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Gabriela Liliana Bravo Montenegro
Author of
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-52 - Clinical Response to Osimertinib in a Patient with Metastatic NSCLC Harboring EGFR A763_Y764insFQEA Exon 20 Insertion Mutation: A Case Report (Now Available) (ID 1268)
09:45 - 18:00 | Presenting Author(s): Gabriela Liliana Bravo Montenegro
- Abstract
Background
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations represent approximately 4-10% of EGFR-mutant non-small-cell lung cancer (NSCLC). The majority of EGFR exon 20 insertion mutations do not respond to approved EGFR tyrosine kinase inhibitors (EGFR-TKIs). Preclinical data suggest that EGFR A763_Y764insFQEA mutation is associated with sensitivity to EGFR-TKI therapy.
A few case reports have shown that patients with this rare variant of EGFR exon 20 insertion mutation may respond to first- and second-generation EGFR-TKIs. However, efficacy of the third-generation EGFR-TKI osimertinib against the EGFR A763_Y764insFQEA mutation has not been described. Here, we present a patient with metastatic NSCLC harboring EGFR A763_Y764insFQEA alteration treated with osimertinib.
Method
A 56-year-old never-smoker Asian female presented with complete atelectasis of the left upper lobe, a left circumferential pleural effusion, and diffuse osseous sclerotic lesions. Pathology confirmed the diagnosis of metastatic lung adenocarcinoma. Circulating tumor DNA (ctDNA) assay utilizing InVisionSeqTM Tagged-Amplicon next-generation sequencing (NGS) identified EGFR A763_Y764insFQEA, MET amplification, and TP53 G266*. The patient was started on osimertinib 80 mg once a day. Later, tumor NGS came back positive for EGFR A763_Y764insFQEA, TP53 G266*, and BRCA-2 A2351G.
Result
The patient’s symptoms of cough and shortness of breath started to improve shortly after initiation of osimertinib. A CT scan of the thorax and abdomen obtained 5 weeks after starting osimertinib showed improvement in aeration of the previously collapsed left upper lobe, visualization of a 1.9 x 1.4 cm spiculated left upper lobe lung mass, improved infiltrative soft-tissue in the left hilum, and improved partially loculated left pleural effusion, suggesting response to osimertinib.
Conclusion
In this patient with the EGFR A763_Y764insFQEA mutation, osimertinib has shown effectiveness as monotherapy, suggesting it could serve a viable therapeutic treatment option in NSCLC with this rare variant of exon 20 insertion mutations. Future studies should validate this finding.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-100 - Spectrum of EGFR Exon 20 Insertion Mutations and Co-Occurring Genetic Alterations in Patients with Non-Small-Cell Lung Cancer (ID 2538)
10:15 - 18:15 | Presenting Author(s): Gabriela Liliana Bravo Montenegro
- Abstract
Background
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations are associated with a low response rate to approved EGFR tyrosine kinase inhibitors (EGFR-TKIs) and short progression-free survival. Pre-clinical studies have shown differences in the affinity of EGFR exon 20 insertion mutations for EGFR-TKIs, suggesting that the location of the insertion within the C-helix may play an important role in determining EGFR-TKI sensitivity. Several EGFR-TKIs designed to target EGFR exon 20 insertion mutations are in clinical development. Comprehensive genomic profiling has allowed for identification of co-occurring genomic alterations, which may help us identify additional pathways that may drive disease progression and drug resistance.
Method
Formalin-fixed paraffin-embedded (FFPE) samples from patients with non-small cell lung cancer (NSCLC) were profiled by targeted next-generation sequencing (NGS) using Caris Molecular Intelligence (Caris Life Sciences, Phoenix, AZ). Mutations and copy number variations (CNV) were assessed for each gene included in the NGS panel. Gene amplification (including low amplifications) was defined as gene copy number ≥ 4 and copy number loss as gene copy number < -1.4.
Result
Among the 1,556 patients with EGFR mutations, 104 (6.7%) patients were found to harbor an EGFR exon 20 insertion mutation. There were 70 (67.3%) females and 34 (32.7%) males with a mean age 62 (± 11.5 years). 61 (58.7%) samples came from primary lung sites and 43 samples (41.3%) came from metastatic sites. The main histological types were: adenocarcinoma 89 (85.5%), acinar adenocarcinoma 6 (5.7%), papillary adenocarcinoma 5 (4.8%), adenocarcinoma with bronchoalveolar features 1 (1%), squamous cell carcinoma 1 (1%) and carcinoma not otherwise specified 2 (2%). The most common exon 20 insertion mutation was A767_V769dup (25%), followed by S768_D770dup (13%), H773_V774insAH (5%) and H773dup (5%). The most common pathogenic mutations (including presumed pathogenic) included TP53 (51%), followed by CTNNB1 (6%), PIK3CA (4%), PTEN (3%), SMAD4 (3%), and CHEK2 (2%). Of the 104 cases, CNVs were available from 54 patients. Among these patients, commonly amplified genes included CDK4 (11%), EGFR (9%), MDM2 (9%), FOXA1 (7%), and HMGA2 (6%). Copy number loss was observed with CDKN2A (7%), CTNNB1 (2%), ATR (2%), BRCA2 (2%), and FANCL (2%).
Conclusion
The diverse spectrum of EGFR exon 20 insertion mutations shows molecular heterogeneity of this rare type of EGFR mutations. The presence of co-occurring genomic alterations that may promote tumor progression and drug resistance suggests that combination approaches may be necessary to overcome resistance to EGFR-TKI therapy in some patients with an EGFR exon 20 insertion mutation.
