Introduction. Pancreatic adenocarcinoma (PAC) remains an incurable disease. The development of a new therapy with antip185HER2 monoclonal antibodies (Trastuzumab, Pertuzumab) has been proposed although the status of HER2 gene in PAC and its correlation with clinical history remain not completely defined. We evaluated the expression of p185HER2, HER2 gene amplification and chromosome 17 centromere (CEP17) copy number in PAC. In addition, we compared p185 HER2 expression and HER2 gene status of primary PAC, matched lymph node metastasis (LMTS) and distant metastasis (DMTS). Materials and methods. We analyzed 93 cases of PAC including 31 PAC at initial diagnosis, 22 LMTS and 40 DMTS. In particular, primary tumours were matched with hepatic DMTS in two cases, with peritoneal and gastric DMTS in one case and with LMTS in eleven cases. We performed IHC, on paraffin-embedded tissues, using the PATHWAY kit by Benchmark XT system (Ventana). To evaluate patterns of membranous immunoreactivity of p185HER2, a score of 0 or 1+ was regarded as IHC negative and 2+ or 3+ as IHC positive in 10% of the tissue section. FISH was performed using the Pathvision® (Abbot) or ZytoLight kit (ZytoVision). HER2 gene amplification was defined as a mean number > 6 signals per nuclei whereas CEP17 aneuploidy by a mean number > 3 signals per nuclei. Results. We found p185HER2 positive expression in 14/93 (15.0%) (all with 2+ score), increased CEP17 with HER2 amplification in 5/93 (5.4%), increased CEP17 without HER2 amplification in 12/93 (12.9%) and disomic HER2 gene amplification in 2/93 (2.1%), of all PAC specimens analysed. In particular, p185HER2 expression was found in 1/31 (3.2%) of primary PAC, in 2/22 (9.1%) of LMTS and in 11/40 (27.5%) of DMTS. CEP17 aneuploidy was associated with HER2 gene amplification in 2/31 (6.4%) cases of primary tumours, in 1/22 (4.6%) cases of LMTS and in 2/40 (5.0%) cases of DMTS. CEP17 aneuploidy status without HER2 gene amplification was found in 1/31 (3.2%) of the primary tumours, in 3/22 (13.6%) of the LMTS and in 8/40 (20.0%) of the DMTS. Finally, disomic HER2 gene amplification was restricted to 2/40 (5.0%) of DMTS (Table 1). Therefore, we compared HER2 status between primary tumours, matched LMTS and matched DMTS. Increased CEP17 was found in 3 cases of LMTS, but not in related primary PAC. One primary PAC showed CEP17 aneuploidy, not found in matched hepatic DMTS and, in one PAC, HER2 amplification detected in primary tumour and in matched gastric DMTS was not found in matched peritoneal DMTS. Discussion. We found high heterogeneity of the HER2 status in primary PAC and between primary PAC, LMTS and DMTS. Our data suggest the need for the pathologist to evaluate more PAC specimens to define the HER2 status finalized to carry out HER2-targeted therapy.

Different HER2 expression, gene amplification and chromosome 17 copy number between primary pancreatic adenocarcinoma, lymph node metastasis and distant metastasis: implication for HER2 status evaluation and therapy

ASIOLI, SOFIA;
2011

Abstract

Introduction. Pancreatic adenocarcinoma (PAC) remains an incurable disease. The development of a new therapy with antip185HER2 monoclonal antibodies (Trastuzumab, Pertuzumab) has been proposed although the status of HER2 gene in PAC and its correlation with clinical history remain not completely defined. We evaluated the expression of p185HER2, HER2 gene amplification and chromosome 17 centromere (CEP17) copy number in PAC. In addition, we compared p185 HER2 expression and HER2 gene status of primary PAC, matched lymph node metastasis (LMTS) and distant metastasis (DMTS). Materials and methods. We analyzed 93 cases of PAC including 31 PAC at initial diagnosis, 22 LMTS and 40 DMTS. In particular, primary tumours were matched with hepatic DMTS in two cases, with peritoneal and gastric DMTS in one case and with LMTS in eleven cases. We performed IHC, on paraffin-embedded tissues, using the PATHWAY kit by Benchmark XT system (Ventana). To evaluate patterns of membranous immunoreactivity of p185HER2, a score of 0 or 1+ was regarded as IHC negative and 2+ or 3+ as IHC positive in 10% of the tissue section. FISH was performed using the Pathvision® (Abbot) or ZytoLight kit (ZytoVision). HER2 gene amplification was defined as a mean number > 6 signals per nuclei whereas CEP17 aneuploidy by a mean number > 3 signals per nuclei. Results. We found p185HER2 positive expression in 14/93 (15.0%) (all with 2+ score), increased CEP17 with HER2 amplification in 5/93 (5.4%), increased CEP17 without HER2 amplification in 12/93 (12.9%) and disomic HER2 gene amplification in 2/93 (2.1%), of all PAC specimens analysed. In particular, p185HER2 expression was found in 1/31 (3.2%) of primary PAC, in 2/22 (9.1%) of LMTS and in 11/40 (27.5%) of DMTS. CEP17 aneuploidy was associated with HER2 gene amplification in 2/31 (6.4%) cases of primary tumours, in 1/22 (4.6%) cases of LMTS and in 2/40 (5.0%) cases of DMTS. CEP17 aneuploidy status without HER2 gene amplification was found in 1/31 (3.2%) of the primary tumours, in 3/22 (13.6%) of the LMTS and in 8/40 (20.0%) of the DMTS. Finally, disomic HER2 gene amplification was restricted to 2/40 (5.0%) of DMTS (Table 1). Therefore, we compared HER2 status between primary tumours, matched LMTS and matched DMTS. Increased CEP17 was found in 3 cases of LMTS, but not in related primary PAC. One primary PAC showed CEP17 aneuploidy, not found in matched hepatic DMTS and, in one PAC, HER2 amplification detected in primary tumour and in matched gastric DMTS was not found in matched peritoneal DMTS. Discussion. We found high heterogeneity of the HER2 status in primary PAC and between primary PAC, LMTS and DMTS. Our data suggest the need for the pathologist to evaluate more PAC specimens to define the HER2 status finalized to carry out HER2-targeted therapy.
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S. Salvi; S. Asioli; S. Boccardo; P. Ferro; N. Gorji; P. Dessanti; M.C. Franceschini; M. Truini; S. Colli; F.Fedeli; M.P. Pistillo; S. Roncella
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/220469
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