Long-term survival after stereotactic body radiotherapy combined with immunotherapy plus anti-angiogenesis therapy in patients with advanced non-small cell lung cancer and EGFR exon 20 insertion mutation: a report of two cases.

Background: Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutation is the third most common EGFR-mutant form, accounting for 10-12% of all EGFR mutations in non-small cell lung cancer (NSCLC). Chemotherapy was the first-line treatment for patients with EGFR ex20ins mutation in the era when EGFR ex20ins tyrosine kinase inhibitors (EGFR ex20ins-TKIs) were inaccessible. Although EGFR ex20ins-TKIs have since then demonstrated certain efficacy, the population benefit rate is not high due to the high cost of the drug and limited benefit to the population. Therefore, the choice of treatment modality when a patient does not have access to EGFR ex20ins-TKIs or are resistant to them remains an avenue worth exploring. Case Description: In this report, we present two cases of patients with lung adenocarcinoma and EGFR ex20ins mutation. The two patients were middle-aged Asian women with no smoking history, and both had one or more metastatic lesions. Both achieved long-term clinical benefit (progression-free survival ≥12 months) after receiving combined treatment, suggesting that this is a promising treatment modality. Conclusions: To the best of our knowledge, this is the first report supporting the combination of stereotactic body radiotherapy and apatinib and camrelizumab as an effective treatment strategy in patients with advanced EGFR ex20ins-positive NSCLC who have been previously treated with chemotherapy. The therapy described in this report might serve as a potential alternative approach for clinical oncologists.

[Progress in Detection of EGFR Exon 20 Insertion Mutation and Targeted Therapies 
in Non-small Cell Lung Cancer].

Epidermal growth factor receptor exon 20 insertion (EGFR ex20ins) is one of the earliest driver gene activation mutations in non-small cell lung cancer (NSCLC). However, due to the unique structure of protein variation caused by this mutation, most patients with EGFR ex20ins mutation (except A763_Y764insFQEA) have poor response to the launched first/second/third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). With the successive approval of new specific targeted drugs for EGFR ex20ins in Food and Drug Administration (FDA) and other national regulatory agencies, the development and clinical research of targeted drugs for EGFR ex20ins in China have also developed rapidly and Mobocertinib has been approved recently in China. It is worth noting that EGFR ex20ins is a variant type with strong molecular heterogeneity. How to detect it comprehensively and accurately in clinical practice, so as to enable more patients to benefit from targeted therapy, is a very important and urgent problem to be solved. This review introduces the molecular typing of EGFR ex20ins, then discusses the importance of EGFR ex20ins detection and the differences of various detection methods, and summarizes the research and development of new drugs progress of EGFR ex20ins, in order to optimize the diagnosis and treatment path of EGFR ex20ins patients by selecting accurate, rapid and appropriate detection methods, so as to improve the clinical benefits of the patients.
.

[Advances in the Treatment of EGFR Exon 20ins Mutant NSCLC].

Lung cancer has become one of the most dangerous cancers to human health and the mortality rate is the highest among all the causes of cancer death. Non-small cell lung cancer (NSCLC) accounts for about 80%-85% of lung cancer. Chemotherapy is the main treatment for advanced NSCLC, but the 5-year survival rate is low. Epidermal growth factor receptor (EGFR) mutations are the most common driver mutations in lung cancer, but EGFR exon 20 insertions (EGFR ex20ins) mutation belongs to one of the rare mutations, accounting for about 4%-10% of overall EGFR mutations, thus around 1.8% of advanced NSCLC patients. In recent years, targeted therapies represented by EGFR tyrosine kinase inhibitors (TKIs) have become an important treatment option for patients with advanced NSCLC, however, NSCLC patients with EGFR ex20ins mutation are not sensitive to most of EGFR-TKIs treatments. Currently, some of the targeted drugs for EGFR ex20ins mutation have achieved significant efficacy, while some of them are still under clinical investigation. In this article, we will describe various treatment methods for EGFR ex20ins mutation and their efficacy.
.

Case report: sequential use of almonertinib based on the EGFR exon 20 insertion mutation achieves long-term control for advanced non-small cell lung cancer patients.

Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) play a dominant role in the treatment of non-small cell lung cancer (NSCLC); however, to date, targeted treatment options have not been identified for patients with EGFR exon 20 insertion (ex20ins) mutations. Almonertinib, as the third generation EGFR-TKI, can irreversibly bind to EGFR ATP binding region and has a favorable therapeutic effect in EGFR + multiple targets inhibition. Almonertinib is suitable for the treatment of NSCLC patients with disease progression and T790M drug resistance mutation positive after other EGFR-TKI treatment. Case Description: We report the case of a female patient with NSCLC with an EGFR ex20ins mutation (p.Ala767_Val769dup) identified by next-generation sequencing (NGS). The patient received systemic chemotherapy after surgical resection of the lesion. After the progression of first-line chemotherapy, the patient received sequential targeted therapy with afatinib and poziotinib, achieving progression-free survival (PFS) of 3.2 and 10.4 months, respectively. After the progression, we chose almonertinib when the patient refused to re-chemotherapy. Under the treatment of almonertinib, the PFS time of the patient reached 14 months. Conclusions: Almonertinib had the most substantial effect, and its use has not been previously reported for NSCLC patients with EGFR ex20ins mutations. The successful application of almonertinib reported here indicates that is a potential new treatment regimen for patients with EGFR ex20ins mutations.

Homozygous Insulin Promotor Gene Mutation Causing Permanent Neonatal Diabetes Mellitus and Childhood Onset Autoantibody Negative Diabetes in the Same Family.

PURPOSE: To report a family with a homozygous INS promotor gene mutation causing permanent neonatal diabetes mellitus (PNDM) in one sibling and autoantibody negative childhood onset diabetes in another sibling. CASE PRESENTATION: Patient 1 is a 12-year-old girl born at term with low birth weight to a consanguineous family, diagnosed with PNDM at 26 days of life. She presented with ketoacidosis and has a severe course of disease with high insulin requirement. Patient 2 is a 9-year-old girl born at term with normal weight, who presented with ketoacidosis at 2 years of age. Both subjects have negative type 1 autoantibodies. On genetic testing, a mutation in the promoter region of INS gene c.-331 C>G was found in homozygous state in both subjects and in a heterozygous state in parents. CONCLUSION: Homozygous INS gene promotor mutations may present with either PNDM or later onset autoantibody negative diabetes in childhood. This suggests that homozygous INS gene promotor mutations show marked heterogeneity in clinical presentation within individuals in the same family. The pathophysiology of this is not well known but could be related to a number of factors, including the position of the variant, penetrance, other associated genetic defects, HLA etc. Premarital screening and genetic counselling is recommended for highly consanguineous families to reduce occurrence of such conditions.

Successful treatment using targeted therapy, radiotherapy, and intrathecal chemotherapy in a patient with leptomeningeal metastasis with an epidermal growth factor receptor exon 20 insertion mutation: a case report.

Leptomeningeal metastasis (LM) is a disastrous complication in lung cancer. LM patients with oncogene-addicted non-small cell lung cancer (NSCLC) have a relatively better prognosis than those with the wild-type counterpart; however, overall post-LM survival is short. Additionally, the high heterogenicity of the LM entity creates a treatment challenge, and to date, no standard strategy has been established. This article describes a female lung adenocarcinoma patient with a resistant epidermal growth factor receptor (EGFR) exon20ins mutation who developed LM only 11 months after radical surgery IIIA (pT1bN2). Intrathecal chemotherapy (ITC), whole-brain radiotherapy (WBRT) with a simultaneous integrated boost (SIB) followed by Osimertinib was initiated. The cerebrospinal fluid (CSF) cytology turned negative. The first remission lasted 6 months, then bone metastases occurred, and the LM progressed. An Ommaya reservoir was implanted. ITC with pemetrexed and anlotinib was administered. A CSF next-generation sequencing (NGS) examination revealed EGFR exon20ins (p. A767_V769 dup 1.5%), which was different from that of the primary tumor (p. V769_D770 ins ASV 17.48%). The CSF cytology then turned negative again; however, the patient succumbed to the disease in December 2020. The patient's post-LM overall survival (OS) time was 13.5 months. This case is novel and of great value. Clinicians should pay special attention to populations at high risk of developing LM. Early detection followed by active intervention, including ITC, RT, and systemic treatment, will result in a better prognosis. The NGS of CSF is fundamental to understanding the genetic profiles of LM and providing effective and precise treatment.

Pembrolizumab and chemotherapy in non-small cell lung cancer with EGFR ex20ins mutation: A case report.

The efficacy of immunotherapy in non-small cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations is not well clarified, even though immunotherapy has brought revolutionary improvements in EGFR wild-type NSCLC. In addition, pseudoprogression has increased the difficulty in immunotherapy management and data on the incidence of pseudoprogression in patients with EGFR exon 20 insertions (ex20ins) is rarely reported. Here, we discuss the case of an advanced lung adenocarcinoma patient with EGFR ex20ins alteration. The patient received pembrolizumab plus chemotherapy as first-line therapy and disease control was achieved. Progression-free survival (PFS) was 9 months. The patient was subsequently treated with pembrolizumab plus docetaxel and bevacizumab as second-line therapy and the disease remained stable. After two cycles of first-line treatment, the patient showed improvement in performance and the primary left upper lung lesion was stable; however, there was an increase in size as well as number of small diffuse bilateral pulmonary nodules. Therapy was maintained with the original regimen and complete regression of the bilateral lung nodules was achieved after a third cycle of treatment. Pseudoprogression was diagnosed. In the case reported here, we advocate the use of a PD-L1 inhibitor plus conventional chemotherapy in advanced NSCLC patients harboring EGFR ex20ins mutation and hope that our experience might be beneficial to other clinicians in distinguishing pseudoprogression from true progression.

Identification of insulin gene variants in patients with neonatal diabetes in the Chinese population.

AIMS/INTRODUCTION: Neonatal diabetes mellitus is created by alterations in the genes responsible for beta-cell mass and/or function. The present study aimed to evaluate the genetic variants in the insulin gene (INS) in four Chinese infants aged <12 months with diabetes onset, and to explore the clinical and genetic characteristics of permanent neonatal diabetes mellitus caused by INS mutations. MATERIALS AND METHODS: The complete coding sequences of KCNJ11, ABCC8 and INS were detected using Sanger sequencing. The pathogenicity of the mutations was determined based on the American College of Medical Genetics and Genomics, and the structure of wild-type and mutant proteins was predicted using the web-based tool, Phyre2. RESULTS: One novel mutation (p.I99_C100insSI) and three previously reported variants (p.G32S, p.R89C and p.C96R) in INS were identified in four infants with early-onset diabetes. All the mutations in the four patients were de novo. Except for mutation R89C, which causes permanent neonatal diabetes mellitus through the addition of an additional cysteine residue at the cleavage site of the A chain and C-peptide, the other three mutations affected disulfide bonds. The patients had diabetes with marked hyperglycemia or diabetic ketoacidosis, and were then treated with exogenous insulin. Mutations in crucial regions of the INS might give rise to diabetes with varying severity. CONCLUSIONS: This study enriches our awareness of the mutant spectrum in INS, and suggests the important role of INS in the development of permanent neonatal diabetes mellitus.

A novel mutation in INS gene linked to permanent neonatal diabetes mellitus.

PURPOSE: Neonatal diabetes mellitus (NDM) is caused by mutations in the genes responsible for pancreatic ß cell mass or function. This study aimed to screen the mutations in the KCNJ11, ABCC8, and INS genes in a Chinese patient with clinical features of NDM. METHODS: The entire coding sequence and exon/intron boundaries of KCNJ11, ABCC8, and INS genes were detected by Sanger sequencing. The pathogenicity of the mutation was determined by using online prediction programs SIFT and Mutation Taser. The conformational alterations which contribute to the change of protein function were analyzed at the structural level. RESULTS: A novel mutation L35Q (B11) of the INS gene was discovered in the patient. As L35 residue contributes to its hydrophobic core of the protein, the L35Q substitution is predicated to affect B19-A20 disulfide bond and therefore disrupt the folding of the proinsulin, which ultimately results in beta cell apoptosis by inducing ER stress. CONCLUSIONS: This case could help us understand the role of the INS mutation in the development of diabetes.