Epidemiology of EGFR Mutation in Adenocarcinoma NSCLC Patients in India: A Systematic Review and Meta-Analysis

Ankita Jain^1*, Kumar Prabhash², Venkatraman Radhakrishnan³, Shashank Srinivasan¹

¹Pfizer Products India Private Limited, Mumbai, India.
²Tata Memorial Hospital, Mumbai, India.
³Cancer Institute (W.I.A.), Chennai, India.

DOI: 10.4236/alc.2024.131001                

Abstract

Studies reporting the Indian prevalence of Epidermal Growth Factor Receptor (EGFR) mutation are mostly single centers with small sample sizes. This systematic review and meta-analysis summarized the available evidence of EGFR mutation epidemiology in Indian patients with adenocarcinoma (ADC) Non-Small Cell Lung Cancer (NSCLC). We conducted a structured literature search in PubMed, and EMBASE databases from January 2004 through October 2019. The primary outcome of interest was prevalence of EGFR mutation by gender, smoking status, and mutation subtype. The review included 34 studies. EGFR mutation prevalence was 39.5% in patients with ADC, and significantly higher in females, non-smokers, and patients with exon 19 deletions. The EGFR mutation frequency in Indian patients with ADC was higher than reported in Caucasians but at a lower range of that reported in East Asians. These findings support the use of EGFR mutation testing to guide choice of treatment.

Keywords

Epidemiology, Epidermal Growth Factor Receptor, Adenocarcinoma, Non-Small Cell Lung Cancer, India

1. Introduction

Lung cancer is the predominant cause of the global cancer burden. As per GLOBOCAN 2020, lung cancer is the leading cause of cancer-related death in men, with an incidence rate of 14.3% (1.4 million new cases) and a mortality rate of 21.5% (1.2 million deaths). In women, lung cancer is the third most common cancer, with an incidence rate of 8.4% (0.7 million new cases) and a mortality rate of 13.7% (0.6 million deaths) [1] . In the Indian scenario, the National Cancer Registry Program report published in 2020 predicted that 1 in 68 males in India would develop lung cancer during their lifetime. Further, lung cancer was projected to be among the 5 most common cancers in both sexes in 2020. Most lung cancer cases present in advanced stages in both sexes with 44% and 47.6% cases in males and females respectively being metastatic at presentation [2] .

Lung cancer is broadly categorized as Small Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC) based on histology. Despite various advances in treatment strategies, lung cancer still has a poor prognosis, with a relatively low 5-year survival rate [3] .

Non-small cell lung cancer is further classified as Adenocarcinoma (ADC), squamous, and large cell carcinoma. Adenocarcinoma begins in the glandular tissue that forms the alveolar lining of the lung [4] .

Tobacco consumption is one of the most important risk factors for NSCLC [5] . However, ADC was a more common subtype among women and never smokers [6] . Molecular profiling of patients with NSCLC has revealed the presence of oncogenic driver mutations, which may drive carcinogenesis in more than 80% of the ADC cases, including Epidermal Growth Factor Receptor (EGFR) mutations [7] . Therefore, a better understanding of these oncogenic driver mutations, particularly EGFR mutations, will change the treatment landscape for NSCLC patients [8] . Epidermal growth factor, a cell surface receptor, regulates cell proliferation, apoptosis, angiogenesis, adhesion, and motility through intracellular signaling and controls tumor progression [8] . Sensitizing EGFR mutations are the most common actionable driver mutations that may induce Tyrosine Kinase (TK) activation and phosphorylation of downstream pathways, resulting in aggravating cancer [9] [10] . In-frame deletions in exon 19 and point mutations in exon 21 (L858R) are the most common EGFR mutations [8] . Tyrosine Kinase Inhibitors (TKIs) are an important new class of molecularly targeted anti-cancer agents that block corresponding kinases from phosphorylating tyrosine residues of their substrates and then inhibit the activation of downstream signaling pathways involved in cancer proliferation, invasion, metastasis, and angiogenesis [11] . Use of TKIs against these EGFR-sensitizing mutations in advanced NSCLC patients as the first line of treatment can improve survival and quality of life [12] . Therefore, EGFR tumor genotyping acts as an essential guide in making treatment decisions regarding the use of EGFR TKIs in NSCLC patients. Mutation testing empowers patients with EGFR mutation-positive NSCLC of ADC histology to undergo personalized treatment with EGFR TKIs. Based on the tumor’s molecular characteristics, these TKIs directly act on EGFR oncogenes, resulting in improved treatment outcomes [7] .

Various epidemiological factors, such as race, sex, and age, affect the incidence of an oncogenic driver mutation. EGFR gene mutations are predominantly observed in women and non-smokers of East Asian ethnicity [13] . Further, the frequency of EGFR mutation was higher in East Asians (40% - 55%) compared to Caucasians (5% - 15%) [14] . These considerable variations in the prevalence and pathology of the disease at the global level indicate the need for regional research for a detailed appreciation of molecular epidemiology and clinical management. Therefore, genetic testing might be beneficial for countries like India, where genetic variability is common [15] . Few Indian studies have reported data regarding EGFR mutation in ADC NSCLC patients [7] [16] - [21] . However, information that would be helpful to policymakers and service providers is scarce. Therefore, this systematic review and meta-analysis is aimed to assess the EGFR mutations epidemiology in ADC NSCLC patients in India and compare it with Caucasian and East Asian data.

2. Methodology

2.1. Data Sources and Selection

A structured literature search was conducted in PubMed and EMBASE databases from January 2004 through October 2019 for articles reporting data on EGFR mutations in ADC NSCLC patients in India. Appropriate keywords and database-specific subject terms related to “epidemiology, non-small cell lung cancer, adenocarcinoma, epidermal growth factor receptor positivity, Indian population” were employed, along with suitable Boolean operators for the search. The literature search was restricted to only human studies. Further, relevant conference abstracts and papers, articles in the press, short surveys, and errata were also searched to identify the grey literature not captured by the formal searches.

2.2. Study Selection

We included studies on EGFR mutations in ADC NSCLC patients from India, published in English from January 2004 to October 2019 for evidence synthesis. Studies with the non-Indian population, other cancer types, not specifying the type of NSCLC or not including ADC patients, reviews, meta-analyses, and studies not in scope (such as guidelines and in-vitro studies) were excluded. Duplicate publications were checked, and the validity of the article titles was verified. Abstracts and full texts were reviewed in-depth in the following phase. Two reviewers handled the study selection independently.

2.3. Data Extraction

The data collected from each study included the following details: study title, the first author, journal, publication year, study design, study location, number of NSCLC patients (sample size), number of patients with an EGFR mutation, age, study period, diagnostic method, the prevalence of EGFR positivity in NSCLC and ADC, and different mutation subtypes (such as exon 19 deletions, exon 21 substitutions, exon 20, and exon 18 mutations). Two reviewers handled the data extraction independently, and any disagreements were resolved by a third reviewer to reach a consensus.

2.4. Outcome Measure and Subgroup Variables

The primary outcome of interest in the review is the EGFR mutation and its prevalence determined using mutation testing by gender (male or female), smoking status (never or ever-smokers, according to the definitions of the original studies), and mutation subtype (exon 19 deletions or exon 21 substitutions).

2.5. Data Analysis

Rev Man 5 software by Cochrane Collaboration was used to perform the random-effects meta-analysis using the Inverse variance method with a dichotomous data type to calculate the Odds Ratio (OR) with 95% confidence intervals. Furthermore, subgroup analysis was performed according to gender (males/females), smoking status (smokers/non-smokers), and exon subtype (exon 19 deletion/exon 21 substitution). The random-effects model was used to consider the diversity and heterogeneity in the studies included in the review. The Cochran’s Q-test and the I² statistic were applied to evaluate the statistical heterogeneity among the studies and were considered significant at a p value ≤ 0.10 for the Cochran’s Q-test or an I² ≥ 50% for study heterogeneity [22] .

3. Results

A structured search from PubMed resulted in 268 articles; likewise, EMBASE search yielded 1326 articles. Supplementary search resulted in four articles resulting in a total of 1598 articles. After removing 176 duplicates, title, and abstract screening were performed on 1422 articles. After excluding 1367 records [country other than India (13), not in scope studies (1291), reviews/meta-analyses (14), and other cancer types (4)], 55 records met the criteria for full-text review. Among these 55 articles, 27 full text articles (lacking complete information regarding NSCLC, ADC) were excluded. Finally, 34 eligible studies were included in the qualitative and quantitative synthesis to understand the role of NGS-guided precision oncology in improving overall patient outcomes in advanced cancer. A PRISMA flow chart explaining the procedure to select the study is explained in Figure 1.

The general characteristics of the studies reporting EGFR positivity in ADC NSCLC patientsare summarized in Table 1. All the studies were observational, mostly retrospective (70.6%) and cross-sectional (14.7%) study designs. The median number of patients included in these studies was found to be 123, which ranged from 35 [23] to 3351 [24] .

Figure 1. Flow diagram of studies included in the systematic review and meta-analysis.

Most of the studies were from the Northern part of India (35%), followed by studies from the South (20.6%) and Central India (20.6 %). The remaining studies were either from the East (5.8%), west (3%) or without regional details (14.7%). Six percent of the studies were multi-centric, while most (94%) were single-center studies.

3.1. Biases and Confounding Patient Characteristics

Information on age was available for 94% (32 out of 34) of studies and was primarily reported as medians (67.6%) and means (17.6%), while the rest was presented as the age range (8.8%) (Table 1). Gender-related information was available for 94% (32 out of 34) of studies (Table 2). Among these studies, females were 33%, and males constituted 67% of the study population. Smoking-related information was available for 79% of studies. Heterogeneous distribution of smoking patterns was observed amongst the studies, with the percentage of smokers varying from 14% [25] to 81% [21] and non-smokers varying from 15% [21] to 81% [26] . Among the 27 studies with information on smoking, 41% were smokers, and 54% were non-smokers (Table 3). Information regarding exon subtypes was available for 67.6% of studies. Among these studies, exon 19 deletion was predominant, varying from 45% [27] to 81% [28] [29] , followed by exon 21 substitution, varying from 15% [29] to 46% [16] among the EGFR-positive patients. The homogeneity of studies included in the review was assessed based on the detection methods of the EGFR mutation. Information on the techniques used for detecting the EGFR mutation was available for 97% of the studies, in which most of the studies used Real-Time Polymerase Chain Reaction (RT-PCR) (44%) and PCR (35.3%), followed by immunohistochemistry (14.7%) and fluorescence in situ hybridization (2.9%) (Table 1).

The screening of the studies followed by data extraction was performed by two reviewers independently, and a third reviewer was consulted to resolve the discrepancies to avoid selection bias.

Table 1. Basic Characteristics of the included studies.

NSCLC: Non-Small Cell Lung Cancer; ADC: Adenocarcinoma; EGFR: Epidermal Growth Factor Receptor; NR: Not Reported; PCR: Polymerase Chain Reaction; RT-PCR: Real-Time Polymerase Chain Reaction; IHC: Immunohisto Chemistry; FISH: Fluorescence in Situ Hybridization. *EGFR positive/EGFR mutated, 33/145 (23%); **EGFR positive/EGFR mutated, 24/120 (24%); #EGFR positive/EGFR mutated, 47/134 (35%); ##EGFR positive/EGFR mutated, 748/2653 (28.2%); *#EGFR positive/EGFR mutated, 38/42 (90%).

Table 2. Male-female distribution of lung cancer patients.

EGFR: Epidermal Growth Factor Receptor; NA: Not Available.

Table 3. Distribution of NSCLC patients by smoking habits.

EGFR: Epidermal Growth Factor Receptor; NA: Not Available. *Smoking data were available for 25 patients only.

Table 4. Distribution of EGFR mutations in ADC NSCLC patients by mutation types.

ADC: Adenocarcinoma; EGFR: Epidermal Growth Factor Receptor; NSCLC: Non-Small Cell Lung Cancer.

3.2. EGFR Mutation Frequency

The 34 studies included in the systematic review had 10,342 NSCLC patients, of which ADC was reported in 8463 patients. Adenocarcinoma in NSCLC patients ranged from 25% [18] to 100% in ten studies [16] [24] [28] [30] - [36] . Among the ADC patients, EGFR mutation prevalence was reported to be 39.5%, which varied from 10.8% [20] to 100% [18] among the studies. Moreover, information regarding the mutation subtype was available for 1416 subjects. The major mutation subtypes of ADC were exon 19 deletion (60.3%), which was followed by exon 21 substitution (32.5%), exon 18 mutation (4.4%), and exon 20 mutation (2.7%) (Table 4).

3.3. Subgroup Analysis of EGFR Mutation

In this review, the influence of gender, smoking patterns, and exon subtype on EGFR mutation prevalencein ADC NSCLC patients was assessed using meta-analysis. EGFR mutation prevalence was higher in femalescompared to males (OR, 2.27; 95% CI, 1.79 - 2.87). The results indicated a significant effect of gender on EGFR mutation (p < 0.00001). High heterogeneity (I² = 64%, p < 0.0001) was indicated by the test results (Figure 2). Likewise, non-smokers had a significantly higher EGFR mutation prevalencethan smokers (OR, 2.58; 95% CI, 1.91 - 3.49), which emphasizes the positive association between non-smokers and EGFR mutations (p < 0.00001). Substantial variation (I² = 71%, p < 0·00001) was observed in the studies included in the analysis (Figure 3).

In the case of exon subtypes, the prevalence of exon 19deletions was significantly higher than exon 21 substitutions (OR, 4.20; 95% CI, 2.98 - 5.92), which emphasizes the positive association between exon 19 deletions and EGFR mutations (p < 0.00001). Moreover, substantial variation (I² = 75%, p < 0·00001) was observed in the studies included in the analysis (Figure 4).

Figure 2. Odds ratio for prevalence of EGFR mutation by gender.

Figure 3. Odds ratio for prevalence of EGFR mutation by smoking pattern.

Figure 4. Odds ratio for prevalence of EGFR mutation by mutation subtype.

4. Discussion

Globally, lung cancer is the commonest cause of cancer-related deaths in both genders [1] , with NSCLC constituting most cases. Moreover, advanced NSCLC has a poor prognosis with a low survival rate [12] [22] [37] [38] . However, research in the past two decades on oncogenic driver mutations, such as EGFR in ADC NSCLC patients, led to novel molecular targeted therapies, resulting in revolutionizing treatment strategies with improved efficacy and survival rate [39] .

Apart from smoking, other risk factors for lung cancers include passive smoke inhalation, household radon, occupational exposures, infection, and genetic variability, which increases the burden on minorities and socioeconomically challenged population [40] . Hence, in developing countries with substantial genetic variability like India, genetic testing of lung cancer can be considered beneficial in the treatment and management of lung cancer. However, most of the studies conducted in India to estimate EGFR mutations in ADC NSCLC are single-centered and might not estimate the true prevalence. Further, the small sample sizes and patients’ clinical selection result in overestimating the incidence rate [41] . Therefore, a systematic review and meta-analysis were conducted to assess epidemiology and estimate EGFR mutations in ADC NSCLC patients in the Indian scenario. Further, the influence of gender, smoking pattern, and exon subtype was assessed, which can be major players in influencing the epidemiology of ADC NSCLC.

The current systematic review and meta-analysis included 34 Indian studies with 10,342 NSCLC patients, of which 8643 patients with ADC had 2659 EGFR-positive patients. Based on information available for gender, 3347 patients were found to be females and 6827 were males. According to smoking status, there were 2508 smokers and 3128 non-smokers. The overall prevalence of EGFR positivity was 25.9% (95% CI, 22.7 - 29.3) in NSCLC patients while it was 39.5% (95% CI, 32.1 - 47.1) in ADC patients. In the current study, the EGFR mutation prevalence in ADC NSCLC patients was variable based on gender, smoking pattern, and mutation subtype. Overall, EGFR positivity was significantly higher in females (females vs. males: 42.8 vs. 24.3%; OR, 2.27; 95% CI, 1.79 - 2.87), non-smokers (non-smokers vs. smokers: 39.8 vs. 21.3%; OR, 2.58; 95% CI, 1.91 - 3.49), and patients with exon 19 deletions subtype (exon 19 deletions vs. exon 21 substitutions (61.9 vs. 29.2%; OR, 4.20; 95% CI, 2.98 - 5.92) (Table 5).

Table 5. Prevalence of EGFR positivity.

In this review, the EGFR positivity was reported to be 39.5% in ADC NSCLC cases, which was found to be in line with the findings of an Indian multi-centric study that reported the EGFR mutation prevalence to be 33% in the ADC NSCLC patients [30] . EGFR mutation prevalence was reported as 23% by Choughule et al. [18] Another Indian multi-centric study reported a varied prevalence of EGFR mutations in these patients ranging from 22% to 51.8% [42] . A prospective study by Shi et al. reported EGFR mutation frequency of 22% in Indian patients with advanced lung adenocarcinoma compared to 51.4% in other Asian populations [43] .

Geographical location, ethnicity, and many other factors influence the mutation rate. The EGFR mutation rate among the Spanish NSCLC patients, consisting majorly Caucasians, was 11.6% [44] . Another study conducted in an unselected Caucasian population reported this rate to be 5% [45] . Melosky et al. in their meta-analysis, estimated EGFR mutation prevalence in NSCLC patients in Caucasians as 12.8% and 49.1% in East Asians [46] . A study by Kohno et al. also presented similar results where this rate was reported as 5% - 15% in Caucasians and 40% - 55% in East Asians [14] . A study conducted by Chougule et al. reported EGFR mutation incidencein NSCLC patients of Indian ethnicity o be intermediate (23%) compared to Caucasians (10% - 15%) and East Asians (27% - 62%) [41] . The current systematic review, however, indicates that the prevalence of EGFR mutations in India is 39.5%, which is higher than previously reported and is at the low range of the prevalence reported in East Asian ethnicity. Further, the variations in the EGFR prevalence among Asian countries highlight the genetic heterogeneity among Asians.

In the current review, females and non-smokers were found to have a higher EGFR mutation prevalence. A study with Moroccan patients has reported that women and never smokers had a considerably higher EGFR mutation rate [47] . Research also indicated that indoor air pollution and occupational exposures might have a larger influence on female lung cancer in the Asian sub-continent [40] . Other studies have reported similar findings of a significantly higher EGFR mutatiorateste in non-smokers as compared to smokers or ex-smokers [48] . The current review also reported a higher frequency of EGFR mutations in the exon 19 deletion subtype compared to exon 21 substitution. A similar finding was reported by a study where a higher frequency of EGFR mutations was detected in exon 19 deletions (69%) compared to exon 21 substitutions (21%) in the Moroccan patients [47] .

The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) recommend screening for EGFR mutations in all patients with non-squamous cell carcinoma that is advanced or metastatic NSCLC [22] . The limitations with standard chemotherapy encourage the testing of EGFR mutations, which may improve the overall prognosis by allowing patients to receive first-line EGFR-TKI treatment sooner.

This review has extensively screened studies to estimate EGFR mutations in ADC NSCLC patients in India. The meta-analysis used for subgroups revealed the risk associated with females, non-smokers, and exon 19 deletions subtype. Further, the review emphasized the need for regular genetic screening for EGFR mutations in ADC NSCLC patients. The findings of this review may provide first-hand information to researchers and policymakers regarding the accurate estimate of EGFR mutation prevalence in ADC NSCLC patients in India. However, considering the shortcomings, the findings of this systematic analysis should be interpreted with caution. Firstly, the small sample size observed in a few studies would reduce the detection power to estimate the true prevalence. Secondly, the limited data on gender, smoking status, age, and differences in the study settings may result in heterogeneity. Thirdly, most of the included studies are retrospective and cross-sectional. Despite the limitations, this systematic review enhances our knowledge of the prevalence of EGFR mutations in ADC NSCLC patients in India. It provides a comparative analysis of the Asian and Caucasian populations [14] [46] . This review further highlights the need for information on EGFR mutation that may be immensely useful for treating Indian ADC NSCLC patients.

5. Conclusions

This systematic review provides a precise estimate of the epidemiology of EGFR mutations in ADC NSCLC patients in India. Further, the frequency of EGFR mutations in the Indian population was found to be higher than in Caucasians but at a lower range of that reported in East Asians, emphasizing the genetic heterogeneity among Asians. The meta-analysis in the subgroup highlighted the association of female gender, non-smoking population, and exon 19 deletions with the higher incidence of EGFR mutations. These findings encourage the implementation of extensive regular testing in the advanced setting to enhance therapeutic outcomes for these individuals.

The results of this review should be taken into consideration while noting the limitations. More extensive studies or cooperative group registries are required to understand EGFR positivity rate, the patient profile of EGFR-positive patients, and its treatment outcome in Indian ADC NSCLC patients.

6. Summary Points

1) Evidence concerning the epidemiology of Epidermal Growth Factor Receptor (EGFR) mutations is beneficial in managing lung cancer. However, most studies reporting the prevalence of EGFR mutations in India are single-center studies with small sample sizes.

2) We conducted a systematic review and meta-analysis to summarize the available evidence of the epidemiology of EGFR mutation in Indian patients with Adenocarcinoma (ADC) Non-Small Cell Lung Cancer (NSCLC).

3) Out of 1598 studies, 34 were included for evidence synthesis. All the studies were observational, mostly retrospective (70.6%) and cross-sectional (14.7%) study designs.

4) The 34 studies included in the review consisted of 10,342 NSCLC patients, of which 8643 patients with ADC had 2659 EGFR-positive patients. The overall prevalence of EGFR-positive mutations was 25.9% in NSCLC patients and 39.5% in ADC patients.

5) The prevalence of EGFR-positive mutations in ADC NSCLC patients was found to vary based on gender, smoking pattern, and exon subtype. Overall, the prevalence of EGFR mutation was reported to be higher in females (females vs. males: 42.8 vs. 24.3%; OR, 2.27, 95% CI, 1.79 - 2.87), non-smokers (non-smokers vs. smokers: 39.8 vs. 21.3%; OR, 2.58, 95% CI, 1.91 - 3.49), and exon 19 deletions (exon 19 deletions vs. exon 21 substitutions: 61.9 vs. 29.2%; OR, 4.20, 95% CI, 2.98 - 5.92).

6) The prevalence of EGFR mutations in ADC NSCLC patients in India (39.5%) was found to be higher than in Caucasians and at a lower range of that reported in East Asians (40% - 55%), highlighting the genetic heterogeneity among Asians.

7) Conclusions drawn from this systematic analysis should be interpreted with caution. All the included studies are observational; few had a small sample size. Limited data on gender, smoking status, age, and differences in the study settings might have resulted in heterogeneity.

8) This systematic review enhances our knowledge of the prevalence of EGFR mutations in ADC NSCLC patients in India despite the limitations. It provides a comparative analysis of the Asian and Caucasian populations.

9) This review further highlights the need for information on EGFR mutation that may be of immense use for treating Indian ADC NSCLC patients.

Acknowledgements

Medical writing and editorial support were provided by Dr. Sivaprasad Mudili and Ruchira Das at Turacoz Healthcare Solutions (https://www.turacoz.com/) and was funded by Pfizer. Kumar Prabhash: Grants from Alkem Laboratories, Roche India Pvt Ltd, and Cadilla Pharma (all grants received towards research have gone to the employer). All authors have contributed to the manuscript in significant ways and have reviewed and agreed upon the contents of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

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