Aims:

Risk classification of localised PCa relies on staging and pathological grading criteria that are focused on the appearance of the epithelium. The histological sub-type IDC-P has not been incorporated into grading, but has been associated with poor cancer outcomes. We determined to examine the relevance of IDC-P in a longitudinal model of PCa.

Methods:

With project-specific ethics approval, we developed patient derived xenografts (PDXs) of localised high-risk sporadic or familial PCa using tissue obtained at radical prostatectomy. Eight patient tissues with adenocarcinoma and IDC-P were selected for PDX (N=5 sporadic high-risk by D’Amico criteria; N=3 familial cases). Specimens were established as PDXs in host mice for 4-8 weeks, followed by castration for 4 weeks and then testosterone-restoration for 4 weeks. The primary study endpoints were tumour volume and proliferation assessed by Ki-67 immunohistochemistry.

Results:

At baseline, IDC-P was the predominant phenotype in high-risk patient tissues. IDC-P was present in PDXs of both sporadic and in familial PCa samples. Castration resulted in prominent regression of IDC-P, as with adenocarcinoma. However, following testosterone replacement there was clear regeneration of IDC-P, indicating the presence of castrate-tolerant cells.

Conclusions:

These data demonstrate that IDC-P cells are able to survive castration in a PDX model of high risk PCa, suggesting an ongoing role for IDC-P in the pathogenesis of PCa. The molecular features and key drivers of IDC-P warrant further study.  In men with localized PCa, the presence of IDC-P may identify a high-risk patient cohort likely to benefit from further adjuvant therapies.