Significant Benefits of Osimertinib Against Adenosquamous Carcinoma Harboring Germline T790M Mutation

Huo, Ran; Li, Jinghua; Li, Xiaofang; Shi, Junping; Wang, Kunjie; Jen, Jin; Shang, Yue

doi:10.1634/theoncologist.2019-0938

Cited by 3 publications

(2 citation statements)

References 28 publications

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“…EGFR T790Mmediated resistance can effectively be reversed by the third-generation EGFR-TKI Osimertinib (9,10). Similar Case Report to clinical findings about the benefits of Osimertinib therapy for patients with acquired T790M from first-or second-generation EGFR-TKI therapy (9,10), first-line Osimertinib therapy has been shown to benefit NSCLC patients who harbor either somatic T790M at baseline or germline T790M with concomitant EGFR sensitizing mutation (8,11). In this paper, we discuss a Chinese patient with advanced lung adenocarcinoma harboring germline EGFR T790M who developed Osimertinib resistance despite a durable partial response.…”

Section: Introductionmentioning

confidence: 57%

“…Germline EGFR T790M has been reported in non-smokers and is associated with inherited lung cancer susceptibility (3)(4)(5)(6). The EGFR activating mutation rate is between 40-50% among Chinese NSCLC patients (7); however, germline EGFR T790M is rare (6,8). EGFR T790Mmediated resistance can effectively be reversed by the third-generation EGFR-TKI Osimertinib (9,10).…”

Section: Introductionmentioning

confidence: 99%

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The emergence of various genetic alterations mediated the Osimertinib resistance of a patient harboring heterozygous germline EGFR T790M: a case report

Liu¹,

Qin²,

Yin³

et al. 2021

Ann Transl Med

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Epidermal growth factor receptor (EGFR) T790M is the major mechanism mediating resistance to first-and second-generation EGFR tyrosine kinase inhibitors. Despite the high frequency of EGFR activating mutations among East Asian lung cancer patients, germline T790M has been the subject of very little research. Questions remain as to whether germline T790M develops resistance to Osimertinib and if so, through which mechanisms. This study examined a patient harboring germline EGFR T790M who acquired resistance to Osimertinib therapy. After the failure of first-line icotinib therapy, which was administered for only 3 months, targeted next-generation sequencing of plasma samples collected at icotinib progression and the re-analysis of the baseline tissue biopsy sample revealed EGFR T790M with allelic frequencies approximating 50%. Lymphocyte genomic deoxyribonucleic acid (DNA) sequencing confirmed the germline heterozygous status of the T790M mutation. In addition to the EGFR T790M, a concurrent EGFR L858R was detected from the baseline tissue sample. Osimertinib therapy was initiated resulting in a partial response within 1 month of the commencement of the therapy. After 15.2 months of Osimertinib therapy, disease progression was evaluated due to the presence of pleural effusion. The targeted sequencing of plasma and pleural effusion samples revealed the emergence of EGFR G719A, tumor protein p53 (TP53) Q136X, and the co-amplification of Cyclin D1, fibroblast growth factor (FGF) 19, FGF3, and FGF4. This case highlights the importance of conducting next-generation sequencing-based molecular testing during both diagnostic and disease progression assessments to reveal sensitizing mutations and mutations that could mediate primary and acquired resistance to targeted therapeutics.

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Section: Introductionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

The emergence of various genetic alterations mediated the Osimertinib resistance of a patient harboring heterozygous germline EGFR T790M: a case report

Liu¹,

Qin²,

Yin³

et al. 2021

Ann Transl Med

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Benefits of osimertinib treat a lung adenocarcinoma patient with germline EGFR T790M, somatic EGFR 19-Del, TP53 and PIK3CA mutations

Li,

Zheng

et al. 2024

Hered Cancer Clin Pract

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Background Somatic mutations in the EGFR gene occur in about 50% of non-small cell lung cancers, with the T790M mutation significantly contributing to secondary resistance against EGFR-TKI drugs. However, EGFR T790M germline mutations rarely occur. Case presentation In this study, we report a case of a lung adenocarcinoma family lineage linked to a germline EGFR T790M mutation. The main subject was diagnosed with stage IV lung adenocarcinoma and experienced a 19-month period without disease progression while treated with Osimertinib. We collected both clinicopathological and familial data from a patient with lung adenocarcinoma. Next-generation sequencing of 40 key genes was performed on the proband’s tumor tissue. To detect EGFR germline mutations, Sanger sequencing was conducted on peripheral blood mononuclear cells from the proband and his two daughters. Mutations such as EGFR T790M, EGFR 19-Del, TP53, and PIK3CA were identified in the proband’s lung cancer tissue. Additionally, germline EGFR T790M mutations were confirmed in the proband and his daughters through sequencing of their peripheral blood samples. CT scans revealed multiple pulmonary nodules in both daughters. Conclusions These observations suggest that germline mutations in EGFR T790M could be strongly linked to a familial predisposition to lung cancer.

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A Nationwide Study on the Impact of Routine Testing for EGFR Mutations in Advanced NSCLC Reveals Distinct Survival Patterns Based on EGFR Mutation Subclasses

Koopman

Garcia

Kuijpers³

et al. 2021

Cancers

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EGFR mutation analysis in non-small-cell lung cancer (NSCLC) patients is currently standard-of-care. We determined the uptake of EGFR testing, test results and survival of EGFR-mutant NSCLC patients in the Netherlands, with the overall objective to characterize the landscape of clinically actionable EGFR mutations and determine the role and clinical relevance of uncommon and composite EGFR mutations. Non-squamous NSCLC patients diagnosed in 2013, 2015 and 2017 were identified in the Netherlands Cancer Registry (NCR) and matched to the Dutch Pathology Registry (PALGA). Overall, 10,254 patients were included. Between 2013–2017, the uptake of EGFR testing gradually increased from 72.7% to 80.9% (p < 0.001). Multi-gene testing via next-generation sequencing (increased from 7.8% to 78.7% (p < 0.001), but did not affect the number of detected EGFR mutations (n = 925; 11.7%; 95% confidence interval (CI), 11.0–12.4) nor the distribution of variants. For patients treated with first-line EGFR inhibitors (n = 651), exon 19 deletions were associated with longer OS than L858R (HR 1.58; 95% CI, 1.30–1.92; p < 0.001) or uncommon, actionable variants (HR 2.13; 95% CI, 1.60–2.84; p < 0.001). Interestingly, OS for patients with L858R was similar to those with uncommon, actionable variants (HR 1.31; 95% CI, 0.98–1.75; p = 0.069). Our analysis indicates that grouping exon 19 deletions and L858R into one class of ‘common’ EGFR mutations in a clinical trial may mask the true activity of an EGFR inhibitor towards specific mutations.

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Significant Benefits of Osimertinib Against Adenosquamous Carcinoma Harboring Germline T790M Mutation

Cited by 3 publications

References 28 publications

The emergence of various genetic alterations mediated the Osimertinib resistance of a patient harboring heterozygous germline EGFR T790M: a case report

The emergence of various genetic alterations mediated the Osimertinib resistance of a patient harboring heterozygous germline EGFR T790M: a case report

Benefits of osimertinib treat a lung adenocarcinoma patient with germline EGFR T790M, somatic EGFR 19-Del, TP53 and PIK3CA mutations

A Nationwide Study on the Impact of Routine Testing for EGFR Mutations in Advanced NSCLC Reveals Distinct Survival Patterns Based on EGFR Mutation Subclasses

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