HER2/neu overexpression in the development of muscle-invasive transitional cell carcinoma of the bladder

Abstract

The mortality from transitional cell carcinoma (TCC) of the urinary bladder increases significantly with the progression of superficial or locally invasive disease (pTa/pT1) to detrusor muscle-invasive disease (pT2 þ ). The most common prognostic markers in clinical use are tumour stage and grade, which are subject to considerable intra-and interobserver variation. Polysomy 17 and HER2/neu gene amplification and protein overexpression have been associated with more advanced disease. Standardised techniques of fluorescence in situ hybridisation and immunohistochemistry, which are currently applied to other cancers with a view to offering anti-HER2/neu therapies, were applied to tumour pairs comprising pre-and postinvasive disease from 25 patients undergoing treatment for bladder cancer. In the preinvasive tumours, increased HER2/neu copy number was observed in 76% of cases and increased chromosome 17 copy number in 88% of cases, and in the postinvasive group these values were 92 and 96%, respectively (not significantly different P ¼ 0.09 and 0.07, respectively). HER2 gene amplification rates were 8% in both groups. Protein overexpression rates were 76 and 52%, respectively, in the pre-and postinvasive groups (P ¼ 0.06). These results suggest that HER2/neu abnormalities occur prior to and persist with the onset of muscle-invasive disease. Gene amplification is uncommon and other molecular mechanisms must account for the high rates of protein overexpression. Anti-HER2/neu therapy might be of use in the treatment of TCC.

HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization

“…Consistent with other published studies of HER2 immunohistochemical staining in urothelial carcinoma, 9,[12][13]15,20 we considered carcinomas positive if they exhibited 2 þ or 3 þ immunostaining.…”

“…19 However, The literature surrounding HER2 expression in urothelial cancer often defines overexpression as both 2 þ and 3 þ staining. 9,[12][13]15,20 Similarly, previous papers have defined gene amplification as a HER2/CEP17 ratio of 42. We have attempted to meld the definitions of previous literature with the guidelines outlined by the American Society of Clinical Oncology to make our paper comparable with previous studies but accurate with the universal definitions.…”

The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis

“…These include increased sensitivity to certain cytotoxic chemotherapeutic agents, resistance to certain hormonal agents and increased propensity to metastasize to the brain (Ross et al, 2003;Gabos et al, 2006). HER2 overexpression and amplification is also seen in subsets of gastric, esophageal and endometrial cancers, also associated with worse disease (Mimura et al, 2005;Morrison et al, 2006;Yano et al, 2006) and also seen rarely in cancers of the oropharynx, lung and bladder (Hirsch et al, 2002;Khan et al, 2002;Latif et al, 2003). The etiologic role of HER2 overexpression in diseases other than breast cancer remain to be defined.…”

Evaluación de la sobreexpresión de proteína HER2 en cáncer vesical no músculo invasivo con énfasis en el grado tumoral y en la recurrencia

“…Según nuestra experiencia, la valoración de la sobreexpresión de la HER en este grupo podría contribuir a predecir su comportamiento. Otros autores han indicado ya que podría permitir decidir qué pacientes podrían beneficiarse más de la terapia BCG 2,16 . En los modelos contemporáneos de evolución del CCT vesical se comparan los tumores pTaGIII con los pT1GIII en cuanto a número de copias de HER y en una sobreexpresión de la proteína que apunta hacia la equivalencia 17 .…”

“…En la mayoría de los estudios, la variabilidad inter e intraobservador para clasificar y estadificar las lesiones y, más concretamente, en que la TUR-B sea completa, son variables que inducen a confusión. El error de clasificación del estadiaje a la baja, que se da entre el 23 y el 41%, y que puede encontrarse en series grandes de cistectomías, se debe en su mayor parte a la ausencia de una segunda TUR-B antes de la cistectomía 5,16 . Esta última identificaría invasión muscular en el 18-34% de los casos diagnosticados inicialmente como tumores no invasivos del músculo.…”