|Ahead of print
|The Study of Druggable Targets in Nonsquamous Non-Small-Cell Lung Cancer in the Middle East and North Africa
Abdul Rahman Jazieh1, Adda Bounedjar2, Fouad Al Dayel3, Shamayel Fahem3, Arafat Tfayli4, Kakil Rasul5, Hassan Jaafar6, Mohammad Jaloudi6, Turki Al Fayea7, Hatim Q Al Maghrabi8, Hanaa Bamefleh1, Khaled Al Kattan3, Blaha Larbaoui9, Taha Filali10, Hamed Al Husaini3, Yosra Ali1, in collaboration with the Arab Collaborative Hematology Oncology Group (ACHOG)11
1 King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, KSA
2 BLIDA 1 University, CHU BLIDA, Algeria
3 King Faisal Specialist Hospital and Research Center, Riyadh, KSA
4 The American University of Beirut, Lebanon
5 Weill Cornell Medical College/Hamad Medical Corporation, Qatar
6 Tawam Hospital, UAE
7 Princess Noorah Oncology Center, King Abdulaziz Medical City, Jeddah, KSA
8 King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Jeddah, KSA
9 Anti Cancer Center, Oran, Algeria
10 Centre Hospitalo Universitaire Ben Badis de Constantine, Constantine, Algeria
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Background: Druggable molecular targets are very important in the management of non-small-cell lung cancer (NSCLC). The purpose of our study is to determine the pattern of testing and mutation prevalence in the Middle East and North Africa population. Patients and Methods: Data of consecutive patients with nonsquamous NSCLC were collected from 10 centers in five countries; Saudi Arabia, UAE, Qatar, Lebanon, and Algeria. Statistical analysis was performed to delineate the prevalence of druggable targets and other relevant information. Results: Five hundred and sixty-six patients were included in the study. Majority were males (78.1%) with a median age of 61 years (22–89), 50% were current or ex-smokers and 370 patients (65.4%) were Stage IV. The epidermal growth factor receptor (EGFR) testing was performed on 164 patients of all stages. EGFR mutation was detected in 30 out of 96 patients (31.3%) with metastatic disease and in 12 out of 68 patients (17.6%) with Stage I to III. Female sex (39.5% vs. 22% males, P = 0.032), Stage IV (31.2% vs. 17.6% in Stage I to III, P = 0.049), and positive immunohistochemical-TTF1 (31.4% vs. 8.7% negative, P = 0.026) were predictors of mutation on univariate analysis. The multivariate analysis showed that patients with stage IV have three times higher positivity than lower stages (odds ratio = 3.495, P = 0.036). Anaplastic lymphoma kinase fusion was present in seven out of 89 patients (7.8%) of all stages, and only three out of 52 patients (5.8%) with metastatic disease. The reasons for not performing the tests in all of the 370 patients with metastatic disease were: physicians do not know where and how to send the test (62.3%), lack of funding to perform the test (11.1%), insufficient tissue (10.1%), and other reasons (16.6%). Conclusions: Only a small fraction of patients with NSCLC are tested for druggable targets and the prevalence of EGFR mutation is prevalence higher than the Western population. Overcoming the challenges of testing requires systematic plans to address education and resource allocation.
Keywords: Druggable, druggable targets, lung cancer, non-small-cell lung cancer, nonsquamous non-small-cell lung cancer
|How to cite this URL:|
Jazieh AR, Bounedjar A, Al Dayel F, Fahem S, Tfayli A, Rasul K, Jaafar H, Jaloudi M, Al Fayea T, Al Maghrabi HQ, Bamefleh H, Al Kattan K, Larbaoui B, Filali T, Al Husaini H, Ali Y, in collaboration with the Arab Collaborative Hematology Oncology Group (ACHOG). The Study of Druggable Targets in Nonsquamous Non-Small-Cell Lung Cancer in the Middle East and North Africa. J Immunother Precis Oncol [Epub ahead of print] [cited 2019 Jan 16]. Available from: http://www.jipoonline.org/preprintarticle.asp?id=249992
| Introduction|| |
Lung cancer is a major cancer killer worldwide affecting about 1.8 million people. The majority of the lung cancer cases are of non-small-cell lung cancer (NSCLC) subtype.
The management of NSCLC has rapidly evolved over the last decade as a result of a better understanding of the disease biology and the discovery of important actionable targets. The most widely used targets in NSCLC include epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK)-EML4 translocation, ROS1, and others.,
The prevalence of these actionable targets varies among the different population with a higher prevalence of EGFR mutation in Far Eastern population (40%–50%) compared to the Western Caucasian population (10%–20%).,,,,, There are multiple available treatment options that improve disease response, patient survival, and quality of life. Therefore, identifying these targets is a critical step in providing proper management for NSCLC patients.
Data about the expression of these targets in the Middle Eastern and North Africa (MENA) population is scarce, and usually, they are from one country or center.,, The rate of testing for these targets and the challenges of performing the tests are not known. Our prior study of EGFR mutation prevalence in the Gulf countries revealed that 33% of the patients had EGFR mutation. However, that study included those who already underwent testing which means they were selected by physicians to be tested. Therefore, the study might have included patients who were thought by oncologists to have the mutation (clinically enriched population) and therefore, the study may have missed other patients who were not tested. The aim of the current study is to determine the frequency of testing of these targets, their prevalence rate and the challenges for testing in the MENA region.
| Patients and Methods|| |
This is a retrospective study that included all consecutive NSCLC patients seen at the participating centers between January 2013 and January 2014.
Ten centers from five countries participated in the study including Saudi Arabia, Algeria, United Arab Emirates, Lebanon, and Qatar.
All consecutive NSCLC cases during the study were included from participating centers to avoid selection bias during the study.
Our study included only EGFR and ALK tests as testing for other targets were not performed in our region at the study period. EGFR tests were conducted by polymerase chain reactions for exons. ALK-EML4 fusion was done using fluorescence in situ hybridization technique.
Statistical analysis plan
Demographic data and disease characteristics were collected along with testing for molecular targets. The results of the tests and reasons for not testing were captured.
SAS V9.2 (SAS Institute, NC, USA) was used for data analysis. Both descriptive and analytic inferential statistics were conducted. A two-tailed P ≤ 0.05 was accepted as statistically significant for all statistical tests. All variables were analyzed descriptively for their demographic, clinical, and pathological characteristics. Counts and proportions for all categorical variables, proportions of patients underwent molecular testing for their tumor, besides calculating the prevalence of different lung cancer molecular markers (EGFR and ALK fusion) among tested patients were done. Different reasons for not performing molecular tests were calculated. Continuous variables including age were described as mean ± standard deviation or median with range.
Both univariate and multivariate analyses were applied to assess the correlation between the demographic and clinical characteristics of interest in relation to EGFR status where Chi-square and odds ratio (OR) with their significance level were reported, respectively, to show the magnitude of the correlation.
Institutional Review Board approvals were obtained before the commencement of the study.
| Results|| |
Five hundred and sixty-six patients were included in the study. [Table 1] depicts the patients and disease characteristics. Majority of patients were males (78%) with a median age of 61 years (22–89), 50% were current or ex-smokers and 370 patients (65.4%) were stage IV. EGFR testing was performed on 164 patients of all stages [Table 2]. EGFR mutation was detected in 30 out of 96 patients (31.3%) with metastatic disease and in 12 out of 68 patients (17.6%) with Stage I to III. Female sex (39.5% vs. 22% males, P = 0.032), Stage IV (31.2% vs. 17.6% in Stage I to III, P = 0.049), and positive immunohistochemical-TTF1 (31.4% vs. 8.7% negative, P = 0.026) were predictors of mutation on univariate analysis [Table 3]. The multivariate analysis showed that patients with stage IV have three times higher mutation rate than earlier stages (OR = 3.495, P = 0.036) [Table 4].
|Table 2: Results of epidermal growth factor receptor and anaplastic lymphoma kinase testing|
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|Table 3: Univariate analysis for the association between epidermal growth factor receptor results and patient characteristics|
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|Table 4: Multivariate analysis for the association between epidermal growth factor receptor results and patient characteristics|
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On the other hand, ALK fusion was positive in seven out of 89 patients (7.8%) of all stages, and only three out of 52 patients (5.8%) with metastatic disease [Table 3].
The reasons for not performing the tests in all of the 370 patients with metastatic disease were: physicians do not know where and how to send the test (62.3%), lack of funding to perform the test (11.1%), insufficient tissue (10.1%), and other reasons (16.6%) [Table 5].
|Table 5: Reasons for not performing molecular studies in stage IV non-small-cell lung cancer (n = 199)|
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| Discussion|| |
Our study, which is thefirst multisite multi-countries in the Middle East, revealed low penetration of molecular testing. This low rate may be explained by the slow dissemination of new practice changes in some regions which may not be due to a lack of knowledge only but also due to lack of logistics and infrastructure support. Further investigation into the challenges of performing molecular testing is needed to recommend proper interventions. For example, funding was the main reason for the drop in EGFR testing in Canada. Although in our study, the lack of funding reported by a small number of physicians, having more physicians trying to do the test may raise more concerns about the issue of funding. Most physicians did not know what to do, therefore, coordinating such services and providing logistic support would help these physicians. Easy access to laboratory and referral center (Central Laboratory) would facilitate testing. The access to these tests should be planned at the national level with proper referral network and processes coupled with education of physician and implementation of a multidisciplinary approach.,
However, our study might have captured the early curve of diffusion of these tests and this may represent the early adoption phase of a new technology, which will take off rapidly after the initial phase of early adoption. Nevertheless, multiple challenges resulted in the limited diffusion of the testing in country like the US, where only 59% of the patients met the guideline of EGFR testing in a community setting. The emergence of liquid biopsy may help overcome some of these challenges but will not eliminate them completely.
The prevalence of EGFRMut in our population is higher than the Western population and lower than that in the Far Eastern population. This reflects the difference in ethnic and racial composition of the studied population and being geographically in the middle of these two ethnic groups may be a reason for having mixed pools of gene from both population.,
The higher prevalence in EGFR mutation in metastatic disease compared to the earlier stage is intriguing and warrant further evaluation. Not previously reported, it may reflect different disease biology, but this observation requires validation with larger sample size.
Our study is the largest study that included multisite and multi-countries in our region. The retrospective design is one of the limitations of our study. However, the large sample size and the inclusion of consecutive patients helped in getting a real-life data and avoiding selection bias. The number of tested patients is small and having more patients tested will give better picture of the prevalence of these mutations.
Finally, our study highlights the need for systemic education and approach to disseminate and apply a new practice changing evidence in our region. In a recently published study, investigators reported a gap in knowledge among Canadian physicians of various disciplines and showed that an educational intervention would help in improving their knowledge which resulted in 12% increase (57% relative) in EGFR testing requests.
| Conclusions|| |
Our study revealed that EGFR mutation is prevalent in good percentage of our patient population, but there is a need to enhance the process of testing for more patients in a timely fashion to offer the most appropriate treatment.
Consorted efforts to implement intervention are needed to facilitate the testing for all actionable targets in NSCLC.
Financial support and sponsorship
The authors disclosed no funding related to this article.
Conflicts of interest
Blaha Larbaoui disclosed the following conflicts of interest: consulting and advisory roles for Roche, Merck, Novartis, Jansen, and Amgen. The other authors disclosed no conflicts of interest related to this article.
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Abdul Rahman Jazieh,
Department of Oncology, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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