ERBB2-Mutated Metastatic Non-Small Cell Lung Cancer: Response and Resistance to Targeted Therapies.
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.
Division of Hematology and Oncology, Stanford Hospital and Clinics, Stanford, California.
Jody C
JC
Chuang
Stanford Cancer Institute, Stanford University, Stanford, California.
Henning
H
Stehr
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.
Ying
Y
Liang
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California; Palo Alto Veterans Administration Health Care System, Palo Alto, California.
Millie
M
Das
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California.
Jane
J
Huang
Stanford Cancer Institute, Stanford University, Stanford, California; Department of Radiation Oncology, Stanford University, Stanford, California.
Maximilian
M
Diehn
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California.
Heather A
HA
Wakelee
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California. Electronic address: jwneal@stanford.edu.
Joel W
JW
Neal
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D018734:Genes, erbB-2; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D017239:Paclitaxel / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D012189:Retrospective Studies; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab / Q000008:administration & dosage; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
D011799:Quinazolines; D043823:Taxoids; D008453:Maytansine; D000077143:Docetaxel; D000077716:Afatinib; D014747:Vinblastine; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D000068878:Trastuzumab; D017239:Paclitaxel; D000077235:Vinorelbine; D000080044:Ado-Trastuzumab Emtansine
Afatinib; ERBB2; HER2; Targeted therapy; Trastuzumab