Prevalence of rare EGFR gene mutations in nonsmall-cell lung cancer: a multicenter study on 3856 Polish Caucasian patients

Krawczyk, Paweł; Reszka, Katarzyna; Ramlau, Rodryg; Powrózek, Tomasz; Pankowski, Juliusz; Wojas‐Krawczyk, Kamila; Kalinka, Ewa; Szczęsna, Aleksandra; Nicoś, Marcin; Jarosz, Bożena; Szyszka-Barth, Katarzyna; Bryl, Maciej; Adamowicz, Krzysztof; Szumiło, Justyna; Milanowski, Janusz

doi:10.1093/annonc/mdv553

Cited by 19 publications

(12 citation statements)

References 4 publications

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“…Such tests have confirmed that rare EGFR mutations occur more frequently than previously thought Results from the French National Cancer Institute network (ERMETIC-IFCT) indicated that ~10% of EGFR-mutated NSCLC patients may have rare EGFR gene mutations (10). Similarly, in our recent multicenter study in Poland, we showed that 14.77% of patients with EGFR-mutated NSCLC had rare mutations (11). Despite this, only a few retrospective analyses have investigated the efficacy of EGFR-TKIs in patients with rare EGFR mutations.…”

Section: Introductionsupporting

confidence: 78%

Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non-small cell lung cancer in patients with common and rare EGFR gene mutations

et al. 2017

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Abstract. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are routinely used to treat non-small cell lung cancer (NSCLC) in patients with common activating mutations of the EGFR gene. The aim of the study was to compare the efficacies of EGFR-TKIs in patients with common (exon 19 deletions and exon 21 p.Leu858Arg) and rare EGFR mutations. A retrospective analysis of 180 NSCLC patients with common (n=167) and rare (n=13) EGFR mutations treated with erlotinib (n=98), gefitinib (n=66) and afatinib (n=16) was performed. EGFR mutations were determined using RT-PCR and the EntroGen EGFR Mutations Analysis kit. Partial and complete response (PR and CR), progression-free survival (PFS), and overall survival (OS) were analyzed. Demographic and clinical factors had no impact on PFS or OS in patients treated with EGFR-TKIs. Erlotinib, gefitinib, and afatinib showed similar efficacies based on treatment response, median PFS, and OS. The type of EGFR mutation had no impact on median OS; however, median PFS was significantly longer in patients with the exon 19 deletion compared to patients with the exon 21 p.Leu858Arg substitution and rare EGFR gene mutations (P=0.013). Patients with common EGFR mutations showed significantly longer median PFS than those with rare EGFR mutations (10 vs. 5 months; P=0.009). Erlotinib, gefitinib, and afatinib show similar efficacies in NSCLC patients with both common and rare EGFR mutations. When undergoing EGFR-TKI treatment, patients with rare EGFR mutations showed similar OS but poorer PFS. Further investigation into the associations between particular rare EGFR mutations and EGFR-TKIs treatment outcomes is required.

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Section: Introductionsupporting

confidence: 78%

Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non-small cell lung cancer in patients with common and rare EGFR gene mutations

et al. 2017

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“…Multiple studies have confirmed that upward of 80% to 90% of patients with EGFR-mutated NSCLC will have either an exon 19 deletion or an L858R point mutation. 4,40,45 Individual trials of erlotinib and gefitinib have been underpowered to detect differences in outcome by mutation subtype. In most clinical trials of EGFR TKIs, patients with uncommon mutations are either excluded or molecular stratification is simplified into common (exon 19 deletions and exon 21 L858R substitutions) and uncommon mutations.…”

Section: Major Egfr Mutationsmentioning

confidence: 99%

Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR -Mutated Non–Small Cell Lung Cancer

Castellanos

Feld

Horn

2017

Journal of Thoracic Oncology

210

137

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EGFR-mutated NSCLC is a genetically heterogeneous disease that includes more than 200 distinct mutations. The implications of mutational subtype for both prognostic and predictive value are being increasingly understood. Although the most common EGFR mutations-exon 19 deletions or L858R mutations-predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), it is now being recognized that outcomes may be improved in patients with exon 19 deletions. Additionally, 10% of patients will have an uncommon EGFR mutation, and response to EGFR TKI therapy is highly variable depending on the mutation. Given the growing recognition of the genetic and clinical variation seen in this disease, the development of comprehensive bioinformatics-driven tools to both analyze response in uncommon mutation subtypes and inform clinical decision making will be increasingly important. Clinical trials of novel EGFR TKIs should prospectively account for the presence of uncommon mutation subtypes in study design.

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“…Such mutations, which most commonly occur as either small in‐frame deletions in exon 19 (Ex19del) or point mutations in exon 21 (L858R), confer constitutive activity of the EGFR tyrosine kinase and sensitivity to EGFR TKIs . Uncommon EGFR alterations, including rare point mutations and gene rearrangements, such as kinase domain duplications (KDDs) and gene fusions, have also been identified in previous studies …”

Section: Introductionmentioning

confidence: 99%

“…4 Uncommon EGFR alterations, including rare point mutations and gene rearrangements, such as kinase domain duplications (KDDs) and gene fusions, have also been identified in previous studies. [5][6][7] EGFR-KDDs typically result from in-frame tandem duplication of EGFR exons 18-25 and constitutively activate EGFR signaling by forming an intramolecule dimer. Such a recurrent alteration is often observed in lung, brain, and soft tissue cancers.…”

Section: Introductionmentioning

confidence: 99%

Clinical outcomes of EGFR kinase domain duplication to targeted therapies in NSCLC

Wang

Xue³

et al. 2018

Intl Journal of Cancer

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Kinase domain duplications of the epidermal growth factor receptor (EGFR‐KDD) have been identified and implicated to be oncogenic in nonsmall cell lung cancers (NSCLCs). However, its prevalence and clinical contributions in lung cancer are largely unknown. Here, we conducted a multicenter record review of 10,759 NSCLC patients who underwent genetic testing using next‐generation sequencing (NGS) targeting EGFR exons and the introns involved in EGFR‐KDD rearrangements. EGFR‐KDDs were identified in a total of 13 patients, which is approximately 0.12% of the total population reviewed, and also consisted of 0.24% (13/5394) of EGFR mutation‐positive patients. A total of 85% of patients (11/13) were identified with the canonical EGFR‐KDD duplication of exons 18–25, while the remaining two cases harbored duplications of EGFR exons 14–26 and exons 17–25, which have not been previously described. Importantly, none of the 13 patients had other coexisting driver mutations, highlighting the potential oncogenic role of this type of alteration. Three out of five patients who had exon 18–25 duplications showed partial antitumor responses to targeted therapies, while the other two patients demonstrated no clinical improvement. Furthermore, our data suggested that the EGFR T790 M mutation and EGFR amplification may represent the major resistance mechanisms against targeted therapies in tumors bearing EGFR‐KDD. In summary, our findings provide valuable insight into the prevalence of EGFR‐KDDs in NSCLCs and their clinical outcomes to targeted therapies.

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Prevalence of rare EGFR gene mutations in nonsmall-cell lung cancer: a multicenter study on 3856 Polish Caucasian patients

Cited by 19 publications

References 4 publications

Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non-small cell lung cancer in patients with common and rare EGFR gene mutations

Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non-small cell lung cancer in patients with common and rare EGFR gene mutations

Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR -Mutated Non–Small Cell Lung Cancer

Clinical outcomes of EGFR kinase domain duplication to targeted therapies in NSCLC

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