ABSTRACT
Background: Although first- and second-generation EGFR TKIs are considered first-line treatment in EGFRm+ NSCLC, most patients develop resistance and progress, commonly, EGFR T790M mutation. The third-generation EGFR-TKI has demonstrated efficacy in patients with progressive disease harboring the T790M mutation and in the first-line setting, bypassing this mode of resistance. The primary objectives of this study are to describe the proportion of EGFRm+ NSCLC patients treated with first-, second- and third-generation EGFR TKIs, and cytotoxic chemotherapy in the first-line setting, and the time on treatment for each category. Secondary objectives are to determine the dropout rate, the rates for T790M mutation testing at disease progression and the type of subsequent treatment. Methods: This multicenter retrospective study utilized data from the Malaysian Lung Cancer Registry that actively registers all lung cancer patients ≥18 years, with primary lung cancer confirmed histologically or cytologically. All patients diagnosed with advanced stages (ie stages IIIB, IIIC and IV) EGFRm+ NSCLC from 1st of January 2015 to 31st December 2019 were included. Results: Of 406 patients with EGFRm+ NCSLC, 351 were treated. Types of first-line treatment were as follows: EGFR-TKIs (first generation - 54.1%, second generation - 25.6% and third-generation - 12.5%) and chemotherapy (7.7%). The median time of treatment for each generation of EGFR-TKI was 12 months, 12 months and 24 months, and 2 months for chemotherapy. The dropout rate was 28.7% (n = 101). Nearly half (49.4%) of patients who were on first- or second-generation EGFR-TKI had further genetic testing via liquid or tissue biopsies upon disease progression. About 24.9% of those who developed disease progression after first- or second-generation EGFR TKI were started on a third-generation EGFR TKI. Conclusion: In the real-world, the management of EGFRm+ advanced NSCLC patients in an Asian cost-restrictive setting may adversely affect the choice of first-line therapy, time on each line of treatment and subsequently the overall survival of patients.
Subject(s)
Dementia/diagnosis , Membrane Glycoproteins/genetics , Primary Progressive Nonfluent Aphasia/diagnosis , Receptors, Immunologic/genetics , Adult , Dementia/genetics , Dementia/pathology , Dementia/physiopathology , Female , Humans , Mutation , Primary Progressive Nonfluent Aphasia/genetics , Primary Progressive Nonfluent Aphasia/pathology , Primary Progressive Nonfluent Aphasia/physiopathologyABSTRACT
OBJECTIVE: Blau syndrome is characterized by noncaseating granulomatous arthritis, dermatitis, and uveitis, and results from gain-of-function NOD2 mutations. This study was undertaken to identify the genetic cause of the disease in a family with 3 members with Blau syndrome. METHODS: We studied a family with 3 affected members across 2 consecutive generations. The children's symptoms started early (at 6 and 7 months of age) and included polyarthritis, dermatitis, uveitis, and fever. In contrast, the father's symptoms started later (at 22 years of age) and included noncaseating granulomatous dermatitis and uveitis. We analyzed the NOD2 gene in all patients by both the Sanger method of DNA sequencing and amplicon-based deep sequencing using an Ion Torrent PGM platform. RESULTS: Sanger chromatograms revealed the heterozygous c.1001G>A transition in both children, which resulted in the p.Arg334Gln mutation that causes Blau syndrome. In contrast, the father's chromatograms revealed a small peak of adenine at the c.1001 position, suggesting the presence of a somatic NOD2 mutation. To evaluate this hypothesis, we performed amplicon-based deep sequencing using DNA from different tissues, which confirmed a variable degree (0.9-12.9%) of somatic NOD2 mosaicism. The previous detection of the NOD2 mutation in his daughters strongly suggests the presence of gonosomal (somatic plus gonadal) NOD2 mosaicism in the father. Comparative analyses with Blau syndrome patients carrying the germline p.Arg334Gln NOD2 mutation revealed late onset of the disease, a mild inflammatory phenotype, and an absence of complications in patients with NOD2 mosaicism. CONCLUSION: This is the first description of gonosomal NOD2 mosaicism as the cause of intrafamilial recurrence of Blau syndrome. Our findings also indicate that Blau syndrome includes more diverse and milder phenotypes than previously described.
