p95HER2 truncated form in resected non-small cell lung cancer.
BACKGROUND
Recent studies suggested that p95HER2, the NH2-terminally truncated form of human epidermal growth factor receptor 2 (HER2), could confer resistance to monoclonal antibodies against HER2 (HER2-mab). The aim of this study was to investigate the role of p95HER2 according to HER2 gene copy number (GCN) and HER2 mutation in non-small cell lung cancer (NSCLC).


METHODS
The study included 447 resected NSCLC patients evaluated for P95HER2 status by immunofluorescence. Data were correlated with HER2 GCN evaluated by fluorescence in situ hybridization (FISH) and HER2 mutations. Tumors were scored as positive for p95HER2 expression if any cytoplasmic staining was detected.


RESULTS
P95HER2 was successfully evaluated in 431 patients and was positive (p95HER2+) in 33 (7.6%) cases. HER2 GCN was evaluable in 439 patients, and increased GCN (at least four copies in at least 40% cells) was found in 60 cases, of which 22 (5.0%) displayed gene amplification (GA). Among the 22 patients with HER2 amplification, only one resulted P95HER2+. To further investigate whether the receptor is truncated in presence of gene mutation, in addition to the study cohort, we analyzed p95HER2 status in eight NSCLC samples harboring HER2 mutation, and only one case resulted p95HER2+. In the whole population, p95HER2- patients had numerically higher risk of death than p95HER2+ (hazard ratio = 1.4, p = 0.2). No difference in survival was observed between patients with or without HER2 GA (median 38 versus 41 months, p = 0.46). HER2 GA was significantly associated with EGFR and MET GA, with no effect on survival.


CONCLUSIONS
HER2 truncation and HER2 increased GCN are not prognostic in resected NSCLC. P95HER2 is a very rare event in individuals displaying HER2 gene amplification or mutation.
Department of Oncology, Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy. f.cappuzzo@gmail.com
Federico
F
Cappuzzo
Yong Gon
YG
Cho
Andrea
A
Sacconi
Greta
G
Alì
Olimpia
O
Siclari
Matteo
M
Incarbone
Annarita
A
Destro
Luigi
L
Terracciano
Gabriella
G
Fontanini
Antonio
A
Marchetti
Massimo
M
Roncalli
Marileila
M
Varella-Garcia
D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015996:Survival Rate; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human