% of the studies (see Table A.1 for study characteristics). In total, 30,466 patients with an EGFR mutation were reported among 115,815 patients with NSCLC. The overall pooled prevalence of all EGFR mutations and EGFR exon 19 or 21 mutations was 32.3% (95% CI: 30.9% to 33.7%) and 32.2% (95% CI: 29.6% to 34.8%), respectively (Table 1). EGFR mutation prevalence varied by study location and ethnicity: Asia had the highest prevalence (38.4%, 95% CI: 36.5% to 40.3%) [China: 38.4% (95% CI: 35.7% to 41.1%); Japan: 36.6% (95% CI: 33.2% to 40.0%); Korea 32.4% (95% CI: 28.0% to 36.8%)], followed by North and South America (24.4%, 95% CI: 22.1% to 26.8%) and Europe (14.1%, 95% CI: 12.7% to 15.5%). The prevalence among different ethnicities were similar to study locations, with the prevalence of 38.8% (95% CI: 36.8% to 40.8%) in Asian populations, 17.4% (95% CI: 15.8% to 18.9%) in Caucasians, 17.2% (95% CI: 5.7% to 28.8%) in AfricanAmericans, and 27.0% (95% CI: 22.6% to 31.4%) in mixed populations. Many study or patient characteristics had little influence on EGFR mutation prevalence rates, including the disease stage at diagnosis, history of chemotherapy, mutation detection methods (post-hoc analysis of methods reported in 10+ studies) or year of study publication (posthoc analysis) (Table A.2 for post-hoc analysis). Table 2 provides associations between of EGFR mutation prevalence and gender, smoking status, and www.impactjournals.com/oncotarget
DISCUSSION In this study, we found that approximately onethird of NSCLC patients harbor an EGFR mutation. Patients who are Asian, female, non-smokers, and have adenocarcinoma are more likely to harbor an EGFR mutation, which is consistent with previous studies [23, 29, 31–33]. Some previous systematic reviews were published reporting the prevalence of EGFR mutation in patients with non-small cell lung cancer [34–38]. These previously published work focused on patient subgroups such as smokers, adenocarcinomas or studies only in Chinese population. Moreover, all these previous reviews did not employ meta-analysis method to pool the prevalence from original studies. Despite of these difference, the pooled prevalence estimates we generated were similar to these smaller systematic reviews. The overall pooled prevalence in our study is similar to some existing large individual studies, though there is considerable variation among 78986
Oncotarget
countries and individual studies may not be relied upon for accurate prevalence rates [39–41]. Individual study divergence from the pooled estimates likely reflects the patient characteristics within studies. EGFR mutation prevalence is clearly influenced by these characteristics and thus, this large review of whole populations and subgroups provides the best evidence for EGFR mutation prevalence [42, 43].
Recent clinical guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) recommend all patients with advanced or metastatic non-squamous NSCLC to receive EGFR mutation testing [2, 44]. A costeffectiveness analysis also supports mutation testing vs. no testing for eligibility of second-line gefitinib treatment, after the failure of platinum-containing doublet [45]. However,
Figure 1: The flow chart of study selection. This figure provides detailed information for the study inclusion and exclusion. www.impactjournals.com/oncotarget
78987
Oncotarget
Table 1: The pooled prevalence of EGFR mutation in different NSCLC patient subgroups Group variables
Tests of heterogeneity P I2(%)
No. of studies
Mutation prevalence, % (95%CI)
456
32.3(30.9 to 33.7)
