Clinical significance of epidermal growth factor receptors in non-small cell lung cancer and a prognostic role for HER2 gene copy number in female patients.
BACKGROUND
To compare the efficacy of silver in situ hybridization (SISH) and immunohistochemistry (IHC) in detecting HER2 alterations and to investigate the prevalence and prognostic significance of Erb family members in non-small cell lung cancer (NSCLC).


METHODS
Stage I to IIIA tumors from 335 patients with NSCLC were immunohistochemically tested for protein expression of all Erb family members. Membranous HER2 expression was compared with its gene copy number by SISH in paraffin-embedded, formalin-fixed material. Correlations were made with clinicopathological variables.


RESULTS
Synchronous high immunohistochemical expression of all Erb family members was seen in 8% of tumor samples. There was a significant correlation between the HER2 gene copy number and HER2 protein expression (p = 0.003). High nuclear HER3 expression correlated significantly with high HER2 gene copy numbers (p = 0.015). In univariate analyses, high HER2 gene copy number was a highly significant negative prognostic indicator for disease-specific survival in women (p = 0.005), whereas it did not show prognostic influence in men (p = 0.9). Neither polysomy of chromosome 17 nor the IHC expression of Erb family member proteins as singles or pairs correlated significantly with survival. In the multivariate analysis, high HER2 gene copy number in tumor epithelial cells (p = 0.03) was an independent prognostic factor for disease-specific survival in female patients.


CONCLUSIONS
IHC does not consistently identify patients likely to have a poor prognosis, whereas SISH provides superior prognostic information for female patients with NSCLC. High HER2 gene copy number in tumor epithelial cells is an independent predictor of inferior survival in female patients with primary NSCLC.
Al-Saad
Samer
S
Institute of Medical Biology, Faculty of Health Sciences, University of Tromso, Norway. samer.al-saad@unn.no
Al-Shibli
Khalid
K
Donnem
Tom
T
Andersen
Sigve
S
Bremnes
Roy M
RM
Busund
Lill-Tove
LT
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage; D018734:Genes, erbB-2 / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011879:Radiotherapy Dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012189:Retrospective Studies; D046888:Tissue Array Analysis
D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human