Male breast cancer is uncommon, accounting for less than 1% of all breast cancers. Carcinoma metastatic to the male breast is also unusual, with metastatic prostatic carcinoma being among the most common primary sites from which such tumours derive. Metastatic prostatic cancer and primary breast cancer may be histologically indistinguishable without immunohistochemistry because both often infiltrate with a cribriform architecture. Distinguishing between primary and metastatic disease within the breast is important because the treatment options for each are radically different. Following a case in which metastatic prostatic disease was initially wrongly diagnosed as primary breast cancer, a small series of male breast cancers was examined for expression of prostate specific antigen (PSA) and prostatic acid phosphatase to assess the usefulness of these markers in making this distinction. Focal expression of PSA was found in one of 11 cases of male breast cancer. These results indicate that PSA should be used with caution in this context.
breast cancer; male; prostate specific antigen
Despite advances in therapy options, few guidelines or reviews address the optimal timing or methodology for the radiographic detection of metastatic disease in patients with advanced prostate cancer. This review discusses the current status of predicting the presence of metastatic disease, with a particular emphasis on the detection of the M0 to M1 transition, and reviews current data on newer imaging technologies that are changing the way metastases are detected.
The therapeutic landscape for the treatment of advanced prostate cancer is rapidly evolving, especially for those patients with metastatic castration-resistant prostate cancer (CPRC). Despite advances in therapy options, the diagnostic landscape has remained relatively static, with few guidelines or reviews addressing the optimal timing or methodology for the radiographic detection of metastatic disease. Given recent reports indicating a substantial proportion of patients with CRPC thought to be nonmetastatic (M0) are in fact metastatic (M1), there is now a clear opportunity and need for improvement in detection practices. Herein, we discuss the current status of predicting the presence of metastatic disease, with a particular emphasis on the detection of the M0 to M1 transition. In addition, we review current data on newer imaging technologies that are changing the way metastases are detected. Whether earlier detection of metastatic disease will ultimately improve patient outcomes is unknown, but given that the therapeutic options for those with metastatic and nonmetastatic CPRC vary, there are considerable implications of how and when metastases are detected.
Imaging; Lymph nodes; Magnetic resonance imaging; Neoplasm metastasis; Prostatic neoplasms; Radionuclide imaging
To understand the T cell response to prostate cancer, we created transgenic mice that express a model antigen in a prostate-restricted pattern and crossed these animals to TRAMP mice that develop spontaneous prostate cancer. Adoptive transfer of prostate-specific CD4 T cells shows that, in the absence of prostate cancer, the prostate gland is mostly ignored. Tumorigenesis allows T cell recognition of the prostate gland—but this recognition is tolerogenic, resulting in abortive proliferation and ultimately in hyporesponsiveness at the systemic level. Androgen ablation (the most common treatment for metastatic prostate cancer) was able to mitigate this tolerance—allowing prostate-specific T cells to expand and develop effector function after vaccination. These results suggest that immunotherapy for prostate cancer may be most efficacious when administered after androgen ablation.
Several new agents—cabazitaxel, abiraterone acetate, enzalutamide, and radium-223—are changing the treatment options and management of patients with metastatic castration-resistant prostate cancer. This review article is summarizes the latest data on novel agents and current treatment strategies for patients with metastatic castration-resistant prostate cancer.
The arrival of several new agents—cabazitaxel, abiraterone acetate, enzalutamide, and radium-223—is changing the treatment options and management of patients with metastatic castration-resistant prostate cancer (mCRPC). Many other novel agents are also being investigated. As new drugs become approved, new treatment strategies and markers to best select which patients will best respond to which drug are needed. This review article is a summary of a European Treatment Practices Meeting, which was convened to discuss these latest data on novel agents and current treatment strategies in the mCRPC setting.
Metastatic castration-resistant; Prostate cancer; Treatment; Docetaxel; Cabazitaxel; Abiraterone acetate; Enzalutamide
Prostate cancer is the most common cancer in men in United States and the fifth most common cancer in men in Korea. Although the majority of patients with metastatic prostate cancer initially respond to androgen deprivation therapy, almost all patients will eventually progress to develop castration-resistant prostate cancer (CRPC). Treatment options for CRPC remain limited. Prostate cancer was considered unresponsive to chemotherapy until the mid-1990s, when mitoxantrone combined with prednisone was shown to play a role in the palliative treatment of patients with CRPC. In 2004, two large randomized clinical trials demonstrated for the first time a small but significant survival advantage of docetaxel-based chemotherapy compared with mitoxantrone in patients with metastatic CRPC. Recently, cabazitaxel was shown to improve survival in patients with metastatic CRPC who progressed after docetaxel-based chemotherapy. Sipuleucel-T was also demonstrated to improve overall survival in patients with asymptomatic or minimally symptomatic metastatic CRPC. Along with mitoxantrone and docetaxel, cabazitaxel and sipuleucel-T are now approved for use in metastatic CRPC by the US Food and Drug Administration. There have been multiple early-phase clinical trials of various agents for the treatment of CRPC, and some are in phase III development. This review focuses on the key clinical trials of various treatment options of CRPC currently in use and under investigation.
Drug therapy; Immunotherapy; Molecular targeted therapy; Prostatic neoplasms; Survival
Historically, chemotherapy has remained the most commonly utilized therapy in patients with metastatic cancers. In prostate cancer, chemotherapy has been reserved for patients whose metastatic disease becomes resistant to first line castration or androgen deprivation. While chemotherapy palliates, decreases serum prostate specific antigen and improves survival, it is associated with significant side effects and is only suitable for approximately 60% of patients with castrate-resistant prostate cancer. On that basis, exploration of other therapeutic options such as active secondary hormone therapy, bone targeted treatments and immunotherapy are important. Until recently, immunotherapy has had no role in the treatment of solid malignancies aside from renal cancer and melanoma. The FDA-approved autologous cellular immunotherapy sipuleucel-T has demonstrated efficacy in improving overall survival in patients with metastatic castrate-resistant prostate cancer in randomized clinical trials. The proposed mechanism of action is reliant on activating the patients’ own antigen presenting cells (APCs) to prostatic acid phosphatase (PAP) fused with granulocyte-macrophage colony stimulating factor (GM-CSF) and subsequent triggered T-cell response to PAP on the surface of prostate cancer cells in the patients body. Despite significant prolongation of survival in Phase III trials, the challenge to health care providers remains the dissociation between objective changes in serum PSA or on imaging studies after sipleucel-T and survival benefit. On that basis there is an unmet need for markers of outcome and a quest to identify immunologic or clinical surrogates to fill this role. This review focuses on the impact of sipuleucel-T on the immune system, the T and B cells, and their responses to relevant antigens and prostate cancer. Other therapeutic modalities such as chemotherapy, corticosteroids and GM-CSF and host factors can also affect immune response. The optimal timing for immunotherapy, patient selection and best sequencing with other prostate cancer therapies remain to be determined. A better understanding of immune response may help address these issues.
castrate resistant prostate cancer; immunotherapy; biomarkers; sipuleucel-T; immune response
The natural history of non-metastatic castrate refractory prostate cancer is unknown and treatment options are limited. We present a retrospective review of 13 patients with locally advanced or high risk prostate cancer, initially treated with hormone monotherapy and then treated with prostate radiation after becoming castration refractory.
Median PSA response following prostate radiation was 67.4%. Median time to biochemical progression following radiotherapy was 15 months and to detection of metastatic disease was 18.5 months. Median survival from castration resistance (to date of death or November 2011) was 60 months, with median survival from RT 42 months.
Prostate radiation appears to be beneficial even in patients with potential micrometastatic disease, which supports the hypothesis that the primary tumour is important in the progression of prostate cancer. These results are an interesting addition to the literature on the biology of prostate cancer especially as this data is unlikely to be available in the future due to combined prostate radiation and androgen deprivation therapy now being the standard of care.
Prostate cancer; Prostate radiation; Castrate refractory
Prostate circulating tumor cells (PCTCs) in circulation are shed from either a primary tumor or metastases, which are directly responsible for most prostate cancer deaths. Quantifying exfoliated PCTCs may serve as an indicator for the clinical management of prostate cancer, isolating and removing of PCTCs could potentially reduce prostate cancer metastasis, and culturing and characterizing captured PCTCs could facilitate the development of personalized treatment options. Prostate-specific membrane antigen (PSMA) is an established biomarker for prostate cancer being strongly expressed on prostate tumor cells associated with high-grade primary, androgen independent, and metastatic tumors.
Suspensions of PSMA+ (LNCaP) cells were pre-targeted with the irreversible PSMA inhibitor biotin-PEG12-CTT-54 to serve as a bait to capture PSMA+ cells using streptavidin-coated magnetic beads. Decreasing numbers of LNCaP cells were spiked into blood to determine the cell captured efficiency, recovery and viability.
High selectivity, recovery, and viability were achieved for the capture of PSMA+ cells in both model experiments with mixtures of LNCaP cells and WBCs as well as blood samples spiked with LNCaP cells. As low as 10 cells were captured from 1 mL of blood with nearly 90% viability. More importantly, captured cells could be subsequently propagated in vitro.
This methodology for the detection, isolation, and culture of PCTCs from peripheral blood can serve as an effective tool for the detection of metastatic prostate cancer, treatment monitoring, and the development of personalized therapy based on the responsiveness of PCTCs to chemotherapeutic strategies.
prostate cancer; circulating tumor cells; PSMA; prostate-specific membrane antigen; flow cytometry; magnetic bead
Prostate cancer is the most common cancer among men in American and the second leading cause of cancer death. The treatment options employed for patients with advanced and metastatic prostate cancer are limited. As a critical mediator of oncogenic signaling, STAT3 is active in 82% of patients with prostate cancer. STAT3 has become a very important molecular target for prostate cancer therapy since it upregulates the oncogenes encoding apoptosis inhibitors, cell-cycle regulators, and inducers of angiogenesis. However, no anti-tumor drug whose primary mode of action is to target STAT3 has yet reached the clinic. To this end, we have laid the initial groundwork to develop the STAT3-inhibiting G-quartet oligodeoxynucleotide (GQ-ODN), T40214, for treatment of prostate cancers.
We employed in vitro and in vivo assays, including western blots, EMSA, cell cycle analysis, TUNEL and xenograft models, to determine the drug efficacy and mechanism of T40214/PEI complex.
The results demonstrated that (i) T40214 significantly inhibited STAT3 activation and induced apoptosis in both androgen-dependent and androgen-independent prostate cancer cells; (ii) T40214 delivered by PEI (ployethylenimine) significantly suppressed prostate tumor growth in tumor-bearning nude mice due to that T40214 inhibited STAT3 activation and then greatly promoted apoptosis, reduced angiogenesis and cell proliferation in prostate tumors.
Our studies suggested that STAT3 is a critical oncogenic signal, which strongly influences the progression of prostate cancers and that T40214/PEI complex is a promising candidate for treatment of patients with prostate tumors and represents a novel strategy for prostate cancer therapy.
Although treatment options for men with metastatic castrate-resistant prostate cancer have improved in recent years, the outlook for patients remains poor, with overall survival in the region of 2 years. Response rates with chemotherapy are modest and disease progression is usually observed within months of stopping treatment.
We present a case of a 72-year-old White man of British origin with metastatic castrate-resistant prostate cancer with bulky lymphadenopathy and a serum prostate-specific antigen of 295μg/L. He received treatment with docetaxel chemotherapy plus prednisolone, but received just 3 cycles before treatment was stopped due to toxicity and lack of response (prostate-specific antigen was 276μg/L 4 weeks after the last dose and there was a confirmed stable appearance on computed tomography scan). Unexpectedly, at follow-up 4 months later, the patient was clinically better; his prostate-specific antigen had dramatically improved to 4.1μg/L and a re-staging computed tomography scan revealed complete resolution of his bulky lymphadenopathy. At the time, he was receiving a luteinising hormone-releasing hormone analogue but no other disease-modulating treatment. He remains well and asymptomatic, with his most recent serum prostate-specific antigen measuring 0.14μg/L, 18 months after last receiving chemotherapy.
We report a case of complete and durable regression of metastatic castrate-resistant prostate cancer following palliative chemotherapy which, to the best of our knowledge, has not previously been reported in the literature.
Castrate-resistant prostate cancer; Chemotherapy; Complete response; PSA
In recent years, great success has been achieved on many fronts in the treatment of men with metastatic castration-resistant prostate cancer (CRPC), including novel chemotherapeutics, immunotherapies, bone microenvironment-targeted agents, and hormonal therapies. Numerous agents are currently in early-phase clinical trial development for the treatment of advanced prostate cancer. These novel therapies target several areas of prostate tumor biology, including the upregulation of androgen signaling and biosynthesis, critical oncogenic intracellular pathways, epigenetic alterations, and cancer immunology. Importantly, the characterization of the prostate cancer genome offers the potential to exploit conserved genetic alterations, which may increase the efficacy of these targeted therapies. Predictive and prognostic biomarkers are urgently needed to maximize therapeutic efficacy and safety of these promising new treatments options in prostate cancer.
Prostate cancer; Novel; Treatments; Castration-resistant; Androgen receptor; Metastatic; PI3 kinase inhibitors; Androgen synthesis inhibitors; Immunotherapies; Epigenetic; Epithelial mesenchymal transition
If metastatic prostate cancer gets resistant to antiandrogen therapy, there are few treatment options, because prostate cancer is not very sensitive to cytostatic agents. Temozolomide (TMZ) as an orally applicable chemotherapeutic substance has been proven to be effective and well tolerated with occasional moderate toxicity especially for brain tumors and an application to prostate cancer cells seemed to be promising. Unfortunately, TMZ was inefficient in the treatment of symptomatic progressive hormone-refractory prostate cancer (HRPC). The reasons could be a low sensitivity against TMZ the short plasma half-life of TMZ, non-adapted application regimens and additionally, the aneuploid DNA content of prostate cancer cells suggesting different sensitivity against therapeutical interventions e.g. radiation therapy or chemotherapy. Considerations to improve this unsatisfying situation resulted in the realization of higher local TMZ concentrations, sufficient to kill cells regardless of intrinsic cellular sensitivity and cell DNA-index. Therefore, we reformulated the TMZ by ligation to a peptide-based carrier system called TMZ-BioShuttle for intervention. The modular-composed carrier consists of a transmembrane transporter (CPP), connected to a nuclear localization sequence (NLS) cleavably-bound, which in turn was coupled with TMZ. The NLS-sequence allows an active delivery of the TMZ into the cell nucleus after transmembrane passage of the TMZ-BioShuttle and intra-cytoplasm enzymatic cleavage and separation from the CPP. This TMZ-BioShuttle could contribute to improve therapeutic options exemplified by the hormone refractory prostate cancer. The next step was to syllogize a qualified method monitoring cell toxic effects in a high sensitivity under consideration of the ploidy status. The high-resolution flow cytometric analysis showed to be an appropriate system for a better detection and distinction of several cell populations dependent on their different DNA-indices as well as changes in proliferation of cell populations after chemotherapeutical treatment.
TMZ-BioShuttle; Prostate Cancer Cells; Flow Cytometry
Although most prostate cancers respond well to initial treatments, a fraction of prostate cancers are more aggressive and will recur and metastasize. At that point, there are few treatment options available. Significant efforts have been made to identify biomarkers that will identify these more aggressive cancers to tailor a more vigorous treatment in order to improve outcome. Polycomb Group protein Enhancer of Zeste 2 (EZH2) was found to be overexpressed in metastatic prostate tumors, and is considered an excellent candidate for such a biomarker. Scattered studies have found that EZH2 overexpression causes neoplastic transformation, invasion, and growth of prostate cells. However, these studies utilized different systems and cell lines, and so are difficult to correlate with one another.
In this study, a comprehensive evaluation of the phenotypic effects of EZH2 in a panel of five prostate cancer cell lines was performed. By using multiple cell lines, and examining overexpression and knockdown of EZH2 concurrently, a broad view of EZH2's role in prostate cancer was achieved.
Overexpression of EZH2 led to more aggressive behaviors in all prostate cell lines tested. In contrast, downregulation of EZH2 reduced invasion and tumorigenicity of androgen-independent cell lines CWR22Rv1, PC3, and DU145, but not of androgen-dependent cell lines LAPC4 and LNCaP.
Findings from this study suggest androgen-independent prostate tumors are more dependent on EZH2 expression than androgen-dependent tumors. Our observations provide an explanation for the strong correlation between EZH2 overexpression and advanced stage, aggressive prostate cancers.
EZH2; Prostate; Cancer; Growth; Aggression
Prostate cancer dissemination is difficult to detect in the clinic, and few treatment options exist for patients with advanced-stage disease. Our aim was to investigate the role of tumor lymphangiogenesis during metastasis. Further, we implemented a noninvasive molecular imaging technique to facilitate the assessment of the metastatic process. The metastatic potentials of several human prostate cancer xenograft models, LAPC-4, LAPC-9, PC3 and CWR22Rv-1 were compared. The cells were labeled with luciferase, a bioluminescence imaging reporter gene, to enable optical imaging. After tumor implantation the animals were examined weekly during several months for the appearance of metastases. Metastatic lesions were confirmed by immunohistochemistry. Additionally, the angiogenic and lymphangiogenic profiles of the tumors were characterized. To confirm the role of lymphangiogenesis in mediating metastasis, the low-metastatic LAPC-9 tumor cells were engineered to overexpress VEGF-C, and the development of metastases was evaluated. Our results show CWR22Rv-1 and PC3 tumor cell lines to be more metastatic than LAPC-4, which in turn disseminates more readily than LAPC-9. The difference in metastatic potential correlated with the endogenous production levels of lymphangiogenic growth factor VEGF-C and the presence of tumor lymphatics. In agreement, induced overexpression of VEGF-C in LAPC-9 enhanced tumor lymphangiogenesis leading to the development of metastatic lesions. Taken together, our studies, based on a molecular imaging approach for semiquantitative detection of micrometastases, point to an important role of tumor lymphatics in the metastatic process of human prostate cancer. In particular, VEGF-C seems to play a key role in prostate cancer metastasis.
lymphatics; vascular endothelial growth factor; lung; luciferase; lymph node
Hormonal deprivation therapy is well established for the treatment of locally advanced and metastatic prostate cancer, as well as the adjuvant treatment of some patients with localized disease. Long-acting gonadotropin releasing hormone (GnRH) agonists have become a mainstay of androgen deprivation therapy, due to their efficacy, tolerability, and convenience of use. One-month, 3-month, and 4-month depot leuprorelin formulations are well established and widely used to this end. Recently, a 6-month depot leuprorelin has been approved for use in advanced and metastatic prostate cancer patients. With similar efficacy and side effect profiles to earlier formulations, 6-month depot leuprorelin is a convenient treatment option for these patients. This review will highlight the role of GnRH agonists in the treatment of prostate cancer with a focus on the clinical efficacy, pharmacology, and patient-focused outcomes of the newer 6-month 45 mg depot leuprorelin formulation in comparison to available shorter-acting products.
prostate cancer; leuprorelin; hormonal deprivation therapy
Prostate cancer is the most common non-cutaneous cancer in US men and mainly affects elderly patients, with most new diagnoses occurring in those over 65. As the geriatric population in the US continues to grow, the incidence of this disease is likewise expected to rise. Many older patients are diagnosed with advanced disease or are treated only when their disease becomes symptomatic or metastatic. The treatment options for advanced prostate cancer have increased dramatically in the last decade. It is important to understand the nuances of caring for an elderly cancer patient in order to optimally treat prostate cancer, such as the importance of using a geriatric assessment to uncover overlooked or under-reported vulnerabilities. In addition, many of the newly approved agents for the treatment of advanced prostate cancer have a unique mechanism of action and toxicities that warrant consideration when choosing therapies for older patients. This review focuses on the importance of a geriatric assessment as well as the considerations of treating elderly patients with the newer agents approved for prostate cancer.
To evaluate the outcome of prostate cancer patients with initial PSA value >40 ng/ml.
The outcome of prostate cancer patients with very high initial PSA value is not known and patients are frequently treated with palliative intent. We analyzed the outcome of radical combined hormonal treatment and radiotherapy in prostate cancer patients with initial PSA value >40 ng/ml.
Between January 2003 and December 2007 we treated, with curative intent, 56 patients with non-metastatic prostate cancer and initial PSA value >40 ng/ml. The treatment consisted of two months of neoadjuvant hormonal treatment (LHRH analog), radical radiotherapy (68–78 Gy, conformal technique) and an optional two-year adjuvant hormonal treatment.
The median time of follow up was 61 months. 5-Year overall survival was 90%. 5-Year biochemical disease free survival was 62%. T stage, Gleason score, PSA value, and radiotherapy dose did not significantly influence the outcome. Late genitourinal and gastrointestinal toxicity was acceptable.
Radical treatment in combination with hormonal treatment and radiotherapy can be recommended for this subgroup of prostate cancer patients with good performance status and life expectancy.
Prostate cancer; PSA; High risk; Radiotherapy
The management of men with metastatic castration-resistant prostate cancer (CRPC) has taken several leaps forward in the past year, with the demonstration of improved overall survival with three novel agents (sipuleucel-T, cabazitaxel with prednisone and abiraterone acetate with prednisone), and a significant delay in skeletal-related events observed with denosumab. The pipeline of systemic therapies in prostate cancer remains strong, as multiple agents with a diverse array of mechanisms of action are showing preliminary signs of clinical benefit, leading to more definitive phase III confirmatory trials. In this review, which represents part 1 of a two-part series on metastatic CRPC, we will summarize the mechanisms of resistance to hormonal and chemotherapies and discuss the evolving landscape of treatment options for men with CRPC, with a particular focus on currently approved and emerging treatment options following docetaxel administration, as well as prognostic factors in this post-docetaxel state. As docetaxel remains the standard initial systemic therapy for men with metastatic CRPC for both palliative and life-prolonging purposes, knowledge of these evolving standards will help to optimize delivery of care and long-term outcomes.
castrate-resistant prostate cancer; docetaxel-refractory; cabazitaxel; abiraterone; sipuleucel-T
The three main treatment options for primary prostate cancer are surgery, radiation, and active surveillance. Surgical and radiation intervention for prostate cancer can be associated with significant morbidity. Therefore, accurate stratification predictive of outcome for prostate cancer patients is essential for appropriate treatment decisions. Nomograms that use clinical and pathologic variables are often used for risk prediction. Favorable outcomes exist even among men classified by nomograms as being at high risk of recurrence.
Previously, we identified a set of DNA-based biomarkers termed Genomic Evaluators of Metastatic Prostate Cancer (GEMCaP) and have shown that they can predict risk of recurrence with 80% accuracy. Here, we examined the risk prediction ability of GEMCaP in a high-risk cohort and compared it to a Kattan nomogram.
We determined that the GEMCaP genotype alone is comparable with the nomogram, and that for a subset of cases with negative lymph nodes improves upon it.
Thus, GEMCaP shows promise for predicting unfavorable outcomes for negative lymph node high-risk cases, where the nomogram falls short, and suggests that addition of GEMCaP to nomograms may be warranted.
This article discusses radical prostatectomy as a treatment option for high-risk prostate cancer in men older than 70 years.
Prostate cancer affects a high proportion of men over 70 years of age, who are likely to have high-risk disease and a substantial risk of prostate-cancer-specific death. With life expectancy increasing worldwide, the burden of prostate cancer is also expected to rise. Thus, effective management of this high-risk senior patient group is increasingly important. Radical prostatectomy can increase survival and decrease the risk of metastatic progression. Postsurgery complications are affected more by comorbidity than by age. In patients without comorbidities, surgery is associated with a low risk of mortality. Advanced age may increase the likelihood of incontinence following radical prostatectomy, but patients with higher risk disease are no more likely to experience this complication compared with lower risk groups. Treatment decisions should be made after considering the health status and life expectancy of the individual patient. If eligible, the patient should be offered radical prostatectomy as a potentially curative treatment, without a rigid restriction to a certain chronological age.
Curative therapy; Cancer-specific mortality; Localized disease; High risk
Prostate cancer is the second most common cause of cancer-related death in US men. Along with initial therapy using surgery, radiotherapy, or cryotherapy, hormonal therapy is the mainstay of treatment. For men with advanced (metastatic) disease, docetaxel-based chemotherapy is US Food and Drug Administration (FDA)-approved, and provides a significant survival advantage. This relative paucity of treatment options drives an ongoing quest for additional treatment modalities; among these is immunotherapy. The concept that prostate cancer is a malignancy that can be targeted by the immune system may seem counterintuitive; certainly kidney cancer and melanoma are more traditionally thought of as immune responsive cancers. However, prostate cancer arises in a relatively unique organ and may express a number of proteins (antigens) against which an immune response can be generated. More importantly, several of these agents have now demonstrated a significant survival benefit in randomized controlled clinical trials, and one agent in particular (Sipuleucel-T, Dendreon Corporation, Seattle, WA) could be FDA-approved in 2010. This update summarizes recent clinical developments in the field of prostate cancer immunotherapy, with a focus on dendritic cell vaccines, virus-based vaccines, DNA-based vaccines, and cell-based vaccines. In addition, the notion of agents that target immune checkpoints is introduced. Enthusiasm for prostate cancer immunotherapy is founded upon its potential to mediate targeted, specific, tumor cell destruction without significant systemic toxicity; however, this has yet to be fully realized in the clinical arena.
Immunotherapy; Immune checkpoints; Prostate cancer; T cell; Vaccine; CTLA-4; PD-1; GVAX; ProstVac VF; Sipuleucel-T
There are notable differences in the incidence and mortality rates for prostate cancer between Asia and Western countries. It is also recognized that there are differences in thinking with regard to treatment options. Recently it is also the case that opinions have been reported concerning the differences between Asian and Western patients with regard to their reaction to androgen depletion therapy (ADT). Given that ADT is a method of treatment that focuses on the elimination of testosterone, an inevitable symptom of its administration is testosterone losing syndrome. It is for this reason that in Western countries ADT has only been recommended in cases of advanced or metastatic cancer. On the other hand, in Asia, ADT is used in relatively many cases, including non-metastatic localized cancer and invasive localized cancer. To date, however, there has been little substantive discussion concerning this difference in utilization of ADT. ADT-related drugs for prostate cancer and the development of new drugs for castration resistant prostate cancer (CRPC) have been actively tested in recent years. It could be the case that analyzing the differences in concepts about ADT between Asia and the West could contribute to the effective use of ADT-related drugs and also help to build new treatment strategies for prostate cancer.
Androgen depletion therapy; prostate cancer; Asia
Genome-wide association studies (GWAS) have identified multiple novel prostate cancer predisposition loci. Whether these common genetic variants are associated with incident metastatic prostate cancer or with recurrence after surgical treatment for clinically localized prostate cancer is uncertain.
Twelve SNPs were selected for study in relation to prostate metastatic cancer and recurrence, based on their genome-wide association with prostate cancer in the Cancer Genetic Markers of Susceptibility (CGEMS) (1, 2). To assess risk for metastatic disease, we compared genotypes for the 12 SNPs by logistic regression of 470 incident metastatic prostate cancer cases and 1945 controls in 3 case-control studies. To assess the relationship of these SNPs to risk for prostate cancer recurrence, we used Cox regression in a cohort of 1412 men treated for localized prostate cancer, including 328 recurrences, and used logistic regression in a case-case study, comparing 450 recurrent versus 450 nonrecurrent prostate cancer cases. Study-specific RRs for risk of metastatic disease and recurrence were summarized using meta-analysis, with inverse variance weights.
MSMB rs10993994 (per variant allele summary RR=1.24, 95% CI=1.05-1.48), 8q24 rs4242382 (RR=1.40, 95% CI=1.13-1.75) and 8q24 rs6983267 (RR=0.67, 95% CI=0.50-0.89) were associated with risk for metastatic prostate cancer. None of the 12 SNPs was associated with prostate cancer recurrence.
SNPs in MSMB and 8q24 which predispose to prostate cancer overall are associated with risk for metastatic prostate cancer, the most lethal form of this disease. SNPs predictive of prostate cancer recurrence were not identified, among the predisposition SNPs. GWAS specific to these two phenotypes may identify additional phenotype-specific genetic determinants.
Therapeutic options for patients with metastatic castration-resistant prostate cancer are increasing, spurring an urgent need to better understand which treatments are best for individual patients. The recent approval of a first-in-class agent, sipuleucel-T, has intensified this need. This therapeutic cancer vaccine has demonstrated a survival advantage in 2 phase III trials, but does not alter progression in the short term. Therefore, a new therapeutic approach for patients with metastatic castration-resistant prostate cancer is taking shape, based on broader understanding of available therapies. This new clinical approach seeks to maximize patient benefit from treatment, minimize associated toxicities, and may have far-reaching implications for other therapeutic cancer vaccines currently in clinical development.
prostate cancer; therapeutic cancer vaccines; emerging therapies; treatment paradigm
•New drugs approved for treatment of castration resistant prostate cancer.•Prime targets: androgen receptor, bone cells, cell division, immune system.•Several promising drugs disappointed in clinical trials.•Further efforts necessary to optimize the sequence and combinations of drugs.•New biomarkers required for stratification of patient and therapy selection.
Prostate cancer is a leading cause of cancer death in men in developed countries. Once the tumor has achieved a castration-refractory metastatic stage, treatment options are limited with the average survival of patients ranging from two to three years only. Recently, new drugs for treatment of castration-resistant prostate cancer (CRPC) have been approved, and others are in an advanced stage of clinical testing. In this review we provide an overview of the new therapeutic agents that arrived in the clinical praxis or are tested in clinical studies and their mode of action including hormone synthesis inhibitors, new androgen receptor blockers, bone targeting and antiangiogenic agents, endothelin receptor antagonists, growth factor inhibitors, novel radiotherapeutics and taxanes, and immunotherapeutic approaches. Results and limitations from clinical studies as well as future needs for improvement of CRPC treatments are critically discussed.
AR, androgen receptor; CRPC, castration-resistant prostate cancer; ET, endothelin; IGF, insulin-like growth factor; OS, overall survival; PCa, prostate cancer; PDGFR, platelet-derived growth factor receptor; PFS, progression free survival; PSA, prostate-specific antigen; RANK-L, RANK ligand; SD, stable disease; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; Castration-resistant prostate cancer; Androgen receptor; Bone metastasis angiogenesis; Immunotherapy; Radiotherapy; Chemotherapy; Growth factor receptor inhibitors