Development and validation of circulating tumour cell enumeration (Epic Sciences) as a prognostic biomarker in men with metastatic castration-resistant prostate cancer.

PURPOSE: To evaluate the prognostic significance of circulating tumour cell (CTC) number determined on the Epic Sciences platform in men with metastatic castration-resistant prostate cancer (mCRPC) treated with an androgen receptor signalling inhibitor (ARSI). PATIENTS AND METHODS: A pre-treatment blood sample was collected from men with progressing mCRPC starting either abiraterone or enzalutamide as a first-, second- or third-line systemic therapy at Memorial Sloan Kettering Cancer Center (Discovery cohort, N = 171) or as a first- or second-line therapy as part of the multicenter PROPHECY trial (NCT02269982) (Validation cohort, N = 107). The measured CTC number was then associated with overall survival (OS) in the Discovery cohort, and progression-free survival (PFS) and OS in the Validation cohort. CTC enumeration was also performed on a concurrently obtained blood sample using the CellSearch® Circulating Tumor Cell Kit. RESULTS: In the MSKCC Discovery cohort, CTC count was a statistically significant prognostic factor of OS as a dichotomous (<3 CTCs/mL versus ≥ 3 CTCs/mL; hazard ratio [HR] = 1.8 [95% confidence interval {CI} 1.3-3.0]) and a continuous variable when adjusting for line of therapy, presence of visceral metastases, prostate-specific antigen, lactate dehydrogenase and alkaline phosphatase. The findings were validated in an independent datas et from PROPHECY (HR [95% CI] = 1.8 [1.1-3.0] for OS and 1.7 [1.1-2.9] for PFS). A strong correlation was also observed between CTC counts determined in matched samples on the CellSearch® and Epic platforms (r = 0.84). CONCLUSION: The findings validate the prognostic significance of pretreatment CTC number determined on the Epic Sciences platform for predicting OS in men with progressing mCRPC starting an ARSI.

Population-based analysis of treatment modalities and survival for clinically localized small-cell carcinoma of the prostate.

BACKGROUND: Small-cell carcinoma of the prostate is an aggressive cancer whose rarity has prevented the development of a consensus management approach. The objective of the current study was to determine the treatment patterns and evaluate factors affecting overall survival for patients with localized small-cell carcinoma of the prostate. METHODS: After querying the National Cancer Database, we identified all patients diagnosed with localized small-cell carcinoma of the prostate between 1998 and 2011 (n=287). Using Kaplan-Meier curves and Cox regression analyses, we assessed the effect of treatment and clinical stage on overall survival. RESULTS: Treatments included radiation therapy in 46% (n=131), chemotherapy in 38% (n=107), androgen deprivation therapy (ADT) in 22% (n=63) and radical prostatectomy in 13% (n=38). Median overall survival was 14.8 months. Upon multivariate analysis, local therapy (radical prostatectomy or radiation therapy) was associated with improved survival (hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.14-0.38, P<0.001). Advanced clinical stage predicted worse survival among all men (cT3: HR 2.83, 95% CI 1.27-6.32, P=0.011; cT4: HR 3.26, 95% CI 1.50-7.07, P=0.003) and men who received local therapy (cT3: HR 4.67, 95% CI 1.41-15.44, P=0.012; cT4: HR 4.01, 95% CI 1.14-14.08, P=0.03) but not among men who received no local therapy (cT3: HR 1.64, 95% CI 0.51-5.27, P=0.4; cT4: HR 2.35, 95% CI 0.74-7.48, P=0.15). Age, receipt of chemotherapy and ADT, and clinical stage T2 disease (compared with T1) did not predict survival. CONCLUSION: Men with localized small-cell carcinoma of the prostate have a poor overall survival. Local therapy may represent a suitable and underused modality for select patients.

A randomized, phase II study of pazopanib in castrate-sensitive prostate cancer: a University of Chicago Phase II Consortium/Department of Defense Prostate Cancer Clinical Trials Consortium study.

BACKGROUND: Intermittent androgen suppression (IAS) is an increasingly popular treatment option for castrate-sensitive prostate cancer. On the basis of previous data with anti-angiogenic strategies, we hypothesized that pan-inhibition of the vascular endothelial growth factor receptor using pazopanib during the IAS off period would result in prolonged time to PSA failure. METHODS: Men with biochemically recurrent prostate cancer, whose PSA was <0.5 ng ml(-1) after 6 months of androgen deprivation therapy were randomized to pazopanib 800 mg daily or observation. The planned primary outcome was time to PSA progression >4.0 ng ml(-1). RESULTS: Thirty-seven patients were randomized. Of 18 patients randomized to pazopanib, at the time of study closure, 4 had progressive disease, 1 remained on treatment and 13 (72%) electively disenrolled, the most common reason being patient request due to grade 1/2 toxicity (8 patients). Two additional patients were removed from treatment due to adverse events. Of 19 patients randomized to observation, at the time of study closure, 4 had progressive disease, 7 remained under protocol-defined observation and 8 (42%) had disenrolled, most commonly due to non-compliance with protocol visits (3 patients). Because of high dropout rates in both arms, the study was halted. CONCLUSIONS: IAS is a treatment approach that may facilitate investigation of novel agents in the hormone-sensitive state. This trial attempted to investigate the role of antiangiogenic therapy in this setting, but encountered several barriers, including toxicities and patient non-compliance, which can make implementation of such a study difficult. Future investigative efforts in this arena should carefully consider drug toxicity and employ a design that maximizes patient convenience to reduce the dropout rate.

Resistance to thyroid hormone does not abrogate the transient thyrotoxicosis associated with gestation: report of a case.

We report the occurrence of transient thyrotoxicosis during pregnancy in a subject with resistance to thyroid hormone. Before pregnancy, the subject was euthyroid, with normal serum TSH and elevated levels of free T(3) and free T(4) caused by a mutation in the TRbeta gene (R243Q). Beginning at the fourth week of gestation serum levels of free T(3) and T(4) increased in parallel with an increase in hCG. At 6-7 wk gestation she manifested hypermetabolic features, with mild nausea and vomiting. Peak levels of serum hCG and thyroid hormone concentrations were attained at 12 wk gestation, when serum TSH was fully suppressed. In the following weeks of gestation, thyroid hormone levels declined, with amelioration of the symptoms. A baby boy also affected with resistance to thyroid hormone harboring the same TRbeta gene mutation was born by normal vaginal delivery.