Updates on therapeutic targets and agents in castration-resistant prostate cancer.

Prostate cancer (PCa) is the most commonly diagnosed noncutaneous cancer in men accounting for 28% of all newly diagnosed cancer cases and it is the second to third most common cause of cancer death in the Western world. Nearly all patients with metastatic disease will eventually experience disease progression despite castration as the median duration of response is between 18-24 months. Hence, development of castration-resistant prostate cancer (CRPC) is only a matter of time in these patients. CRPC is defined by disease progression despite androgen-deprivation therapy. CRPC presents a spectrum of disease ranging from rising PSA levels to metastases and significant debilitation from cancer symptoms. Prognosis is associated with several factors, including performance status, presence of bone pain, extent of disease on bone scan, and serum levels of alkaline phosphatase. Based on our enhanced understanding of tumor biology, including the role of tumor, host, and hormonal signaling, there has been rational development of new therapies for CRPC. Over the last decade, several clinical trials have been launched to study novel agents targeting different mechanisms of PCa progression, and have culminated success of new agents for CRPC (docetaxel, cabazitaxel, sipuleucel-T, denosumab, and abiraterone acetate) and several more molecules are on the horizon. The purpose of this review is to discuss the new therapeutic targets in CRPC focusing on new promising agents.

Application of Hereditary Renal Cell Carcinoma Risk Criteria to a Large Prospective Database.

AIMS: To evaluate the clinical impact of the Canadian criteria for identifying patients and families at risk for hereditary renal cell carcinoma (RCC). MATERIALS AND METHODS: The Canadian hereditary RCC risk criteria were applied to patients from 16 centres in the Canadian Kidney Cancer information system (CKCis) prospective database. The primary end point was the proportion of patients who met at least one criterion. RESULTS: Between January 2011 and May 2017, 8388 patients were entered in the database; 291 had inadequate risk data; 2827 (35%) met at least one criterion for genetic testing (at-risk population). Most (83%) met just one criterion. The criterion of non-clear cell histology contributed the largest proportion of at-risk patients (59%), followed by age ≤ 45 years (28%). Sixty-one patients had documentation of genetic testing, with 56 being classified at-risk (2% of at-risk). Twenty patients (35%) of the patients at risk and tested for hereditary RCC were found to harbour a germline mutation. CONCLUSIONS: Application of the Canadian hereditary RCC risk criteria to a large prospective database resulted in 35% of patients being identified at risk for hereditary RCC who could qualify for genetic testing. However, the true incidence of hereditary RCC in this population is unknown as most patients did not have documented genetic testing carried out and, thus, the sensitivity and specificity of the criteria cannot be determined. The low proportion of at-risk patients who underwent genetic testing is disappointing and highlights that there may be gaps in reporting, knowledge and/or barriers in access to genetic testing.

The contemporary role of surgery in kidney cancer.

The diagnosis and treatment of renal cell carcinoma (RCC) has been the subject of major changes since the late 1980s. Initially, surgery was the only treatment available, but more recently, systemic therapies have been developed, and their introduction has modified some of the surgical indications for rcc. In addition, refinements in surgical technique and the introduction of minimally invasive approaches have revolutionized patient care and bear the promise of even more improvements to come. This paper provides an up-to-date overview of recent developments in the surgical treatment of RCC.

Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial.

Importance: In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown. Objective: To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib. Design, Setting, and Participants: This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied. Interventions: Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy. Main Outcomes and Measures: Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Overall survival (OS), adverse events, and postoperative progression were secondary end points. Results: The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n = 50) and 43% in the deferred CN arm (n = 49) (P = .61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P = .03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol recommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%). Conclusions and Relevance: Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib. Trial Registration: ClinicalTrials.gov identifier: NCT01099423.

Bone health in nonmetastatic prostate cancer: what's the big deal?

Since 2000, the medical community has become increasingly aware of bone health in men with prostate cancer on androgen deprivation therapy (ADT)-mainly because of new therapies that have been shown to reduce bone loss and associated fractures in this patient population. The threat of bone complications has become even more concerning in the prostate-specific antigen era, because ADT is initiated earlier (with biochemical recurrence after local treatment) and maintained longer before the appearance of metastatic disease. The present review examines the relevance of bone health in nonmetastatic prostate cancer, with a discussion of the new treatment modalities available.

Gleason score on biopsy: is it reliable for predicting the final grade on pathology?

OBJECTIVE: To assess the correlation of the Gleason score on biopsy and the final pathology after radical prostatectomy (RP) for prostate adenocarcinoma. PATIENTS AND METHODS: In a retrospective analysis within a tertiary-care centre, the charts of 537 patients who had undergone radical prostatectomy from April 1989 to November 2000 were reviewed. The RPs were undertaken in one institution; 167 biopsies were taken and interpreted in the referring centres, and 355 were taken and interpreted in the authors' institution by up to 15 pathologists. All the final pathology specimens were interpreted by the same group of pathologists. The main outcome measures were: the pathological report of the biopsy including the primary and secondary Gleason grade; the final pathological grade (primary and secondary); the margin status; and the identification of the pathologist for the biopsy and final pathology. RESULTS: In all, 390 patients had inclusion criteria (the Gleason grade before and after RP) available. For the individual scores 38.2% of tumours were undergraded, 32.6% overgraded and only 29.2% had identical grading in preoperative biopsies and final specimens. When grouped into more meaningful categories (Gleason 2-4, 5-6, 7 and 8-10) the correlation improved, with 48.5% of patients remaining in the same group after RP. For 39 patients the same pathologist assessed the biopsy and final specimen; in these cases individual scores were identical in 49% and group scores were identical in 64%. CONCLUSION: Gleason grading of the prostate biopsy remains a poor predictor of pathological outcome. Assessment by the same pathologist reduces the discrepancy but over half the patients are under- or overgraded on final pathology. Clinicians should be aware of these limitations when using the biopsy Gleason grade in decision making.

NF-kappa B nuclear localization and its prognostic significance in prostate cancer.

OBJECTIVE: To detect the subcellular localization of NF-kappa B (p65) in human prostate cancer tissues of different histological grades, and to test whether NF-kappa B localization alone, or combined with the histological grade, can be used to predict patient outcome. PATIENTS AND METHODS: Prostate cancer tissues were obtained from radical prostatectomy specimens; the histological grade was determined using the Gleason grading system. Clinical outcomes were defined as good (5-year disease-free survival with undetectable levels of prostate specific antigen) or poor (progression to bone metastases). The subcellular localization of NF-kappa B was visualized by immunohistochemistry using an anti-p65 antibody. RESULTS: The NF-kappa B subcellular localization was initially assessed in 45 specimens; in these samples a nuclear localization of NF-kappa B was specific to cancer tissues, but did not correlate with the Gleason score (P = 0.089). NF-kappa B was then assessed as a prognostic marker to complement Gleason score in predicting cancer progression. Tumour tissues from 30 men with a known clinical outcome were included; 10 of 17 patients who had a poor outcome were positive for NF-kappa B nuclear staining, whereas only two of 13 with a good outcome were positive (P = 0.026). When NF-kappa B subcellular localization and Gleason score were combined, two risk categories of progression were defined. Eleven of 13 specimens from those with a good outcome were in the low-risk category (Gleason 2-4 or Gleason 5-7 with negative nuclear NF-kappa B) and 12 of 17 in the poor outcome group were in the high-risk category (Gleason 8-10 or Gleason 5-7 with positive nuclear NF-kappa B; P = 0.004). CONCLUSION: NF-kappa B is detectable in the nucleus in prostate cancer tissues and positivity can be used to help predict patient outcome. Multivariate analyses using other clinical and molecular variables are underway, and will validate the usefulness of NF-kappa B as a prognostic factor.