الفهرس 
E PIDEMIOLOGY AND R ISK F ACTORS OF L UNG C ANCEROnly 14 pages are availabe for public view
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Abstract
Background: The management of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) has dramatically changed following the introduction of target therapy in the last 15 years. Comprehensive reflex biomarker testing, including EGFR, is recommended for all patients with a diagnosis of non-squamous NSCLCs, regardless of disease stage and should be initiated by the pathologist at the time of initial diagnosis.
Objective: To compare the response to Geftinib between EGFR mutation exon 19 and EGFR mutation exon 21 in non- small cell lung cancer in Egyptian patients.
Methods: Our retrospective analysis examined 60 patients with advanced NSCLC who had received gefitinib therapy and the specimen were available at Shefa Alorman Oncology Hospital from June 2017 to May 2020.
Results: Our study showed no statistically difference as regard response to first line treatment between exon 19 deletion and exon 21 mutation with P Value= 0.1273. Our study showed no statistically significance as regard progression free survival after first line treatment Gefitinib between exon 19 deletion and exon21 mutation with median PFS 12 months for patient with exon 19 deletion compared to 10 months for patients with exon 21 mutation (Hazard ratio of progression or death 1.57; 95 % confidence interval 0.87 – 2.82; P- Value= 0.1269).Median PFS of study population was 12 months. The median survival was 27 months for exon 21 group while median survival not reached for exon 19 group (Hazard ratio for death 2.95; 95 % confidence interval 0.78 – 11.20). Median survival of whole study population was 33 months.
Conclusion: The EGFR mutation subtype should be considered when making treatment decisions for designing new clinical trials for chemotherapy-naïve, EGFR mutation-positive patients with advanced NSCLC.
Keywords: Geftinib; EGFR Mutations; Non-Small Cell Lung Cancer
INTRODUCTION
Lung cancer is the second most common cancer in women (after breast cancer) and in men (after prostate cancer) but is the most common cause of cancer-related death (Siegel et al., 2019).
Every year, more than 1.7 million patients die of lung cancer worldwide. About 70% of patients are diagnosed in advanced stages of disease, when the probability of cure is low. In Egypt, there was about 6538 newly diagnosed patients with lung cancer in 2020 (figure 2), that sets lung cancer as the 5th most common cancer type after liver, breast, bladder and non- Hodgkin lymphoma (Sung et al., 2021).
As in other malignancies, novel systemic therapies for the treatment of NSCLC have shifted from cytotoxic chemotherapy to molecularly targeted agents.
To date, one of the most successful classes of novel targeted agents for the treatment of NSCLC used inhibition of EGFR pathway.
All patients diagnosed with advanced non-small cell lung cancer, especially those specifically diagnosed with adenocarcinoma, are evaluated for EGFR genetic mutations.
The presence of an EGFR mutation is determined by molecular profiling (gene testing). The process conducted with a lung biopsy to get a tissue sample that is then tested in a lab. The DNA of the tumor cells is analyzed to determine if it contains any mutations in the EGFR gene.
We may also be able to check for the mutations via a special blood test called a liquid biopsy, which analyzes DNA that has been shed from tumor cells in your blood. Often, the DNA sample from a blood draw is not significant enough to make a clear diagnosis, but research is being done to find effective ways to use liquid biopsies in the diagnosis or monitoring of lung cancer.
The EGFR gene is divided into 28 numbered sections called exons, each of which are at risk for mutation. The most common EGFR mutations include missing genetic material on exon 19 (19-del) or damage to exon 21 (21-L858R). These two mutations account for about 85% of the EGFR mutations of lung cancer cells. Exon 20 insertion mutations may also occur, but they are much rarer. It’s estimated that EGFR and other driver mutations (i.e., DNA changes that determine the development of the cancer) are present in as many as 70% of people with lung adenocarcinoma (Hong et al., 2019).
Historically, chemotherapy had been the first course of treatment for almost all cases of advanced non-small cell lung cancer, but FDA-approved targeted therapy drugs are now the main choice for treating tumors with EGFR mutations (Han et al., 2017).
These medications tend to have fewer side effects than chemotherapy and will not kill healthy cells. The introduction of targeted therapy medications over the past decade has given patients new opportunities to stop lung cancer from advancing while improving survival rates and quality of life (Inoue et al., 2013).
The targeted therapy drugs Tagrisso (osimertinib), Tarceva (erlotinib), Gilotrif (afatinib), and Iressa (gefitinib) are known as tyrosine kinase inhibitors because they prevent the EGFR protein on mutated cells from triggering tyrosine kinase, an enzyme within cells that activates cell division and, thus, multiplies cancer cells.
Tremendous progress has been made in both the identification of genetic changes with lung cancer and targeted therapies to treat these changes. There are many clinical trials looking at other medications to treat EGFR mutation-positive lung cancer, as well as treatments for other molecular changes in cancer cells.
AIM OF THE WORK
This study aims to compare the response rate and progression free survival of the two common EGFR mutations subtypes (exon 19 del and L858R) to geftinib in Egyptian patients with advanced EGFR mutant NSCLC as primary endpoint and to assess the overall survival and toxicity of study population as secondary end points.
PATIENTS AND METHODS
This retrospective cohort study was done on 60 patients with EGFR mutated stage IV non- small cell lung cancer (non- squamous histology) who were recruited from medical oncology department at Shefa Alorman hospital, Luxor, Egypt during the period from June 2017 to May 2020.
Patients were enrolled in the study according to the following inclusion criteria: Diagnosed with stage IV non small cell lung cancer, pathologically proved adenocarcinoma, large cell or NSCLC NOS (non-squamous histology) with EGFR mutation either with exon 19 deletion or exon 21 (L858R) mutations, patients with ECOG performance status (PS) 0–2, all patients had been treated with gefitinib as first line treatment for metastatic disease until disease progression, measurable disease by response evaluation criteria in solid tumor (mRECIST), and adequate hematological, renal and hepatic function. While patients with squamous cell carcinoma histology, double malignancy, prior systemic therapy for advanced NSCLC, other uncommon subtypes of EGFR mutations and unavailable follow up data were excluded from the study.
Clinic epidemiological data, significant dates and information about treatment toxicity were manually retrieved from the medical records of all patients included in this study; then were properly collected, revised and analyzed. Clinical and pathological tumor characteristics were collected using patient charts and pathology reports. Tumor tissues obtained from paraffin-embedded mutations in EGFR exons 18–21 were analyzed by direct sequencing and Results were collected from patients medical records at Shefa –Elorman hospital. All patients underwent pretreatment evaluation: Clinical examination, baseline assessment of hematological, renal and hepatic function, baseline evaluation of the tumor burden using radiological images (computed tomography {CT scan}, magnetic resonance image {MRI} or positron emission tomography {PET scan}). All patients received Gefitinib at a dose of 250 mg daily. The treatment was continued until progression or development of unacceptable toxicity. All the measurable disease was evaluated using the modified RECIST criteria. All the patients were evaluated for best response achieved every 3 months using the same baseline imaging study used according to the modified RECIST criteria. Evaluation could be done earlier in case of frank signs/ symptoms of progression. Toxicity assessment during treatment was recorded using Common Toxicity Criteria – NCI version 4.03.
Sampling Method: Consecutive sampling (all eligible patients in the previously determined period fulfilling the eligibility criteria were included).
Ethical consideration: All documentations were anonymous, collected by the researcher himself from patients medical records.
Study primary end points: Evaluate 1) response rate. 2) progression-free survival. 3) toxicity related to Geftinib between EGFR mutation exon 19 and EGFR mutation exon 21.
Study secondary endpoint: Assess the overall survival for the study population.
Statistical Analysis: Data were collected, revised, coded and entered to the Statistical Package for Social Science (IBM SPSS) version 20. The qualitative data were presented as number and percentages while quantitative data were presented as mean, standard deviations and ranges when their distribution found parametric. Then the appropriate statistical analyses were applied. The confidence interval was set to 95 % and the margin of error accepted was set to 5 %.