HER family receptor abnormalities in lung cancer brain metastases and corresponding primary tumors.
OBJECTIVE
To compare the characteristics of deregulation of HER receptors and their ligands between primary tumor and corresponding brain metastases of non-small cell lung carcinoma (NSCLC).


METHODS
Fifty-five NSCLC primary tumors and corresponding brain metastases specimens were examined for the immunohistochemical expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, Her2, Her3, and phosphorylated Her3, and their ligands EGF, transforming growth factor-alpha, amphiregulin, epiregulin, betacellulin, heparin-binding EGFR-like growth factor, neuregulin (NRG) 1, and NRG2. Analysis of EGFR copy number using fluorescence in situ hybridization and mutation by PCR-based sequencing was also done.


RESULTS
Metastases showed significantly higher immunohistochemical expression of EGF (membrane: brain metastases 66.0 versus primary tumors 48.5; P = 0.027; nucleus: brain metastases 92.2 versus 67.4; P = 0.008), amphiregulin (nucleus: brain metastases 53.7 versus primary tumors 33.7; P = 0.019), phosphorylated EGFR (membrane: brain metastases 161.5 versus primary tumors 76.0; P < 0.0001; cytoplasm: brain metastases 101.5 versus primary tumors 55.9; P = 0.014), and phosphorylated Her3 (membrane: brain metastases 25.0 versus primary tumors 3.7; P = 0.001) than primary tumors did. Primary tumors showed significantly higher expression of cytoplasmic transforming growth factor-alpha(primary tumors 149.8 versus brain metastases 111.3; P = 0.008) and NRG1 (primary tumors 158.5 versus brain metastases 122.8; P = 0.006). In adenocarcinomas, a similar high frequency of EGFR copy number gain (high polysomy and amplification) was detected in primary (65%) and brain metastasis (63%) sites. However, adenocarcinoma metastases (30%) showed higher frequency of EGFR amplification than corresponding primary tumors (10%). Patients whose primary tumors showed EGFR amplification tended to develop brain metastases at an earlier time point.


CONCLUSIONS
Our findings suggest that NSCLC brain metastases have some significant differences in HER family receptor-related abnormalities from primary lung tumors.
Sun
Menghong
M
Departments of Pathology, Thoracic/Head and Neck Medical Oncology, Biostatistics, and Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-4009, USA.
Behrens
Carmen
C
Feng
Lei
L
Ozburn
Natalie
N
Tang
Ximing
X
Yin
Guosheng
G
Komaki
Ritsuko
R
Varella-Garcia
Marileila
M
Hong
Waun Ki
WK
Aldape
Kenneth D
KD
Wistuba
Ignacio I
II
D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D018628:Gene Dosage / Q000235:genetics / Q000502:physiology; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D008297:Male; D008875:Middle Aged; D017354:Point Mutation / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism*
D066246:ErbB Receptors; D008024:Ligands; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C512478:EGFR protein, human; C508053:ERBB2 protein, human