Durable Response to Tyrosine Kinase Inhibitor Therapy in a Lung Cancer Patient Harboring Epidermal Growth Factor Receptor Tandem Kinase Domain Duplication

Baik, Christina S.; Wu, David; Smith, Christina; Martins, Renato; Pritchard, Colin C.

doi:10.1097/jto.0000000000000586

Cited by 32 publications

(49 citation statements)

References 6 publications

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“…EGFR‐KDD of exons 18–25 is the most frequent kinase domain duplication variant. Baik and colleagues reported the first case of this kind in a 45‐year‐old woman who was diagnosed with a nonmucinous bronchoalveolar carcinoma . The patient demonstrated a partial response to the first‐generation EGFR TKIs, including gefitinib and erlotinib, while resistance subsequently developed with the emergence of EGFR T790 M and CTNNB1 S37F missense mutations (Table ).…”

Section: Discussionmentioning

confidence: 59%

“…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: 90%

“…Such a recurrent alteration is often observed in lung, brain, and soft tissue cancers . A few reports showed that patients with lung adenocarcinomas harboring the EGFR‐KDD alteration had significant antitumor responses to EGFR TKI therapies, including gefitinib, erlotinib, and afatinib . Thus, those findings suggested that EGFR‐KDD represents a driver aberration and a therapeutically actionable target in NSCLC patients.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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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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“…The same report also describes a case of advanced chemotherapyprogressive EGFR-KDD mutated lung adenocarcinoma with a 7-month partial response to afatinib (doses not provided) and subsequent progression due to amplification of the EGFR-KDD allele (34). Another case report of a prolonged multi-year response to gefitinib and then erlotinib has been described for advanced EGFR-KDD mutated lung adenocarcinoma (37). Therefore, it seems these variants are responsive to 1 st and 2 nd generation EGFR TKIs in the clinic.…”

mentioning

confidence: 92%

Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements

Costa¹

2016

Transl. Lung Cancer Res.

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Epidermal growth factor receptor (EGFR) mutations were first identified as driver oncogenes in non-small-cell lung cancers (NSCLCs) in 2004 by three separate independent groups (1-3), and originally thought to consistent of only inframe deletions, insertions (i.e., indels) or point mutations within exons 18 to 21 of the kinase domain of EGFR (4). The most abundant EGFR mutations are deletions/indels (around amino-acid residues 747 to 752) of exon 19 (these account for ~45% of all EGFR mutations, with the most common delE746_A750) and the exon 21 point mutation L858R mutation (~35% of all EGFR mutations). Inhibition of mutant EGFR in preclinical models through tyrosine kinase inhibitors (TKIs) unsettles the intracellular signaling cascade, generating cell cycle arrest and apoptosis (5). In the clinic, the 1 st generation EGFR TKIs gefitinib and erlotinib, both reversible ATP mimetics with a favorable therapeutic window in relation to the wild-type (WT) EGFR (4,6), induce overall response rate (ORR), EditorialKinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements that comprehensive molecular profiling may be necessary to maximize the identification of all cases that can benefit from precision oncology.

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“…These trials used PCR-based ‘hotspot’ testing, which typically interrogate for EGFR point mutations and small indels in exons 18–21. More recently, next-generation sequencing (NGS) of tumor samples has allowed for the identification of additional mechanisms whereby the EGF receptor may become aberrantly activated (7,8), further documenting the importance of EGFR signaling in the pathogenesis of lung cancer. Here, we report, for the first time in lung cancer, the presence of oncogenic EGFR fusions, most commonly EGFR-RAD51 , which contain the entire EGFR tyrosine kinase domain fused to RAD51, a protein involved in DNA damage responses.…”

Section: Introductionmentioning

confidence: 99%

EGFR Fusions as Novel Therapeutic Targets in Lung Cancer

et al. 2016

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Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKIs) with documented anti-tumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration.

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Durable Response to Tyrosine Kinase Inhibitor Therapy in a Lung Cancer Patient Harboring Epidermal Growth Factor Receptor Tandem Kinase Domain Duplication

Cited by 32 publications

References 6 publications

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

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

Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements

EGFR Fusions as Novel Therapeutic Targets in Lung Cancer

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