Non-Small Cell Lung Cancer (NSCLC) and EGFR Mutations: Analysis

This report examines the relationship between EGFR mutations and non-small cell lung cancer (NSCLC), focusing on uncommon EGFR mutations and their impact on treatment effectiveness and patient prognosis. The research, based on a study of patients from Taiwan, explores various EGFR mutations, including exon 19 deletions and L858R, and their responses to tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib. The study analyzes the clinical features, treatment outcomes, and survival rates associated with different EGFR mutations. The report highlights the mechanisms of action for gefitinib, erlotinib, and afatinib, and compares the objective response rates and progression-free survival among patients receiving different TKI therapies. The conclusion emphasizes the potential of afatinib for effective treatment, while also acknowledging limitations such as the observational study design and the need for larger-scale research. The report provides insights into the complexities of NSCLC treatment and the importance of considering specific EGFR mutations when selecting therapeutic approaches.

Running head: EGFR & NSCLC
EGFR & NSCLC
Name of the student
Name of the university
Author’s name

1EGFR & NSCLC
Introduction
Lung cancer has been considered as the major reason for the death in the men and breast
cancer has been considered as the major reason for death in the women (Faehling et al., 2017).
There are two types of lunch cancer – NSCLC (Non-small cell lung cancer) and SCLC (Small
cell lung cancer). In the paper of Chang, Lim, Chang, Chen, Shih and Yu (2019), the researchers
have discussed about the NSCLC. The researchers have tried to prove that the EGFR (Epidermal
growth factor receptor) mutation results in the NSCLC. The EGFR gene is the manufacture
industry of the EGFR trans-membrane protein which acts as a receptor for the epidermal growth
factor family (EGF family) of extracellular protein ligands. It has been seen that in around 40–
80per cent NSCLCs, the EGFR mutation is the major cause (Keam et al., 2014). Though,
NSCLCs has been shown to have a number of mutations, majorly involving the mutation of the
EGFR and KRAS (Kutkowska, Porębska & Rapak, 2017). Along with these, there are two most
commonly mentioned mutations have been discussed which are Exon 19 deletion and L858R
mutation in exon 21 of the EGFR, as a result it predicts a good response to EGFR-TKI (tyrosine
kinase inhibitors) (Choi et al., 2018). Other than the exon 19 deletions and L858R EGFR
mutations, all the other type of mutations are measured as ‘uncommon mutations’. In the paper
of Chang, Lim, Chang, Chen, Shih and Yu (2019), the researchers have tried to investigate other
possible mutations that result in the NSCLC expect the mutations which have been already been
mentioned.

2EGFR & NSCLC
Methodology
For the following research, the researchers selected patients with NSCLC harboring
EGFR mutations within the year 2011 – 2017. The settings for conducting the research were
three hospitals - National Taiwan University Hospital, Far Eastern Memorial Hospital and
National Taiwan University Hospital all of which were located in Taiwan. The stage of the lung
cancer was determined using the 7th edition of American Joint Committee on Cancer staging
system. MassARRAY genotyping (Sequenom, San Diego, CA), polymerase chain reaction-direct
sequencing and e-cobas EGFR Mutation Test (Roche) were the tools using which the researchers
did EGFR mutation testing. Along with these, other EGFR mutations data and plasma circulating
tumour DNA test results were also accumulated.
Discussion
According to a report, the major reasons behind the occurrence of NSCLC except the
genetic mutations are smoking cigarettes, exposure to asbestos and certain paints or chemicals.
For the treatment of this disease, the patients were separated into two groups initially. One group
was given 250 mg of gefitinib/150 mg of erlotinib as the first line therapy and another group was
given 30 mg or 40 mg of afatinib relying on the decision of the doctor. During the EGFR-TKI
treatment, imaging techniques were also conducted, that is chest and brain CT during the period
of f 8 to 12 weeks and 2 - 4 weeks correspondingly. The best treatment plan was appraised using
the Response Evaluation Criteria in Solid Tumours, version 1.1. Further data were analyzed
using the Chi-square tests. Consistent variables were articulated as medians with range or
interquartile ranges (IQRs). The variances of progression-free survival (PFS) and overall survival
(OS) among the patient groups of gefitinib/erlotinib and afatinib were evaluated using the log

3EGFR & NSCLC
rank test and designed by a Kaplan-Meier method. Multivariate evaluation of the PFS and OS
were conducted utilizing the Cox regression models. Eventually, all the statistical analysis was
done using the SPSS 22.
Mechanism of action
 Gefitinib - Gefitinib binds with the binding site of the adenosine triphosphate (ATP) of
the enzyme and as a result, it inhibits the EGFR-tyrosine kinase. Therefore, the role of the
EGFR-TKI in initiating the anti-apoptotic Ras signal transduction cascade is stopped, and
malignant cells are destroyed or reduced (Segovia-Mendoza, González-González,
Barrera, Díaz & García-Becerra, 2015).
 Erlotinib – The mechanism of action for the erlotinib has not yet been fully researched,
and thus there is limited number of information. Though, as per the study, erlotinib
restricts the intracellular phosphorylation of TKI linked to the EGFR (Cheung et al.,
2016).
 Afatinib – It is a protein kinase inhibitor that also permanently constrains human EGFR-
2 (Her2) and EGFR kinases (Saber, Hiltermann, Kok & Groen, 2016).
Result
For the study, total 1983 patients were selected in the EGFR-mutated NSCLC study. The
researchers found that 62.7per cent of the patients had single mutation, which involved 31.1per
cent patients with G719X mutation, 25.4per cent patients with L861Q, 3.4per cent patients with
S861I mutation, 2.3per cent patients with E709X mutation and 0.6per cent patients with L747P
mutation. Rest of the 37.3per cent of patients had NSCLC concealing more than one type of
EGFR mutation along with which there were 20.3per cent patients who had exon 19 deletion or

4EGFR & NSCLC
L858R mutation and 16.9per cent of patients without these mutations. For the treatment outcome
analysis, 72 patients were selected who had advanced stage of NSCLC and were receiving
EGFR-TKIs as the first-line therapy.
After this phase, 39 patients or 54.2per cent of patients were selected who were receiving
EGFR-TKI therapy, comprising 26 (36.1per cent) gefitinib and 13 (18.1per cent) erlotinib, while
33 (45.8per cent) established afatinib, the second-generation EGFR-TKI. The research showed
an objective response rate (ORR) of 35.8per cent and a median PFS of 8.8 months in the patient
group who had gefitinib/erlotinib. Whereas patients who received afatinib therapy had an ORR
of 60.6per cent, and the median PFS was 12.0 months. The NSCLC concealing non-resistant
uncommon type of mutation are considered to be less sensitive to the 1st generation EGFR-TKI
compared to that of the common mutations, while the treatment efficiency of afatinib on NSCLC
harboring common and non-resistant uncommon mutation may not be considerably diverse.
Conclusion
Even though the researchers were able to identify the common and uncommon type of
EGFR mutations resulting in the NSCLC, there were significant numbers of limitations. Since it
was an observational study, thus all the decision was based on the clinical judgment of the doctor
which caused a selection bias. Then, the case number was found to be too small, due to which
subgroup analyses became challenging. Ultimately, the research failed to identify the rare type of
mutations such as the V717G and I719V. The paper concluded that afatinib can be used for
effective treatment but survival benefits can only be found in the gefitinib or erlotinib for
patients with NSCLC harboring non-resistant uncommon EGFR mutations. The researchers also

5EGFR & NSCLC
suggested for a large-scale research regarding the NSCLC harboring non-resistant uncommon
EGFR mutation.

6EGFR & NSCLC
References
Chang, L. C., Lim, C. K., Chang, L. Y., Chen, K. Y., Shih, J. Y., & Yu, C. J. (2019). Non-small
cell lung cancer harbouring non-resistant uncommon EGFR mutations: Mutation patterns,
effectiveness of epidermal growth factor receptor-tyrosine kinase inhibitors and
prognostic factors. European Journal of Cancer, 119, 77-86.
Cheung, P. W., Nomura, N., Nair, A. V., Pathomthongtaweechai, N., Ueberdiek, L., Lu, H. A. J.,
... & Bouley, R. (2016). EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–
Mediated Renal Water Reabsorption. Journal of the American Society of
Nephrology, 27(10), 3105-3116.
Choi, Y. W., Jeon, S. Y., Jeong, G. S., Lee, H. W., Jeong, S. H., Kang, S. Y., ... & Sheen, S. S.
(2018). EGFR Exon 19 Deletion is Associated With Favorable Overall Survival After
First-line Gefitinib Therapy in Advanced Non–Small Cell Lung Cancer
Patients. American journal of clinical oncology, 41(4), 385-390.
Faehling, M., Schwenk, B., Kramberg, S., Eckert, R., Volckmar, A. L., Stenzinger, A., & Sträter,
J. (2017). Oncogenic driver mutations, treatment, and EGFR-TKI resistance in a
Caucasian population with non-small cell lung cancer: survival in clinical
practice. Oncotarget, 8(44), 77897.
Keam, B., Kim, D. W., Park, J. H., Lee, J. O., Kim, T. M., Lee, S. H., ... & Heo, D. S. (2014).
Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine
kinase inhibitor in patients with non-small cell lung cancer. International journal of
clinical oncology, 19(4), 594-600.

7EGFR & NSCLC
Kutkowska, J., Porębska, I., & Rapak, A. (2017). Non-small cell lung cancer-mutations, targeted
and combination therapy. Postepy higieny i medycyny doswiadczalnej (Online), 71, 431-
445.
Saber, A., Hiltermann, T. J. N., Kok, K., & Groen, H. J. M. (2016). Resistance mechanisms after
tyrosine kinase inhibitors afatinib and crizotinib in non-small cell lung cancer, a review
of the literature. Critical reviews in oncology/hematology, 100, 107-116.
Segovia-Mendoza, M., González-González, M. E., Barrera, D., Díaz, L., & García-Becerra, R.
(2015). Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib,
lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and
clinical evidence. American journal of cancer research, 5(9), 2531.