Testosterone levels and androgen receptor copy number variations in castration-resistant prostate cancer treated with abiraterone or enzalutamide.

PURPOSE: Our study aims to investigate the association between copy number of the androgen receptor (AR) and testosterone levels in metastatic castration-resistant prostate cancer (mCRPC) treated with second-generation antiandrogen therapies. MATERIALS AND METHODS: We retrospectively collected data from mCRPC treated with abiraterone acetate and enzalutamide. Serum testosterone levels were collected at baseline, at 3 months since the start of therapy and at disease progression. A cohort of cases treated with docetaxel was also used to evaluate the impact of testosterone levels. RESULTS: Patients treated with abiraterone with AR copy number aberrations and basal testosterone levels below 0.09 nmol/L had worse progression-free survival (PFS) compared to patients with no AR copy number abnormalities (8.5 vs 2.9 months, P = 0.005). No relevant differences were observed in the enzalutamide group with a PFS of 3.9 months (no AR gain) vs 2.7 months ( AR gain, P = 0.004) for patients with below 0.09 nmol/L testosterone levels. Similar results are obtained for univariate analysis for overall survival (OS). The negative prognostic role of AR copy number gain in OS for both treatment groups (25.5 vs 10.6 months, P = 0.0002 for abiraterone and 14.1 vs 8.3 months, P = 0.031 for enzalutamide) was confirmed, and it was recognized the negative prognostic impact of testosteronemia below 0.09 only for patients treated with enzalutamide (8.8 vs 42.8 months, P = 0.016). On multivariate analysis for patients treated with abiraterone, low testosterone levels below 0.09 and plasma AR gain were significantly associated with worse PFS and OS. These data are confirmed in the enzalutamide group for PFS. CONCLUSIONS: Testosterone levels and the AR copy number alterations were considered as independent prognostic factors. The results of this study show that serum testosteronemia associated with changes in copy number of AR gene could represent a noninvasive biomarker useful to identify a subgroup of patients with worse prognosis that can benefit less from second-generation antiandrogen therapies in the mCRPC setting.

Role and relevance of quality indicators in the selection of first-line treatment of patients with metastatic renal cell carcinoma: a position paper of the MeetURO Group.

Tyrosine kinase inhibitors still play a very important role in the treatment of metastatic renal cell carcinoma despite a continuously changing scenario, in which immunotherapy and several combination-based approaches are also available. In this light, patient-reported outcomes and health-related quality of life are important factors in the selection of the best first-line treatment. This Review focuses on the existing evidence on patient-reported outcomes and health-related quality of life with several tyrosine kinase inhibitors (pazopanib, sunitinib, cabozantinib and tivozanib) used as first-line treatment for metastatic renal cell carcinoma.

Reclassification of good-risk seminoma: prognostic factors, novel biomarkers and implications for clinical management.

Germ cell tumors represent 11% of the cancers diagnosed in adolescent males and are the most common solid tumors in adult men between the ages of 20 and 35. Pure seminoma accounts for around 50% of all testicular germ cell tumors. The prognostic classification of the International Germ Cell Cancer Collaborative Group for good-prognosis seminoma includes both nodal disease and pulmonary visceral metastases. In this article, we analyzed recent data on prognosis and outcome of good-prognosis seminoma to revise the traditional classification of the disease and improve tailored treatment.

Immune System and DNA Repair Defects in Ovarian Cancer: Implications for Locoregional Approaches.

In the last few years, substantial progress has been made in the treatment of ovarian cancer, with increased knowledge about the biology of the disease. Ovarian cancer is a neoplasm strongly linked to defects in DNA repair mechanisms, where deficiency in the homologous recombination (HR) system results in a better response of ovarian cancers to therapy, whether platinum-based chemotherapy, anthracyclines, or poly (ADP-ribose) polymerase (PARP) inhibitors. More recently, it has been demonstrated that different ovarian cancer histotypes may have different immunogenicity. Interestingly, defects in HR systems are associated more frequently with higher tumor infiltrating lymphocytes, providing a rationale for developing combination therapy with immune-modulating agents and PARP inhibitors. Again, locoregional therapies combining heat shock and chemotherapy delivery have been shown to induce an anticancer immune response in vitro. Thus, the potential for locoregional therapeutic approaches that may impact the immune system, perhaps in combination with immune-modulating agents or PARP inhibitors, needs to be further explored. With this premise, we reviewed the main biological and clinical data demonstrating a strict interplay between the immune system, DNA repair mechanisms, and intraperitoneal therapies in ovarian cancer, with a focus on potential future therapeutic implications.

Docetaxel rechallenge in metastatic castration-resistant prostate cancer: any place in the modern treatment scenario? An intention to treat evaluation.

BACKGROUND: We evaluated the possible advantages of a docetaxel (DCT) rechallenge strategy in metastatic castration-resistant prostate cancer (mCRPC) patients, also given the possible earlier positioning of this treatment option in the modern scenario. PATIENTS & METHODS: All mCRPC patients planned for DCT chemotherapy rechallenge in our institutions were evaluated. RESULTS: Of 128 patients, 98 achieved disease control on the initial DCT round. After a treatment holiday of 8.3 months, the 98 responsive patients underwent a second DCT round, with 56 cases achieving again disease control. After a 5.7-month off-treatment period, 32 of these cases underwent a third DCT round, and 16 responded. Lastly, after a further 4.2-month treatment holiday, eight patients underwent a fourth DCT round and two responded. Median time to definitive disease progression for the whole population was 16.4 months. CONCLUSIONS: Rechallenge with DCT may be considered a suitable treatment option for mCRPC patients recurring after a successful DCT chemotherapy. The interest in this strategy may be increased because of the showed efficacy of early DCT chemotherapy in patients with bulky disease (CHAARTED study) and the potential lower efficacy of the new hormonal agents abiraterone acetate and enzalutamide when used in a immediate sequencing.

Endometriosis and endometrial cancer: A propensity score-adjusted real-world data study.

Endometriosis is a benign condition characterized by the presence of ectopic endometrial tissue. Our study investigated the effect of endometriosis on the risk of endometrial cancer (EC) and the prognosis of endometriosis-associated EC. In our study, 197,196 patients with endometriosis and without a previous diagnosis of EC were compared with 6,455,556 females encountering health services for examinations, with body mass index (BMI) data, and without endometriosis or EC. A propensity score generated 197,141 matched pairs. In the endometriosis cohort, 875 cases of EC were seen, whereas 558 were in the control group: the hazard ratio (HR) was 1.56 (95% CI 1.40-1.73, p < 0.001). Women with endometriosis were more likely to develop invasive endometrioid (p = 0.005) and clear cell (p < 0.001) EC. There was no difference in overall survival between endometriosis-associated EC and EC without endometriosis. Our epidemiological findings were consistent with the evidence of an association between endometriosis and EC.

Inherited Mutations in DNA Damage Repair Genes in Italian Men with Metastatic Prostate Cancer: Results from the Meet-URO 10 Study.

Background: The prevalence of pathogenic germline mutations in DNA damage repair (gDDR) genes in the Italian population is unknown. Objective: In this prospective multicenter cohort study, we evaluated the prevalence of gDDR alterations in the Italian population affected by metastatic prostate cancer (mPCa) and analyzed the impact on response to therapy, survival, and time to castration resistance. Design setting and participants: In an observational prospective trial, 300 consecutive Italian mPCa patients, enrolled in the Meet-Uro-10 trial from three academic Italian centers, were recruited between 2017 and 2019 and were screened for gDDR mutations in 107 genes. Outcome measurements and statistical analysis: The primary endpoint was to assess the prevalence of gDDR mutations in the Italian population of patients with mPCa. The secondary endpoints included the association of gDDR subgroups with metastatic onset, Gleason score, and time to castration resistance. Results and limitations: We identified 297 valuable patients. Forty-six patients had a pathogenic/likely pathogenic variant (15.5%, 95% confidence interval: 11.4-19.6): the more frequent was gBRCA2 found in nine cases (3%), followed by gATM in five cases (1.7%). In patients without mutations, longer median overall survival was observed with the sequence docetaxel-androgen receptor signaling inhibitor (ARSI) than with the sequence ARSI-docetaxel (87.9 vs 42 mo, p = 0.0001). In a univariate analysis, the median time to castration resistance in gDDR mutated patients was 19.8 mo, versus 23.7 mo in no mutated patients (p = 0.024). There were no associations of gDDR subgroups with metastatic onset and Gleason score ≥8. In our cohort, variants of unknown significance in gDDR genes were found in 80 patients and might have a prognostic relevance. Conclusions: The study reported the prevalence of gDDR in the Italian population. The presence of gBRCA2 mutations correlates with a shorter time to the onset of castration resistance disease. Patient summary: The prevalence of gBRCA2 in the Italian population is 3%, which is similar to that in the Spanish population, identifying similarities between people of the Western Mediterranean area.

Multimodality treatment of gynecomastia in patients receiving antiandrogen therapy for prostate cancer in the era of abiraterone acetate and new antiandrogen molecules.

Gynecomastia is a pathological enlargement of male breasts due to hormonal imbalance and elevation of estrogens at the expense of testosterone. It is very important to diagnose this disease precociously because it can be the expression of different underlying pathologies. Besides genetic, chromosomal or chronic diseases, drugs often represent the principal cause of this hormonal disequilibrium. In the elderly population, antiandrogen therapy for prostate cancer frequently induces gynecomastia, thus negatively affecting the patients' compliance to treatment because of physical and psychological discomfort deriving from this condition; gynecomastia can in fact be associated with severe breast pain, and it can modify how patients see their own body. During the past decades and even today, many different surgical, radiotherapeutic or clinical approaches have been proposed to prevent or treat this hypertrophy. This article focuses on gynecomastia associated with antiandrogen-based hormonal treatment and shortly reviews the currently most often used therapeutic options for preventing and treating this pathology.

Clinical and pathological features of primary renal synovial sarcoma: analysis of 64 cases from 11 years of medical literature.

OBJECTIVE: To describe, for the first time, the clinical characteristics of primary renal synovial sarcoma (SS) and to examine the association of histological features with the expression of immunohistochemical markers. PATIENTS AND METHODS: We collated published data on all cases of primary renal SS, from its first description in 2000 to September 2011. Data on clinical and pathological characteristics were extracted and used to create a database. Disease-free survival (DFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method with Rothman's 95% confidence intervals (CIs) and compared across the groups using the log-rank test. The associations between tumour extension and histological features were evaluated using the non-parametric Spearman rank test. A chi-squared test was used to assess the differences between groups. RESULTS: In the overall cohort, the median OS was 48 months (95% CI, 14.1-81.9). Cox analysis showed that the risk of death at diagnosis was greatly increased in patients with metastatic disease compared with those with non-metastatic disease (hazard ratio [HR]: 343.9, 95% CI, 2.8-42,000; P= 0.017). The median DFS was 33.0 months (95% CI, 16.8-49.2), and patients who develop metastatic disease have a very poor prognosis with a median survival of 6 months (95% CI, 5.1-6.9). Microscopic features were monophasic, biphasic and poorly differentiated synovial sarcoma in 76, 16 and 8% of patients, respectively. Significant differences in expression of immunohistochemical markers or genetic mutation were found between different subtypes. CONCLUSIONS: Despite its retrospective nature, this study shows that renal SS comprises different histological subtypes, which are characterized by specific immunohistochemical stains and by specific translocations. When diagnosed at metastatic stage, the prognosis was very poor compared with that for non-metastatic disease, even though one out of three patients with non-metastatic disease had disease relapse. Cooperative efforts and publication of cases with adequate follow-up are necessary to better define prognosis and therapeutic strategies for this rare disease.

Endometrioid Cancer Associated With Endometriosis: From the Seed and Soil Theory to Clinical Practice.

Endometriosis is a benign condition characterized by the presence of ectopic endometrial tissue. It is still debated whether endometriosis is a disease that can predispose to the pathogenesis of endometrial cancer outside the uterus. Deficiencies in mismatch repair (MMR) genes are a known risk factor for developing endometrioid cancer. Starting from two cases of patients with abnormal MMR endometrioid carcinoma of the uterus and synchronous endometrioid carcinoma in non-ovarian and ovarian endometriosis, we performed a somatic mutation profile and phylogenetic analysis of the lesions in order to identify if they were metastasis or primary de novo tumors. In the first case, we identified de novo activating mutations in PIK3CA and KRAS in endometrioid cancer lesions but not in endometriosis. Although the acquisition of a de novo mutation in ESR1 and a decrease in mutant allele fraction (MAF) from the endometrial tumor to the localizations in the endometriosis lesions, the clonal relationship was confirmed by the limited number of heteroplasmic mutations in D-loop mitochondrial DNA region. In the other case, the clonal behavior was demonstrated by the overlap of MAF at each site. Our data support the hypothesis of a retrograde dissemination of tumor cells, moving from the primary carcinoma in the endometrium to ectopic sites of endometriosis where localizations of tumor arise.

Combining liquid biopsy and functional imaging analysis in metastatic castration-resistant prostate cancer helps predict treatment outcome.

Plasma tumour DNA (ptDNA) is a potential early noninvasive biomarker of treatment outcome in metastatic castration-resistant prostate cancer (mCRPC). Herein, we investigated whether pretreatment ptDNA levels reflect metabolic tumour burden in mCRPC and better predict treatment outcome in combination with functional imaging. Targeted next-generation sequencing was performed to estimate the ptDNA fraction from 102 mCRPC patients receiving abiraterone or enzalutamide. The maximum standardized uptake value (SUVmax), total lesion activity (TLA) and metabolic tumour volume (MTV) were evaluated on 18 F-fluorocholine positron emission tomography/computed tomography. We assessed a Weibull multiple regression model to determine the combined impact of clinical, molecular and imaging characteristics on overall survival (OS) and progression-free survival (PFS), and to obtain prognostic scores. A significant association was seen between ptDNA and SUVmax, MTV and TLA. For survival analysis, patients were randomly allocated into a training (n = 68) and a validation (n = 34) set. In the training set, multivariable analyses showed that ptDNA, MTV and serum lactate dehydrogenase together with visceral metastasis were independent predictors of both OS and PFS. Prognostic scores were generated, with the identification of three groups of patients with significantly different median OS (29.2, 15.9 and 8.7 months) and PFS (13.3, 7.7 and 3.2 months) probabilities. The differences in median survival between risk groups were confirmed in the validation cohort for both OS and PFS. In our study, we showed that integrating plasma DNA analysis with functional imaging may improve prognostic risk stratification and treatment selection in mCRPC.

Palonosetron plus 3-day aprepitant and dexamethasone to prevent nausea and vomiting in patients receiving highly emetogenic chemotherapy.

BACKGROUND: The combination of a neurokinin-1 receptor antagonist, dexamethasone, and a 5-HT(3) receptor antagonist is currently the standard antiemetic treatment in patients receiving cisplatin-based high emetogenic chemotherapy (HEC). The aim of this study was to evaluate the efficacy of a combination of palonosetron, a unique second-generation 5-HT(3) receptor antagonist, aprepitant, the only approved neurokinin-1 receptor antagonist, and dexamethasone as antiemetic prophylaxis in patients receiving HEC (cisplatin ≥50 mg/mq). METHODS: Chemotherapy-naïve adult patients, receiving cisplatin-based HEC, were treated with palonosetron 0.25 mg/i.v., dexamethasone 20 mg/i.v., and aprepitant 125 mg/p.o., 1-h before chemotherapy. Aprepitant 80 mg/p.o. and dexamethasone 4 mg p.o. were administered on days 2-3. Primary end point was complete response (CR; no vomiting and no use of rescue medication), during the overall study period (0-120 h). Secondary end points were complete control (CR and no more than mild nausea), emesis-free rate, and nausea-free rate during the acute (0-24 h), delayed (24-120 h), and overall (0-120 h) periods. Safety was also evaluated. RESULTS: A total of 222 patients were included in the study. Median age was 62 years, 76.6% were male and 23.4% female, and most common tumors were lung (66.7%) and head and neck (15.8%); 70.3% of patients achieved CR during the overall study period. Complete control, emesis-free rate, and nausea-free rate were 70.3%, 92.8%, and 59.9%, respectively, during the overall phase. The most commonly reported side effects were constipation (39% of patients) and headache (5%). CONCLUSIONS: This study shows that palonosetron in combination with aprepitant and dexamethasone is effective to prevent chemotherapy-induced nausea and vomiting in patients treated with cisplatin-based HEC.

Immunotherapy and Its Development for Gynecological (Ovarian, Endometrial and Cervical) Tumors: From Immune Checkpoint Inhibitors to Chimeric Antigen Receptor (CAR)-T Cell Therapy.

Gynecological tumors are malignancies with both high morbidity and mortality. To date, only a few chemotherapeutic agents have shown efficacy against these cancer types (only ovarian cancer responds to several agents, especially platinum-based combinations). Within this context, the discovery of immune checkpoint inhibitors has led to numerous clinical studies being carried out that have also demonstrated their activity in these cancer types. More recently, following the development of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, this strategy was also tested in solid tumors, including gynecological cancers. In this article, we focus on the molecular basis of gynecological tumors that makes them potential candidates for immunotherapy. We also provide an overview of the main immunotherapy studies divided by tumor type and report on CAR technology and the studies currently underway in the area of gynecological malignancies.

Melphalan as a Promising Treatment for BRCA-Related Ovarian Carcinoma.

INTRODUCTION: Melphalan, as a bifunctional alkylating agent has been shown to be selectively efficient in BRCA-deficient case reports of epithelial ovarian cancer (EOC). The clinical benefit of melphalan on unselected platinum-resistant EOC population and stratified by BRCA status has not been clearly elucidated. We aimed to determine the response to melphalan in patients with recurrent EOC after platinum-based therapy. MATERIAL AND METHODS: This retrospective observational study included patients with recurrent EOC treated with melphalan between February 2007 to July 2020. Eligibility criteria included having a histological confirmation of EOC, previous treatment with carboplatin plus paclitaxel regimens, and disease recurrence during treatment with or within 6 months of the end of the platinum-based chemotherapy. RESULTS: A total of 75 platinum-resistant EOC patients were enrolled. Median age was 69 years (range 41-82). Median of previous therapies before melphalan was 4 (range 1-7). We observed a median follow-up of 32 months (range 1-62), progression-free survival (PFS) and overall survival (OS) of 3.6 months (range 2.9-4.7) and 9.5 months (range 8.0-14.1), respectively. In the whole population, 1 complete response, 6 partial responses and 37 stable diseases were registered with an overall clinical benefit rate of 58.7%. In BRCA1/2 mutant patients, we showed a significant longer PFS compared to BRCA1/2 wild type patients (6.2 versus 2.6 months; hazard ratio (HR) 0.25, 95% confidence interval (CI) 0.10-0.61; p=0.002). Moreover, a trend was seen for BRCA1/2 mutants to have a better OS (25.9 versus 8.0 months; HR 0.38; 95% CI 0.12-1.19; p=0.097). CONCLUSIONS: Our study represents the largest cohort of heavily-pretreated EOC patients receiving melphalan treatment. Here, we report a considerable clinical activity of melphalan chemotherapy, more evident in a subset of BRCA1/2 mutated patients. Prospective studies to validate these findings are warranted.

Plasma AR Copy Number Changes and Outcome to Abiraterone and Enzalutamide.

Introduction: Plasma androgen receptor (AR) copy number (CN) status identifies castration-resistant prostate cancer (CRPC) patients with worse outcome on abiraterone/enzalutamide. However, the impact of AR CN changes on clinical outcome in CRPC is unknown. Materials and Methods: Plasma samples from 73 patients treated with abiraterone or enzalutamide were collected at baseline and at the time of progression disease (PD). Droplet digital polymerase chain reaction was used to assess AR CN status. Results: We showed that 11 patients (15.1%) changed AR CN status from baseline to PD (9 patients from normal to gain, 2 from gain to normal). Patients changing AR CN status from normal at baseline to gain at PD had intermediate median overall survival (OS) of 20.5 months (95% CI = 8.0-44.2) between those who remained AR CN normal from baseline to PD (27.3 months [95% CI = 21.9-34.4]) and those who remained AR CN gain from baseline to PD (9.1 months [95% CI = 3.8-14.5], p < 0.0001). Patients changing AR CN from normal at baseline to gain at PD had a median progression-free survival (PFS) of 9.2 months (95% CI = 2.0-14.7), patients who remained AR CN normal had a median PFS of 9.1 months (95% CI = 7.2-10.1), and patients who remained AR CN gain had a median PFS of 5.4 (95% CI = 3.6-6.5, p = 0.0005). Both OS and PFS were not significantly different between patients with AR CN that changes from normal to gain and patients with stable AR CN normal. Conclusions: We showed that CRPC patients changing AR CN status from baseline to progression time point had intermediate OS and we suggested that AR CN evaluation at baseline could be the most informative for clinical outcome of CRPC patients treated with abiraterone or enzalutamide. Larger prospective studies are warranted.

A comprehensive review of the role of immune checkpoint inhibitors in elderly patients affected by renal cell carcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been revolutionizing the treatment landscape of metastatic renal cell carcinoma (mRCC). The use of ICIs in elderly RCC patients has become a daily practice, although their real impact in elderly patients is nowadays not completely clarified. It has been hypothesized that ICIs might not perform as effectively in the elderly as in younger patients, likely because of the gradual deterioration of the immune system brought on by natural age advancement, namely immunosenescence. METHODS: We reviewed all clinical trials with ICIs in mRCC focusing on efficacy and toxicity of elderly patients. RESULTS: Among the 21 trials reviewed, only 5 of them provided data on elderly patients. With the limits of low accrual and events for elderly patients, the efficacy of ICIs in patients ≥ 65 years seems as relevant as for younger patients, but not reliable for patients ≥ 75 years, group with overall low number of events, both in pre- or previously untreated mRCC patients. These currently available data seem not to support the hypothesis of a lower efficacy of ICIs in elderly patients, at least for mRCC. These trials reported very few data about toxicities in the specific population of elderly patients. CONCLUSIONS: Although available data from clinical trials are poor, currently, they do not support the efficacy of ICIs is less in elderly mRCC patients.

Potential Application of Chimeric Antigen Receptor (CAR)-T Cell Therapy in Renal Cell Tumors.

Currently, renal cell carcinoma is characterized by encouraging benefits from immunotherapy that have led to significant results in treatment outcome. The approval of nivolumab primarily as second-line monotherapy and, more recently, the approval of new combination therapies as first-line treatment have confirmed the importance of immunotherapy in this type of tumor. In this context, the chimeric antigen receptor (CAR)-T represents a further step forward in the field of immunotherapy. Initially tested on hematological malignancies, this new therapeutic approach is also becoming a topic of great interest for solid tumors. Although the treatment has several advantages over previous T-cell receptor-dependent immunotherapy, it is facing some obstacles in solid tumors such as a hostile tumor microenvironment and on-tumor/off-tumor toxicities. Several strategies are under investigation to overcome these problems, but the approval of CAR-T cell therapy is still some way off. In renal cancer, the significant advantages obtained from immune checkpoint inhibitors represent a good starting point, but the potential nephrological toxicity of CAR-T cell therapy represents an important risk. In this review, we provide the rationale and preliminary results of CAR-T cell therapy in renal cell malignancies.

Enzalutamide for the treatment of nonmetastatic castration-resistant prostate cancer.

INTRODUCTION: Enzalutamide is the first characterized second-generation nonsteroidal androgen receptor inhibitor (ARi). Its efficacy has been established in several clinical trials evaluating its role in different settings of prostate cancer. Recently, enzalutamide has been approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). AREAS COVERED: In this paper, the authors describe the chemical structure and pharmacologic characteristics of enzalutamide, providing a summary of clinical trials evaluating its efficacy and safety in prostate cancer patients. EXPERT OPINION: Enzalutamide adds to the growing arsenal of ARi used in nmCRPC. An improvement in metastasis-free survival was observed with the use of these new treatment options; recently released preliminary data report also an OS benefit. These novel agents are generally well tolerated, but their safety profiles differ slightly. Since head-to-head comparisons between ARi in nmCRPC are lacking, the adverse events profile, as well as drug availability, costs, and considerations on treatment-sequencing, would most likely influence the selection of the individual agent in this setting. Further research is needed to improve treatment selection and clarify many unsolved issues. Abbreviations ARi: nonsteroidal androgen receptor inhibitor; nmCRPC: nonmetastatic castration resistant prostate cancer; ADT: androgen deprivation therapy; OS: overall survival; PSA: prostate specific antigen; FDA: Food and Drug Administration; AR: Androgen Receptor; MFS: metastasis free survival; PSA-DT: PSA doubling time; HR: hazard ratio; CI: confidence interval; AEs: adverse events; mCRPC: metastatic castration resistant prostate cancer; mHSPC: metastatic hormone-sensitive prostate cancer; rPFS: radiographic progression-free survival; OR: odds ratio.

Prognostic Role of Systemic Inflammatory Indexes in Germ Cell Tumors Treated With High-Dose Chemotherapy.

High-dose chemotherapy (HDCT) has curative potential in relapsed/refractory germ cell tumors (GCT). Due to the complexity of this population and the toxicity of HDCT, we evaluated the association between blood-based systemic inflammatory indexes and the outcome of GCT patients undergoing salvage treatment with HDCT in order to define additional prognostic factors able to orient clinical decision. Baseline characteristics, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and the systemic immune-inflammation index (SII) of 62 patients undergoing HDCT for GCT were retrospectively collected. The aim is to evaluate the correlation between each inflammatory marker (NLR, PLR, and SII) and response to HDCT, overall survival (OS), and progression-free survival (PFS). Using the receiver operating curve to identify the best cutoff values, it was found that patients with GCT with NLR ≥3.3 and SII ≥844,000 had shorter PFS and inferior OS. In the multivariable analysis including inflammatory markers, the International Prognostic Factor Study Group (IPFSG) risk group, age, and previous line of treatment, NLR ≥3.3 and SII ≥844,000 were identified to be independently associated with shorter PFS and OS. Moreover, NLR, PLR, and SII significantly correlate with overall response to HDCT. Associating IPFSG prognostic score to inflammatory markers at baseline of HDCT may improve prognostic information and could help physicians to make more personalized treatment decisions.

Inflammatory Biomarkers as Predictors of Response to Immunotherapy in Urological Tumors.

Immunotherapy represents the new era of cancer treatment because of its promising results in various cancer types. In urological tumors, the use of the immune-checkpoint inhibitors (ICIs) is increasingly spreading. Although not all patients and not all diseases respond equally well to immunotherapy, there is an increasing need to find predictive markers of response to ICIs. Patient- and tumor-related factors may be involved in primary and secondary resistance to immunotherapy: tumor-derived protein and cytokines, tumor mutational burden, and patient performance status and comorbidities can condition tumor response to ICIs. Recently, some of these factors have been evaluated as potential biomarkers of response, with conflicting results. To date, the expression of programmed death-ligand 1 (PD-L1) and the presence of deficient mismatch repair (dMMR) in tumor tissue are the only biomarkers capable of guiding the clinician's decision in urothelial cancer and prostate cancer, respectively. In this review, we performed a comprehensive search of the main publications on biomarkers that are predictive of response to ICIs in urological cancers. Our aim was to understand whether existing data have the potential to drive clinical decision-making in the near future.