Clinical and Preclinical Treatment Aspects of Castration Resistant Prostate Cancer (CRPC)

In the Western countries prostate cancer is the most frequently diagnosed cancer, except for skin cancer, and the second leading cause of male cancer deaths. Prostate cancer tends to develop in men over the age of fifty and although it is one of the most prevalent types of cancer in men, many patients may never have symptoms, undergo no therapy, and eventually die from other causes. This is because cancer of the prostate is, in many cases, slow-growing, symptom-free, and since men with the condition are older they often die from causes unrelated to the prostate cancer. Men diagnosed with clinically localized prostate cancer have several treatment options available, including watchful waiting, definitive radiation therapy and surgery. However, a significant proportion of patients who present with cancer that appears to be localized will eventually develop incurable metastatic disease and ultimately succumb to death as a result of advanced disease. In patients with advanced disease androgen-deprivation therapies typically result in rapid responses, but eventually nearly all patients develop progressive castration-resistant disease. Historically, clinical management for metastatic castration resistant prostate cancer (CRPC) has been primarily focused on relieving symptoms. In the last decade the therapeutic spectrum has changed dramatically, and our understanding of the biology of patients with prostate cancer has become far more sophisticated. The treatment paradigm first changed with the publication of 2 pivotal randomized clinical trials in 2004, which demonstrated for the first time a survival benefit with docetaxel-based therapy in patients with metastatic CRPC. Since then, docetaxel chemotherapy has become the standard first-line treatment in patients with CRPC (Chapter 2). Recently, the landscape for CRPC treatment has changed again with the FDA approval of three additional therapies, sipuleucel-T5, cabazitaxel6 and abiraterone acetate7. While the addition of these new treatment options is a great advance for patients with metastatic CRPC, there are many new questions arising regarding the optimal sequencing of these treatments as well as potential combinations of and old drugs

AR splice variants in circulating tumor cells of patients with castration-resistant prostate cancer: relation with outcome to cabazitaxel

The androgen receptor splice variant (AR-V) 7 in circulating tumor cells (CTCs) is a predictor for resistance to anti-AR-targeted treatment, but not to taxane-based chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). In this study, we investigated whether the presence of two constitutively active variants (AR-V3, AR-V7) and two other conditionally activated variants (AR-V1, AR-V9) vs full-length androgen receptor (AR-FL) measured in CTCs from patients with mCRPC were associated with outcome to therapy with the taxane cabazitaxel. Blood was collected at baseline and after two cycles of cabazitaxel from 118 mCRPC patients starting cabazitaxel in a prospective phase II trial. CellSearch-enriched CTCs were enumerated and in parallel characterized for the presence of the AR-Vs by reverse transcription quantitative polymerase chain reaction. Correlations with CTC and prostate-specific antigen response to cabazitaxel as well as associations with overall survival (OS) were investigated. All AR-Vs were frequently pre

Circulating tumor cell enumeration and characterization in metastatic castration-resistant prostate cancer patients treated with cabazitaxel

(1) Background: Markers identifying which patients with metastatic, castration-resistant prostate cancer (mCRPC) will benefit from cabazitaxel therapy are currently lacking. Therefore, the aim of this study was to identify markers associated with outcome to cabazitaxel therapy based on counts and gene expression profiles of circulating tumor cells (CTCs). (2) Methods: From 120 mCRPC patients, CellSearch enriched CTCs were obtained at baseline and after 6 weeks of cabazitaxel therapy. Furthermore, 91 genes associated with prostate cancer were measured in mRNA of these CTCs. (3) Results: In 114 mCRPC patients with an evaluable CTC count, the CTC count was independently associated with poor progression-free survival (PFS) and overall survival (OS) in multivariable analysis with other commonly used variables associated with outcome in mCRPC (age, prostate specific antigen (PSA), alkaline phosphatase, lactate dehydrogenase (LDH), albumin, hemoglobin), together with alkaline phosphatase and hemoglobin. A five-gene expression profile was generated to predict for outcome to cabazitaxel therapy. However, even though this signature was associated with OS in univariate analysis, this was not the case in the multivariate analysis for OS nor for PFS. (4) Conclusion: The established five-gene expression profile in CTCs was not independently associated with PFS nor OS. However, along with alkaline phosphatase and hemoglobin, CTC-count is independently associated with PFS and OS in mCRPC patients who are treated with cabazitaxel

[Characterisation of families with hereditary prostate cancer in the Netherlands]

Item does not contain fulltextOBJECTIVE: To inventory the characteristics of Dutch families with hereditary prostate carcinoma (HPC). DESIGN: Descriptive. METHOD: From a national registry of families that meet the criteria of HPC, information was collected about patients with HPC and their first-degree relatives from 1995 through to 30 June 2001. The ages of the HPC patients at diagnosis were compared with those of all patients with prostate cancer in the Dutch population during the period 1990 to 1996. The cumulative risk of prostate cancer for HPC families was calculated on the basis of the ages of the patients with prostate cancer and their first-degree male relatives. RESULTS: A total of 70 families fulfilled the criteria. The families included 273 patients with prostate cancer. The diagnosis had been confirmed in 208 (76%) of these patients. Two cases of prostate cancer were observed in 3 families, 3 cases were found in 31 families, and in the remaining families 4-8 cases of prostate cancer were observed. The mean age at diagnosis of prostate cancer was 65.5 years (range: 46-89). Of the 273 HPC patients, 128 (47%) were younger than 65 years at the time of diagnosis, whereas in unselected cases of prostate cancer this figure was 16%. The risk of developing prostate cancer before the age of 70 years for members of HPC families was 39%. The mean age of death due to prostate cancer was 71 years (54-84). The mean value of prostate specific antigen (PSA), known for 47 (17%) of the HPC patients, was 36.8 ng/ml (2.1-280)

Effect of environmental factors on the trans/cis ratio of unsaturated fatty acids in Pseudomonas putida S12.

The membrane reactions of Pseudomonas putida S12 to environmental stress were investigated. Cells reacted to the addition of six different heavy metals with an increase in the ratio of trans to cis unsaturated fatty acids. A correlation among the increase in the trans/cis ratio, the toxic effects of the heavy metals, and nonspecific permeabilization of the cytoplasmic membrane, as indicated by an efflux of potassium ions, was measured. Cells previously adapted to toxic concentrations of toluene exhibited increased tolerance to all applied concentrations of zinc compared with nonadapted cells. Cells exposed to different temperatures grew optimally at 30(deg)C. The degree of saturation of the membrane fatty acids of these cells decreased with decreasing temperature. An increase in the trans/cis ratio of unsaturated fatty acids took place only at higher temperatures. Osmotic stress, expressed as reduced water activity, was obtained by using different types of solutes. Only in the presence of toxic concentrations of sodium chloride or sucrose did the trans/cis ratio increase. At no applied water activity a significant effect of glycerol on the trans/cis ratio was measured. When cells were exposed to different pHs, a distinct optimum cis/trans isomerase activity was measured at pHs between 4.0 and 5.0, whereas at higher or lower pHs no reaction occurred. This optimum coincided with a loss of viability between pH 4 and 5

Survival after adjuvant 5-FU treatment for stage III colon cancer in hereditary nonpolyposis colorectal cancer.

In vitro studies suggest that a deficient mismatch repair (MMR) system reduces 5-Fluorouracil cytotoxicity. Colon cancer (CC) in hereditary nonpolyposis colorectal cancer (HNPCC) is due to a dysfunctioning MMR gene that leads to microsatellite instability (MSI). Clinical studies on the efficacy of 5-Fluorouracil (5-FU) in MSI high tumours are contradictory. In a retrospective study, we compared the survival of subjects with stage III CC from HNPCC families that were treated with and without adjuvant 5-FU. The Dutch HNPCC family registry was used. Information on adjuvant chemotherapy for stage III CC was obtained from subjects of families with a mutation and/or who fulfilled the AMS criteria or who were strongly suspicious for HNPCC. CC specific survival was calculated. Observation time was measured either until the date of death, date of a second primary CC or until the closing date of the study, i.e., June 1, 2001. Statistical analysis was done by Kaplan-Meier survival analysis. A total of 92 subjects with stage III CC were included. Twenty-eight of them (17 males) had adjuvant treatment with 5-FU. The median follow-up was 4 (range: 1-17) years; 8 subjects died of CC. The 5-year survival was 70% (95% Cl: 49-90). Sixty-four subjects (36 males) did not have adjuvant therapy. Their median follow-up was 6 (range: 0-23) years. Twenty of them died of CC. The 5-year survival in this group was also 70% (95% Cl: 59-83). To date, the selection of patients with CC for 5-FU treatment is based on the stage rather than the biology of the tumour. In our study, the 5-year survival of subjects treated with and without adjuvant 5-FU did not differ. Further studies are necessary to elucidate the role of MSI in 5-FU treatment of MSI-H tumours in HNPCC

Randomised phase II/III study of docetaxel with or without risedronate in patients with metastatic Castration Resistant Prostate Cancer (CRPC), the Netherlands Prostate Study (NePro)

Item does not contain fulltextBACKGROUND: This multicentre, randomised, open label, phase II/III study aimed to investigate the potential benefit of adding risedronate (R) to docetaxel (D) in patients with metastatic Castration Resistant Prostate Cancer (CRPC). PATIENTS AND METHODS: CRPC patients with bone metastasis were randomly assigned to receive D 75 mg/m(2) every 3 weeks and prednisone as first line chemotherapy, with or without R 30 mg oral once daily. The primary end-point was time to progression (TTP). A composite end-point of objective progression by RECIST criteria, PSA progression, or pain progression, whichever occurred first, was applied. The study had 80% power to detect an improvement of 30% in median TTP in the DR group (two-sided alpha=0.05). RESULTS: Five hundred and ninety-two men (301 D versus 291 DR) were randomised. TTP was 7.4 [D] versus 6.5 [DR] months (p=0.75). PSA and pain response rates were similar, 66.3% [D] versus 65.9% [DR] and 27.9% [D] versus 31.2% [DR], respectively. Median overall survival (OS) was 18.4 [D] versus 19.2 [DR] months (p=0.33). There were no differences in toxicity. CONCLUSION: The addition of the third generation bisphosphonate, risedronate, in the setting of effective first line docetaxel based chemotherapy did not increase efficacy, as indicated by the lack of improvement in TTP, OS, PSA- and pain response