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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 2  |  Page : 48-53

Prevalence and Clinicopathologic Risk Factors for Epidermal Growth Factor Receptor, Anaplastic Lymphoma Kinase, and ROS-1 Fusion in Metastatic Non-small Cell Lung Carcinoma


1 Department of Medical Oncology, Artemis Hospital, Gurugram, Haryana, India
2 Department of Psychiatry, Esic Medical College and Hospital, Faridabad, Haryana, India

Date of Submission08-Oct-2021
Date of Acceptance14-Oct-2021
Date of Web Publication15-Nov-2021

Correspondence Address:
Dr. Raghav Kesri
Department of Medical Oncology, Artemis Hospital, Gurugram, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_43_21

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  Abstract 

Purpose: The purpose of he study was to evaluate the prevalence of epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK), and ROS-1 fusions in the patients with metastatic nonsquamous nonsmall cell lung carcinoma (NSCLC) and their relation with different demographic and clinical variables. Methods: A cross-sectional study was carried out on 87 adult patients >18 years of age with a confirmed diagnosis of Stage IV metastatic NSCLC. All the patients were studied for EGFR mutations, ALK, and ROS-1 fusions. The outcome measures were the presence of EGFR, ALK, and ROS-1 fusions among the patients with NSCLC and the risk association with age, gender, smoking, and tumor differentiation. Results: Out of 87 patients, 26 (29.89%) patients tested positive for EGFR mutations, 4 (4.6%) for ALK, and a single case for ROS-1 fusion. The mean age of the patients who were EGFR positive was significantly younger than the mean age of those without EGFR mutation (56.77 ± 12.01 vs. 66.69 ± 11.34, P = 0.0004). As for the gender, females had significantly more EGFR mutations (53.85% vs. 46.15%, P = 0.013) with an odds ratio (OR) of 3.281 (1.257–8.562). Ex-smokers or nonsmokers showed an increased risk of EGFR mutation with an OR of 87.212 and 38.405 (P < 0.0001). There was no association of histology or grading with EGFR mutation. ALK and ROS-1 showed no significant association with clinical variables (P > 0.05). Conclusion: EGFR mutation is the most common occurrence in NSCLC, with other minor mutations being ALK fusion and ROS-1 rearrangements. Females, young age, and nonsmoking behavior carry a significantly higher risk of EGFR mutation, which usually confers a good prognosis.

Keywords: Anaplastic lymphoma kinase fusion, epidermal growth factor receptor mutations, lung carcinoma, smoking


How to cite this article:
Kesri R, Goyal H, Gupta G, Bharti D, Sharma R. Prevalence and Clinicopathologic Risk Factors for Epidermal Growth Factor Receptor, Anaplastic Lymphoma Kinase, and ROS-1 Fusion in Metastatic Non-small Cell Lung Carcinoma. J Radiat Cancer Res 2022;13:48-53

How to cite this URL:
Kesri R, Goyal H, Gupta G, Bharti D, Sharma R. Prevalence and Clinicopathologic Risk Factors for Epidermal Growth Factor Receptor, Anaplastic Lymphoma Kinase, and ROS-1 Fusion in Metastatic Non-small Cell Lung Carcinoma. J Radiat Cancer Res [serial online] 2022 [cited 2022 Aug 17];13:48-53. Available from: https://www.journalrcr.org/text.asp?2022/13/2/48/330506


  Introduction Top


Lung cancer is the leading cause of cancer-related mortality worldwide.[1],[2] As per the World Health Organization, 2 million new cases and more than 1.7 million deaths were caused by lung cancer in 2018.[3] Lung cancer at 8.5% is the second most frequent cause of cancer-related incidence and mortality according to GLOBOCAN 2018.[4]

In India, lung cancer at present is implicated as the third most typical cause of cancer-related death. Among men, it is the second most commonly detected cancer and cause of cancer-related death, and in females, it is the fifth leading cause of death.[4]

Smoking has been implicated as a cause of lung cancer in innumerable studies. Smoking causes a 10-fold or greater risk of cancer among smokers when compared to nonsmokers.[5],[6] Smoking a pack of cigarettes a day for a year can cause normal lung cells to accumulate on an average of 150 mutations.[7] Further, such mutations have also been inherited in such patients, including p53 (Li-Fraumeni syndrome) and retinoblastoma genes.[8],[9] Mutation involving the epidermal growth factor receptor (EGFR) within exon 20 resulting in T790M amino acid substitution from threonine to methionine (T790M) has been linked to increased lung cancer susceptibility even in never-smokers.[10],[11],[12] Thus, multiple genetic factors determine the way carcinogens are metabolized by an individual. This, in turn, determines the individual susceptibility to the development of lung cancer.

Literature has seen therapeutic advancements for lung cancer in the form of chemotherapeutic agents such as bevacizumab, ramucirumab, nintedanib,[13],[14],[15],[16] and targeted therapy to genetic mutations such as EGFR, anaplastic lymphoma kinase (ALK), Kirsten rat sarcoma viral oncogene homolog (KRAS gene), and receptor tyrosine kinase ROS-1 for limiting cancer-related morbidity and mortality.[17],[18] This has mainly come through due to human genome sequencing. With the shift in histology from squamous cell carcinoma to adenocarcinoma,[19],[20],[21] Theranostics has focused primarily on this subset of lung cancer.[18]

To our knowledge, most of the Indian studies on theranostics have been done in Southern, Central, or Eastern parts of our country. The studies from the North are either from Jammu and Kashmir or from the capital city New Delhi. There is a void of studies from rural India. Our center is a tertiary care center located in Gurugram, Haryana, with the presenting patients mostly from the rural Haryana and Rajasthan belt and engaged in farming and related activities. Most of the patients were bidi or hookah smokers with exposure to fertilizers, stubble burning, fumes being the other etiological factors they are exposed too. This is in contrast to most of the aforementioned studies for the urban population. Our study aims to determine the clinical and epidemiological profile of the patients with lung cancer in correlation with major oncogene mutations (EGFR, ALK, and ROS-1) in metastatic nonsquamous nonsquamous non-small cell lung carcinoma (NSCLC) presenting to our center.


  Methods Top


A cross-sectional study was carried out from July 2018 to January 2020 at a tertiary care facility in Gurugram under the guidance of the Department of Medical Oncology and Department of Pulmonology and Pathology. An institutional ethical committee approval was obtained before starting the study.

Adult patients >18 years of age with a confirmed diagnosis of Stage IV metastatic Nonsmall cell nonsquamous lung Carcinoma (NSCLC) were included. Pregnant, breastfeeding mothers, and patients with a secondary malignancy were excluded. The sample size calculation was based on the study of Mohan A et al.,[2] who observed that EGFR mutations and ALK rearrangements were present in 25.3% and 11.5% patients, respectively. These values were taken as a reference to apply the formula “N ≥ (p[1-p])/(ME/Zα)[2]” where Zα denotes two-sided alpha error of 5%, ME represents a 10% margin of error, and P is the percentage of patients with positive EGFR mutations or ALK rearrangements. The minimum sample required for the present study was 73 patients, which was extended to 87 during the patient enrolment in the study period. Written informed consent was obtained from all patients.

In patients of NSCLC, demographic variables such as age, sex, smoking status, and alcohol history were recorded. Biopsies of the lesions were taken, and histopathology samples were sent for a type of cancer, tumor differentiation, EGFR mutation, ALK, and ROS-1 rearrangement. Formalin-fixed paraffin-embedded tissue blocks were used for the analysis of these mutations. Exons[18],[19],[20],[21] of the EGFR gene were screened for mutation by real-time-based amplification refractory mutation system-polymerase chain reaction assay.

For ALK, immunohistochemistry (IHC) antibodies used were D5F3 (Cell Signaling Technology, Danvers, MA, USA), 5A4 (Novocastra, Newcastle, UK), and ALK clone ZAL4. EML4-ALK gene rearrangement was looked for in the analysis. Detection of ROS-1 rearrangement was based on in situ (IHC, fluorescence in situ hybridization) and extractive non-in situ assays.

The outcome measures were the presence of EGFR, ALK, and ROS-1 fusions among the patients with NSCLC and the risk association of various clinical variables for the occurrence of these mutations.

Statistical analysis

The data were entered into an excel sheet and represented in the tables as n (%) and means ± standard deviation. Further, an association of clinical variables with mutation status was analyzed using Statistical Package for Social Sciences (SPSS) software, IBM manufacturer, Chicago, USA, ver 21.0.

The association of age, which was quantitative and normally distributed in nature, was analyzed using the independent t-test. The association of gender with EGFR mutation was analyzed using the Chi-square test. Fisher's exact test was used for the association of histology, smoking, and histological grading with EGFR, ALK, and ROS1 mutations and association of gender with ALK and ROS1 mutations. The odds ratio with a 95% confidence interval (CI) was calculated for age, gender, histology, smoking, and histological grading for positive EGFR, ALK, and ROS1 mutations.


  Results Top


The mean age of our study population was 63.72 ± 12.4 years with a range of 34–88 years with 65.52% of males and 34.4% of females. Eighty percent were from rural areas, while 20% were from urban areas. In the patient population, 6 (6.9%) patients used to consume alcohol, with the rest 81 (93.1%) being nonconsumers. Of the 87 patients enrolled in the study, 44 (50.57%) were active smokers, with 48.28% being nonsmokers and one patient being a reformed smoker. Adenocarcinomas were the predominant histology, comprising 93.1% cases, with large cell carcinoma comprising 6.9% cases. All the cases of large cell carcinoma were poorly differentiated, while among adenocarcinoma, 57 were well differentiated, 12 were moderately differentiated, and 12 were poorly differentiated [Table 1].
Table 1: Clinical and demographic profile of the study population

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In our study, 26 (29.89%) patients tested positive for EGFR mutations. Of these 26, Exon 19 was the most common mutation expressed in 11 (42.31%) cases. This was followed by Exon 21 (34.62%), Exon 20 (19.23%), and Exon 18 (3.85%) [Table 2].
Table 2: Distribution of mutations

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The mean age of the patients who were EGFR positive was significantly younger than the mean age of those without EGFR mutation (56.77 ± 12.01 vs. 66.69 ± 11.34, P = 0.0004). Statistically, increasing age showed a significantly lower risk of EGFR mutation with an OR of 0.931 (95% CI: 0.892–0.972). As for the gender, females had significantly more EGFR mutations (53.85% vs. 46.15%, P = 0.013) with an OR of 3.281 (1.257–8.562). Ex-smokers or nonsmokers showed an increased risk of EGFR mutation with an OR of 87.212 and 38.405 (P < 0.0001). There was no association of histology or grading with EGFR mutation [Table 3].
Table 3: Association of clinical and demographic characteristics with epidermal growth factor receptor mutation

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ALK fusion mutation was seen in 4 (4.6%) cases, while other cases had wild alleles. Among the four cases of ALK fusion mutation, the mean age was 59.75 ± 4.86 years, with three males (1 smoker) and one female (nonsmoker). All the cases were of adenocarcinoma, among which three were well differentiated and one was poorly differentiated. Due to the small number of cases of ALK mutation, their statistical association with the clinical variables could not be determined.

Only one patient (1.15%) tested positive for ROS-1 fusion. The single case of ROS-1 fusion was a female of age 63 years. She was a nonsmoker who was diagnosed with poorly differentiated adenocarcinoma.


  Discussion Top


Theranostics is a branch of science that deals with the targeted therapy to arising mutations in lung cancer. To further advance this science, the present study holds relevance in elaborating the data about the prevalence of mutations in our hospital catering to patients from nearby rural areas of northern India. We found a prevalence of 29.89% EGFR mutation, 4.6%ALK mutation, and 1.15% ROS-1 fusion among metastatic nonsquamous NSCLC.

EGFR, or ErbB1, or HER1 is a component of the receptor tyrosine kinases family involved in the cascade of signaling pathways such as RAS-RAF and MAPK for cell growth and survival. EGFR may become activated by activating mutations or enhanced ligand production in malignancy.[18]

Compared to our reported EGFR mutation rate of 29.89%, studies across different continents and countries have reported 10%–13.5%. Regional differences have varied from 65% in the South Indian population, as compared to 33% in the North Indian population.[17] This high rate of mutation is promising enough for continuing research on the application of tyrosine kinase inhibitors (such as gefitinib and erlotinib) or monoclonal antibodies (such as cetuximab).[18] The most common EGFR mutation was in exon 19, as reported in 42.31% of cases against the literature reports of up to 60% of cases.[18]

The detection of EGFR mutation should be considered as a positive prognostic factor in terms of survival because of its good therapeutic response to TKI in patients with NSCLC.[22] In a previous study,[23] the OS of 72 patients with EGFR mutation was 9.3 months after instituting TKI, which was significantly higher than 6 months as seen with conventional treatment.[24]

The index study is limited by the survival analysis data and the follow-up but holds strength in determining the association of EGFR with clinical variables. EGFR mutation was predominantly higher in females, young age (fifties), and nonsmokers. Histology and tumor differentiation was not associated with the EGFR mutation status of the patients. Literature has also associated young age, female gender, and nonsmoking status with EGFR mutation, not only from the prevalence point of view but also in overall survival. These have been proposed to be better prognostic factors in patients with EGFR mutation.[23] Besides these factors, hemoglobin <12 g/dl, clinical stage, functional status, and second-line treatment with chemotherapy have also shown an association with EGFR status and survival.[25],[26],[27] It is hypothesized that EGFR mutation is affected by estrogen balance and levels in women. However, a detailed analysis by Bell DW et al.[28] negated the effects of functional variants of estrogen metabolic pathways, thus laying the path for further research on the association of females with EGFR mutations.

The presence of increased EGFR at a lesser age must be interpreted cautiously. The mean age in the present study for EGFR mutation was 56.77 years. The age of fifties can be considered a decent target for EGFR advocating good prognosis 30, but a younger age of <45 years has not been deemed favorable for EGFR target therapy and invariably carries poor prognosis despite the presence of EGFR mutation.[29],[30]

The increased risk of EGFR mutation in nonsmokers or previous history of smokers has been endorsed in the literature with a prevalence of 11%–43%.[31] Similar to our study, Pham et al. observed that smoking history may be a promoter of low-frequency EGFR mutation.[32] The negative correlation of smoking and EGFR mutation was also observed in a Japanese study[33] based on which EGFR mutation has been regarded as an “oncogenic driver mutation of lung cancer in nonsmokers and light smokers.”[34],[35] In a meta-analysis by Ren et al.,[34] the odds ratio (OR) for the EGFR mutation in nonsmokers relative to smokers was 4.829 (95% CI: 3.598–6.482; P < 0.001).

However, the reason for such an association still remains an enigma. As smoking is a significant risk factor for lung carcinoma, it can be suggested that smoking inhibits the occurrence of EGFR mutation since EGFR carries a good prognosis. Future prospective studies among smokers and nonsmokers need to be conducted to compare the EGFR mutation and survival among them.

The ALK-EML4 fusion, as seen in the Lung cancer gene, was first described as ALK-NPM fusion in a case with non-Hodgkin lymphoma.[36],[37] The EML4-ALK fusion oncogene shows a lower prevalence of 3%–7%[38] (our study 4.6%), as compared to EGFR mutation. Similar to EGFR, ALK fusions are also more likely in relatively younger patients (fifties), nonsmokers, or light smokers.[39] However, their association with the female subset remains elusive. We here in this study observed higher ALK fusions in young age nonsmokers, but the analysis failed to cross the statistical boundaries (P > 0.05). The occurrence of ALK fusion remains unassociated with EGFR mutation, and by itself, ALK fusion does not provide a favorable prognosis since literature showed that patients with and without treatment based on ALK fusion (crizotinib, ceritinib) have similar outcomes.[40],[41]

Both EGFR and ALK-fusion have shown TKI resistance based on the amplification of ALK, upregulations of human epidermal growth factor receptor (HER2) and HER3, and cKIT amplification. In such cases, newer drugs have been applied such as ceritinib and alectinib, which hold promise for the future.[18]

ROS1 rearrangements are one of the least common mutations. However, since its expression is high in normal lung tissue, the gene is being explored. The prevalence rate of its mutation was 1.15%, as against the literature reports of 1%–2%. Its mutation is also linked with cancer through signaling pathways such as RAS/MAPK and mTOR pathways. Similar to ALK, it has been seen more in young nonsmokers. Due to its homology with ALK, similar therapeutic targets work against it. The treatment in relation to this gene is under research in the form of foretinib, subsequent to which the effect on survival can be stated.[18]

Limitations of the study

A major limitation of our study was the small sample size. This can be explained by the enrolment being done from a single center and also the shorter period over which the enrolment could be done (one and a half years). A greater number of patients would have led to more comprehensive results and may be a better understanding of the relation of these mutations with different variables. Second, the follow-up of the patients could not be completed as the patients were referred to nearby centers due to the onset of pandemic of COVID-19.


  Conclusion Top


EGFR mutation is the most common occurrence in NSCLC, with other minor mutations being ALK fusion and ROS-1 rearrangements. Females, young age, and nonsmoking behavior carry a significantly higher risk of EGFR mutation, which usually confers a good prognosis. The association of other minor mutations with clinical variables was found insignificant due to the small sample size. The findings might help in predicting the prognosis and deciding the targeted therapy accordingly in a different subset of populations who present in the last stage of lung cancer.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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