MINISTRY OF EDUCATION AND TRAINING
MINISTRY OF HEALTH
HANOI MEDICAL UNIVERSITY
LE HOAN
CLINICAL, SUBCLINICAL FEATURES AND
RESISTANCE TO TYROSINE KINASE INHIBITOR
OF LUNG CANCER PATIENTS WITH
EGFR MUTATIONS
SPECIALTY: PULMONARY MEDICINE
CODE: 62.72.01.44
SUMMARY OF PHD THESIS
HA NOI - 2020
THE RESEARCH WAS COMPLETED
IN HANOI MEDICAL UNIVERSITY
Supervisor: Prof. NGO-QUY Chau, MD. PhD
Reviewer 1: A. Prof. NGUYEN Dinh Tien, MD. PhD
Reviewer 2: A. Prof. NGUYEN Tuyet Mai, MD. PhD
Reviewer 3: A. Prof. CHU Thi Hanh, MD. PhD
The thesis is defended in front of the Thesis Committee of the
University at Hanoi Medical University.
The thesis can be accessed at:
- Vietnam National Library
- Hanoi Medical University Library
INTRODUCTION
1. Rationale
Lung cancer is recently the leading cause of cancer related mortality in
the world. Until now, a number of gene mutations have been identified to be
related to the pathogenesis of lung cancer with the most common ones are
mutations of EGFR gene. The targeted therapy with tyrosine kinase inhibitors
(TKIs) is proved to be an effective therapy for non small cell lung cancer with
EGFR mutation. However, researches showed that after 12 to 24 months with
EGFR-TKIs therapy, most of patients developed the drug-resistance. Several
mechanisms underlying drug-resistance to EGFR-TKIs have been identified
such as the development of new mutations of EGFR gene, the amplification or
increasing the expression of other genes; as well as the transformation of
cancer cells. Among those, the most important mechanisms are induced
T790M mutation and MET amplification, which account for over 70% of
EGFR-TKIs resistant cases. In Viet Nam, EGFR mutations targeted therapies
have been used recently and drug-resistance has been found in clinical practice.
Therefore, it is necessary to study the EGFR-TKIs resistance in lung cancer
patients in order to identify the mechanism of the resistance and to point out
the strategy for the next period of those patients.
2. Objectives
1. To describe the clinical and subclinical features of lung cancer
patients with EGFR mutations before TKIs therapy and in the
relapsed period.
2. To identify the T790M mutation and MET amplification in patients
with lung cancer and EGFR-TKIs resistance and the relationship with
clinical and subclinical features.
3. Scientific and practical meanings
Identification of the clinical and subclinical features of lung cancer
patients with EGFR mutations help us to generalize specific features of this
patients group, for individualizing in treatment. Knowing the features of
patients at the time of they develop EGFR-TKIs resistance can support for the
recommendations of clinical practice to find out the resistance early.
Studying the mechanism underlying EGFR-TKIs resistance in lung cancer
patients with EGFR mutations is the scientific evidence to choose the
following therapy for those patients. Patients with EGFR-T790M can be
treated with the later generations of EGFR-TKIs such as afatinib, dacomitinib,
osimertinib,…While patients with MET amplification can be treated with MET
inhibitors like crizotinib, tivantinib,...
4. Novelty
It is the first research in Viet Nam to study of clinical and subclinical
features of lung cancer patients with EGFR mutations and the mechanism
underlying EGFR-TKIs resistance. The results of this research can provide
clinical doctors with the view of targeted therapy including treatment outcome,
drug resistance, therefore they can have a appropriate approach for patients
developing drug resistance.
5. Thesis structure
The thesis includes 118 pages (without References and Appendix),
divided into 7 parts:
- Introduction: 3 pages
- Chapter 1: Literature review, 35 pages
- Chapter 2: Methodology, 15 pages
- Chapter 3: Results, 29 pages
- Chapter 4: Discussions, 31 pages
- Conclusions: 4 pages
- Recommendations: 1 page
The thesis includes 26 tables, 23 charts, 09 figures. It has 148 references
in Vietnamese and English. Appendixes include Research Forms and the list of
66 lung cancer patients.
Chapter 1: LITERATURE REVIEW
1. Overview of lung cancer
Lung cancer is the most common and has the highest rate of mortality in all
kinds of cancer. According to the GLOBOCAN 2018 database, it was estimated
2.09 millions new lung cancer cases and 1.76 millions lung cancer deaths
worldwide. In the United States, lung cancer is the leading cause of cancer death
and the second-ranked cancer incidence in both genders. There was an estimated
228150 new lung cancer cases and 142670 lung cancer deaths in the US in 2019,
account for 23% of all cancer deaths.
According to researches, lung cancer is more common in males. In 2018,
it was estimated that there were 1377500 lung cancer cases in males,
accounting for 66% all lung cancer cases, with the gender rate of 1.94/1. In
developing countries, the gender rate may be higher, while in developed
countries, the prevalence of lung cancer in female is rising. In the US in 2019,
those numbers was 116440 cases and 111710 cases respectively. In Viet Nam,
according to GLOBOCAN 2018 database, there was an estimated 23667 new
lung cancer cases, with the 2nd ranked in all cancers, after liver cancer.
Smoking is considered the major risk factor of lung cancer, that
approximately 80- 85% of lung cancer patients in the world smoked. Other risk
factors of lung cancer include: air pollution, ionized radiation, occupational
exposure, virus, diet, history of respiratory diseases.
Researches of molecular level revealed that the development of lung
cancer had several periods with the interactions of some factors, the
sensitization of genes, cumulative process of gene mutations of oncogenes and
tumor suppressor genes. Genes regulations is originally smooth and tight, when
it is impaired it can lead to the abnormal enhancement or inhibition of
functional genes.
With whole genome sequencing of a clone of lung cancer cells, it is partly
understood about intracellular mediators signaling pathway related to the
activation of oncogenes and deactivation of suppressor genes. The activation of
oncogenes through the signaling pathway of EGFR and other tyrosine kinase
receptors such as MET, Her-2, c-KIT, IGF-1R... in addition with the following
activation of RAS/RAF/MEK/MAPK, PI3K/AKT and JAK/STAT can lead to
the nonstop proliferation, differentiation, invasion, metastasis and resistance to
apoptosis.
In normal cells, the activation of EGFR is necessary for several crucial
functions of cells such as the proliferation and differentiation. But the extreme
activation due to gene mutations can lead to the abnormal proliferation as well
as the transformation of cells. In addition, the impaired activity of EGFR due to
gene mutation can lead to maglinant disorders. The mutation in exon 18- 21
makes EGFR to be in activating status independent from mediators.
Features of EGFR mutations in NSCLC patients include: high rate in non-
smokers, more common in adenocarcinoma type compared to other types of
NSCLC, females are more common than males, higher rate in East Asian
patients compared to other races.
2. EGFR-TKIs therapy for lung cancer
EGFR mutations had a quite high prevalence in NSCLC patients,
especially the adenocarcinoma and in non-smokers. Researches in Europe and
North America showed the prevalence of mutations is approximately 17%,
while it is up to 78.8% in East Asia. With whole genome sequencing,
researchers can identify a number of mutations of EGFR influencing the
response to TKIs. The common mutation of EGFR being sensitive to TKIs is
LREA (exon 19) and L858R (exon 21). Some EGFR-TKIs being used recently
are erlotinib, gefitinib, afatinib. Clinical trials showed that EGFR-TKIs help
prolong non-disease survival time better than standard chemotherapy. 6 phase