Plasma microRNA Signature as Companion Diagnostic for Abiraterone Acetate Treatment in Metastatic Castration-Resistant Prostate Cancer: A Pilot Study.

Abiraterone acetate (AA) serves as a medication for managing persistent testosterone production in patients with metastatic castration-resistant prostate cancer (mCRPC). However, its efficacy varies among individuals; thus, the identification of biomarkers to predict and follow treatment response is required. In this pilot study, we explored the potential of circulating microRNAs (c-miRNAs) to stratify patients based on their responsiveness to AA. We conducted an analysis of plasma samples obtained from a cohort of 33 mCRPC patients before and after three, six, and nine months of AA treatment. Using miRNA RT-qPCR panels for candidate discovery and TaqMan RT-qPCR for validation, we identified promising miRNA signatures. Our investigation indicated that a signature based on miR-103a-3p and miR-378a-5p effectively discriminates between non-responder and responder patients, while also following the drug's efficacy over time. Additionally, through in silico analysis, we identified target genes and transcription factors of the two miRNAs, including PTEN and HOXB13, which are known to play roles in AA resistance in mCRPC. In summary, our study highlights two c-miRNAs as potential companion diagnostics of AA in mCRPC patients, offering novel insights for informed decision-making in the treatment of mCRPC.

Novel Treatment Strategies for Hormone Receptor (HR)-Positive, HER2-Negative Metastatic Breast Cancer.

Estrogen receptor (ER)-positive breast cancer (BC) is the most common BC subtype. Endocrine therapy (ET) targeting ER signaling still remains the mainstay treatment option for hormone receptor (HR)-positive BC either in the early or in advanced setting, including different strategies, such as the suppression of estrogen production or directly blocking the ER pathway through SERMs-selective estrogen receptor modulators-or SERDs-selective estrogen receptor degraders. Nevertheless, the development of de novo or acquired endocrine resistance still remains challenging for oncologists. The use of novel ET combined with targeted drugs, such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, has significantly improved long-term outcome rates, thus changing the therapeutic algorithm for metastatic BC (MBC) and recently the therapeutic strategy in the adjuvant setting for early high-risk BC. Eluding the resistance to CDK4/6 inhibitors combined with ET is currently an unmet medical need, and there is disagreement concerning the best course of action for patients who continue to progress after this combination approach. Genetic changes in the tumor along its growth uncovered by genomic profiling of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict the response or resistance to specific agents, suggesting the best therapeutic strategy for each patient by targeting the altered ER-dependent pathway (novel oral SERDs and a new generation of anti-estrogen agents) or alternative ER-independent signaling pathways such as PI3K/AKT/mTOR or tyrosine kinase receptors (HER2 mutations or HER2 low status) or by inhibiting pathways weakened through germline BRCA1/2 mutations. These agents are being investigated as single molecules and in combination with other target therapies, offering promising weapons to overcome or avoid treatment failure and propose increasingly more personalized treatment approaches. This review presents novel insights into ET and other targeted therapies for managing metastatic HR+/HER2- BC by exploring potential strategies based on clinical evidence and genomic profiling following the failure of the CDK4/6i and ET combination.

Clinical Outcomes and Prognostic Factors in Patients With Penile Carcinoma: A Sub-Analysis From Meet-URO 23 (I-RARE) Registry Study.

INTRODUCTION: Penile squamous cell carcinoma (PSCC) is a rare tumor with an aggressive behavior. The Meet-URO 23/I-RARE registry includes rare genitourinary malignancies. We extracted patients with PSCC to conduct a retrospective study aimed at assessing clinical outcomes and prognostic factors. PATIENTS AND METHODS: Primary endpoints were overall survival and progression-free survival. Prognostic factors for OS and PFS were analyzed using univariate and multivariate analysis. From the Meet-URO 23/I-RARE database, we extracted 128 patients with diagnosis of PSCC. About 48% of patients underwent first-line of therapy. RESULTS: In the overall population, median OS from diagnosis was 34.6 months. Significant differences in median OS were observed according to ECOG PS at diagnosis (57.3 months vs. 8.3 months; P < .001), and median age (≤77y 88.8 months vs. >77y 26 months; P = .013). At multivariate analysis, ECOG PS 2-4 at diagnosis (HR 3.04) and lymph node metastases (HR 2.49) were independently associated with a higher risk of death. Among patients undergoing first-line therapy (n = 61), median OS was 12.3 months, and a statistically significant difference was found according to type of response to first-line (DCR 24.4 months vs. PD 7.1 months; P < .001). Multivariate analysis showed that only age >77 years was associated with a worse OS (HR 2.16). A statistically significant difference in PFS was found according to platinum plus 5-fluorouracil versus platinum plus taxane (4.9 vs. 3.4 months; P = .036) and regimens with 2 versus 3 drugs (3.4 vs. 8.6 months; P = .019). At the multivariate analysis only regimens with platinum plus taxane were associated with worse PFS (HR 2.83). CONCLUSION: In our registry study, PSCC is confirmed to be an aggressive disease. Poor ECOG PS, presence of lymph node metastases, and higher age at diagnosis appear to be associated with worse survival outcomes.

Global real-world experiences with pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy: the ARON-2 study.

BACKGROUND: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. PATIENTS AND METHODS: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors. RESULTS: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001). CONCLUSIONS: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations.

The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.

Time to strategy failure and treatment beyond progression in pretreated metastatic renal cell carcinoma patients receiving nivolumab: post-hoc analysis of the Meet-URO 15 study.

Background: Immunotherapies exhibit peculiar cancer response patterns in contrast to chemotherapy and targeted therapy. Some patients experience disease response after initial progression or durable responses after treatment interruption. In clinical practice, immune checkpoint inhibitors may be continued after radiological progression if clinical benefit is observed. As a result, estimating progression-free survival (PFS) based on the first disease progression may not accurately reflect the actual benefit of immunotherapy. Methods: The Meet-URO 15 study was a multicenter retrospective analysis of 571 pretreated metastatic renal cell carcinoma (mRCC) patients receiving nivolumab. Time to strategy failure (TSF) was defined as the interval from the start of immunotherapy to definitive disease progression or death. This post-hoc analysis compared TSF to PFS and assess the response and survival outcomes between patients treatated beyond progression (TBP) and non-TBP. Moreover, we evaluated the prognostic accuracy of the Meet-URO score versus the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score based on TSF and PFS. Results: Overall, 571 mRCC patients were included in the analysis. Median TSF was 8.6 months (95% CI: 7.0 - 10.1), while mPFS was 7.0 months (95% CI: 5.7 - 8.5). TBP patients (N = 93) had significantly longer TSF (16.3 vs 5.5 months; p < 0.001) and overall survival (OS) (34.8 vs 17.9 months; p < 0.001) but similar PFS compared to non-TBP patients. In TBP patients, a median delay of 9.6 months (range: 6.7-16.3) from the first to the definitive disease progression was observed, whereas non-TBP patients had overlapped median TSF and PFS (5.5 months). Moreover, TBP patients had a trend toward a higher overall response rate (33.3% vs 24.3%; p = 0.075) and disease control rate (61.3% vs 55.5%; p = 0.31). Finally, in the whole population the Meet-URO score outperformed the IMDC score in predicting both TSF (c-index: 0.63 vs 0.59) and PFS (0.62 vs 0.59). Conclusion: We found a 2-month difference between mTSF and mPFS in mRCC patients receiving nivolumab. However, TBP patients had better outcomes, including significantly longer TSF and OS than non-TBP patients. The Meet-URO score is a reliable predictor of TSF and PFS.

Initial management approach for localized/locally advanced disease is critical to guide metastatic castration-resistant prostate cancer care.

BACKGROUND: Currently, several therapies are available for metastatic castration-resistant prostate cancer (mCRPC) but no specific clinical factors to personalize treatment. We first sought the prognostic value of duration on androgen-deprivation therapy (ADT) for hormone-sensitive prostate cancer (HSPC) in patients receiving androgen-receptor-signaling inhibitors (ARSI) for mCRPC. METHODS: A multicenter cohort of mCRPC patients who started ARSI between July 2011 and October 2021 was identified. Based on their initial disease burden and duration on ADT for HSPC, primary progressive (PP) men were classified into four groups: low/intermediate-risk localized disease (LOC) and high-risk localized/locally advanced disease (LAD) and short-term (ST) < 24 vs. long-term (LT) ADT ≥ 24 months, whereas de novo (DN) mHSPC were subdivided into short-time vs. long-time to CRPC. RESULTS: We included 919 mCRPC patients with a median age of 77 years [interquartile range (IQR) = 71-82)]. Median ADT duration in HSPC was 24 months (IQR = 14-40). Median follow-up was 91 months (IQR = 62-138), median OS and PFS from ARSI start were 20 (IQR 10-32) and 10 months (IQR = 5-19), respectively. In PP developing metastatic disease (n = 655, 71.3%), LOC and LAD with ST ADT had a greater than almost double-risk of death compared to LT ADT (LOC/ST: hazard ratio [HR] = 2.01; 95% CI 1.54-2.64; LAD/ST: HR = 1.73; 95% CI 1.34-2.24; p < 0.001). In the multivariate analysis including age, prognostic cohort, Gleason, ECOG, radical radiotherapy and prostatectomy, groups with ST ADT were associated with worse OS compared to LT ADT (LOC/ST: HR = 1.84; 95% CI 1.38-2.45; p < 0.001; LAD/ST: HR = 1.59; 95% CI 1.21-2.10; p < 0.001), along with ECOG > 2 (HR = 1.55; 95% CI 1.06-2.26; p = 0.03). There were also similar results of PFS. Moreover, long-time to CRPC in patients with history of DN mHSPC (n = 264, 28.7%) resulted in a better OS/PFS (HR = 0.76, 95% CI 0.56-1.02, p = 0.064 and HR = 0.74, 95% CI 0.55-0.99, p = 0.042, respectively). CONCLUSIONS: Our study showed that duration on ADT for mHSPC was significantly associated with survival in mCRPC undergoing ARSI. These findings suggest a possible connection between initial management of prostate tumour and a better prognostication in mCRPC. Prospective trials are warranted.

Risk of cardiovascular toxicity with combination of immune-checkpoint inhibitors and angiogenesis inhibitors: a meta-analysis.

Introduction: Combinations of immune checkpoint inhibitors (ICIs) and angiogenesis inhibitors (AIs) have been investigated for the treatment of several tumor types. Both ICIs and AIs may lead to cardiovascular adverse events, and their combination may potentially increase the risk for cardiovascular toxicity. In the present meta-analysis, we aim to assess the cardiovascular toxicity of ICIs plus AIs vs. AIs alone. Secondary objectives are non-cardiovascular adverse events and efficacy. Methods: Systematic review was performed according to PRISMA statement. Phase II and III randomized clinical trials were identified by searching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts, from inception to June 2022. The pooled risks for overall response rate (ORR), 1-year progression-free survival (PFS), adverse events (AEs), immune-related AEs, (irAEs), hypertension, and vascular events defined as stroke, myocardial infarction and pulmonary embolisms, were calculated. Results: In terms of cardiovascular toxicity, we found higher risk for severe hypertension among patients treated with ICIs plus AIs as compared with those receiving AIs (OR 1.24, 95% CI: 1.01-1.53), but no significant difference was found for any-grade hypertension, and for vascular events. There was also no difference in terms of overall AEs, whereas the incidence of irAEs was increased in the ICIs plus AIs arm, as expected. In terms of efficacy, ICIs plus AIs achieved better ORR (OR 2.25, 95% CI: 1.70-2.97) and PFS (HR 0.49, 95% CI: 0.39-0.63) as compared to AIs alone. Conclusion: The addition of ICIs to AIs significantly increased the risk of high-grade hypertension, but not that of acute vascular events.

Sterile inflammation via TRPM8 RNA-dependent TLR3-NF-kB/IRF3 activation promotes antitumor immunity in prostate cancer.

Inflammation is a common condition of prostate tissue, whose impact on carcinogenesis is highly debated. Microbial colonization is a well-documented cause of a small percentage of prostatitis cases, but it remains unclear what underlies the majority of sterile inflammation reported. Here, androgen- independent fluctuations of PSA expression in prostate cells have lead us to identify a prominent function of the Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) gene in sterile inflammation. Prostate cells secret TRPM8 RNA into extracellular vesicles (EVs), which primes TLR3/NF-kB-mediated inflammatory signaling after EV endocytosis by epithelial cancer cells. Furthermore, prostate cancer xenografts expressing a translation-defective form of TRPM8 RNA contain less collagen type I in the extracellular matrix, significantly more infiltrating NK cells, and larger necrotic areas as compared to control xenografts. These findings imply sustained, androgen-independent expression of TRPM8 constitutes as a promoter of anticancer innate immunity, which may constitute a clinically relevant condition affecting prostate cancer prognosis.

A phase II study evaluating the efficacy of enzalutamide and the role of liquid biopsy for evaluation of ARv7 in mCRPC patients with measurable metastases including visceral disease (Excalibur study).

Background: Up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) develop visceral metastases, which are associated with a poor prognosis. Objectives: Efficacy of enzalutamide in mCRPC patients with measurable metastases, including visceral and/or extra-regional lymph nodes. Methods: In this phase II multicenter study, patients with mCRPC and measurable metastases received enzalutamide as the first line. Primary endpoint: 3-month (mo) disease control rate (DCR) defined as the proportion of patients with complete (CR) or partial response (PR) or stable disease (SD) as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoint: safety. Exploratory endpoint: the association between ARv7 splicing variants in basal circulating tumor cell (CTC)-enriched blood samples and treatment response/resistance using the AdnaTest ProstateCancerSelect kit and the AdnaTest ProstateCancer Panel AR-V7. Results: From March 2017 to January 2021, 68 patients were enrolled. One patient never started treatment. Median age: 72 years. A total of 52 patients (78%) received enzalutamide as a first line for mCRPC. The median follow-up was 32 months. At the 3-month assessment, 24 patients presented an SD, 1 patient achieved a CR, and 23 patients had a PR (3-mo-DCR of 72%). Discontinuations due to adverse events (AEs), disease-related death, or disease progression occurred in 9%, 6%, and 48% of patients. All patients reported at least one grade (G) 1-2 AE: the most common were fatigue (49%) and hypertension (33%). Six G3 AEs were reported: two hypertension, one seizure, one fatigue, one diarrhea, and one headache. Basal detection of ARv7 was significantly associated with poor treatment response (p = 0.034) and a nonsignificant association (p = 0.15) was observed between ARv7 detection and response assessments. At month 3, ARv7 was detected in 57%, 25%, and 15% of patients undergoing progressive disease, SD, and PR, respectively. Conclusion: The study met its primary endpoint, showing the efficacy of enzalutamide in men with mCRPC and measurable metastatic lesions in visceral and/or lymph node sites. Trial registration: ClinicalTrials.gov Identifier: NCT03103724. First Posted: 6 April 2017. First patient enrollment: 19 April 2017.

Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation.

Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive therapy response and outcome differences. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy. We developed a targeted DNA methylation assay to detect CRPC-NE using plasma cell-free DNA (cfDNA). The assay quantifies tumor content and provides a phenotype evidence score that captures diverse CRPC phenotypes, leveraging regions to inform transcriptional state. We tested the design in independent clinical cohorts (n = 222 plasma samples) and qualified it achieving an AUC > 0.93 for detecting pathology-confirmed CRPC-NE (n = 136). Methylation-defined cfDNA tumor content was associated with clinical outcomes in two prospective phase II clinical trials geared towards aggressive variant CRPC and CRPC-NE. These data support the application of targeted DNA methylation for CRPC-NE detection and patient stratification. SIGNIFICANCE: Neuroendocrine prostate cancer is an aggressive subtype of treatment-resistant prostate cancer. Early detection is important, but the diagnosis currently relies on metastatic biopsy. We describe the development and validation of a plasma cell-free DNA targeted methylation panel that can quantify tumor fraction and identify patients with neuroendocrine prostate cancer noninvasively. This article is featured in Selected Articles from This Issue, p. 384.

Real-world Outcome of Patients with Advanced Renal Cell Carcinoma and Intermediate- or Poor-risk International Metastatic Renal Cell Carcinoma Database Consortium Criteria Treated by Immune-oncology Combinations: Differential Effectiveness by Risk Group?

BACKGROUND: Renal c carcinoma (RCC) is one of the most common urinary cancers worldwide, with a predicted increase in incidence in the coming years. Immunotherapy, as a single agent, in doublets, or in combination with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), has rapidly become a cornerstone of the RCC therapeutic scenario, but no head-to-head comparisons have been made. In this setting, real-world evidence emerges as a cornerstone to guide clinical decisions. OBJECTIVE: The objective of this retrospective study was to assess the outcome of patients treated with first-line immune combinations or immune oncology (IO)-TKIs for advanced RCC. DESIGN, SETTING, AND PARTICIPANTS: Data from 930 patients, 654 intermediate risk and 276 poor risk, were collected retrospectively from 58 centers in 20 countries. Special data such as sarcomatoid differentiation, body mass index, prior nephrectomy, and metastatic localization, in addition to biochemical data such as hemoglobin, platelets, calcium, lactate dehydrogenase, neutrophils, and radiological response by investigator's criteria, were collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. The median follow-up was calculated by the inverse Kaplan-Meier method. RESULTS AND LIMITATIONS: The median follow-up time was 18.7 mo. In the 654 intermediate-risk patients, the median OS and PFS were significantly longer in patients with the intermediate than in those with the poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (38.9 vs 17.3 mo, 95% confidence interval [CI] p < 0.001, and 17.3 vs 11.6 mo, 95% CI p < 0.001, respectively). In the intermediate-risk subgroup, the OS was 55.7 mo (95% CI 31.4-55.7) and 40.2 mo (95% CI 29.6-51.6) in patients treated with IO + TKI and IO + IO combinations, respectively (p = 0.047). PFS was 30.7 mo (95% CI 16.5-55.7) and 13.2 mo (95% CI 29.6-51.6) in intermediate-risk patients treated with IO + TKI and IO + IO combinations, respectively (p < 0.001). In the poor-risk subgroup, the median OS and PFS did not show a statistically significant difference between IO + IO and IO + TKI. Our study presents several limitations, mainly due to its retrospective nature. CONCLUSIONS: Our results showed differences between the IO + TKI and IO + IO combinations in intermediate-risk patients. A clear association with longer PFS and OS in favor of patients who received the IO + TKI combinations compared with the IO-IO combination was observed. Instead, in the poor-risk group, we observed no significant difference in PFS or OS between patients who received different combinations. PATIENT SUMMARY: Renal cancer is one of the most frequent genitourinary tumors. Treatment is currently based on immunotherapy combinations or immunotherapy with tyrosine kinase inhibitors, but there are no comparisons between these.In this study, we have analyzed the clinical course of 930 patients from 58 centers in 20 countries around the world. We aimed to analyze the differences between the two main treatment strategies, combination of two immunotherapies versus immunotherapy + antiangiogenic therapy, and found in real-life data that intermediate-risk patients (approximately 60% of patients with metastatic renal cancer) seem to benefit more from the combination of immunotherapy + antiangiogenic therapy than from double immunotherapy. No such differences were found in poor-risk patients. This may have important implications in daily practice decision-making for these patients.

Integrating extracellular vesicle and circulating cell-free DNA analysis using a single plasma aliquot improves the detection of HER2 positivity in breast cancer patients.

Multi-analyte liquid biopsies represent an emerging opportunity for non-invasive cancer assessment. We developed ONCE (ONe Aliquot for Circulating Elements), an approach for the isolation of extracellular vesicles (EV) and cell-free DNA (cfDNA) from a single aliquot of blood. We assessed ONCE performance to classify HER2-positive early-stage breast cancer (BrCa) patients by combining EV-associated RNA (EV-RNA) and cfDNA signals on n=64 healthy donors (HD) and non-metastatic BrCa patients. Specifically, we isolated EV-enriched samples by a charge-based (CB) method and investigated EV-RNA and cfDNA by next-generation sequencing (NGS) and by digital droplet PCR (ddPCR). Sequencing of cfDNA and EV-RNA from HER2- and HER2+ patients demonstrated concordance with in situ molecular analyses of matched tissues. Combined analysis of the two circulating analytes by ddPCR showed increased sensitivity in ERBB2/HER2 detection compared to single nucleic acid components. Multi-analyte liquid biopsy prediction performance was comparable to tissue-based sequencing results from TCGA. Also, imaging flow cytometry analysis revealed HER2 protein on the surface of EV isolated from the HER2+ BrCa plasma, thus corroborating the potential relevance of studying EV as companion analyte to cfDNA. This data confirms the relevance of combining cfDNA and EV-RNA for HER2 cancer assessment and supports the ONCE as a valuable tool for multi-analytes liquid biopsies' clinical implementation.

Sodium Levels and Outcomes in Patients With Metastatic Renal Cell Carcinoma Receiving Nivolumab.

Importance: Low sodium levels have been associated with negative outcomes among patients with metastatic renal cell carcinoma (mRCC) receiving therapies other than immune checkpoint inhibitors (ICIs). Objective: To investigate the role of natremia in patients with mRCC receiving nivolumab as a second-line or subsequent therapy. Design, Setting, and Participants: In this retrospective cohort study, the clinical and biochemical data of patients with mRCC receiving nivolumab were collected from October 2015 to November 2019 as part of a multicenter Italian study. Data analysis was performed from February to March 2023. Exposure: Nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks and, since May 2018, at a fixed dose of 240 mg every 2 weeks or 480 mg every 4 weeks. Patients were divided into 2 groups according to their median serum sodium value (<140 or ≥140 mEq/L). Main Outcomes and Measures: The primary outcomes were the associations of pre-ICI and post-ICI sodium levels with overall survival (OS), progression-free survival (PFS), objective response rate, and disease control rate (DCR). The Kaplan-Meier method was used to estimate PFS and OS, and differences between groups were compared using the log-rank test. Results: A total of 401 patients with mRCC receiving nivolumab as second-line therapy were evaluated, and 355 eligible patients (median [range] age, 76 [44-84] years; 258 male patients [72.7%]) were included in the final cohort. Among patients with pre-ICI sodium greater than or equal to 140 mEq/L compared with those with sodium less than 140 mEq/L, the median PFS was 9.3 months (95% CI, 6.5-11.5 months) vs 7.4 months (95% CI, 4.6-10.1 months; P = .90), and the median OS was 29.2 months (95% CI, 21.8-35.9 months) vs 20.0 months (95% CI, 14.1-26.8 months; P = .03). Patients with post-ICI sodium values greater than or equal to 140 mEq/L had longer PFS (11.1 months [95% CI, 8.5-1.5 months] vs 5.1 months [95% CI, 4.1-7.5 months]; P = .01) and OS (32.9 months [95% CI, 25.1-42.6 months] vs 17.1 months [95% CI, 12.6-24.5 months]; P = .006) compared with patients with sodium values less than 140 mEq/L. Patients with both pre-ICI and post-ICI sodium values greater than or equal to 140 mEq/L exhibited a significant improvement in clinical outcomes compared with those with a value less than 140 mEq/L (PFS, 11.5 months [95% CI, 8.8-16.4 months] vs 5.8 months [95% CI, 4.4-8.3 months]; P = .008); OS, 37.6 months [95% CI, 29.0-49.9 months] vs 19.4 months [95% CI, 14.1-24.5 months]; P = .01). Moreover, sodium levels greater than or equal to 140 mEq/L were associated with significantly better DCR than lower sodium levels. Conclusions and Relevance: In this retrospective cohort study of patients with mRCC receiving nivolumab, sodium values greater than or equal to 140 mEq/L, both before and/or after ICI, were associated with better OS and PFS, as well as a higher DCR, compared with levels less than 140 mEq/L. These findings suggest that sodium levels may be associated with survival outcomes in patients with mRCC and may have potential use as variables to consider in patients' risk scores.

Oral selective estrogen receptor degraders (SERDs): The new emperors in breast cancer clinical practice?

Endocrine therapy (ET) targeting estrogen receptor (ER) signaling is still the mainstay treatment option for early or advanced ER-positive breast cancer (BC) and may involve suppressing estrogen production by means of aromatase inhibitors or directly blocking the ER pathway through selective estrogen receptor modulators such as tamoxifen or selective estrogen receptor degraders such as fulvestrant. However, despite the availability of this armamentarium in clinical practice, de novo or acquired resistance to ET is the main cause of endocrine-based treatment failure leading to the progression of the BC. Recent advances in targeting, modulating, and degrading ERs have led to the development of new drugs capable of overcoming intrinsic or acquired ET resistance related to alterations in the ESR1 gene. The new oral selective estrogen receptor degraders, which are capable of reducing ER protein expression and blocking estrogen-dependent and -independent ER signaling, have a broader spectrum of activity against ESR1 mutations and seem to be a promising means of overcoming the failure of standard ET. The aim of this review is to summarize the development of oral selective estrogen receptor degraders, their current status, and their future perspectives.

Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study.

BACKGROUND: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. METHODS: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. CONCLUSIONS: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.

Integrating Red Blood Cell Features and Hemoglobin Levels in Metastatic Renal Cell Carcinoma Patients Treated with Pazopanib or Cabozantinib: An Easily Exploitable Prognostic Score.

BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has revolutionized the metastatic renal cell carcinoma (mRCC) therapeutic landscape. Nevertheless, tyrosine-kinase inhibitors (TKIs) targeting the vascular endothelial growth factor (VEGF) axis still play a key role. The aim of the present study was to explore the prognostic performance of an integrated blood score, based on hemoglobin (Hb) concentration, mean corpuscular volume (MCV), and red cell distribution width (RDW), in mRCC patients treated with anti-VEGF TKIs. The primary endpoint was to correlate Hb, MCV, and RDW with progression-free survival (PFS) and overall survival (OS). MATERIALS AND METHODS: Our multicenter retrospective observational study involved mRCC patients treated with pazopanib or cabozantinib from January 2012 to December 2020 in nine Italian centers. Clinical records and laboratory data, including Hb levels, MCV, and RDW, were collected at baseline. Descriptive statistics and univariate and multivariate analyses were performed. RESULTS: We enrolled 301 mRCC patients of which 179 (59%) underwent pazopanib, and 122 (41%) cabozantinib. We considered baseline Hb ≥12 g/dL, MCV >87 fL, and RDW ≤16% as good prognostic factors; hence, developing a multiparametric score capable of delineating 4 different categories. The number of good prognostic factors was associated with significantly longer PFS and OS (p < 0.001 for both). Therefore, we developed a red blood cell-based score by stratifying cases into two groups (2-3 versus 0-1, good factors). The impact on PFS and OS was even more striking (median PFS (mPFS): 16.3 vs 7.9 months; median OS (mOS): 33.7 vs 14.1 months)), regardless of the TKI agent. When challenged with univariate and multivariate analysis, the blood score maintained its high prognostic significance in terms of OS (multivariate analysis HR for OS: 0.53, 95% CI 0.39-0.75; p < 0.001, respectively), while the impact on PFS resulted in borderline significance. CONCLUSIONS: Our analyses demonstrate the prognostic role of a multiparametric score based on easily exploitable blood parameters, such as Hb concentration, MCV, and RDW. The red blood cell-based score may underlie the upregulation of the HIF-1α pathway and VEGF axis, thereby identifying a selected population who is likely to benefit from TKI therapy.

Geographical differences in the management of metastatic de novo renal cell carcinoma in the era of immune-combinations.

BACKGROUND: The upfront treatment of metastatic renal cell carcinoma (mRCC) has been revolutionized by the introduction of immune-based combinations. The role of cytoreductive nephrectomy (CN) in these patients is still debated. The ARON-1 study (NCT05287464) was designed to globally analyze real-world data of mRCC patients receiving first-line immuno-oncology combinations. This sub-analysis is focused on the role of upfront or delayed partial or radical CN in three geographical areas (Western Europe, Eastern Europe, America/Asia). METHODS: We conducted a multicenter retrospective observational study in mRCC patients treated with first-line immune combinations from 55 centers in 19 countries. From 1152 patients in the ARON-1 dataset, we selected 651 patients with de novo mRCC. 255 patients (39%) had undergone CN, partial in 14% and radical in 86% of cases; 396 patients (61%) received first-line immune-combinations without previous nephrectomy. RESULTS: Median overall survival (OS) from the diagnosis of de novo mRCC was 41.6 months and not reached (NR) in the CN subgroup and 24.0 months in the no CN subgroup, respectively (P<0.001). Median OS from the start of first-line therapy was NR in patients who underwent CN and 22.4 months in the no CN subgroup (P<0.001). Patients who underwent CN reported longer OS compared to no CN in all the three geographical areas. CONCLUSIONS: No significant differences in terms of patients' outcome seem to clearly emerge, even if the rate CN and the choice of the type of first-line immune-based combination varies across the different Cancer Centers participating in the ARON-1 project.

The role of mean corpuscular volume and red cell distribution width in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors: the MARECAP retrospective study.

Background: Tyrosine-kinase inhibitors (TKIs) and immunotherapy represent the backbone treatment for metastatic renal cell carcinoma (mRCC) patients. The aim of the present study was to describe mean corpuscular volume (MCV) and red cell distribution width (RDW) in mRCC patients treated with pazopanib or cabozantinib, and to explore their potential impact on oncological outcomes. Materials and methods: We conducted a multicenter retrospective observational study in mRCC patients treated with pazopanib or cabozantinib between January 2012 and December 2020 in nine Italian centers. Descriptive statistics, univariate, and multivariate analyses were performed. Objectives: The primary endpoints were the incidence and trend over time of anemia, macrocytosis (elevated MCV), and anisocytosis (elevated RDW). The secondary endpoints were the correlations of MCV and RDW with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: A total of 301 patients were enrolled; mean Hb value was 12.5 g/dl, a mean increase of 1 g/dl was observed at day 15 and maintained at 3 months. Most patients had baseline macrocytosis (MCV levels > 87 fl), with a significant mean increase after 3 months of treatment. At univariate analysis patients with macrocytosis had better ORR, longer PFS, and OS. About one third of patients had baseline anisocytosis (RDW > 16%), with a significant mean increase after 3 months of treatment. At univariate analysis, patients with RDW values ⩽ 16% had higher ORR, longer PFS, and OS. At multivariate analysis, baseline macrocytosis was significantly associated with better PFS in patients treated with pazopanib and baseline anisocytosis with shorter OS in all patients. Conclusions: mRCC patients treated with pazopanib or cabozantinib may have baseline macrocytosis and anisocytosis. A significant increase of Hb, MCV, and RDW after TKIs start was observed. Baseline macrocytosis is positively correlated with PFS in patients treated with pazopanib and baseline anisocytosis affects survival of patients treated with TKIs.