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Ref Type Journal Article
PMID (28167203)
Authors Chuang JC, Stehr H, Liang Y, Das M, Huang J, Diehn M, Wakelee HA, Neal JW
Title ERBB2-Mutated Metastatic Non-Small Cell Lung Cancer: Response and Resistance to Targeted Therapies.
Journal Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
Vol
Issue
Date 2017 Feb 04
URL
Abstract Text Erb-b2 receptor tyrosine kinase 2 gene (ERBB2) (also called HER2) has long been recognized as an oncogenic driver in some breast and gastroesophageal cancers in which amplification of this gene confers sensitivity to treatment with Erb-b2 receptor tyrosine kinase 2 (ERBB2)-directed agents. More recently, somatic mutations in ERBB2 have been reported in 1% to 2% of patients with lung adenocarcinoma. Previous case series have suggested clinical tumor responses using anti-ERBB2 small molecules and antibody therapies.Here we report the outcomes of nine patients with metastatic lung adenocarcinoma with ERBB2 mutations being treated with ERBB2-targeted therapies.Four of the nine patients had response to targeted therapies, with durations of response ranging from 3 to 10 months. We identified a de novo phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation and ERBB2 copy number gain as potential resistance mechanisms.We showed patients with ERBB2-mutated lung adenocarcinoma can respond to targeted therapies, and we identified potential resistance mechanisms upon progression to targeted therapies.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ERBB2 L755A missense unknown ERBB2 (HER2) L755A lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). L755A has been identified in the scientific literature (PMID: 28167203, PMID: 29989854), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020).
PIK3CA R425L missense unknown PIK3CA R425L lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). R425L has been identified in the scientific literature (PMID: 28167203), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Apr 2020).
RB1 R320L missense unknown RB1 R320L does not lie within any known functional domains of the Rb1 protein (UniProt.org). R320L has been identified in sequencing studies (PMID: 26343386, PMID: 28167203), but has not been biochemically characterized and therefore, its effect on Rb1 protein function is unknown (PubMed, Mar 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 exon 20 ins lung non-small cell carcinoma predicted - sensitive Trastuzumab Case Reports/Case Series Actionable In a clinical study, targeted therapy with Gilotrif (afatinib) or Herceptin (trastuzumab) resulted in an objective response rate of 44% (4/9) in non-small cell lung carcinoma patients harboring ERBB2 (HER2) mutations that progressed during previous therapies, all four responders harbored ERBB2 (HER2) exon 20 insertions (PMID: 28167203). 28167203
ERBB2 A775_G776insYVMA PIK3CA R425L lung non-small cell carcinoma predicted - resistant Trastuzumab Case Reports/Case Series Actionable In a clinical study, the PIK3CA R425L mutation was identified as a potential resistance mechanism in a non-small cell lung carcinoma patient harboring ERBB2 (HER2) A775_G776insYVMA, that progressed during Herceptin (trastuzumab) treatment (PMID: 28167203). 28167203
ERBB2 mutant lung non-small cell carcinoma predicted - sensitive Trastuzumab + Vinorelbine Case Reports/Case Series Actionable In a clinical study, treatment with Herceptin (trastuzumab) in combination with chemotherapy resulted in an objective response rate of 67% (4/6) in non-small cell lung carcinoma patients harboring ERBB2 (HER2) mutations that progressed during previous therapies (PMID: 28167203). 28167203
ERBB2 exon 20 ins lung non-small cell carcinoma predicted - sensitive Afatinib Case Reports/Case Series Actionable In a clinical study, targeted therapy with Gilotrif (afatinib) or Herceptin (trastuzumab) resulted in an objective response rate of 44% (4/9) in non-small cell lung carcinoma patients harboring ERBB2 (HER2) mutations that progressed during previous therapies, all four responders harbored ERBB2 (HER2) exon 20 insertions (PMID: 28167203). 28167203