Localised prostate cancer is clinically heterogeneous. Patients within the same risk category can have divergent outcomes, from cure to lethal disease. New markers that accurately stratify patients and pinpoint aggressive tumours are required. Previously, we showed that a distinct growth pattern of prostate cancer, intraductal carcinoma of the prostate (IDC-P), is associated with adverse clinical features. Despite this, IDC-P is not routinely reported in pathology and its functional significance remains poorly understood. Thus, we investigated the clinical relevance and underlying molecular features of IDC-P.
To define the prevalence of IDC-P, we conducted a systematic review encompassing >7000 patients. This revealed that IDC-P was most prevalent in high-risk prostate cancer1. Therefore, we examined the biological features of IDC-P using patient-derived xenografts (PDXs) from 43 high-risk patients. IDC-P persisted within PDXs for up to 1,000 days. Moreover, tumours with IDC-P established serially-transplantable PDXs more often (10 of 23) than tumours without IDC-P (1 of 16). IDC-P was also associated with larger tumour volume and shorter patient survival. Using classical castration-hormone regeneration experiments, we showed that IDC-P contained a subset of “therapy tolerant” cells that persisted after androgen deprivation2.
We further investigated the aggressive phenotype of tumours with IDC-P with whole genome sequencing of patient specimens. This showed that IDC-P arose from the same tumour clone as invasive carcinoma within each patient, but diverged with tumour evolution3. Furthermore, copy number aberrations associated with poor prognosis were more common in tumours with IDC-P versus tumours without IDC-P.
In summary, this work demonstrates that IDC-P is associated with clinical, functional and molecular traits of high risk prostate cancer. Therefore, this pathological feature of prostate cancer warrants greater recognition and reporting as it may improve patient risk stratification.