Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients.
OBJECTIVE
In non-small-cell lung cancer (NSCLC), response to tyrosine kinase inhibitors (TKIs) is significantly associated with the presence of increased copy number and/or activating mutations of the epidermal growth factor receptor gene (EGFR). Preclinical data indicate that HER2, a member of the EGFR family, could enhance TKI sensitivity.


METHODS
HER2 gene copy numbers per cell were evaluated by fluorescent in situ hybridization (FISH) in 102 NSCLC patients treated with gefitinib, and previously evaluated for EGFR status by FISH, immunohistochemistry, and presence of mutations.


RESULTS
Patients with HER2 high copy number (high polysomy and gene amplification [HER2 FISH positive]) represented 22.8% of patients, and compared with patients with no or low gain (HER2 FISH negative), had significantly better objective response (OR, 34.8% v 6.4%; P = .001), disease control rate (DCR, 56.5% v 33.3%; P = .04), time to progression (TTP, 9.05 v 2.7 months; P = .02), and a trend toward longer overall survival (OS, 20.8 v 8.4 months; P = .056). HER2 protein expression investigated by immunohistochemistry was positive in only five of 72 (7%) patients analyzed and all 89 patients tested by DNA sequencing were negative for mutations in HER2 exon 20. Patients with HER2 FISH-positive tumors displaying increased expression of EGFR protein, gene gain, or mutations (EGFR positive) had a significantly better OR, DCR, TTP, and OS than patients negative for both receptors.


CONCLUSIONS
Increased copy number of the HER2 gene is associated with gefitinib sensitivity in EGFR-positive patients, supporting use of HER2 FISH analysis for selection of patients for TKI therapy.
Cappuzzo
Federico
F
University of Colorado Cancer Center, Department of Medicine and Pathology, Aurora, CO 80010, USA.
Varella-Garcia
Marileila
M
Shigematsu
Hisayuki
H
Domenichini
Irene
I
Bartolini
Stefania
S
Ceresoli
Giovanni L
GL
Rossi
Elisa
E
Ludovini
Vienna
V
Gregorc
Vanesa
V
Toschi
Luca
L
Franklin
Wilbur A
WA
Crino
Lucio
L
Gazdar
Adi F
AF
Bunn
Paul A
PA
Hirsch
Fred R
FR
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000097:blood*; D000077156:Gefitinib; D018628:Gene Dosage; D020869:Gene Expression Profiling; D018734:Genes, erbB-2; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib