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.

Background. In patients with metastatic breast cancer, the evaluation of the biological characteristics of metastatic bone deposits may be a valuable adjunct in clinical practice. We assessed the discordance in expression levels for estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) between primary tumor and bone metastases and its clinical impact on patient management. Material and methods. We retrospectively reviewed 363 CT-guided bone biopsies performed from January 1997 to December 2009. The proportions of ER, PgR and HER2 positive tumors at primary diagnosis and bone metastases, determined by IHC and/or FISH, were compared using McNemar's test. The impact of the biopsy reassessment on treatment choice was evaluated with Fisher's exact test. Results. We selected 109 metastatic breast cancer patients with histologically confirmed bone metastases. Among 107 assessable patients the overall discordance rate was detected in 22 (20.5%) and in 47 (43.9%) patients for ER and PgR, respectively, and in six of 86 assessable patients (6.9%) for HER2 status. The indication to change endocrine therapy occurred in 62% and 30% of patients with ER discordance and ER concordance, respectively (p = 0.01). The indication to change targeted therapy occurred in 67% and 8% of patients with HER2 discordance and HER2 concordance, respectively (p = 0.002). Conclusions. We confirm that biopsy of metastases, including bone metastases, for reassessment of biology should be considered, since it is likely to impact on treatment choice.

Obesity is a well-known risk factor for renal cell carcinoma (RCC) development. However, the RCC–obesity link has not been fully addressed when considering a comprehensive scenario starting from pathogenetic aspects through pathological issues up to the outcome of medical treatment. We therefore conducted an electronic PubMed search using keywords “obesity”, “body mass index”, “overweight”, “renal cell carcinoma/kidney cancer”, “medical treatment”, “targeted therapy”, and “immunotherapy/immune checkpoint inhibitors”. The selected data supported a crosstalk between adipose tissue (adipocytes and other white adipose tissue cells) and cancer cells inducing several signaling pathways that finally stimulated angiogenesis, survival, and cellular proliferation. Accurate sampling of renal sinus fat correlated with a prognostic value. Retrospective clinical evidence in metastatic RCC patients with higher body mass index (BMI) and treated with targeted therapies and/or immune checkpoint inhibitors showed advantageous survival outcomes. Therefore, obesity may influence the course of RCC patients, although the interplay between obesity/BMI and RCC warrants a large prospective confirmation. We are therefore still far from determining a clear role of obesity as a prognostic/predictive factor in metastatic RCC patients undergoing targeted therapy and immunotherapy.

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.

Fulvestrant is effective in postmenopausal women with estrogen receptor‐positive advanced breast cancer (ABC). So far, no published data exist on fulvestrant combined with chemotherapy. We retrospectively assessed the role of combining oral metronomic cyclophosphamide and methotrexate (CM) to fulvestrant in two cohorts (A and B) of heavily pre‐treated estrogen receptor‐positive advanced ABC patients. From October 2006 to September 2009, 33 postmenopausal patients received fulvestrant 250 mg via i.m. injection q28 days. In A, 20 patients added metronomic cyclophosphamide (50 mg p.o. daily) and methotrexate (2.5 mg p.o. twice daily on day 1 and day 4 weekly) after disease progression, continuing fulvestrant at the same dose. In B, 13 patients started fulvestrant plus metronomic CM upfront. Thirty‐two patients were evaluable for response. Clinical benefit (partial response + stable disease >24 months) for A + B was 56% (95% CI 38–74%). The addition of metronomic CM did not determine relevant toxicities. Treatment with fulvestrant plus metronomic CM was effective in advanced ABC and was minimally toxic providing long‐term disease control in a high proportion of patients. The prolonged clinical benefit, often desirable in such patients, supports this regimen as an additional and useful therapeutic tool.