Morphologic, Molecular and Clinical Features of Aggressive Variant Prostate Cancer

The term aggressive variant prostate cancer (AVPCa) refers to androgen receptor (AR)-independent anaplastic forms of prostate cancer (PCa), clinically characterized by a rapidly progressive disease course. This involves hormone refractoriness and metastasis in visceral sites. Morphologically, AVPCa is made up of solid sheets of cells devoid of pleomorphism, with round and enlarged nuclei with prominent nucleoli and slightly basophilic cytoplasm. The cells do not show the typical architectural features of prostatic adenocarcinoma and mimic the undifferentiated carcinoma of other organs and locations. The final diagnosis is based on the immunohistochemical expression of markers usually seen in the prostate, such as prostate-specific membrane antigen (PSMA). A subset of AVPCa can also express neuroendocrine (NE) markers such as chromogranin A, synaptophysin and CD56. This letter subset represents an intermediate part of the spectrum of NE tumors which ranges from small cell to large cell carcinoma. All such tumors can develop following potent androgen receptor pathway inhibition. This means that castration-resistant prostate cancer (CRPCa) transdifferentiates and becomes a treatment-related NE PCa in a clonally divergent manner. The tumors that do not show NE differentiation might harbor somatic and/or germline alterations in the DNA repair pathway. The identification of these subtypes has direct clinical relevance with regard to the potential benefit of platinum-based chemotherapy, poly (ADP-ribose) polymerase inhibitors and likely further therapies

New Frontiers in Prostate Cancer Treatment: Are We Ready for Drug Combinations with Novel Agents?

Medical treatment for metastatic castration-resistant prostate cancer (mCRPC) patients has progressively been evolving from a nonspecific clinical approach to genomics-oriented therapies. The scientific community is in fact increasingly focusing on developing DNA damage repair (DDR) defect-driven novel molecules, both as single-agent therapy and in combined treatment strategies. Accordingly, research is under way into combined drug therapies targeting different pathways, e.g. androgen receptor signaling (ARS) and poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes, immune checkpoint (IC) and PARP, IC, and ARS, and prostate-specific membrane antigen (PSMA). In an attempt to formulate evolving treatment paradigms in mCRPC patients, here we selected clinical research into patients undergoing therapies with emerging molecules, with particular emphasis towards PARP-, IC-, and PSMA-inhibitors. In order to focus on those molecules and drug combinations most likely to be translated into routine clinical care in the near future, we selected only those clinical studies currently recruiting patients. A PubMed search focusing on the keywords “prostate cancer”, “metastatic castration-resistant prostate cancer”, “DDR pathways”, “ARS inhibitors”, “PARP inhibitors”, “IC inhibitors”, “PSMA-targeting agents”, and “drug combinations” was performed

Update on Circulating Tumor Cells in Genitourinary Tumors with Focus on Prostate Cancer

Current developments in the treatment of genitourinary tumors underline the unmet clinical need for biomarkers to improve decision-making in a challenging clinical setting. The detection of circulating tumor cells (CTCs) has become one of the most exciting and important new approaches to identifying biomarkers at different stages of disease in a non-invasive way. Potential applications of CTCs include monitoring treatment efficacy and early detection of progression, selecting tailored therapies, as well as saving treatment costs. However, despite the promising implementation of CTCs in a clinical scenario, the isolation and characterization of these cells for molecular studies remain expensive with contemporary platforms, and significant technical challenges still need to be overcome. This updated, critical review focuses on the state of CTCs in patients with genitourinary tumor with focus on prostate cancer, discussing technical issues, main clinical results and hypothesizing potential future perspectives in clinical scenarios

Androgen Receptor Signaling Pathway in Prostate Cancer: From Genetics to Clinical Applications

Around 80–90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient’s response to androgen ablation therapy is variable, and 20–30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensitive setting, and combination therapies with other drugs

Narrative review: update on immunotherapy and pathological features in patients with bladder cancer

Over the last few years efficacy of immunotherapy using immune checkpoint inhibitors (ICI) has been investigated in patients with bladder cancer (BC) at all stages. The present article aims to assess new therapeutic options with emerging agents in BC patients, shedding light on ICI-based treatments encompassing all disease stages, from non-muscle invasive (NMIBC) to muscle-invasive (MIBC) BC, concluding with metastatic MIBC. In bacillus Calmette-Guerin (BCG) unresponsive patients with carcinoma in situ, pembrolizumab has been recently approved. In the neoadjuvant setting, results from two clinical trials seem to identify pathological and genomic features of highly responsive tumors. Squamous cells and lymphoepithelioma/like histotypes, programmed cell-death ligand 1 (PD-L1) expression and high levels of activate T cells have been associated with higher response rate. In the metastatic setting, only 30% of patient may respond to ICI. A panel of biomarkers for patient selection is an actual need since the correlation between response and PD-L1 expression seem inconsistent across clinical trials, with some exceptions. Molecular characterization of BC, tumor mutation burden and immune-gene expression profiling might introduce new molecular biomarkers, hopefully transferable into the clinical-pathological practice

Androgen Receptor Signaling Pathway in Prostate Cancer: From Genetics to Clinical Applications

Around 80–90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient’s response to androgen ablation therapy is variable, and 20–30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensitive setting, and combination therapies with other drugs

New Frontiers in Prostate Cancer Treatment: Are We Ready for Drug Combinations with Novel Agents?

Medical treatment for metastatic castration-resistant prostate cancer (mCRPC) patients has progressively been evolving from a nonspecific clinical approach to genomics-oriented therapies. The scientific community is in fact increasingly focusing on developing DNA damage repair (DDR) defect-driven novel molecules, both as single-agent therapy and in combined treatment strategies. Accordingly, research is under way into combined drug therapies targeting different pathways, e.g. androgen receptor signaling (ARS) and poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes, immune checkpoint (IC) and PARP, IC, and ARS, and prostate-specific membrane antigen (PSMA). In an attempt to formulate evolving treatment paradigms in mCRPC patients, here we selected clinical research into patients undergoing therapies with emerging molecules, with particular emphasis towards PARP-, IC-, and PSMA-inhibitors. In order to focus on those molecules and drug combinations most likely to be translated into routine clinical care in the near future, we selected only those clinical studies currently recruiting patients. A PubMed search focusing on the keywords “prostate cancer”, “metastatic castration-resistant prostate cancer”, “DDR pathways”, “ARS inhibitors”, “PARP inhibitors”, “IC inhibitors”, “PSMA-targeting agents”, and “drug combinations” was performed

Chemoprevention and Lifestyle Modifications for Risk Reduction in Sporadic and Hereditary Breast Cancer

Female breast cancer is the most commonly diagnosed malignancy worldwide. Risk assessment helps to identify women at increased risk of breast cancer and allows the adoption of a comprehensive approach to reducing breast cancer incidence through personalized interventions, including lifestyle modification, chemoprevention, intensified surveillance with breast imaging, genetic counseling, and testing. Primary prevention means acting on modifiable risk factors to reduce breast cancer occurrence. Chemoprevention with tamoxifen, raloxifene, anastrozole, and exemestane has already shown benefits in decreasing breast cancer incidence in women at an increased risk for breast cancer. For healthy women carrying BRCA 1 or BRCA 2 pathogenic/likely pathogenic (P/LP) germline variants, the efficacy of chemoprevention is still controversial. Adopting chemoprevention strategies and the choice among agents should depend on the safety profile and risk–benefit ratio. Unfortunately, the uptake of these agents has been low. Lifestyle modifications can reduce breast cancer incidence, and the recommendations for BRCA 1 or BRCA 2 P/LP germline variant carriers are comparable to the general population. This review summarizes the most recent evidence regarding the efficacy of chemoprevention and lifestyle interventions in women with sporadic and hereditary breast cancer

Use of metronomic chemotherapy in oncology: results from a national Italian survey

Aims and background.Metronomic chemotherapy refers to the administration of low doses of cytotoxic agents over a prolonged period of time with no or only short drug-free intervals. It is designed to overcome acquired tumor resistance to chemotherapy and reduce neo-angiogenesis despite a lower toxicity than with standard chemother-apy. The role of metronomic chemotherapy remains controversial, and its optimal therapeutic use has not yet been defined. Methods and study design.The present survey was designed as a short questionnaire and was sent to the medical oncologists registered with Medikey, a national database listing all the Italian oncology specialists linked with the Italian Council of Medica

Metabolomic Profiling in Renal Cell Carcinoma Patients: News and Views

Background: We address novelty regarding metabolomic profiling in renal cell carcinoma (RCC) patients, in an attempt to postulate potential treatment strategies. Methods: A large-scale literature search in existing scientific websites focusing on the keywords “renal cell carcinoma”, “clear cell histology”, “papillary histology”, “metabolomic profiling”, and “therapeutics” was performed. Results: The PI3K/Akt signaling pathway is key in clear cell RCC metabolism and accordingly several drugs are presently available for routine use in clinical practice. Along this line, new treatment combinations against PI3K/Akt family members are currently under clinical investigation. On the other hand, new developed targets such as c-Met tyrosine kinase domain, glutathione (GSH) metabolism, and histone deacetylases enzymes (HDAC), as well as therapeutic strategies targeting them are currently being tested in clinical trials and here discussed. Conclusions: In RCC patients, the PI3K/Akt signaling is still the most effective targetable pathway. Targeting other metabolic pathways such as c-Met, GSH, and HDAC appears to be a promising approach and deserve further insights