Assessment of HER-2 status in pancreatic adenocarcinoma: correlation of immunohistochemistry, quantitative real-time RT-PCR, and FISH with aneuploidy and survival.
HER-2 is a transmembrane growth factor receptor recognized in overexpression as an independent adverse prognostic factor in several cancers. This study measured HER-2 overexpression in pancreatic adenocarcinoma at the genetic, transcriptional, and translational level. Expression was gauged with regard to stage, grade, and survival. Pancreatic adenocarcinoma samples (n = 30) were analyzed with immunohistochemical labeling for HER-2 protein, Quantitative real-time reverse transcriptase polymerase chain reaction (Q-RT-PCR) measurement of HER-2 mRNA and fluorescence in situ hybridization (FISH) analysis of HER-2 gene expression. HER-2 expression in benign pancreatic lesions (n = 10) provided a control. Five (17%) of the pancreatic adenocarcinomas scored maximal 3+ immunohistochemistry (IHC) labeling, seven (23%) had significantly increased expression of HER-2 mRNA, while only one (3%) exhibited low level HER-2 gene amplification. Ten (33%) tumors demonstrated aneuploidy. In general, concordance between methodologies was poor, but the best agreement was seen between FISH aneuploidy status and Q-RT-PCR mRNA overexpression (80% agreement), followed by IHC and Q-RT-PCR (73% agreement). The least agreement was seen between IHC and FISH aneuploidy status (67% agreement). Tumor stage was positively associated with HER-2 mRNA and protein expression, but tumor grade and other patient characteristics did not reach statistical significance. A poor survival outcome was demonstrated with positive HER-2 status in all three measures of overexpression (Kaplan-Meier log-rank score; P < 0.01 [IHC], P = 0.05 [Q-RT-PCR], P = 0.02 [FISH]). Discordance in expression at the nuclear, cytoplasmic, and cell surface levels highlights the limitations of immunohistochemical evaluation alone and stresses the need for further evaluation of response to anti-HER-2 targeted therapies in tumors displaying overexpression in gene copy, mRNA, and receptor protein.
Saxby
Alex J
AJ
University of Sydney, Department of Surgery, Royal North Shore Hospital, Australia.
Nielsen
Aiqun
A
Scarlett
Christopher J
CJ
Clarkson
Adele
A
Morey
Adrienne
A
Gill
Anthony
A
Smith
Ross C
RC
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000782:Aneuploidy; D014408:Biomarkers, Tumor / Q000032:analysis; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D015996:Survival Rate
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases