An approach to genetic testing in patients with metastatic castration-resistant prostate cancer in Singapore.

Introduction: There has been a rapid evolution in the treatment strategies for metastatic castration-resistant prostate cancer (mCRPC) following the identification of targetable mutations, making genetic testing essential for patient selection. Although several international guidelines recommend genetic testing for patients with mCRPC, there is a lack of locally endorsed clinical practice guidelines in Singapore. Method: A multidisciplinary specialist panel with representation from medical and radiation oncology, urology, pathology, interventional radiology, and medical genetics discussed the challenges associated with patient selection, genetic counselling and sample processing in mCRPC. Results: A clinical model for incorporating genetic testing into routine clinical practice in Singapore was formulated. Tumour testing with an assay that is able to detect both somatic and germline mutations should be utilised. The panel also recommended the "mainstreaming" approach for genetic counselling in which pre-test counselling is conducted by the managing clinician and post-test discussion with a genetic counsellor, to alleviate the bottlenecks at genetic counselling stage in Singapore. The need for training of clinicians to provide pre-test genetic counselling and educating the laboratory personnel for appropriate sample processing that facilitates downstream genetic testing was recognised. Molecular tumour boards and multidisciplinary discussions are recommended to guide therapeutic decisions in mCRPC. The panel also highlighted the issue of reimbursement for genetic testing to reduce patient-borne costs and increase the reach of genetic testing among this patient population. Conclusion: This article aims to provide strategic and implementable recommendations to overcome the challenges in genetic testing for patients with mCRPC in Singapore.

Chemotherapy-induced monoamine oxidase expression in prostate carcinoma functions as a cytoprotective resistance enzyme and associates with clinical outcomes.

To identify molecular alterations in prostate cancers associating with relapse following neoadjuvant chemotherapy and radical prostatectomy patients with high-risk localized prostate cancer were enrolled into a phase I-II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pre-treatment prostate tissue was acquired by needle biopsy and post-treatment tissue was acquired by prostatectomy. Prostate cancer gene expression measurements were determined in 31 patients who completed 4 cycles of neoadjuvant chemotherapy. We identified 141 genes with significant transcript level alterations following chemotherapy that associated with subsequent biochemical relapse. This group included the transcript encoding monoamine oxidase A (MAOA). In vitro, cytotoxic chemotherapy induced the expression of MAOA and elevated MAOA levels enhanced cell survival following docetaxel exposure. MAOA activity increased the levels of reactive oxygen species and increased the expression and nuclear translocation of HIF1α. The suppression of MAOA activity using the irreversible inhibitor clorgyline augmented the apoptotic responses induced by docetaxel. In summary, we determined that the expression of MAOA is induced by exposure to cytotoxic chemotherapy, increases HIF1α, and contributes to docetaxel resistance. As MAOA inhibitors have been approved for human use, regimens combining MAOA inhibitors with docetaxel may improve clinical outcomes.

Diagnostic and prognostic utility of a DNA hypermethylated gene signature in prostate cancer.

We aimed to identify a prostate cancer DNA hypermethylation microarray signature (denoted as PHYMA) that differentiates prostate cancer from benign prostate hyperplasia (BPH), high from low-grade and lethal from non-lethal cancers. This is a non-randomized retrospective study in 111 local Asian men (87 prostate cancers and 24 BPH) treated from 1995 to 2009 in our institution. Archival prostate epithelia were laser-capture microdissected and genomic DNA extracted and bisulfite-converted. Samples were profiled using Illumina GoldenGate Methylation microarray, with raw data processed by GenomeStudio. A classification model was generated using support vector machine, consisting of a 55-probe DNA methylation signature of 46 genes. The model was independently validated on an internal testing dataset which yielded cancer detection sensitivity and specificity of 95.3% and 100% respectively, with overall accuracy of 96.4%. Second validation on another independent western cohort yielded 89.8% sensitivity and 66.7% specificity, with overall accuracy of 88.7%. A PHYMA score was developed for each sample based on the state of methylation in the PHYMA signature. Increasing PHYMA score was significantly associated with higher Gleason score and Gleason primary grade. Men with higher PHYMA scores have poorer survival on univariate (p = 0.0038, HR = 3.89) and multivariate analyses when controlled for (i) clinical stage (p = 0.055, HR = 2.57), and (ii) clinical stage and Gleason score (p = 0.043, HR = 2.61). We further performed bisulfite genomic sequencing on 2 relatively unknown genes to demonstrate robustness of the assay results. PHYMA is thus a signature with high sensitivity and specificity for discriminating tumors from BPH, and has a potential role in early detection and in predicting survival.

Does periprostatic block increase the transrectal ultrasound (TRUS) biopsy sepsis rate in men with elevated PSA?

INTRODUCTION: Periprostatic nerve block (PPNB) is a common local anaesthetic technique in transrectal ultrasound-guided (TRUS) prostate biopsy, but concerns remain over the increased theoretical risks of urinary tract infection (UTI) and sepsis from the additional transrectal needle punctures. This study reviewed our biopsy data to assess this risk. MATERIALS AND METHODS: Retrospective data collected from 177 men who underwent TRUS biopsy between July 2007 and December 2009 in a single institution were analysed. PPNB was administered using 1% xylocaine at the prostatic base and apex and repeated on the contralateral side under ultrasound guidance. Complications, including UTI sepsis, bleeding per rectum and acute retention of urine (ARU) were noted. Every patient was tracked for the first 2 weeks for complications until his clinic review. Demographic profi le, biopsy parameters and histological fi ndings were reviewed. Univariate and multivariate analysis of possible risk factors for development of sepsis after TRUS biopsy were performed. Statistical analysis was performed using SPSS 17.0. RESULTS: Ninety (51%) men received PPNB and 87 (49%) did not. The groups were matched in age (PPNB: mean 62.7 ± 5.8 years; without PPNB: mean 64.4 ± 5.7 years) and prebiopsy prostate specific antigen (PSA) levels (PPNB: mean 8.2 ± 3.9 ng/mL; without PPNB: mean 8.3 ± 3.7 ng/mL). The PPNB group had a larger prostate volume, with more cores taken (P <0.05). On univariate and multivariate analysis controlling for age, PSA, prostate volume, number of cores taken and histological prostatitis, PPNB was not a significant risk factor for sepsis. Sepsis rates were 5.6% in the PPNB group and 5.7% in the other group (P = 0.956). Overall prostate cancer detection rate was 33.3%. CONCLUSION: The risk of sepsis was not increased in patients who received PPNB, even though this group had larger gland volumes and more biopsy cores taken.

8q24 and 17q prostate cancer susceptibility loci in a multiethnic Asian cohort.

OBJECTIVES: Recently, several genome-wide association studies have demonstrated a cumulative association of 5 polymorphic variants in chromosomes 8q24 and 17q with prostate cancer (CaP) risk in Caucasians, particularly those harboring aggressive clinicopathologic characteristics. The purpose of this study was to evaluate the influence of these variants on CaP susceptibility in Singaporean Asian men. MATERIALS AND METHODS: We performed a case-control study in 289 Chinese CaP patients and 412 healthy subjects (144 Chinese, 134 Malays, and 134 Indians), and examined the association of the 5 single nucleotide polymorphisms (SNPs) with CaP. RESULTS: In the healthy subjects, rs16901979 A-allele frequency was highest amongst Chinese (0.32) compared with Malays (0.13; P < 0.0001) or Indians (0.09; P < 0.0001); rs6983267 G-allele was highest in Indians (0.51) compared with Chinese (0.42; P = 0.041) or Malays (0.43; P = 0.077); whereas rs1859962 G-allele frequency was highest amongst Indians (0.56) compared with Chinese (0.40; P = 0.0002) or Malays (0.38; P < 0.0001). Individuals with the rs4430796 TT genotype were at increased CaP risk in the Chinese via a recessive model (odds ratios (OR) = 1.56, 95% CI = 1.04-2.33). Significant associations were observed for rs4430796 TT with Gleason scores of ≥ 7 (OR = 1.76, 95% CI = 1.14-2.73) and prostate-specific antigen (PSA) levels of ≥ 10 ng/ml at diagnosis (OR = 1.63, 95% CI = 1.01-2.63), as well as for rs6983267 GG with stage 3-4 CaPs (OR = 1.91, 95% CI = 1.01-3.61). A cumulative gene interaction influence on disease risk, which approximately doubled for individuals with at least 2 susceptibility genotypes, was also identified (OR = 2.18, 95% CI = 1.10-4.32). CONCLUSIONS: This exploratory analysis suggests that the 5 genetic variants previously described may contribute to prostate cancer risk in Singaporean men.

Management of kidney cancer in Asia: resource-stratified guidelines from the Asian Oncology Summit 2012.

Treatment of renal-cell carcinoma has progressed over the past decade, in terms of surgical and systemic therapy. Current treatment guidelines are based on clinical evidence, but do not take into account resource limitations among different countries. These limitations, which include financial and logistical challenges and lack of skilled health-care professionals, have the greatest effect in low-income countries. This consolidated statement gives treatment recommendations for renal-cell carcinoma that are based on clinical evidence and stratified according to extent of resource availability. The statement was formulated by a panel of urologists, medical oncologists, and clinical oncologists from Asian countries, at a consensus session on kidney cancer that was held as part of the 2012 Asian Oncology Summit in Singapore. Resource levels are defined according to a four-tier system (basic, limited, enhanced, and maximum), and treatment recommendations are specified based on availability of financial, skill, and logistical resources.

Combination of the ERK inhibitor AZD6244 and low-dose sorafenib in a xenograft model of human renal cell carcinoma.

Sorafenib, a multikinase inhibitor, is currently used as monotherapy for advanced renal cell carcinoma (RCC). However, adverse effects associated with its use have been experienced by some patients. In this study, we examined the antitumor and antiangiogenic activities of low-dose sorafenib in combination with the MEK inhibitor AZD6244 (sorafenib/AZD6244) in a preclinical model of RCC. Primary RCC 08-0910 and RCC 786-0 cells as well as patient-derived RCC models were used to study the antitumor and antiangiogenic activities of sorafenib/AZD6244. Changes of biomarkers relevant to angiogenesis and cell cycle were determined by western immunoblotting. Microvessel density, apoptosis and cell proliferation were analyzed by immunohistochemistry. Treatment of RCC 786-0 cells with sorafenib/AZD6244 resulted in G1 cell cycle arrest and blockade of serum-induced cell migration. Sorafenib/AZD6244 induced apoptosis in primary RCC 08-0910 cells at low concentrations. In vivo addition of AZD6244 to sorafenib significantly augmented the antitumor activity of sorafenib and allowed dose reduction of sorafenib without compromising its antitumor activity. Sorafenib/AZD6244 potently inhibited angiogenesis and phosphorylation of VEGFR-2, PDGFR-ß and ERK, p90RSK, p70S6K, cdk-2 and retinoblastoma. Sorafenib/AZD6244 also caused upregulation of p27, Bad and Bim but downregulation of survivin and cyclin B1. These resulted in a reduction in cellular proliferation and the induction of tumor cell apoptosis. Our findings showed that AZD6244 and sorafenib complement each other to inhibit tumor growth. This study provides sound evidence for the clinical investigation of low-dose sorafenib in combination with AZD6244 in patients with advanced RCC.

Renal cell carcinoma in young patients is associated with poorer prognosis.

INTRODUCTION: Renal cell carcinoma (RCC) in young patients is uncommon but thought to represent a distinctive clinical entity from older patients with different clinico-pathologic features and outcomes. We evaluated the association of age at the time of diagnosis with pathological staging, histological parameters, disease recurrence and overall survival (OS) following radical or partial nephrectomy for non-metastatic RCC in native kidneys. MATERIALS AND METHODS: A retrospective review of 316 patients with RCC after nephrectomy at a single institution between January 2001 and June 2008 was performed. Eligible patients included all histologically proven primary non-metastatic RCC treated by radical or partial nephrectomy. They were categorised into group A (≤ 40 years at diagnosis) and B (> 40 years). Differences in clinical parameters were analysed using the Mann Whitney U test. The prognostic potential of age at diagnosis was evaluated using Cox proportional hazards regression. Survival was estimated using the Kaplan Meier method. RESULTS: There were 33 patients in group A and 283 patients in group B. There were more non-clear cell tumours in the younger group (30% vs 14%, P <0.05). No statistical differences were found in the stage and grade of both groups. At a median follow-up time of 41 months, the younger group had a higher metastatic rate (18% vs 10.5%, P <0.05), lower 5-year cancer-specific survival (82% vs 98%, P <0.05) and lower 5-year OS (82 % vs 95%, P <0.05). CONCLUSION: Younger patients were more likely to have non-clear cell RCC with higher disease recurrence and lower OS. They should not be assumed to have similar features and outcomes as screen-detected early RCC in older patients.

Papillary renal cell carcinoma with metastatic laparoscopic port site and vaginal involvement: a case report.

INTRODUCTION: Laparoscopic port-site metastasis is a rare but well recognized outcome following surgery in urological cancers, with its etiology not clearly understood. Additionally, vaginal metastasis in clear cell renal cell carcinoma is rare, and has not been previously reported in the setting of papillary renal cell carcinoma. CASE PRESENTATION: We present the case of a 71-year-old Chinese woman with metastatic type II papillary renal cell carcinoma with histologically verified vaginal involvement and a concurrent laparoscopic port-site metastasis. This was also associated with a unique constellation of widely disseminated metastatic sites, which include a local relapse, the peritoneum and the urethra. CONCLUSION: Laparoscopic port-site metastases are associated with the presence of advanced cancer with multiple sites of metastasis. We hypothesize from the findings of our report and background data that this phenomenon is more likely to be related to tumor factors rather than operative factors. We also present what is, to the best of our knowledge, the first reported case in the literature of vaginal and urethral metastasis and the second reported case of laparoscopic port-site recurrence.

The natural history of voiding function after robot-assisted laparoscopic radical prostatectomy.

OBJECTIVES: We report the natural history of voiding function in men with clinically localized prostate cancer after robot-assisted laparoscopic radical prostatectomy (RLRP), describing the trend of functional recovery, which is currently not well described using the robot-assisted laparoscopic approach. MATERIALS AND METHODS: We determined the impact on voiding function by prospectively evaluating 100 consecutive men who underwent RLRP between May 2005 and December 2006 and compared their reported International Prostate Symptom Score (IPSS) and Quality of Life (QOL) scores at 3, 6, and 12 months with preoperative scores after surgery. Patients with preoperative IPSS of 0-7 and 8-35 were defined as having mild lower urinary tract symptoms (LUTS) and moderate to severe LUTS, respectively. RESULTS: Continence was achieved in 82%, 87%, and 91% of men at 3, 6, and 12 months after RLRP, respectively. There were statistically and clinically significant improvements in both IPSS and QOL preoperative scores at all studied time points for patients with moderate to severe preexisting LUTS. The mean IPSS scores for these patients preoperatively and at 3, 6, and 12 months after surgery were 14.1, 5.2, 3.0, and 2.9, respectively and the corresponding mean QOL scores were 3.4, 2.1, 1.6, and 1.6, respectively. Patients with mild preexisting LUTS showed no statistically significant improvement in IPSS at 3 and 6 months after surgery but significant improvement was found at 1 year (P = 0.04). CONCLUSIONS: Good continence recovery is expected in most patients undergoing RLRP. Patients with moderate to severe preexisting LUTS can expect early and clinically significant symptom and QOL improvements after RLRP. Patients with mild preexisting LUTS show significant symptom improvement at 1 year.

Evaluation of data completeness of the prostate cancer registry after robotic radical prostatectomy.

INTRODUCTION: This study evaluated the data completeness in the registration of prostate cancer after robotic radical prostatectomy (RRP) in the Urological Cancer Registry at the Singapore General Hospital (SGH), and its compliance to the international standards of US Commission on Cancer (CoC). MATERIALS AND METHODS: A certified cancer registrar reviewed all RRP cases between June 2003 and July 2008 in the Urological Cancer Registry at SGH. RESULTS: A total of 365 cases were reviewed. The results showed that 351 (96.2%) of RRP patients' demographic data were captured and 321 (87.9%) of RRP patients were staged. According to the international standards of CoC for an academic institution, the requirement is to capture 100% of all cancer cases and stage at least 90% of them. As for data completeness, 317 (86.7%) of RRP details were captured as compared to the CoC standard requirement of 90%. CONCLUSIONS: The existing manual cancer registry does not fully meet the CoC standards. Hence, the registry increased sources of case-finding and used active case-finding. With improvements made to the data collection methodology, the number of prostate cancer cases identified has been increased by 52.1% from 215 in 2007 to 327 in 2009. The registry is expected to be fully compliant with the CoC standard with the recruitment of more full time cancer registrars when a new web-based cancer registry is in full operation.

A unique pair of monozygotic twins with concordant clear cell renal cell carcinoma: a case report.

INTRODUCTION: Genetic predisposition to clear cell renal cell carcinoma (ccRCC) has been linked to disorders such as von Hippel-Lindau (VHL) syndrome. While twin research is a classic approach for elucidating genetic and environmental contributions to disease, no monozygotic twin-pair concordant for ccRCC in the absence of VHL syndrome has been previously reported in the literature or in major twin registries. CLINICAL PICTURE: We describe a unique monozygotic twin-pair concordant for ccRCC, with discordant but early ages of onset of 25 and 38 respectively. Cytogenetic studies and direct sequencing for VHL gene mutations in the second twin proved unremarkable. CONCLUSIONS: This is the fi rst reported case of monozygotic twins concordant for ccRCC in the absence of VHL gene mutation. The early yet discordant, age of onset of disease in both twins suggests both genetic and environmental contributions to ccRCC.

Intravesical prostatic protrusion predicts clinical progression of benign prostatic enlargement in patients receiving medical treatment.

OBJECTIVES: To assess intravesical prostatic protrusion (IPP) as a novel predictor of clinical progression in patients with benign prostatic enlargement (BPE). METHODS: All patients attending the outpatient clinic at our institution who were being treated for lower urinary tract symptoms (LUTS) secondary to BPE between January 1997 and December 2003 were recruited into the study. International Prostate Symptom Score (IPSS) scores, uroflowmetry parameters, post-void residual urine volume (PVR), IPP and serum prostate-specific antigen (PSA) were collected. IPP was classified into Grade 1, 2 or 3. Patients were stratified to different treatment options including watchful waiting, alpha blockers or 5-alpha reductase inhibitors. Those who developed high post-void residual urine volume (>100 mL), acute urinary retention or a deterioration of at least 4 points in IPSS score were considered to have disease progression. Using the Grade 1 IPP group as a reference, the odds ratio for clinical progression of Grade 2 and Grade 3 IPP were calculated by using multivariate analysis. RESULTS: A total of 259 patients with a mean age of 63 years (range 50-90 years) and mean follow-up time of 32 months were available for analysis. Fifty-two patients were found to have clinical progression. Odds ratio for progression of a Grade 2 IPP was 5.1 (95% confidence interval [CI] 1.6-16.2) and that of a Grade 3 IPP was 10.4 (95% CI 3.3-33.4). CONCLUSION: A higher IPP grade is associated with a higher risk of clinical progression in BPE. IPP is a useful non-invasive predictor for clinical progression in BPE.

Robotic radical prostatectomy in east Asia: development, surgical results and challenges.

PURPOSE OF REVIEW: The shift toward robot-assisted laparoscopic radical prostatectomy has reshaped the surgical approach for localized prostate cancer in America and many parts of Europe. Its impact on Asia, however, has been somewhat delayed and less widespread compared with western countries. We reviewed and surveyed the evolving trends in robotic prostatectomy in east Asia and describe how the influence of cancer demography, financial reimbursement models, refinements in robotic technology and robotic surgical training will alter the future direction of the procedure in this region. RECENT FINDINGS: There are about 50 systems installed in east Asia. Numerous centers have reported successful implementation of robotic prostatectomy program, with transfusion rate of 7-26.4%. Margin positivity for T2 disease ranges from 9.8 to 24%, whereas continence rates range from 75 to 94% over 3-6 months. Significant increase in number of prostatectomy has been observed in some centers. SUMMARY: The outlook for robotic prostatectomy in east Asia remains rosy despite the obstacles in financial reimbursement, patient volume and surgical skill development. Future robotic systems with smaller footprint, leaner instrument arms and lower costs will help to accelerate its integration into more Asian hospitals.

Correlation between prostate needle biopsies and radical prostatectomy specimens: can we predict pathological outcome?

AIMS: Prostate needle biopsy findings provide important information when considering treatment options. We examine the correlation between needle biopsy and radical prostatectomy pathology to predict patients at high risk of harbouring adverse pathological findings. METHODS: We reviewed data from 100 consecutive patients who underwent radical prostatectomy between 1 January 2003 and 31 January 2005 at the Singapore General Hospital. Pre-operative clinical findings and needle biopsy pathological data were prospectively collected and compared with the final histology. RESULTS: The mean pre-biopsy PSA level was 9.4 +/- 5.1 microg/L. Median maximum percent of tumour in any core was 50% (range 5-100) and mean percentage of positive cores was 34.5 +/- 23%. There was under-grading of the final tumour score in 27 (27%) patients on biopsy as compared with the radical prostatectomy, while over-grading occurred in eight (8%) patients. On stratifying patients pre-operatively into low risk and high risk groups, patients in the high risk group had a significantly higher chance of having adverse radical prostatectomy histology such as extraprostatic extension, positive surgical margins or tumour volume >3.0 mL (p = 0.041, OR = 3.96, 95%CI 1.13-13.86). CONCLUSIONS: Our results demonstrated good pathological correlation between prostate needle biopsies and their radical prostatectomies. Patients with Gleason scores of 7 or more, maximum percent of tumour in any core >50%, or percent of positive cores of >50% on needle biopsy had a higher risk of having adverse pathological findings at radical prostatectomy. The converse, however, is not necessarily true, as a result of sampling error during the biopsy.

Tertiary Gleason pattern 5 in Gleason 7 prostate cancer predicts pathological stage and biochemical recurrence.

PURPOSE: Gleason sum 7 prostate cancers are a heterogeneous group with diverse tumor behaviors and disease outcomes. Tertiary Gleason patterns are reported with increasing frequency, particularly in prostatectomy pathology reports. We studied the pathological and biochemical outcome following radical prostatectomy in men with Gleason sum 7 and tertiary Gleason pattern 5. MATERIALS AND METHODS: We reviewed 1,110 cases of clinically localized prostate cancer treated with primary radical prostatectomy between January 1998 and August 2006 through a prospectively collected prostate cancer database. Patients who underwent neoadjuvant or adjuvant hormonal deprivation, radiation or systemic chemotherapy were excluded. RESULTS: Of the 1,110 patients 509 had Gleason sum 7 cancer. Tertiary Gleason pattern was present in 66 of 509 cases (13%) and it was absent in 443 (87%). On multivariate analysis tertiary Gleason pattern 5 was associated with higher pT stage (OR 2.55, 95% CI 1.40-4.65) and biochemical recurrence (HR 1.78, 95% CI 1.00-3.17). On subgroup analysis when patients with Gleason sum 3 + 4 + 5 and 4 + 3 + 5 were compared to their respective referent groups without the tertiary Gleason pattern, the 2 groups showed a trend toward higher pathological stage and prostate specific antigen progression. Patients with Gleason sum 3 + 4 with no tertiary pattern had higher PSA recurrence-free probability than those with Gleason sum 3 + 4 + 5 or 4 + 3 and patients with Gleason sum 4 + 3 + 5 had the lowest PSA recurrence-free probability. CONCLUSIONS: In patients with Gleason sum 7 prostate cancer tertiary Gleason grade 5 is significantly associated with higher pT stage and biochemical recurrence. Larger studies are needed to assess the predictive value of tertiary grade compared to other established parameters in predicting the long-term oncological outcome after radical prostatectomy.

Role of post-chemotherapy surgery in germ cell tumors.

Surgery after systemic chemotherapy for advanced testicular cancer has maintained its role in staging and therapeutic management. The clinical outcome is strongly influenced by patient selection and extent of extirpative surgery. Although extensive predictive modeling has attempted to define appropriate post-chemotherapy surgical candidates based on various clinical and pathologic parameters, the accuracy of these models remains controversial. Complete removal of all post-chemotherapy residual masses in nonseminomatous germ cell tumors remains the standard of care and allows for improved prognostication of the long-term oncologic and functional outcome.