Adapting to hormone-therapy resistance for adopting the right therapeutic strategy in advanced prostate cancer.

INTRODUCTION: The androgen/androgen receptor (AR) axis represents a key driver of treatment resistance in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT) and targeted agents, and a deeper comprehension of resistance mechanisms is fundamental to adopt effective therapeutic strategies. AREAS COVERED: We review the mechanisms of primary or secondary resistance to hormone therapy (HT) in PCa, especially focusing on available data and emerging evidence. EXPERT OPINION: First- and second-generation HT resistance has been associated with several AR-dependent and AR-independent mechanisms, ranging from the amplification of the AR gene locus to somatic AR mutations and the intratumoral synthesis of androgens from adrenal steroids and cholesterol. As reported in the current review, the development of novel and effective treatments is needed to personalize anticancer therapies in this setting and to finally improve clinical outcomes in patients with HT-resistant disease.

An update on safety evaluation of immune-based combinations in patients with advanced renal cell carcinoma.

INTRODUCTION: Significant advances have been made in the first-line therapy of metastatic renal cell carcinoma (mRCC) since the approval of immune-based combinations, including nivolumab plus ipilimumab or cabozantinib, and pembrolizumab plus axitinib or lenvatinib. AREAS COVERED: The aim of this review is to compare the different safety profiles of first-line immune-based combinations versus sunitinib across the four respective pivotal trials (CheckMate 214, CheckMate 9ER, KEYNOTE-426, and CLEAR), with a particular attention to patients' health-related quality of life (HRQoL) assessment. EXPERT OPINION: The concurrent use of an immune-checkpoint inhibitor (ICI) with a tyrosine kinase inhibitor (TKI) as a first-line treatment strategy for mRCC has highlighted the unmet clinical need for prompt detection and consequently proper management of adverse events (AEs), both immune-related and TKI-induced. Overlapping AEs, such as hypertransaminasemia, are most challenging to manage, and evidence is still outlined from clinical practice. The specific patterns of toxicities of the approved first-line immune-based combinations, along with the impact of these interventions on patients' HRQoL, demand a deeper consideration by physicians while choosing the appropriate treatment for each individual mRCC patient. Both safety profile and HRQoL evaluation could be exploited to guide the first-line treatment selection in this setting.

Hypertransaminasemia in metastatic renal cell carcinoma patients receiving immune-based combinations: a meta-analysis.

Aims: We performed a meta-analysis to assess the relative risk (RR) of all-grade and grade 3-4 hypertransaminasemia in studies comparing immune-based combinations with sunitinib in treatment-naive patients with advanced renal cell carcinoma. Materials & methods: Outcomes of interest included all-grade and grade 3-4 hypertransaminasemia measured as RRs and 95% confidence intervals (CIs). Results: RRs for all-grade hypertransaminasemia were 1.73 (95% CI: 1.25-2.4) and 1.63 (95% CI: 1.25-2.12) in patients receiving immunocombinations and sunitinib, respectively. The pooled RRs for grade 3-4 hypertransaminasemia were 3.24 and 3.04 in patients treated with immunocombinations or sunitinib. Conclusion: Immune-based combinations were associated with higher hypertransaminasemia risk. Physicians should pay attention to these common but overlooked events. Careful monitoring of tolerability remains a crucial need.

In our study, we aimed to determine the risk for developing alterations in liver function in treatment-naive patients with metastatic renal cell carcinoma, receiving an immunotherapic compound plus a tyrosine-kinase inhibitor or sunitinib alone. We found that combination treatment, compared with sunitinib, is associated with an increased risk to present this type of liver's toxicity, even a high-grade one.

Adjuvant PD-1 and PD-L1 Inhibitors and Relapse-Free Survival in Cancer Patients: The MOUSEION-04 Study.

BACKGROUND: Adjuvant treatment has always been a cornerstone in the therapeutic approach of many cancers, considering its role in reducing the risk of relapse and, in some cases, increasing overall survival. Adjuvant immune checkpoint inhibitors have been tested in different malignancies. METHODS: We performed a meta-analysis aimed to explore the impact of adjuvant PD-1 and PD-L1 inhibitors on relapse-free survival (RFS) in cancer patients enrolled in randomized controlled clinical trials. We retrieved all phase III trials published from 15 June 2008 to 15 May 2022, evaluating PD-1/PD-L1 inhibitors monotherapy as an adjuvant treatment by searching on EMBASE, Cochrane Library, and PubMed/ Medline, and international oncological meetings' abstracts. The outcome of interest was RFS. We also performed subgroup analyses focused on age and gender. RESULTS: Overall, 8 studies, involving more than 6000 patients, were included in the analysis. The pooled results highlighted that the use of adjuvant PD-1/PD-L1 inhibitors may reduce the risk of relapse compared to control treatments (hazard ratio, 0.72; 95% confidence intervals, 0.67-0.78). In addition, the subgroup analyses observed that this benefit was consistent in different patient populations, including male, female, younger, and older patients. CONCLUSIONS: Adjuvant anti-PD-1/PD-L1 treatment is associated with an increased RFS in the overall population and in subgroups divided according to age and gender.

Prognostic Factors of Survival for High-Grade Neuroendocrine Neoplasia of the Bladder: A SEER Database Analysis.

Background: High-grade neuroendocrine carcinoma (NEC) is a rare and aggressive variant of bladder cancer. Considering its rarity, its therapeutic management is challenging and not standardized. Methods: We analyzed data extracted from the Surveillance, Epidemiology, and End Results (SEER) registry to evaluate prognostic factors for high-grade NEC of the bladder. Results: We extracted data on 1134 patients: 77.6% were small cell NEC, 14.6% were NEC, 5.5% were mixed neuro-endocrine non-neuroendocrine neoplasia, and 2.3% were large cell NEC. The stage at diagnosis was localized for 45% of patients, lymph nodal disease (N+M0) for 9.2% of patients, and metastatic disease for 26.1% of patients. The median overall survival (OS) was 12 months. Multivariate analysis detected that factors associated with worse OS were age being >72 years old (HR 1.94), lymph nodal involvement (HR 2.01), metastatic disease (HR 2.04), and the size of the primary tumor being >44.5 mm (HR 1.80). In the N0M0 populations, the size of the primary tumor being <44.5 mm, age being <72 years old, and major surgery were independently associated with a lower risk of death. In the N+M0 group, the size of the primary lesion was the only factor to retain an association with OS. Conclusions: Our SEER database analysis evidenced prognostic factors for high-grade NEC of the bladder that are of pivotal relevance to guide treatment and the decision-making process.

Treatment Options for Metastatic Urothelial Carcinoma After First-Line Chemotherapy.

Urothelial carcinoma (UC) is a frequently diagnosed tumor and an important cause of cancer deaths worldwide. Until a few years ago, despite the unquestioned role of platinum-based chemotherapy, therapeutic choices beyond the first line were limited and related to unsatisfactory outcomes. Metastatic UC has always been associated with a poor prognosis, with overall survival only slightly above a year. In the recent past, huge progress has been made in our understanding of the molecular and genomic disease characteristics, to enable stratification of patients in terms of prognosis and treatment responses. Unfortunately, we still do not have the perfect combination of clinical biomarkers to tailor the optimal treatment for each patient, despite making several efforts in this direction. The therapeutic arsenal has been augmented by immune checkpoint inhibitors (ICIs), which nowadays represent the backbone of the second-line setting. Equally revolutionary was the FDA's approval of erdafitinib, a potent fibroblast growth factor receptor (FGFR) inhibitor, the use of which is reserved for patients whose tumor harbors specific FGF pathway alterations. Recently, the therapeutic landscape of metastatic UC has been enhanced by the introduction of novel compounds, consisting of antibody-drug conjugates (ADCs). Enfortumab vedotin is an antibody targeting nectin-4, a cell adhesion molecule highly expressed in UC, conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Sacituzumab govitecan is a humanized monoclonal antibody targeting Trop-2, a transmembrane glycoprotein, conjugated to the active metabolite of irinotecan. These two compounds have received accelerated approval by the FDA in patients pretreated with platinum-based chemotherapy and immunotherapy. Several ongoing trials are investigating the role of ICIs combined with chemotherapy, antiangiogenic drugs, or other ICIs, as well as the efficacy of PARP inhibitors and target therapies, hoping to provide information for some important unmet needs. In this review, we aim to evaluate the current potential treatment options after first-line chemotherapy.

A hypothesis-generating analysis on the role of TERT promoter mutation in advanced urothelial carcinoma treated with immunotherapy.

BACKGROUND: The therapeutic scenario of urothelial carcinoma is constantly expanding with the widening of the knowledge on molecular characteristics, thus claiming for the need of prognostic and predictive factors to guide treatment strategy. TERT promoter mutation is one of the most frequent genomic alterations in urothelial carcinoma and could present several implications, from diagnostic to prognostic or potentially even predictive. METHODS: We performed a single-center retrospective analysis on patients with advanced urothelial carcinoma treated with an immune checkpoint inhibitor as second line of therapy to assess the status of the TERT promoter and the potential implication of its mutation on survival outcomes. RESULTS: We analyzed tissue samples from 11 patients with a next-generation sequencing multi-gene panel. The most frequently altered genes were TP53 (54.5%, n = 6) and TERT promoter (36.3%, n = 4). Other mutations found were BRAF, SMAD4, PIK3CA / PDGRFA. The only type of detected TERT promoter mutation was the c 0.124 C>T (n = 4/4, 100%). Of the 4 TERT mutated patients, 2 presented a co-mutation of TP53. Patients with TERT promoter mutation treated with immunotherapy presented a low median overall survival (16.5 months) and progression-free survival (3.8 months). CONCLUSIONS: Our hypothesis-generating analysis suggests that the presence of TERT promoter mutation could have a negative prognostic value and should be further evaluated in wider cohorts.

Bone Targeting Agents in Patients with Prostate Cancer: General Toxicities and Osteonecrosis of the Jaw.

INTRODUCTION: Bone metastases are the most frequent site of secondary localization of prostate cancer (PCa) and are present in about 90% of cases of advanced disease. Consequently, an adequate management of bone involvement is of pivotal importance in the therapeutic approach and skeletal-related events (SREs) need to be closely monitored and promptly assessed and treated. Bone targeting agents (BTAs), consisting in bisphosphonates and denosumab, are an essential part of the treatment of metastatic prostate cancer that accompanies systemic treatments throughout the most part of the history of the disease. Activity and safety of bone targeting agents: These treatments are correlated to better outcomes in terms of reduction of SREs and, in metastatic castration resistant setting, of increased overall survival (OS), but several important adverse events have to be managed and prevented. Of these, osteonecrosis of the jaw (ONJ) is extremely invalidating and should be managed with a special attention. DISCUSSION: The role of BTAs in prostate cancer is pivotal throughout many stages of the disease, but several toxicities should be quickly recognized and treated. We aim at recollecting evidence on clinical benefit of BTAs, common and specific toxicities, and explore the pathophysiology and clinical aspects of osteonecrosis of the jaw. We present a review of the literature to report the role of the different types of bone targeting agents in the management of prostate cancer with bone metastases with a particular focus on common toxicities and ONJ to recollect current evidences on the activity of these compounds and the correct management of their adverse events.

PARP Inhibitors and Radiometabolic Approaches in Metastatic Castration-Resistant Prostate Cancer: What's Now, What's New, and What's Coming?

In recent years, the advances in the knowledge on the molecular characteristics of prostate cancer is allowing to explore novel treatment scenarios. Furthermore, technological discoveries are widening diagnostic and treatment weapons at the clinician disposal. Among these, great relevance is being gained by PARP inhibitors and radiometabolic approaches. The result is that DNA repair genes need to be altered in a high percentage of patients with metastatic prostate cancer, making these patients optimal candidates for PARP inhibitors. These compounds have already been proved to be active in pretreated patients and are currently being investigated in other settings. Radiometabolic approaches combine specific prostate cancer cell ligands to radioactive particles, thus allowing to deliver cytotoxic radiations in cancer cells. Among these, radium-223 and lutetium-177 have shown promising activity in metastatic pretreated prostate cancer patients and further studies are ongoing to expand the applications of this therapeutic approach. In addition, nuclear medicine techniques also have an important diagnostic role in prostate cancer. Herein, we report the state of the art on the knowledge on PARP inhibitors and radiometabolic approaches in advanced prostate cancer and present ongoing clinical trials that will hopefully expand these two treatment fields.

An Insight on Novel Molecular Pathways in Metastatic Prostate Cancer: A Focus on DDR, MSI and AKT.

Prostate cancer is still one of the main causes of cancer-related death in the male population, regardless of the advancements in the treatment scenario. The genetic knowledge on prostate cancer is widely increasing, allowing researchers to identify novel promising molecular targets and treatment approaches. Genomic profiling has evidenced that DNA damage repair genes' alterations are quite frequent in metastatic, castration resistant prostate cancer and specific therapies can interfere with this pathway, showing promising activity in this setting. Microsatellite instability is gaining attention as it seems to represent a predictive factor of the response to immunotherapy. Furthermore, the PTEN-PI3K-AKT pathway is another possible treatment target being investigated. In this review, we explore the current knowledge on these frequent genomic alterations of metastatic prostate cancer, their possible therapeutic repercussions and the promising future treatments under evaluation.

PD-(L)1 inhibitors as single-agent or in combination with chemotherapy for advanced, PD-L1-high non-small cell lung cancer: a meta-analysis.

Introduction: The best treatment for advanced, PD-L1-high non-small-cell lung cancer remains a debated issue. Methods: A meta-analysis of randomized clinical trials (RCTs) was performed to compare the efficacy and safety of PD-(L)1 inhibitors alone or plus chemotherapy (CT) for advanced, PD-L1-high non-small-cell lung cancer. Results: 14 RCTs were included. The combination of a PD-(L)1 inhibitor with CT resulted in the improvement of progression-free survival (HR: 0.59; 95% CI: 0.43-0.79; p = 0.0005) and objective response rate (RR: 1.66; 95% CI: 1.14-2.42; p = 0.008). No overall survival difference was documented (HR: 0.99; 95% CI: 0.77-1.27; p = 0.95). The risk of grade ≥3 treatment-related adverse events was significantly reduced with immune-checkpoint inhibitor single-agent therapy compared with immune-checkpoint inhibitors plus CT (RR: 0.38; 95% CI: 0.32-0.45; p = 0.00001). Conclusion: The combination of a PD-(L)1 inhibitor and CT appears to be associated with improved PFS and ORR, but similar OS, compared with PD-(L)1 inhibitor single-agent therapy in patients with PD-L1-high non-small-cell lung cancer.

The Landscape of Immunotherapy in Advanced NSCLC: Driving Beyond PD-1/PD-L1 Inhibitors (CTLA-4, LAG3, IDO, OX40, TIGIT, Vaccines).

PURPOSE OF REVIEW: In this review, we analyzed the current landscape of non-PD-(L)1 targeting immunotherapy. RECENT FINDINGS: The advent of immunotherapy has completely changed the standard approach toward advanced NSCLC. Inhibitors of the PD-1/PD-L1 axis have quickly taken place as first-line treatment for NSCLC patients without targetable "driver" mutations. However, a non-negligible portion of patients derive modest benefit from immune-checkpoint inhibitors, and valid second-line alternatives are lacking, pushing researchers to analyze other molecules and pathways as potentially viable targets in the struggle against NSCLC. Starting from the better characterized CTLA-4 inhibitors, we then critically collected the actual knowledge on NSCLC vaccines as well as on other emerging molecules, many of them in their early phase of testing, to provide to the reader a comprehensive overview of the state of the art of immunotherapy in NSCLC beyond PD-1/PD-L1 inhibitors.

The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What's the Story Morning Glory?

Non-clear cell renal cell carcinomas are a miscellaneous group of tumors that include different histological subtypes, each one characterized by peculiarity in terms of genetic alteration, clinical behavior, prognosis, and treatment response. Because of their low incidence and poor enrollment in clinical trials, alongside their heterogeneity, additional efforts are required to better unveil the pathogenetic mechanisms and, consequently, to improve the treatment algorithm. Nowadays, tyrosine kinase inhibitors, mTOR and MET inhibitors, and even cisplatin-based chemotherapy and immunotherapy are potential weapons that are still under evaluation in this setting. Various biomarkers have been evaluated for detecting progression and monitoring renal cell carcinoma, but more studies are necessary to improve this field. In this review, we provide an overview on the molecular characteristics of this group of tumors and the recently published trials, giving an insight into what might become the future therapeutic standard in this complex world of non-clear cell kidney cancers.

Single-agent carboplatin in extensive disease small-cell lung cancer patient with liver failure: a case report within the experience of a single institution.

Until recently, platinum-based chemotherapy has represented the benchmark for the treatment of extensive disease small-cell lung cancer (ED-SCLC). ED-SCLC patients are often diagnosed with poor performance status (PS ≥2) and/or compromised organ functions. In fact, up to 63% of ED-SCLC has extensive liver involvement at diagnosis, which correlates with a poor prognosis. Whether to treat patients with tumor-related organ failure is still debated and the selection of those who could benefit from chemotherapy is crucial. Moreover, severe liver impairment contraindicates the administration of etoposide. Among 74 consecutive ED-SCLC patients followed at our institution from January 2017 to November 2019, three patients received single-agent carboplatin as a first-line treatment due to liver failure. We provide a brief description of a former heavy smoker 70-year-old man who was diagnosed with ED-SCLC and severe liver involvement leading to liver failure. The patient received a first-line treatment with single-agent carboplatin, obtaining a partial response, clinical benefit and the normalization of laboratory test, which documented the complete recovery of liver function. The intent of our work is to highlight the feasibility of single-agent carboplatin in ED-SCLC patients with tumor-related hepatic failure but preserved Eastern Cooperative Oncology Group PS, suggesting that this therapeutic option should not be discouraged a priori. Indeed, the identification of specific tools guiding physicians in the selection of patients who might benefit from the treatment is remarkably needed; meanwhile, the use of available prognostic score (e.g. Manchester score) might be of great value and should be considered in clinical practice.

Clinical efficacy of immune checkpoint inhibitors in patients with brain metastases.

Brain metastases (BMs) represent a negative prognostic factor for patients with solid malignancies. BMs are generally approached with loco-regional treatments and the blood-brain barrier limits the efficacy of some systemic drugs. The aim of this review is to summarize current knowledge about the role of immune checkpoint inhibitors for the management of brain metastases in patients with solid malignancies. We performed a review of available literature. Immune checkpoint inhibitors represent the standard treatment for several advanced solid malignancies. However, with the exception of melanoma their clinical role in other solid malignancies is not completely clear due to the exclusion of patients with BM from approval clinical trials. Immune-checkpoint inhibitors may be an effective treatment of brain metastases of melanoma while their clinical role on brain metastases from other solid malignancies is uncertain.

Comparison of Sequential Testing and Next Generation Sequencing in advanced Lung Adenocarcinoma patients - A single centre experience.

OBJECTIVES: Molecular diagnosis determines therapeutic strategies for patients with non-small-cell lung cancer - adenocarcinoma (NSCLC-A) but depends on resources availability. We compared a sequential single-gene testing algorithm to next generation sequencing in NSCLC-A to assess differences in terms of effectiveness, costs, tissue consumption and time. MATERIALS AND METHODS: We analyzed a retrospective cohort of advanced NSCLC-A patients treated at the Sant'Orsola-Malpighi University Hospital. The sequential testing includes a first analysis of EGFR and KRAS status with further molecular testing physician driven. The available NGS panel detects 35 hotspot mutations,19 amplifications and 23 rearrangements. RESULTS: We included 1758 patients; 1221 characterized with the sequential algorithm between January 2014 to February 2019 and 537 with Next Generation Sequencing (NGS) until January 2020. The prevalence of EGFR, ALK and KRAS alterations was similar between the stepwise and NGS group (16.5% vs 14.3%, 6.3% vs 6.3% and 36% vs 33.5%, respectively). Differently, ROS-1 rearrangements prevalence was higher in stepwise respect to NGS group (4.7% vs 0.7%). Similarly, the stepwise group presented higher prevalence than NGS for MET amplification (11.2% vs 2.2%), MET mutations (9.0% vs 2.4%), HER2 amplification (3.3% vs 1.9%) and mutations (9.8% vs 3.0%), and BRAF mutations (4.5% vs 5.6%). Among the NGS group other mutations were found in 141 patients (26.3%) and the presence of concurrent mutations in 131 (24.4%). The stepwise algorithm presented a relevant dropout rate that increased at each step, with 11.4%, 16.4% and 49.3% respectively for ALK, ROS1 and other analysis. Sequential testing's expenditure was 1375 € per patient, vs 770 € for NGS. Moreover, NGS testing can be performed with just a 25 µm slide respect to an estimated 33.3 µm slide for sequential strategy. CONCLUSION: NGS offered a less expensive and more reliable model of diagnosis respect to sequential one for patients affected by NSCLC-A.

Hyperammonemic encephalopathy during XELOX regimen. Is it capecitabine or oxaliplatin responsible?

Hyperammonemic encephalopathy represents a rare adverse effect of several chemotherapeutic agents, occurring in about 0.7% of patients treated with fluoropyrimidines, and it is independent from dihydropyrimidine dehydrogenase deficiency. Instead, its physiopathology is linked to the inhibition of Krebs cycle by fluoroacetate, leading to decreased ATP production, and to the inhibition of the urea cycle. Oxaliplatin seems to induce hyperammonemic encephalopathy in a similar way, acting on mitochondria. Here, we report the intriguing case of acute hyperammonemic encephalopathy in a 65-year-old patient with preserved liver function, who was treated with oxaliplatin and capecitabine for a metastatic, G1, atypical lung carcinoid. We reviewed the literature and found very few reports of oxaliplatin or capecitabine-induced hyperammonemic encephalopathy. Out of five cases of capecitabine-related hyperammonemic encephalopathy analyzed (four plus our case), median time to hyperammonemic encephalopathy onset was 6 days, with median serum ammonia levels of 213 µmol/L. Oxaliplatin-related hyperammonemic encephalopathy analyzed cases were three (two plus ours), with a median time to hyperammonemic encephalopathy of 11 days and median serum ammonia levels of 167 µmol/L. Identified predisposing factors for chemotherapy-induced hyperammonemia, such as dehydration, liver and renal impairment, infections, and sarcopenia were absent in our case. We hypothesize that the combination of a platinum-derivative and a fluoropyrimidine multiplies the risk of hyperammonemic encephalopathy, even in the absence of predisposing factors nor impaired liver function. We therefore suggest to always consider the risk of hyperammonemia when starting fluoropyrimidines-based chemotherapy, especially combined with platinum-derivatives, and to timely investigate neurologic symptoms monitoring ammonia serum levels.