EGFR Exon 20 Insertion Mutations in Sinonasal Squamous Cell Carcinoma

Recurrent epidermal growth factor receptor (EGFR)-activating mutations have been identified in a rare form of head and neck cancer known as sinonasal squamous cell carcinoma (SNSCC), a malignant disease with a 5-year mortality rate of ~40%. Interestingly, the majority of EGFR mutations identified in patients with primary SNSCC are exon 20 insertions (Ex20ins), which is in contrast to non-small-cell lung cancer (NSCLC), where the EGFR exon 19 deletion and L858R mutations predominate. These studies demonstrate that EGFR Ex20ins mutations are not exclusive to lung cancer as previously believed, but are also involved in driving SNSCC pathogenesis. Here we review the landscape of EGFR mutations in SNSCC, with a particular focus on SNSCC associated with inverted sinonasal papilloma (ISP), a benign epithelial neoplasm. Taking lessons from NSCLC, we also discuss potential new treatment options for ISP-associated SNSCC harbouring EGFR Ex20ins in the context of targeted therapies, drug resistance and precision cancer medicine. Moving forward, further basic and translational work is needed to delineate the biology of EGFR Ex20ins in SNSCC in order to develop more effective treatments for patients with this rare disease.

Rectal metastasis in Lung cancer: A case report and review of the literature

Gastrointestinal metastasis in lung cancer is not commonly encountered clinically, of which rectal involvement is a sporadic event. There were few reports about rectal metastasis in lung cancer. All of them had a dismal prognosis. We report a case of synchronous rectal metastasis in a lung cancer patient with a different clinical scenario, treatment, and prognosis. The patient presented with infrequent hematochezia due to a rectal mass confirmed as adenocarcinoma on core biopsy. Computer tomography showed many nodules in both lungs, which raised the initial diagnosis of pulmonary metastasis in rectal cancer. However, we decided to perform immunohistochemistry on the rectal biopsy specimen, which, surprisingly, revealed the site of origin was from the lung. Subsequently, next gene sequencing was performed and detected an exon 19 deletion on the EGFR gene. Though he had infrequent hematochezia, we decided to treat him with Erlotinib (a first-generation TKI) and closely monitored the rectal symptoms. Six months later, he achieved a complete response of both lung and rectal lesions. At present, he has been progression-free for 14 months. Thus, physicians should always be aware of this differential diagnosis in synchronous tumors and carefully consider the optimal treatment to start.

Chẩn đoán đột biến gen EGFR trong ung thư phổi không tế bào nhỏ với các mẫu bệnh phẩm dịch khoang cơ thể

TÓM TẮT Đặt vấn đề: Dựa vào tính chất các mẫu dịch khoang cơ thể có hiện diện các mảnh DNA lơ lửng giúp thực hiện chẩn đoán đột biến EGFR. Từ nguyên lý này, chúng tôi thực hiện nghiên cứu với các mục tiêu sau: Khảo sát tỉ lệ dương tính đột biến EGFR trong các mẫu dịch khoang cơ thể; và hảo sát tỉ lệ chẩn đoán đột biến gen EGFR trong mẫu bệnh phẩm mô học đúc khối parafin với mẫu dịch khoang cơ thể trên cùng một bệnh nhân. Phương pháp nghiên cứu: Hồi cứu, thống kê mô tả cắt ngang. Các trường hợp ung thư phổi không tế bào nhỏ được chẩn đoán đột biến EGFR bằng mẫu bệnh phẩm đúc khối paraffine với Test EGFR Version 1 và mẫu bệnh phẩm dịch các khoang cơ thể (Dịch màng phổi, dịch màng tim, dịch màng bụng, dịch não tủy) với Test EGFR Version 2. Kết quả: Có 117 ca bệnh trong nghiên cứu: Kết quả chẩn đoán đột biến gen EGFR trên mẫu mô học đúc khối paraffine: (+) 49 ca # 41,88%, tương đương với các thống kê ở trong nước và thế giới (Châu Á). Đa số vẫn là hai loại đột biến nhạy thuốc TKIs Exon 19 Deletion và Exon 21 L858R (53% và 23%). Kết quả chẩn đoán đột biến EGFR trên các mẫu dịch khoang cơ thể: Đa số mẫu dịch khoang cơ thể thực hiện chẩn đoán đột biến EGFR là dịch màng phổi (91 ca # 77,77%). Tỉ lệ phát hiện đột biến trong mẫu dịch màng phổi và dịch não tủy cao nhất (29,67% & 83,33%). So sánh tỉ lệ phát hiện đột biến EGFR trên mẫu dịch khoang cơ thể (35 /117 ca # 29,91%) với tỉ lệ phát hiện trên mẫu mô học thấp hơn có ý nghĩa thống kê (29,91% ↔ 41,88% với P = 0,0125). So sánh với các nghiên cứu khác trên thế giới cho thấy đa số các nghiên cứu cho kết quả cao hơn so với nghiên cứu tại bệnh viện Phạm Ngọc Thạch. Kết luận: Khảo sát chẩn đoán đột biến EGFR trong dịch các khoang cơ thể, đặc biệt trong các mẫu dịch có quá ít tế bào ác tính, kết quả dương tính 29,91%. Tỉ lệ cao nhất trong dịch màng phổi và dịch não tủy. Tuy nhiên, khả năng phát hiện đột biến EGFR trong các dịch khoang cơ thể thấp hơn so với trên các bệnh phẩm mô học (29.91% < 41,88%). Và đô tương đồng giữa hai loại bệnh phẩm này là 71,42%. Cần nâng cao kỹ thuật thực hiện chẩn đoán đột biến EGFR trong mẫu dịch khoang cơ thể với các phương pháp có độ nhạy cao hơn: ddPCR, NGS… ABSTRACT DIAGNOSTIC EGFR GENE MUTATIONS IN NON SMALL CELL LUNG CANCER WITH SPECIMENS OF BODY CAVITY FLUIDS Introduction: Based on the nature of the body cavity fluid samples, there is the presence of suspended DNA fragments that help to make an EGFR mutation diagnosis. From this principle, we have conducted this research with the following objectives: Investigate the positive rate of EGFR mutations in body cavity fluid samples, and explore the diagnosis rate of EGFR gene mutations in paraffin block histology samples with body cavity fluid samples in the same patients. Methods: In a retrospective study, cases of NSCLC were diagnosed with EGFR mutations by paraffin block histological specimens with Test EGFR Version 1 and body cavity fluid samples (pleural fluid, pericardial fluid, peritoneal fluid, cerebrospinal fluid) with Test EGFR Version 2. Results: There are 117 cases in the research: Results of EGFR mutation diagnosis on paraffin block histology: (+) 49 cases # 41.88%, equivalent to statistics in Vietnam and the World (Asia). The majority are still two types of drug - sensitive mutants TKIs: Exon 19 Deletion and Exon 21 L858R (53% and 23%). Results of diagnosis of EGFR mutation in samples of body cavity fluids: Most samples of body cavity performing diagnosis of EGFR mutation were pleural fluid (91 cases # 77.77%). The highest rate of detection of mutations in pleural and cerebrospinal fluid samples (29.67% & 83.33%). Comparing the rate of detection of EGFR mutation in body fluid samples (35/117 cases # 29.91%) with the statistically lower rate of detection in histological samples (29.91%-41, 88% with P = 0.0125). Compared with other studies in the world, most studies have higher results than those at Pham Ngoc Thach Hospital. Conclusion: Survey on the diagnosis of EGFR mutations in body cavity fluid samples, especially in fluid samples with too few malignant cells, showed positive results of 29.91%. The highest percentage is in pleural fluid and cerebrospinal fluid. However, the ability to detect EGFR mutations in body cavity fluid samples was lower than in histological specimens (29.91% < 41.88%). And the similarity between these two samples is 71.42%. Therefore, it is necessary to improve the technique of performing EGFR mutation diagnosis in body cavity fluid samples with more sensitive methods: ddPCR, NGS... Keywords: Non small cell lung cancer (NSCLC), Formalin - Fixed Paraffin - Embedded Tissue (FFPET), Body cavity fluids, Cell Free DNA, Cellular DNA.

Front-Line Therapy in EGFR Exon 19 Deletion and 21 Leu858Arg Mutations in Advanced Non-Small Cell Lung Cancer: A Network Meta-Analysis

Objective. This study aimed to compare the efficacy of different first-line strategies based on different EGFR mutation types (19 deletion and 21 Leu858Arg mutations). Methods. We conducted a systematic review and network meta-analysis (NMA) by searching and analyzing RCTs on PubMed, Embase, Cochrane Library, ASCO.org, and ESMO.org, from inception to September 30th, 2020. Results. Nineteen RCTs involving 5450 patients were finally included in this study, covering 10 different treatment strategies. The Bayesian ranking results suggested that, in terms of PFS, in the overall population and in patients with 19del mutation, osimertinib was most likely to rank the first, with the cumulative probabilities of 41.89% and 45.73%, respectively, while for patients with 21 Leu858Arg mutation, standard of care (SoC, represents first-generation EGFR-TKIs in this NMA) + chemotherapy was most likely to rank the first, with the cumulative probabilities of 30.81% in PFS. Moreover, SoC + chemotherapy provided the best overall survival benefit for the overall population and patients with 19del, with the cumulative probabilities of 57.85% and 33.51%, respectively. In contrast, for patients with 21 Leu858Arg mutation, dacomitinib showed the most favorable overall survival, with the cumulative probabilities of 36.73%. Conclusions. In this NMA, osimertinib and SoC combined with chemotherapy would be the optimal first-line treatment options for advanced NSCLC patients harboring EGFR 19 deletion mutation and 21 Leu858Arg mutation, respectively. This finding is likely to be adopted in clinical practice and provide guidance for future clinical study design. Systematic review registration: INPLASY2020100059.

Clinical Characters in Pre-invasive and Invasive Adenocarcinoma with Pulmonary Ground-glass Nodules

Purpose: With the increasing prevalence of pulmonary ground-glass nodules (GGNs) among younger population, its clinicopathologic performance, lung cancer-associated genetic mutation, and immune landscape features between pre-invasive adenocarcinoma and invasive adenocarcinoma (IAC) need to be get well known.Methods: We retrospectively reviewed basic clinical information, analyzed radiological characteristics, and then evaluated the status of mutational hotspots and tumor mutational burden by sequencing genome in tissue. Programmed death ligand 1 (PD-L1) expression was detected by immunohistochemistry staining. Results: Nodules vastly increased the probability of IAC when the diameter of GGNs was more than 1.15 mm or the consolidation-to-tumor ratio was at least 8.5%, with the latter predictor having a better diagnostic specificity. Tumors positive for exon 19 deletion and exon 21 L858R in EGFR mutation had a higher prevalence in IAC. However, there was no difference in PD-L1 expression. As expected, tumor mutational burden in IAC was higher, despite a low background mutational burden as a whole. Conclusions: GGNs should be pay high attention when several aggressive behaviors showed in radiology and inner solid components increased gradually, providing more evidence apt to a diagnosis of IAC. We found that GGNs of IAC performed early genomic alternations events during the slow growth carcinogenesis stage of GGNs, including the most common proto-oncogene EGFR activation, which mainly concentrates on IAC. Indolent GGNs at an early stage usually have negative PD-L1 expression.

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.

An Inherited Cancer Syndrome Due to a Germline Monoallelic EGFR Mutation with Loss of Heterozygosity in Lung and Breast Tumors

The epidermal growth factor receptor (EGFR) exon-19 deletion is one of the most common mutations detected in lung cancer patients. Although exon-19 deletion is frequently detected in adenocarcinoma, observing this mutation in germline cells is very rare. Besides, the co-occurrence of homozygous and heterozygous mutations in dual primary cancers in a person is very uncommon. This article presents a 53-year-old Iranian woman with no history of smoking who was diagnose with two primary cancers; invasive ductal carcinoma, and primary pulmonary lung adenocarcinoma. The case reported a history of breast cancer in her sister and a history of lung cancer in her father. To select the best choice of treatment the EGFR gene was analyzed with Sanger’s sequencing method from DNA extracted from the patient’s lung tissue sample. Observing two primary cancers in this patient and considering her family pedigree, germline cells were also analyzed using samples recruited from the patient’s peripheral blood to investigate any EGFR mutations in her germline cells. The obtained data revealed that the lung tissue of the patient carried a homozygous form of EGFR exon-19 deletion while her peripheral blood contained a heterozygous form of this mutation, which is exceptionally rare.