Andrew Erickson

Loss of PTEN expression in ERG-negative prostate cancer predicts secondary therapies and leads to shorter disease-specific survival time after radical prostatectomy

The clinical course of prostate cancer is highly variable. Current prognostic variables, stage, and Gleason score have limitations in assessing treatment regimens for individual patients, especially in the intermediate-risk group of Gleason score 7. ERG:TMPRSS2 fusion and loss of PTEN are some of the most common genetic alterations in prostate cancer. Immunohistochemistry of PTEN and ERG has generated interest as a promising method for more precise outcome prediction but requires further validation in population-based cohorts. We studied the predictive value of ERG and PTEN expression by immunohistochemistry in two large radical prostatectomy cohorts comprising 815 patients with extensive follow-up information. Clinical end points were initiation of secondary therapy, overall survival, and disease-specific survival. Predictions of clinical outcomes were also assessed according to androgen receptor (AR) activity. PTEN loss, especially in ERG-negative cancers, predicted initiation of secondary treatments and shortened disease-specific survival time, as well as stratifying Gleason score 7 patients into different prognostic groups with regard to secondary treatments and disease-specific survival. High AR immunoreactivity in ERG-negative cancers with PTEN loss predicted worse disease-specific survival. We also observed that in Gleason score 7 ERG-negative cases with PTEN loss and high AR expression have significantly shorter disease-specific survival time compared with ERG-positive cases. Our conclusion is that loss of PTEN is a strong determining factor for shorter disease-specific survival time and initiation of secondary therapies after radical prostatectomy. The predictive value of PTEN immunoreactivity is further accentuated in ERG-negative cancers with high AR expression. Negative PTEN expression, accompanied by ERG status, can be used to stratify patients with Gleason score 7 into different survival groups. Assessment of PTEN and ERG status could provide an additional tool for initial diagnostics when determining the prognosis and subsequent follow-up regimen for patients treated by radical prostatectomy.

PTEN Loss but Not ERG Expression in Diagnostic Biopsies Is Associated with Increased Risk of Progression and Adverse Surgical Findings in Men with Prostate Cancer on Active Surveillance

BACKGROUND Active surveillance (AS) is an option for men with low-risk prostate cancer (PCa). PTEN and ERG have been considered as potential biomarkers of PCa progression and survival. OBJECTIVE To study the role of ERG and PTEN status in the Prostate Cancer Research International: Active Surveillance (PRIAS) trial diagnostic biopsies (DBxs) in predicting surveillance discontinuation and adverse surgical findings in subsequent radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS A total of 231 patients were recruited to the PRIAS between 2007 and 2013 in Helsinki. DBx tissue for immunohistochemistry (IHC) was available from 190 patients. Tissue microarrays (TMAs) were constructed from 57 specimens of subsequent RPs. DBxs containing grade group (GG) 1 PCa and RP TMA sections were stained with ERG and PTEN antibodies, and scored as either negative or positive. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES Outcomes were followed up by biopsy GG upgrade (GG ≥ 2) and protocol-based treatment change, as well as adverse findings in RP (GG ≥ 3 or pathological stage≥3). Clinical variables and biomarker status in DBx were correlated in Cox regression analysis and cumulative survival in Kaplan-Meier analysis, and finally, Grays competing risk analysis was performed and nonprotocol-based discontinuation was considered as a competing event. RESULTS AND LIMITATIONS In both uni- and multivariate Cox regression analyses, only the number of positive cores in the DBx, the number of rebiopsy sessions, and PTEN status at diagnosis were significantly associated with rebiopsy GG upgrade, treatment change, and adverse histopathology in RP. In Kaplan-Meier analysis, PTEN loss was associated with a shorter time to GG upgrade and treatment change. Patients with PTEN loss had a higher probability for protocol-based discontinuation but not for competing risk factors compared with patients with intact PTEN. Biopsy ERG status was concordant with RP TMA ERG status, while PTEN was not. Limitations include a retrospective analysis of prospective cohort data. CONCLUSIONS PTEN status at diagnosis is a potential biomarker for identifying patients with PCa on AS with a high risk for progression or adverse findings on subsequent RP. PATIENT SUMMARY A simple diagnostic biopsy-based analysis of PTEN status may help identify patients with high risk for prostate cancer progression.

Repeat multiparametric MRI in prostate cancer patients on active surveillance

Introduction This study was conducted to describe the changes in repeat multiparametric MRI (mpMRI) occurring in prostate cancer (PCa) patients during active surveillance (AS), and to study possible associations between mpMRI-related parameters in predicting prostate biopsy (Bx) Gleason score (GS) upgrading >3+3 and protocol-based treatment change (TC). Materials and methods The study cohort consisted of 76 AS patients with GS 3+3 PCa and at least two consecutive mpMRIs of the prostate performed between 2006–2015. Patients were followed according to the Prostate Cancer Research International Active Surveillance (PRIAS) protocol and an additional mpMRI. The primary end points were GS upgrading (GU) (>3+3) in protocol-based Bxs and protocol-based TC. Results Out of 76 patients, 53 (69%) had progression (PIRADS upgrade, size increase or new lesion[s]), while 18 (24%) had radiologically stable disease, and 5 (7%) had regression (PIRADS or size decrease, disappearance of lesion[s]) in repeat mpMRIs during AS. PIRADS scores of 4–5 in the initial mpMRI were associated with GU (p = 0.008) and protocol-based TC (p = 0.009). Tumour progression on repeat mpMRIs was associated with TC (p = 0.045) but not with GU (p = 1.00). PIRADS scores of 4–5 predict GU (sensitivity 0.80 [95% confidence interval (CI); 0.51–0.95, specificity 0.62 [95% CI; 0.52–0.77]) with PPV and NPV values of 0.34 (95% CI; 0.21–0.55) and 0.93 (95% CI; 0.80–0.98), respectively. Conclusion mpMRI is a useful tool not only to select but also to monitor PCa patients on AS.

Increased HSF1 expression predicts shorter disease-specific survival of prostate cancer patients following radical prostatectomy

Prostate cancer is a highly heterogeneous disease and the clinical outcome is varying. While current prognostic tools are regarded insufficient, there is a critical need for markers that would aid prognostication and patient risk-stratification. Heat shock transcription factor 1 (HSF1) is crucial for cellular homeostasis, but also a driver of oncogenesis. The clinical relevance of HSF1 in prostate cancer is, however, unknown. Here, we identified HSF1 as a potential biomarker in mRNA expression datasets on prostate cancer. Clinical validation was performed on tissue microarrays from independent cohorts: one constructed from radical prostatectomies from 478 patients with long term follow-up, and another comprising of regionally advanced to distant metastatic samples. Associations with clinical variables and disease outcomes were investigated. Increased nuclear HSF1 expression correlated with disease advancement and aggressiveness and was, independently from established clinicopathological variables, predictive of both early initiation of secondary therapy and poor disease-specific survival. In a joint model with the clinical Cancer of the Prostate Risk Assessment post-Surgical (CAPRA-S) score, nuclear HSF1 remained a predictive factor of shortened disease-specific survival. The results suggest that nuclear HSF1 expression could serve as a novel prognostic marker for patient risk-stratification on disease progression and survival after radical prostatectomy.

Abstract 5732: PI3K/Akt activity regulates androgen receptor expression and predicts poor clinical outcome in non-metastatic hormone-naïve prostate cancer

Activation of PI3K/Akt pathway is associated with adverse outcome and aggressive disease in many cancers. In prostate cancer (PCa), the activity of this pathway has been shown to promote disease progression and metastasis. However, it is still controversial how PI3K/Akt regulates androgen receptor (AR), a central signaling molecule in prostate pathophysiology, and whether it has an active role in hormone naive non-metastatic PCa. Here, we show using immunohistochemistry (IHC) and advanced quantitative multiplexed IHC that the expression of phosphorylated-Akt(S473) and AR are highly correlated in clinical PCa, even at the cellular level. Furthermore, we found that high expression of p-Akt(S473) predicts poor clinical outcome in two independent hormone-naive non-metastatic PCa cohorts. To study whether PI3K/Akt regulates AR expression, we performed an in vitro drug screen with 32 PI3K/Akt/mTOR inhibitors in PC346C, an AR expressing cell line derived from a hormone-naive primary tumor of prostate. We observed a strong correlation between p-Akt(S473) and AR also in vitro in individual cells independent of the inhibitor used. Although both PI3K and Akt specific inhibition reduced cell viability, the response in nuclear expression of AR was highly dependent on the target of inhibition: Akt specific inhibition reduced AR nuclear expression and resulted in large, spindle-shaped cells, whereas PI3K specific inhibition increased AR nuclear expression and resulted in smaller, round-shaped cells. These data suggest that PI3K and Akt have different roles in sustaining AR activity in PCa as perturbations of the two components leads to differential responses in terms of AR nuclear expression and cell morphology. In conclusion, activated Akt associates with AR expression and predicts poor clinical outcome in hormone-naive non-metastatic PCa. Furthermore, the differing roles of PI3K and Akt in AR regulation warrants for further studies as it may have implications in the design of PCa therapy targeting PI3K/Akt, especially when the inhibitors are administered in combination with anti-androgens. Citation Format: Sami Blom, Petra Maki-Teeri, Andrew Erickson, Lassi Paavolainen, Tuomas Mirtti, Antti Rannikko, Swapnil Potdar, Paivi Ostling, Wytske van Weerden, Olli Kallioniemi, Teijo Pellinen. PI3K/Akt activity regulates androgen receptor expression and predicts poor clinical outcome in non-metastatic hormone-naive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5732. doi:10.1158/1538-7445.AM2017-5732

Abstract 4951: FGFRL1 in prostate cancer progression

Prostate cancer (PCa) is a disease with high incidence, however, many PCa patients are over-diagnosed and over-treated. Molecular characterization of PCa provides a valid approach to stratify patients, and thus reduce overtreatment. Fibroblast growth factors and their receptor (FGF/FGFR) signaling pathways are involved in various cellular functions such as proliferation, differentiation, migration, and apoptosis of prostate cancer cells. Dysregulated and constitutively activated FGF/FGFR pathways have been shown to be involved in the initiation and progression of prostate cancer. Fibroblast growth factor receptor like 1 (FGFRL1, FGFR5) is the most recently identified member of the FGFR family. FGFRL1 binds several FGFs but its short intracellular part lacks a tyrosine kinase domain. Therefore, the extracellular domain has been suggested to act as a dominant negative regulator of other FGFRs. However, cellular functions of FGFRL1 remain poorly understood. Aberrant FGFRL1 expression has been reported in ovarian, bladder, colon, and other cancers. In silico data analysis indicated altered FGFRL1 mRNA expression in 17% of PCa cases. To date, there have been no systematic studies of FGFRL1 expression and function in prostate and PCa. We studied FGFRL1 expression and function in PCa cell lines, xenografts and in human PCa specimens. FGRL1 was knocked-down in PC-3M cells, by shRNAs, which showed reduced growth as nude mouse xenografts when compared to control. This argues against a dominant negative function. To study FGFRL1 in human PCas, we collected formalin-fixed paraffin-embedded samples from PCa patients undergoing radical prostatectomy (n = 243), metastatic PCa (n = 36) and castration-resistant PCa (n = 21). Samples were prepared for mRNA analysis, and immunohistochemistry. The overall levels of FGFRL1 immunostaining were significantly increased in PCa compared to normal tissue. In normal tissue, FGFRL1 immunostaining localized to the cell membrane and to a lesser extent to the cytoplasm and nuclei. In PCa, protein expression of FGFRL1 was decreased at the cell membrane, while expression in the cytoplasm and nucleus were increased. Low membrane and high nuclear immunostaining of FGFRL1 correlated with high Gleason grade. High nuclear FGFRL1 also correlated with high levels of preoperative serum PSA and an increased proportion of tumors with positive surgical margins. Our results suggest that FGFRL1 may play an active role in PCa cells and in tumor progression and can possibly be used to assess PCa prognosis. Citation Format: Lan Yu, Andrew Erickson, Mervi Toriseva, Teresa Elo, Johanna Tuomela, Heikki Seikkula, Martti Nurmi, Peter Bostrom, Tuomas Mirtti, Kalle Alanen, Markku Kallajoki, Matthias Nees, Pirkko Harkonen. FGFRL1 in prostate cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4951.