Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib

Naidoo, Jarushka; Sima, Camelia S.; Rodríguez, Katherine; Busby, Natalie; Nafa, Khédoudja; Ladanyi, Marc; Riely, Gregory J.; Kris, Mark G.; Arcila, Maria E.; Yu, Helena A.

doi:10.1002/cncr.29493

Cited by 176 publications

(187 citation statements)

References 37 publications

(113 reference statements)

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“…In particular, the frequency of EGFR TKI-sensitizing activating mutations differs between the East Asian and the Western world 1. The incidence of exon 20 mutation in the East Asian and Western populations ranges from 0% to 5% 6,7,10,11. In our study, we also found the incidence of exon 20 mutation to be 3.5%.…”

Section: Discussionsupporting

confidence: 61%

“…In our series, the S768 I c. 2303 G>T was the most common mutation found. However, in other series (which have reported the mutation types in detail), the most common mutations found were D770_N771insSVD6 and S768_D770dupSVD (Wu) and V769_D770insASV 9. The poor outcomes seen in our series may be a reflection of the different biology of the mutation types.…”

Section: Discussioncontrasting

confidence: 59%

“…The reported median OS in patients with exon 20 mutation is 16–26 months 6–9. In a report by Naidoo et al,6 the survival in exon 20-mutated patients was not statistically different from that in patients with exon 19 deletion.…”

Section: Discussionmentioning

confidence: 93%

“…Limited data regarding demographics, clinical features and outcomes are available from East Asian and Western populations, while we do not have much data from the Indian subcontinent 6–11. The Indian population has a distinct biological makeup with respect to lung cancer.…”

Section: Discussionmentioning

confidence: 98%

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Epidermal growth factor receptor exon 20 mutation in lung cancer: types, incidence, clinical features and impact on treatment

Noronha¹,

Choughule²,

Patil³

et al. 2017

OTT

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Background There are limited data available on the treatment and outcome of epidermal growth factor receptor (EGFR) exon 20-mutated lung cancer patients. Hence, we planned an analysis of the demographic details, clinical profile and survival of lung cancer patients with exon 20 mutations. We compared our results to patients with EGFR tyrosine kinase inhibitor (TKI)-sensitizing activating and EGFR/anaplastic lymphoma kinase (ALK)-negative mutations. Methods This was a retrospective analysis of lung cancer patients who were treated at our center between January 2010 and August 2014. We reviewed the results of EGFR mutation testing by real-time polymerase chain reaction and Sanger sequencing. We also reviewed the data relating to baseline demographics, clinical profile, patient treatment and outcome measures in terms of response and overall survival (OS). Results A total of 580 patients fulfilled the selection criteria. In all, 227 (39.1%) patients had EGFR TKI-sensitizing activating mutations, 20 (3.4%) patients had exon 20 insertion mutations and 333 patients were EGFR/ALK mutation negative (57.5%). The median OS was 5 months (95% confidence interval [CI] 0.17–9.8 months) in exon 20 insertion mutations, 16.1 months (95% CI 12.8–19.5 months) in EGFR TKI-sensitizing activating mutations and 10 months (95% CI 7.9–12.1 months) in EGFR/ALK mutation-negative patients. The median OS was significantly better for the EGFR TKI-sensitizing activating mutation group ( P =0.000, log-rank test) and for the EGFR/ALK-negative group ( P =0.037, log-rank test) compared to the exon 20-mutated group. Conclusion Exon 20 mutation results in a poorer OS prognosis compared to EGFR- and ALK-negative patients and patients harboring EGFR TKI-sensitizing activating mutations. The incidence of de novo exon 20 insertions was 3.4%. Different types of exon mutations seem to have different outcomes.

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Section: Discussionsupporting

confidence: 61%

Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 98%

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Epidermal growth factor receptor exon 20 mutation in lung cancer: types, incidence, clinical features and impact on treatment

Noronha¹,

Choughule²,

Patil³

et al. 2017

OTT

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“…This is also particularly relevant for patients harboring EGFR exon 20 insertion mutations, which are known to be activating, but for which strong evidence supports de novo resistance to EGFR tyrosine kinase inhibitors (TKIs), including third-generation mutant-specific inhibitors (19,20 ). It is unclear from the The importance of proper variant classification in recruitment for clinical trials is also highlighted by the example of a retrospective clinical trial correlating response to MET-targeted therapy in gastric and esophageal cancer to the presence of MET proto-oncogene, receptor tyrosine kinase (MET) alterations.…”

Section: Gene Variant Nomenclaturementioning

confidence: 99%

Clinical Trials in Precision Oncology

et al. 2016

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BACKGROUND Availability of genomic information used in the management of cancer treatment has outpaced both regulatory and reimbursement efforts. Many types of clinical trials are underway to validate the utility of emerging genome-based biomarkers for diagnostic, prognostic, and predictive applications. Clinical trials are a key source of evidence required for US Food and Drug Administration approval of therapies and companion diagnostics and for establishing the acceptance criteria for reimbursement. CONTENT Determining the eligibility of patients for molecular-based clinical trials and the interpretation of data emerging from clinical trials is significantly hampered by 2 primary factors: the lack of specific reporting standards for biomarkers in clinical trials and the lack of adherence to official gene and variant naming standards. Clinical trial registries need specifics on the mutation required for enrollment as opposed to allowing a generic mutation entry such as, “EGFR mutation.” The use of clinical trials data in bioinformatics analysis and reporting is also gated by the lack of robust, state of the art programmatic access support. An initiative is needed to develop community standards for clinical trial descriptions and outcome reporting that are modeled after similar efforts in the genomics research community. SUMMARY Systematic implementation of reporting standards is needed to insure consistency and specificity of biomarker data, which will in turn enable better comparison and assessment of clinical trial outcomes across multiple studies. Reporting standards will facilitate improved identification of relevant clinical trials, aggregation and comparison of information across independent trials, and programmatic access to clinical trials databases.

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Variability of EGFR exon 20 insertions in 24 468 Chinese lung cancer patients and their divergent responses to EGFR inhibitors

Qin

Hong

Tong³

et al. 2020

Molecular Oncology

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EGFR exon 20 insertions (EGFR e20ins) account for up to 10% of EGFR mutations in lung cancer; however, tumors with EGFR e20ins had poor response rates to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, afatinib, and osimertinib, and the heterogeneity of EGFR e20ins further complicates the clinical studies. Here, we retrospectively screened next-generation sequencing (NGS) data from 24 468 lung cancer patients, and a total of 85 unique EGFR e20ins variants were identified in 547 cases (2.24%), with p.A767_V769dup (25.1%) and p.S768_D770dup (17.6%) being the most prevalent ones. Comprehensive genomic profiling revealed that TP53 mutations frequently coexisted with p.H773dup (77.8%, P = 0.0558) and p.A767_V769dup (62.8%, P = 0.0325), while RB1 mutations usually co-occurred with p.H773_V774insAH (33.3%, P = 0.0551), implying that different EGFR e20ins variants might require distinct genomic context for tumorigenesis and/or maintenance. Despite that treatment regimens were highly diverse for EGFR e20ins-positive patients, we observed an overall response rate of 14% and a disease control rate (DCR) of 38.4% in 65 patients who received at least one EGFR TKI. The progression-free survival (PFS) differs significantly in six representative EGFR e20ins variants (P = 0.017), and EGFR p.A763_Y764insF-QEA was associated with better PFS than other EGFR e20ins when treating with various EGFR TKIs. Some EGFR e20ins variants showed at least partial response to first-generation EGFR TKIs, including p.A767_V769dup, p.S768_D770dup, p.N771_H773dup, p.A763_Y764insF-QEA, and p.D770_N771insG. Poziotinib achieved higher DCR for p.S768_D770dup than for p.A767_V769dup, whereas osimertinib showed limited effects for these two insertions when used as the first-line treatment. Overall, our results demonstrated that EGFR e20ins were highly diversified in terms of insertion patterns and co-occurring mutations and these EGFR e20ins variants showed different clinical responses to various EGFR TKIs,

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Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib

Cited by 176 publications

References 37 publications

Epidermal growth factor receptor exon 20 mutation in lung cancer: types, incidence, clinical features and impact on treatment

Epidermal growth factor receptor exon 20 mutation in lung cancer: types, incidence, clinical features and impact on treatment

Clinical Trials in Precision Oncology

Variability of EGFR exon 20 insertions in 24 468 Chinese lung cancer patients and their divergent responses to EGFR inhibitors

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