Epithelial and Stromal Characteristics of Primary Tumors Predict the Bone Metastatic Subtype of Prostate Cancer and Patient Survival after Androgen-Deprivation Therapy

SIMPLE SUMMARY: Metastatic prostate cancer is a lethal disease and metastasis-specific treatments need to be developed. Mechanisms driving metastases and primary tumor growth could be different, but this is largely unexplored. We previously discovered that bone metastases can be separated into transcriptomic-based subtypes, showing different responses to standard androgen-deprivation therapy for metastatic prostate cancer. One subtype, named MetB, is particularly aggressive and has the worst prognosis. Here, we describe similarities and differences between primary tumors and their metastases, and specifically examine if the development of specific subtype of bone metastases can be predicted by analyzing the primary tumor. Results show that many aspects of prostate cancer bone metastases morphology are related to those in the primary tumor, while others are not. Importantly, men with primary tumors with high cell proliferation and low cellular PSA expression tend to develop metastases enriched for the MetB subtype, have poor prognosis, and need complementary treatment to standard hormone treatment. ABSTRACT: Prostate cancer (PC) bone metastases can be divided into transcriptomic subtypes, by us termed MetA-C. The MetB subtype, constituting about 20% of the cases, is characterized by high cell cycle activity, low androgen receptor (AR) activity, and a limited response to standard androgen deprivation therapy (ADT). Complementary treatments should preferably be introduced early on if the risk of developing metastases of the MetB subtype is predicted to behigh. In this study, we therefore examined if the bone metastatic subtype and patient outcome after ADT could be predicted by immunohistochemical analysis of epithelial and stromal cell markers in primary tumor biopsies obtained at diagnosis (n = 98). In this advanced patient group, primary tumor International Society of Urological Pathology (ISUP) grade was not associated with outcome or metastasis subtype. In contrast, high tumor cell Ki67 labeling (proliferation) in combination with low tumor cell immunoreactivity for PSA, and a low fraction of AR positive stroma cells in the primary tumors were prognostic for poor survival after ADT. Accordingly, the same tissue markers were associated with developing metastases enriched for the aggressive MetB subtype. The development of the contrasting MetA subtype, showing the best response to ADT, could be predicted by the opposite staining pattern. We conclude that outcome after ADT and metastasis subtype can, at least to some extent, be predicted by analysis of primary tumor characteristics, such as tumor cell proliferation and PSA expression, and AR expression in stromal cells.