KẾT QUẢ ĐIỀU TRỊ UNG THƯ PHỔI BIỂU MÔ TUYẾN DI CĂN NÃO CÓ ĐỘT BIẾN EGFR BẰNG TKIs THẾ HỆ 1

Mục tiêu: Đánh giá kết quả điều trị ung thư phổi biểu mô tuyến di căn di căn não có đột biến EGFR bằng TKIs thế hệ 1 và một số yếu tố liên quan đến PFS. Đối tượng nghiên cứu: Gồm 66 bệnh nhân UTP biểu mô tuyến di căn não có đột biến gen EGFR (Del exon 19 hoặc L858R exon 21) được điều trị bước 1 bằng Gefitinib 250mg/ngày hoặc Erlotinib 150mg/ngày có kết hợp với xạ toàn não hoặc gamma knife hoặc không tại bệnh viện K từ tháng 10/2015 đến tháng 1/2021. Kết quả: Trung vị PFS đạt 11,5 tháng. PFS trung vị của các nhóm dùng TKIs đơn thuần, TKIs + xạ toàn não, TKIs + gamma knife lần lượt là 11 tháng, 11 tháng và 12,7 tháng. PFS não trung vị đạt 11 tháng. Các yếu tố liên quan đến PFS là có đột biến del 19, đáp ứng tại thời điểm 3 tháng, toàn trạng tốt, không hoặc di căn 1 cơ quan ngoài não. Kết luận: Điều trị TKIs thế hệ 1 trên bệnh nhân UTP biểu mô tuyến di căn não mang lại tỷ lệ đáp ứng chung cũng như đáp ứng tại não cao, kéo dài thời gian sống thêm bệnh không tiến triển, kết quả khả quan ở nhóm điều trị kết hợp với gamma knife.

p53 and EGFR gene mutations in malignant tumors of the lung

Relevance: Increased incidence of lung cancer globally and in Kazakhstan, lack of screening in hereditary cases, high mortality, and low survival of patients necessitate the study of the molecular genetic causes of the disease. At present, gene mutation studies for lung cancer diagnostics are expanding. However, many gene mutations revealed remain undercovered in the scientific literature, and there is not enough data on their prognostic and diagnostic value. The purpose of the study was to discover the specifics of the р53 gene mutations and reveal the EGFR exon 19 deletions and exon 21 L858R mutations in malignant tumors of the lung of various histogenesis. Methods: The mutations were studied in tumors (200 samples) and adjacent tissue (200 samples) of patients with lung cancer (squamous cell carcinoma (SCC) and adenocarcinoma (ADC) of the lung) by polymerase chain reaction (PCR), electrophoresis, and EcoR1- and Pst1-restriction of samples after p53 gene fragments and cDNA amplification and mRNA revertase treatment. Another 263 lung cancer samples were evaluated by real-time PCR for EGFR exon 19 deletions and EGFR exon 21 L858R mutations. Results: The p53 gene was not expressed in 50% of SCC and adenocarcinoma of the lung samples. Restriction revealed p53 mRNA mutations in 100% of SCC and 75% of ADC samples. p53 exon-intron 5-6 was mutated in 50% of ADC and 70% of SCC samples, exon-intron 7-9 – in 60% of SCC cases. EGFR exons 19 and 21 mutations found in 65 of 263 lung tumor samples were associated with increased sensitivity to EGFR tyrosine kinase inhibitors. Conclusion: The p53 gene mutations revealed in most samples of SCC and ADC of the lung could be used to diagnose lung cancer and predict its severity. The identified EGFR mutations allow predicting the effectiveness of targeted therapy

Prevalence and Patterns of EGFR Mutations in Non-Small Cell Lung Cancer in the Middle East and North Africa: A Systematic Review

To summarize current evidence and estimate the prevalence of epidermal growth factor receptor (EGFR) mutation frequency and its association with ethnicity and clinic-pathological features in non-small cell lung cancer (NSCLC) patients in the Middle East (ME) and North Africa (NA), a systematic literature review was undertaken. We conducted a literature search of original articles published in six databases (PubMed, Science Direct, Web of Science, Embase, Scopus, and Google scholar) from the time of inception until April 2021. Search terms included “lung cancer”, “NSCLC”, “EGFR mutation”, “Middle East”, “North Africa”, and specific country names belonging to the considered region. The included studies had to meet the following criteria: the study must relate to the role of the EGFR gene in NSCLC, analyze mutations in exon 18, 19, 20, and 21 or select exons of the EGFR gene, and provide sufficient information on the clinic-pathological characteristics of the included NSCLC patients. A total of 24 eligible studies were included [(66.6%) in the ME and (34.4%) in NA]. Overall, 6544 patients with NSCLC were analyzed for EGFR mutations [(55.1%) in the ME and (44.8%) in NA]. The overall prevalence of EGFR mutations was 17.9%. In the ME, the reported frequency was 17.3%, whereas in NA, the prevalence of EGFR mutations was 18.5%. The most frequently encountered mutations were the exon 19 deletions (45.2%) and exon 21 substitutions (30.9%). Exon 20 alterations were detected in 11.2%, of which, the T790M resistance mutation was the most prevalent (45.5%). Exon 18 mutations were reported in 3.8%. In the ME, 50.5% of NSCLC patients were positive for exon 19 deletions versus 48.3% in NA. Exon 21 mutations were slightly more commonly detected in the ME (36.3%) than NA (31.3%). There was 1.2% of patients that had concurrent EGFR mutations. Overall, EGFR mutations prevalence was higher in females, non-smokers, and patients with adenocarcinoma. Our systematic literature review concurs that EGFR mutation prevalence among MENA populations is slightly higher than that seen in NSCLC patients of Caucasian ethnicity but is lower than that identified in Asian NSCLC patients. The distribution of these mutations varies significantly throughout the MENA region.

DNMT3A knockouts in human iPSCs prevent de novo DNA methylation and reveal growth advantage during hematopoietic differentiation

DNA methyltransferase 3A (DNMT3A) is a frequently mutated gene in many hematological malignancies, indicating that it may be essential for hematopoietic differentiation. Here, we addressed the functional relevance of DNMT3A for differentiation of human induced pluripotent stem cells (iPSCs) by knocking out exon 2, 19, or 23. Exon 19-/- and 23-/- lines revealed absence of almost the entire de novo DNA methylation during mesenchymal and hematopoietic differentiation. Yet, differentiation was only slightly reduced in exon 19-/- and increased in exon 23-/- lines, whereas there was no significant impact on gene expression in hematopoietic progenitors (iHPCs). Notably, DNMT3A-/- iHPCs recapitulate some DNA methylation differences of acute myeloid leukemia with DNMT3A mutations. Furthermore, multicolor genetic barcoding revealed competitive growth advantage of exon 23-/- iHPCs. Our results demonstrate that de novo DNA methylation during hematopoietic differentiation of iPSCs is almost entirely dependent on DNMT3A and exon 23-/- iHPCs even gained growth advantage.

Patients harboring uncommon EGFR exon 19 deletion-insertion mutations respond well to first-generation EGFR inhibitors and osimeritinib upon acquisition of T790M

Background In the existing next generation sequencing (NGS) system, epidermal growth factor receptor (EGFR) exon 19 deletion-insertion (19delins) is still interpreted into the category of EGFR exon 19 deletion (19del). However, the controversy exists whether the two mutation types have the similar responses and resistant mechanisms to first-generation EGFR tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) patients. Methods We successively and retrospectively reviewed the NGS data of 3054 patients diagnosed as advanced NSCLC from November 2017 to September 2020. Finally, 41 patients with EGFR 19delins mutation and 41 patients with EGFR 19del mutation who received first-generation EGFR TKIs as first-line therapy were included in the study. Results A total of 17 genotypes were identified in this study, including L747_P753delinsS (10/41), L747_A750delinsP (9/41), L747_T751delinsP (6/41) and E746_S752delinsV (3/41). Under the same baseline characteristics, the population of EGFR 19delins respond well to first line EGFR TKIs as well as those of EGFR 19del, with little difference in median progression-free survival (mPFS): 10.4 months vs. 13.1 months, p = 0.1076). Interestingly, patients with L747_T751delinsP seem to have a better mPFS than others (18.7 months vs. 13.1 months, p = 0.035). After the disease progression, both EGFR 19delins and EGFR 19del had similar rates of developing EGFR T790M mutation resistance (45.8% vs. 57.8%), and those receiving osimeritinib as second-line treatment obtain the similar survival benefits (mPFS: 12.0 months vs. 12.2 months (p = 0.97). Conclusions This retrospective cohort study furnish the evidence that therapeutic responses and survival of untreated NSCLC population with EGFR 19delins mutation are equal to those with common EGFR 19del mutation after administration of EGFR TKIs therapy.

Efficacy of gefitinib in patients with advanced non-small cell carcinoma of the lung harboring common, uncommon and complex EGFR mutations

Background: As the commonest EGFR-TKI being used in Hong Kong, gefitinib has shown to be efficacious and safe as first line treatment for L858R mutation and exon 19 deletion with less gastrointestinal and cutaneous adverse events than erlotinib and afatinib. However, the evidence for therapeutic efficacy for uncommon and complex EGFR mutations is lacking. Whether gefitinib is efficacious for uncommon and complex EGFR mutations worth studying. Objectives: To assess the therapeutic efficacy of gefitinib, as measured by progression-free survival and overall survival, among advanced stage lung cancer patients with common, uncommon and complex EGFR mutations. Methods: This is a retrospective cohort study that included 241 Chinese patients with advanced non-small cell carcinoma of lung harboring EGFR mutations and received gefitinib 250 mg daily as first-line treatment. The progression-free survival [PFS] and overall survival [OS] for patients with different EGFR mutations, namely exon 19 deletion, L858R mutation in exon 21, uncommon EGFR mutations and complex EGFR mutations were analyzed. Results: Among the 241 patients, 118 [49%] had exon 19 deletion, 104 [43%] had L858R mutation in exon 21, 6 [2.5%] had uncommon EGFR mutations, 13 [5.4%] had complex EGFR mutations. The mean age was 69. 72% of the patients were female and with 81% being non-smoker. For patients with complex EGFR mutations, regardless of the presence of exon 19 deletion and L858R mutation as the component, have better PFS and OS than patients with single common EGFR mutations [Exon 19 deletion or L858R mutation]. Patients with uncommon EGFR mutations have inferior PFS and OS than those with common EGFR mutations. Conclusion: Gefitinib is a possible option for patients with complex EGFR mutations while it may not be the preferred treatment option in patients with single uncommon EGFR mutations.

Tumor-Agnostic Biomarkers: Heed Caution, and Why Cell of Origin Still Matters

Since the very beginnings of cancer therapy with chemotherapy, tumors have been treated according to the organ or tissue of origin. The advent of precision medicine however, has recently led to growing promise for tumor-agnostic biomarkers for targeted therapies and immunotherapies, such as NTRK fusions. Despite this, prominent examples such as BRAF V600E mutations in melanoma compared to colorectal cancer, in which the site of tumor origin dramatically influences the efficacy of targeted therapies, heeds caution against disregarding the importance of cell of origin. Indeed, another illustrative example, is the almost complete absence outside of cancers originating from the lung of the classical activating EGFR mutations—exon 19 deletions and exon 21 L858R mutations. Consequently, an understanding of lineage dependency and lineage-survival oncogenes may still offer significant mechanistic insights into the malignant transformation of tumors to ultimately identify further therapeutic vulnerabilities.

Comprehensive analysis of NGS and ARMS-PCR for detecting EGFR mutations based on 4467 cases of NSCLC patients

Background By comparing the detection rate and type of targeted gene mutations in non-small cell lung cancer (NSCLC) between amplification refractory mutation system PCR (ARMS-PCR) and next-generation sequencing (NGS), the characteristics and application advantages of non-small cell lung cancer detection are explained, providing a basis for clinicians to effectively select the corresponding detection methods. Methods and materials The cases of targeted genes for lung cancer were selected from the First Affiliated Hospital of Chongqing Medical University from January 2016 to October 2020. A sample of 4467 cases was selected, and they were diagnosed with NSCLC by Pathological biopsy. Sample sources include surgical resection, bronchoscope biopsy, metastatic biopsy, blood, sputum, cytology of pleural effusion. Among them, 3665 cases were detected by ARMS-PCR technique, and 802 cases were detected by NGS technology. The detection rate and type of ARMS-PCR and NGS techniques for EGFR gene mutations (including exon 18, exon 19, exon 20, exon 21 and so on) in different NSCLC samples were compared, respectively. Results The total mutation rate of EGFR gene detected by ARMS-PCR was 47.6% while 42.4% detected by NGS which indicated that there was a significant difference between the two methods in detecting total mutation of EGFR gene (P < 0.001). In different exons, the EGFR mutation rate detected by two methods is various. The mutation rate of exon 19 by ARMS-PCR detection was evidently higher than that of NGS detection, while the mutation rate of exons 20 and 21 by ARMS-PCR detection were statistically significantly lower than that of NGS detection. Moreover, the multiple mutation rate detected by NGS was 16.3% which was much higher than the 2.7% detected by ARMS-PCR with statistically different. Conclusion It showed that NGS could direct the drug use for the resistant patients. However, some rare loci could be detected by NGS but the importance and directed meaning are still unknown and the number of rare mutations is rare too. Further research on new biomarkers and technique is still needed for early diagnosis, directing drug use and assessing the therapy prognosis.