Carlo Cattrini

Targeting androgen-independent pathways: new chances for patients with prostate cancer?

Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer (PC). Most patients eventually progress to a condition known as castration-resistant prostate cancer (CRPC), characterized by lack of response to ADT. Although new androgen receptor signaling (ARS) inhibitors and chemotherapeutic agents have been introduced to overcome resistance to ADT, many patients progress because of primary or acquired resistance to these agents. This comprehensive review aims at exploring the mechanisms of resistance and progression of PC, with specific focus on alterations which lead to the activation of androgen receptor (AR)-independent pathways of survival. Our work integrates available clinical and preclinical data on agents which target these pathways, assessing their potential clinical implication in specific settings of patients. Given the rising interest of the scientific community in cancer immunotherapy strategies, further attention is dedicated to the role of immune evasion in PC.

Genitourinary tumours in the targeted therapies era: new advances in clinical practice and future perspectives.

Genitourinary cancers represent a heterogeneous group of malignancies arising from genitourinary tract, and are responsible for almost 359u2009000 newly diagnosed cases and 58u2009420 related deaths in USA. Continuous advances in cancer genetics and genomics have contributed towards changing the management paradigms of these neoplasms. Neoangiogenesis, through the activation of the tyrosine-kinase receptors signalling pathways, represents the key mediator event in promoting tumour proliferation, differentiation, invasiveness and motility. In the last decade, several treatments have been developed with the specific aim of targeting different cell pathways that have been recognized to drive tumour progression. The following review attempts to provide a comprehensive overview of the literature, focusing on new advances in targeted therapies for genitourinary tumours. Furthermore, the promising results of the latest clinical trials and future perspectives will be discussed.

Abiraterone acetate and prednisone in the pre- and post-docetaxel setting for metastatic castration-resistant prostate cancer: A mono-institutional experience focused on cardiovascular events and their impact on clinical outcomes

Background: The aim of this work was to to evaluate the incidence and risk factors of adverse events (AEs), focusing on cardiovascular events (CVEs) and hypokalemia, in patients treated with abiraterone acetate (AA) and prednisone (PDN) outside clinical trials, and their association with survival outcomes. Methods: This was a retrospective cohort study of 105 patients treated from 2011 to 2016. Incidence of AEs was descriptively summarized in the whole cohort and by subgroup (pre- versus post-docetaxel). Multivariable Cox proportional hazards models assessed factors associated with progression-free survival (PFS) and overall survival (OS). Results: Overall, median PFS and OS were 14.9 and 24.6 months, respectively. Prostate-specific antigen (PSA) ⩾ 10 ng/ml (p = 0.007), Gleason Score >7 (p = 0.008), Eastern Cooperative Oncology Group (ECOG) performance status (PS)1–2 (p = 0.002), duration of androgen deprivation therapy (ADT) ⩽ 43.2 months (p = 0.01), and body mass index (BMI) > 25 (p = 0.03) were associated with worse PFS; presence of pain (p = 0.01), ECOG PS1–2 (p = 0.004), duration of ADT ⩽ 43.2 (p = 0.05), and BMI > 25 (p = 0.042) were associated with worse OS. Incidence of CVEs was as follows: hypertension 17.1%, fluid retention 4.8%, cardiac disorders 8.6%. 16.2% of patients developed hypokalemia. Age ⩾ 75 years was associated with higher probability of cardiac disorders (p = 0.001) and fluid retention (p = 0.03). CVEs did not impact on PFS or OS. Hypokalemia was associated with better median OS (p = 0.036). Similar associations were observed after stratification by subgroup. Conclusions: Median PFS and OS estimates and incidence of CVEs and hypokalemia in our series are consistent with those of pivotal trials of AA plus PDN, confirming the efficacy and safety of this regimen also in the real-world setting. Elderly patients have higher odds of developing/worsening CVEs. However, regardless of age, CVEs were not associated with worse outcomes. Treatment-related hypokalemia seemed to be associated with longer OS, albeit this finding needs confirmation within larger, prospective series.

Immunotherapy for genitourinary cancer: state of the art and new perspectives.

In the last few years, cancer immunotherapy has changed the natural history and treatment strategies of a number of solid tumors, including melanoma and lung cancer. The anti-PD-1 nivolumab showed a survival benefit compared with everolimus in the second-line treatment of renal cell carcinoma, resulting in a radical shift in perspective in the treatment of this neoplasia and suggesting a new scenario beyond tyrosine kinase inhibitors. Checkpoint inhibitors might also improve the treatment of urothelial cancer, considering the promising results achieved so far and the relatively low efficacy of currently available treatments. Sipuleucel-T was the first approved immunotherapy for prostate cancer, showing a clear benefit in overall survival, and paved the way for the clinical testing of other novel cancer vaccines. This review provides a comprehensive overview of the current knowledge and new perspectives of immunotherapy in the treatment of urogenital malignancies.

A hnRNP K–AR-related signature reflects progression toward castration-resistant prostate cancer

The major challenge in castration-resistant prostate cancer (CRPC) remains the ability to predict the clinical responses to improve patient selection for appropriate treatments. The finding that androgen deprivation therapy (ADT) induces alterations in the androgen receptor (AR) transcriptional program by AR coregulators activity in a context-dependent manner, offers the opportunity for identifying signatures discriminating different clinical states of prostate cancer (PCa) progression. Gel electrophoretic analyses combined with western blot showed that, in androgen-dependent PCa and CRPC in vitro models, the subcellular distribution of spliced and serine-phosphorylated heterogeneous nuclear ribonucleoprotein K (hnRNP K) isoforms can be associated with different AR activities. Using mass spectrometry and bioinformatic analyses, we showed that the protein sets of androgen-dependent (LNCaP) and ADT-resistant cell lines (PDB and MDB) co-immunoprecipitated with hnRNP K varied depending on the cell type, unravelling a dynamic relationship between hnRNP K and AR during PCa progression to CRPC. By comparing the interactome of LNCaP, PDB, and MDB cell lines, we identified 51 proteins differentially interacting with hnRNP K, among which KLK3, SORD, SPON2, IMPDH2, ACTN4, ATP1B1, HSPB1, and KHDRBS1 were associated with AR and differentially expressed in normal and tumor human prostate tissues. This hnRNP K–AR-related signature, associated with androgen sensitivity and PCa progression, may help clinicians to better manage patients with CRPC.

Overexpression of Periostin in Tumor Biopsy Samples Is Associated With Prostate Cancer Phenotype and Clinical Outcome

Background: Overexpression of periostin (POSTN) is associated with prostate cancer (PCa) aggressiveness. We investigated the prognostic significance of POSTN expression in tumor biopsy samples of patients with PCa. Methods: We scored POSTN expression by immunohistochemistry analysis on 215 PCa biopsy samples using an anti–POSTN‐specific antibody. A total immunoreactive score (T‐IRS) was calculated by adding the POSTN staining scores of stromal and epithelial tumor cells. Prostate‐specific antigen (PSA) progression/recurrence‐free survival (PFS), radiographic progression/recurrence‐free survival (rPFS), and overall survival (OS) were the study end points. Results: A total of 143 patients received therapy with radical attempt, whereas 72 had locally advanced or metastatic disease and received hormone therapy alone. Median T‐IRS was 9 and 12 (range, 0‐20), respectively (P = .001). Overall, we found a weak positive correlation of T‐IRS with prebiopsy PSA levels (r = 0.166, P = .016) and Gleason score (r = 0.266, P < .000). T‐IRS ≥ 8 independently predicted for shorter PSA‐PFS and OS (hazard ratio [HR] [95% confidence interval (CI)] ≥ 8 versus < 8: 1.50 [1.06‐2.14], P = .024 and 1.92 [1.20‐3.07], P = .007, respectively). In the subgroup analysis, the association between T‐IRS and patient outcome was retained in patients who received therapy with radical attempt (HR [95% CI] ≥ 8 vs. < 8: rPFS: 2.06 [1.18‐3.58], P = .01; OS: 2.36 [1.24‐4.50], P = .009) and in those with low to intermediate Gleason scores (HR [95% CI] ≥ 8 vs. < 8: PSA‐PFS: 1.65 [1.06‐2.59], P = .028; rPFS: 2.09 [1.14‐3.87], P = .018; OS: 2.57 [1.31‐5.04], P = .006). Conclusion: POSTN T‐IRS on PCa biopsy samples independently predicted the risk of recurrence, progression, and death in patients with localized disease and in those with low to intermediate Gleason scores.

CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: a systematic review and meta-analysis of randomized trials

PurposeCombining CDK4/6 inhibitors and endocrine therapy (ET) improved outcomes for the treatment of metastatic HR+/HER2− breast cancers. Here, we performed a meta-analysis of randomized clinical trials (RCTs) to better define the benefit and the risk of CDK4/6 inhibitors plus ET for endocrine-sensitive or endocrine-resistant population in metastatic HR+/HER2− breast cancer.MethodA systematic literature search of Pubmed, Embase, and the Cochrane Library was carried out up to 30 June 2018. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS), as well as odds ratios (ORs) for objective response rates, ≥u2009G3–G4 adverse events (AEs), and G3–G4 neutropenia were calculated for each trial. A meta-analysis was carried out using the random-effects model.ResultsEight RCTs were eligible including 4578 breast cancer patients. Adding CDK4/6 inhibitors to ET in endocrine-sensitive (HR 0.55, 95% CI 0.50–0.62) or endocrine-resistant setting (HR 0.51, 95% CI 0.43–0.61) significantly improved the PFS of metastatic HR+/HER2− breast cancers regardless of menopausal status and site of metastasis. Moreover, CDK4/6 inhibitors plus ET meaningfully improved objective response rate in endocrine-sensitive (ORs 0.62, 95% CI 0.52–0.73) or endocrine-resistant setting (ORs 0.33, 95% CI 0.24–0.47). The use of these drugs was characterized by a significant increase of G3–G4 AEs (OR 10.88, 95% CI 6.53–18.14).ConclusionEmerging data provide a new standard treatment for advanced HR+/HER2− breast cancer, regardless of menopausal status, prior hormonal/chemotherapy treatments delivered, sites of metastasis. However, benefits should be balanced with longer treatment duration, toxicities, and costs.

Bone Metastases from Prostate Cancer: Hormonal Therapy

The majority of patients diagnosed with prostate cancer develop bone metastases. If untreated, patients affected by bone metastases experience skeletal events, like bone fractures or spinal cord compression, which complicate the course of disease and can further shorten their life expectancy; furthermore, these events are usually associated with pain and other troublesome symptoms, which can seriously affect patients’ quality of life and become a cause of temporary or permanent disability. For these reasons, the treatment of bone metastases represents a main issue in the management of advanced prostate cancer.