Silvana Giacinti

Genomic and epigenomic alterations in prostate cancer

Prostate cancer (PC) is the second most frequently diagnosed cancer and the second leading cause of cancer deaths in man. The treatment of localized PC includes surgery or radiation therapy. In case of relapse after a definitive treatment or in patients with locally advanced or metastatic disease, the standard treatment includes the androgen-deprivation therapy (ADT). By reducing the levels of testosterone and dihydrotestosterone under the castration threshold, the ADT acts on the androgen receptor (AR), even if indirectly. The effects of the ADT are usually temporary and nearly all patients, initially sensitive to the androgen ablation therapy, have a disease progression after an 18–24 months medium term. This is probably due to the selection of the cancer cell clones and to their acquisition of critical somatic genome and epigenomic changes. This review aims to provide an overview about the genetic and epigenetic alterations having a crucial role in the carcinogenesis and in the disease progression toward the castration resistant PC. We focused on the role of the AR, on its signaling cascade and on the clinical implications that the knowledge of these aspects would have on hormonal therapy, on its failure and its toxicity.

Duration of response to first androgen deprivation therapy, time to castration resistance prostate cancer, and outcome of metastatic castration resistance prostate cancer patients treated with abiraterone acetate

Abiraterone acetate (AA) demonstrated its efficacy in the treatment of patients with metastatic castration resistance prostate cancer (mCRPC) in predocetaxel and postdocetaxel setting. However, we learn from pivotal studies that forms of primary and acquired resistance to this drug exist. Patient selection becomes so crucial to optimize treatment results. Potential predictive biomarkers have been identified but are not yet validated. In this scenario, clinical features and disease characteristics may still be of value in selecting patients for different treatments. The objective of this retrospective study was to assess whether or not a correlation between duration of response to first androgen deprivation therapy (ADT), time to castration-resistant prostate cancer (TTCRPC), and outcome of AA therapy exists. A retrospective analysis of clinical data of mCRPC patients treated with AA at two Italian cancer centers was carried out. The Kaplan–Meier method and Cox proportional hazard model were used to analyze survival data. Correlation between median duration of response to first ADT or median TTCRPC and the outcome of patients treated with AA was analyzed. From January 2015 to November 2015, data of 59 patients with mCRPC were collected. We observed no differences in patient’s median progression-free survival (PFS) and biochemical progression-free survival (bPFS), according to both median duration of response to first-line ADT (duration of first ADT<13 months: median PFS and bPFS were 11 and 5 months, respectively; duration of ADT≥13 months: median PFS and bPFS were 9 and 6 months, respectively) and median TTCRPC (TTCRPC<28 months: median PFS and bPFS were 8 and 5 months, respectively; TTCRPC≥28 months: median PFS and bPFS were 10 and 9 months, respectively). Overall survival, in the same group, did not differ between patients with a duration of response to first ADT over or under 13 months (P=0.90) but in patients with a TTCRPC of 28 months or more, there was a trend toward longer survival than patients with TTCRPC less than 28 months (5-year overall survival was 74 vs. 50%; P=0.14). The duration of response to first-line ADT and the TTCRPC showed no significant association with outcome of AA therapy in patients with mCRPC. However, large prospective trials are desirable to confirm these data.

Heterogeneity of PD-L1 Expression and Relationship with Biology of NSCLC

Immunotherapy with monoclonal antibodies against programmed cell death (PD-1), such as nivolumab and pembrolizumab, has significantly improved the survival of patients with metastatic non-small cell lung cancer (NSCLC). In order to determine the subset of patients that can benefit most from these therapies, biomarkers such as programmed death ligand-1 (PD-L1) have been proposed. However, the predictive and prognostic role of the use of PD-L1 is controversial. Anti-PD-L1 immunohistochemistry may not represent the actual status of the tumour because of individual variability and tumour heterogeneity. Additionally, there may be analytical variability due to the use of different assays and antibodies to detect PD-L1. Moreover PD-L1 expression is also regulated by oncogenic drivers in NSCLC, such as epidermal growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 (EML4) fusion with anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS). Preclinical studies have shown the potential role of targeted therapy in immune escape mechanisms in NSCLC cells. This review summarizes current literature data on the heterogeneity of PD-L1 expression and the relationship with such factors and with clinicopathological features of NSCLC.

Clinical Outcome of Third-Line Pazopanib in a Patient with Metastatic Renal Cell Carcinoma

Background. Renal cell carcinoma accounts for about 2-3% of all malignant tumors. The prevalence of brain metastases from RCC is less than 20% of cases. Traditionally, whole brain radiotherapy as well as the latest stereotactic radiosurgery improves both survival and local tumor control. These treatments also allow stabilization of clinical symptomatology. However, validated treatment guidelines for RCC patients with brain metastases are not yet available on account of the frequent exclusion of such patients from clinical trials. Moreover, limited data about the sequential use of three therapies, changing the class of agent, have been published up to now. Case Report. We report the case of a patient with metastatic RCC who developed disease progression after sunitinib and everolimus as first-line and second-line therapy, respectively. Thus, he underwent a multimodality treatment with pazopanib, as third-line therapy, to control systemic disease and radiosurgery directed on the new brain metastasis. To date, the patient is still receiving pazopanib, with progression-free survival and overall survival of 43 and 103 months, respectively. Conclusion. In a context characterized by different emerging options, with no general consensus on the optimal treatment strategy, the use of pazopanib in pretreated patients could be a suitable choice.