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The prognosis for patients with metastatic castration-resistant prostate cancer (mCRPC) varies, being influenced by blood-related factors such as transcriptional profiling and immune cell ratios. We aimed to address the contribution of distinct whole blood immune cell components to the prognosis of these patients. This study analyzed pre-treatment blood samples from 152 chemotherapy-naive mCRPC patients participating in a phase 2 clinical trial (NCT02288936) and a validation cohort. We used CIBERSORT-X to quantify 22 immune cell types and assessed their prognostic significance using Kaplan-Meier and Cox regression analyses. Reduced CD8 T-cell proportions and elevated monocyte levels were substantially connected with a worse survival. High monocyte counts correlated with a median survival of 32.2 months versus 40.3 months for lower counts (HR: 1.96, 95% CI 1.11-3.45). Low CD8 T-cell levels were associated with a median survival of 31.8 months compared to 40.3 months for higher levels (HR: 1.97, 95% CI 1.11-3.5). These findings were consistent in both the trial and validation cohorts. Multivariate analysis further confirmed the independent prognostic value of CD8 T-cell counts. This study highlights the prognostic implications of specific blood immune cells, suggesting they could serve as biomarkers in mCRPC patient management and should be further explored in clinical trials.
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INTRODUCTION: The administration of proton pump inhibitors (PPIs) is a common practice to reduce gastro-esophageal adverse events associated with drug treatments but may impair absorption and exposure to oncology drugs. This study investigated the effect of concomitant administration of PPIs and pazopanib, sunitinib and cabozantinib on survival of patients with metastatic clear cell renal carcinoma (mRCC). PATIENTS AND METHODS: Total 451 patients receiving pazopanib, sunitinib and cabozantinib as first line treatment were enrolled in this retrospective study. Patients were defined as "no concomitant PPIs (PPI-)" if no PPIs were administered during TKIs, and as "concomitant PPIs (PPI+)" if the administration of PPIs was at least 75% of the time during which TKIs were given. RESULTS: Eighty patients administered pazopanib were PPI- and 86 PPI+; no difference in PFS was observed (10.7 vs. 11.9 months, P = .79). If patients were stratified as short (n = 89) and long (n = 77) responders, there was a significant difference in terms of PFS in PPI+ (n = 47) versus PPI- (n = 30) in long responders, being 24.7 versus 38 months (P = .04), respectively. In the sunitinib cohort, no significant difference of PFS in PPI+ (n = 102) versus PPI- (n = 131) was found, being 11.3 versus 18.1 months, respectively (P=0.15). In the cabozantinib cohort, there was a statistically significant difference in PFS of PPI+ versus PPI- (6 months vs. not reached, P = .04). No correlation with adverse events was found. CONCLUSIONS: This study demonstrates an association between PPIs and impaired PFS in mRCC patients given pazopanib and cabozantinib and recommends caution on their concomitant use.
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Aberrations in the homologous recombination repair (HRR) pathway in prostate cancer (PCa) provide a unique opportunity to develop therapeutic strategies that take advantage of the reduced tumor ability to repair DNA damage. Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have been shown to prolong the survival of PCa patients with HRR defects, particularly in those with Breast Cancer type 1 susceptibility protein/Breast Cancer type 2 susceptibility protein alterations. To expand the benefit of PARPi to patients without detectable HRR alterations, multiple preclinical and clinical studies are addressing potential synergies between PARPi and androgen receptor signaling inhibitors, and these strategies are also being evaluated in combination with other drugs such as immune checkpoint inhibitors. However, the effectiveness of these combining therapies could be hindered by multiple mechanisms of resistance, including also the role played by the immunosuppressive tumor microenvironment. In this review, we summarize the use of PARPi in PCa and the potential synergies with different molecular pathways. However, numerous unanswered questions remain, including the identification of the patient population that could benefit most from PARPi, determining whether to use PARPi as monotherapy or in combination, and finding the optimal timing of PARPi, expanding the use of genomic tests, and optimizing combination therapies.
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DNA-damage repair (DDR) pathways alterations, a growing area of interest in oncology, are detected in about 20% of patient with prostate cancer and are associated with improved sensitivity to poly(ADP ribose) polymerases (PARP) inhibitors. In May 2020, the Food and Drug Administration (FDA) approved two PARP inhibitors (olaparib and rucaparib) for prostate cancer treatment. Moreover, germline aberrations in DDR pathways genes have also been related to familial or hereditary prostate cancer, requiring tailored health-care programs. These emerging scenarios are rapidly changing diagnostic, prognostic and therapeutic approaches in prostate cancer management. The aim of this review is to highlight the five W-points of DDR pathways in prostate cancer: why targeting DDR pathways in prostate cancer; what we should test for genomic profiling in prostate cancer; "where" testing genetic assessment in prostate cancer (germline or somatic, solid or liquid biopsy); when genetic testing is appropriate in prostate cancer; who could get benefit from PARP inhibitors; how improve patients outcome with combinations strategies.
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Dano ao DNA , Reparo do DNA , Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Reparo do DNA/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Dano ao DNA/efeitos dos fármacos , Terapia de Alvo Molecular/métodosRESUMO
Background: The treatment of heavily pretreated patients with metastatic renal cell carcinoma (mRCC) represents an unmet medical need and is still challenging. Objectives: The primary objective was to assess the effectiveness of the lenvatinib plus everolimus combination and the secondary objective was the toxicity profile of this combination. Design: We conducted a longitudinal retrospective study examining mRCC patients pre-treated with one or more lines of therapy among different cancer centers in Italy. Methods: The study included patients who received the combination of lenvatinib plus everolimus as either a second-line treatment or beyond. We assessed progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), response rate (RR), and toxicity profile. In addition, we explored the potential relationship between treatment effectiveness and clinical and laboratory parameters. Results: In all, 33 patients were assessed, the median age was 60 years, 57% had an Eastern Cooperative Oncology Group performance status of 1-2 and. 63% received ⩾ 3 prior lines of therapy. 62% were 'intermediate risk' according to the International Metastatic Renal Cell Carcinoma Database Consortium and 30% were 'poor risk'. The RR was 42% (no complete response), 18% stable disease. Median OS was 11.2 months (95% CI 6.8-19.9), median PFS was 6.7 months (95% CI 0.6-30.8), and median TTF was 6.7 months (95% CI 4.8-16.6). A shorter OS was significantly associated with lymph node metastases (p = 0.043, 95% CI), neutrophils/ lymphocytes ratio (NLR) ⩾ 3 (p = 0.007), hemoglobin/red cell distribution width ratio cutoff value <0.7 was significant (p = 0.03) while a shorter PFS was associated with lung (p = 0.048) and brain metastases (p = 0.023). The most frequent G1 toxicity was diarrhea (24%), G2 was fatigue (30%), and hypertension and skin toxicity (6%) for G3. Conclusion: Our findings suggest a clinically relevant effectiveness of lenvatinib plus everolimus combination with an acceptable toxicity profile for heavily pretreated patients with mRCC.
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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.
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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.
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BACKGROUND: PARP inhibitors (PARPis) are effective treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) as single agents or in combination with androgen receptor-targeted agents (ARTA). However, a clinically relevant adverse effect of these agents is hematological toxicity, a typical class adverse event (AE), which can lead to treatment modifications and discontinuations. OBJECTIVE: We aimed to analyze the risk of hematological AEs, including anemia, neutropenia, and thrombocytopenia secondary to PARPi treatments in mCRPC. PATIENTS AND METHODS: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. We systematically searched the PubMed, EMBASE, and Cochrane databases, the American Society of Clinical Oncology (ASCO), and the European Society of Medical Oncology (ESMO) meeting abstracts for clinical trials concerning the use of PARPis, both as single agents and in combination, in patients with mCRPC. The search deadline was 30 June, 2023. We analyzed the pooled incidence of all grades of and ≥ G3 anemia, neutropenia, and thrombocytopenia. We subsequently calculated risk ratios (RRs) for all grades of and ≥ G3 AEs of PARPis versus non-PARPis from randomized clinical trials (RCTs). RESULTS: Eleven phase 2/3 trials with olaparib, niraparib, rucaparib, and talazoparib administered as single agents or combined with ARTA were selected. Anemia was the most common all grades (38.6%) and ≥ G3 AE (24.9%). In the analysis of relative risk, six RCTs were included. The administration of PARPis significantly increased the risk of developing all grades of anemia (RR = 2.44), neutropenia (RR = 3.15), and thrombocytopenia (RR = 4.66) compared with non-PARPis. Similarly, a significant increase in the risk of ≥ G3 anemia (RR = 5.73) and thrombocytopenia (RR = 5.44), and a not significant increased risk of neutropenia (RR = 3.41), were detected. CONCLUSIONS: In mCRPC, PARPis increase the risk of hematological toxicity compared with other treatments, both as single agents or combined with ARTA (high-quality evidence). Clinicians should be aware of this risk and the correct management, especially with the expected increased PARPis use in mCRPC.
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Anemia , Neutropenia , Neoplasias de Próstata Resistentes à Castração , Trombocitopenia , Masculino , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Anemia/tratamento farmacológico , Anemia/epidemiologia , Mutação , Trombocitopenia/tratamento farmacológico , Trombocitopenia/epidemiologiaRESUMO
The main guidelines and recommendations for the implementation of the BRCA1/2 somatic test do not focus on the clinical application of predictive testing on bone metastases, a frequent condition in metastatic prostate cancer, by analyzing the critical issues encountered by laboratory practice. Our goal is to produce a document (protocol) deriving from a multidisciplinary team approach to obtain high quality nucleic acids from biopsy of bone metastases. This document aims to compose an operational check-list of three phases: the pre-analytical phase concerns tumor cellularity, tissue processing, sample preservation (blood/FFPE), fixation and staining, but above all the decalcification process, the most critical phase because of its key role in allowing the extraction of somatic DNA with a good yield and high quality. The analytical phase involves the preparation of the libraries that can be analyzed in various NGS genetic sequencing platforms and with various bioinformatics software for the interpretation of sequence variants. Finally, the post-analytical phase that allows to report the variants of the BRCA1/2 genes in a clear and usable way to the clinician who will use these data to manage cancer therapy with PARP Inhibitors.
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Proteína BRCA1 , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Proteína BRCA1/genética , Mutação , Proteína BRCA2/genética , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/genética , DNA , BiópsiaRESUMO
Despite remarkable progress in the last decade, metastatic prostate cancer (mPCa) remains incurable. The approval of PARP inhibitors (PARPis) represents a milestone in this field, which definitively enters the era of precision medicine, as mPCa is often enriched for defects of homologous recombination repair genes. PARPis are now used as single agents for patients with metastatic castration-resistant PCa. Moreover, combinations of PARPis plus androgen-receptor targeted agents and immune checkpoint inhibitors, and earlier applications of PARPis in the metastatic hormone-sensitive PCa are under evaluation, representing the possible upcoming applications of these agents. Mechanisms of sensitization and resistance have been only partially elucidated. In our review, we summarize the current clinical evidence regarding PARPis in mPCa and the future directions of these targeted agents.
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Antineoplásicos , Neoplasias da Próstata , Humanos , Antineoplásicos/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Medicina de Precisão , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
Intracranial metastases in prostate cancer are uncommon but clinically aggressive. A detailed molecular characterization of prostate cancer intracranial metastases would improve our understanding of their pathogenesis and the search for new treatment strategies. We evaluated the clinical and molecular characteristics of 36 patients with metastatic prostate cancer to either the dura or brain parenchyma. We performed whole genome sequencing (WGS) of 10 intracranial prostate cancer metastases, as well as WGS of primary prostate tumors from men who later developed metastatic disease (n = 6) and nonbrain prostate cancer metastases (n = 36). This first whole genome sequencing study of prostate intracranial metastases led to several new insights. First, there was a higher diversity of complex structural alterations in prostate cancer intracranial metastases compared to primary tumor tissues. Chromothripsis and chromoplexy events seemed to dominate, yet there were few enrichments of specific categories of structural variants compared with non-brain metastases. Second, aberrations involving the AR gene, including AR enhancer gain were observed in 7/10 (70%) of intracranial metastases, as well as recurrent loss of function aberrations involving TP53 in 8/10 (80%), RB1 in 2/10 (20%), BRCA2 in 2/10 (20%), and activation of the PI3K/AKT/PTEN pathway in 8/10 (80%). These alterations were frequently present in tumor tissues from other sites of disease obtained concurrently or sequentially from the same individuals. Third, clonality analysis points to genomic factors and evolutionary bottlenecks that contribute to metastatic spread in patients with prostate cancer. These results describe the aggressive molecular features underlying intracranial metastasis that may inform future diagnostic and treatment approaches.
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Up to 80% of castration-resistant prostate cancer (CRPC) patients develop bone metastases during the natural history of disease and about 25% harbor mutations in DNA damage repair (DDR) genes. This retrospective observational study evaluated the prevalence of DDR alterations in CRPC patients and their effect on the clinical outcomes associated with bone metastases. The mutational status of CRPC patients was analyzed per FoundationOne® analysis in tissue biopsy or, when it was not possible, in liquid biopsy performed at the onset of metastatic CRPC (mCRPC). The impact of DDR gene mutations on bone-related efficacy endpoints was evaluated at the time of mCRPC diagnoses. In total, 121 mCRPC patients with bone metastases were included: 38 patients had mutations in at least one DDR gene, the remaining 83 ones had a non-mutated DDR status. DDR mutated status was associated with bone metastases volume (p = 0.006), but did not affect SRE (skeletal-related events) incidence and time to SRE onset. Liquid and tissue biopsies were both available for 61 patients with no statistically significant difference in terms of incidence and type of molecular DDR alterations. Mutated DDR status was associated with higher bone metastasic volume, although a not detrimental effect on the other bone-related efficacy endpoints was observed.
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Neoplasias Ósseas , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Mutação , Osso e Ossos/patologia , Reparo do DNA/genéticaRESUMO
Prostate cancer is the most commonly diagnosed cancer but the management of advanced prostate cancer remains a therapeutic challenge, despite the survival benefits imparted by several therapeutic discoveries targeting different molecular pathways. The mechanisms of resistance to androgen deprivation and tumour progression to lethal metastatic variants are often regulated by androgen receptor (AR) bypass mechanisms and/or neuroendocrine differentiation. Moreover, recent data also suggested the involvement of adaptive and innate infiltrated immune cells in prostate tumour progression. Improvements in cancer genome analyses contributed to a better understanding of antitumour immunity and provided solutions for targeting highly cancer-specific neoantigens generated from somatic mutations in individual patients. In this review, we investigated the current knowledge on the interplay between cancer development and the complex mechanisms of immune regulation. Particularly, we focused on the role of tumour immune microenvironment, generally characterised by strong barriers for immunotherapy, and we discuss the rationale for the potential application of single agent and combination immune-targeting strategies that could lead to improved outcomes. Careful selection based on clinical and genomic factors may allow identification of patients who could benefit from this treatment approach in multiple settings (from localised to advanced prostate tumour) and in different histological subtypes (from adenocarcinoma to neuroendocrine prostate cancer).
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Adenocarcinoma , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Antagonistas de Androgênios/uso terapêutico , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: At diagnosis, more than 80% of patients with pancreatic cancer (PC) suffer from significant weight loss due to malnutrition which is a major concern for patient management, and this may negatively impact treatment outcomes and patient prognosis. PATIENTS AND METHODS: We performed an observational, retrospective study on patients with metastatic PC (mPC) undergoing first-line chemotherapy with nab-Paclitaxel containing schedules and receiving or not receiving nutritional support (NS) and pancreatic enzyme replacement therapy (PERT) to investigate their relevance in this setting. RESULTS: We observed that PERT and ancillary dietary interventions are related to longer overall survival (OS; median: 16.5 vs. 7.5 months, P < .001) and have a significant, independent, prognostic impact for better outcomes (P = .013), independently from the therapeutic regimen. Furthermore, PERT and NS prevented weight loss during chemotherapy and obtained an improvement of nutritional parameters such as phase angle and free-fat mass index, after 3 months of anticancer treatment. Consistently, the positive impact on OS correlated also with the prevention of Karnofsky performance status deterioration and a lower incidence of maldigestion-related symptoms. CONCLUSIONS: Our data suggest that an early and well-conducted NS in patients with mPC may impact on survival and preserve performance status, thus improving quality of life.
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Gencitabina , Neoplasias Pancreáticas , Humanos , Desoxicitidina , Estudos Retrospectivos , Qualidade de Vida , Neoplasias Pancreáticas/patologia , Apoio Nutricional , Paclitaxel/efeitos adversos , Redução de Peso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , AlbuminasRESUMO
PURPOSE: Patients with neuroendocrine prostate cancer (NEPC) are often managed with immunotherapy regimens extrapolated from small-cell lung cancer (SCLC). We sought to evaluate the tumor immune landscape of NEPC compared with other prostate cancer types and SCLC. EXPERIMENTAL DESIGN: In this retrospective study, a cohort of 170 patients with 230 RNA-sequencing and 104 matched whole-exome sequencing data were analyzed. Differences in immune and stromal constituents, frequency of genomic alterations, and associations with outcomes were evaluated. RESULTS: In our cohort, 36% of the prostate tumors were identified as CD8+ T-cell inflamed, whereas the remaining 64% were T-cell depleted. T-cell-inflamed tumors were enriched in anti-inflammatory M2 macrophages and exhausted T cells and associated with shorter overall survival relative to T-cell-depleted tumors (HR, 2.62; P < 0.05). Among all prostate cancer types in the cohort, NEPC was identified to be the most immune depleted, wherein only 9 out of the 36 total NEPC tumors were classified as T-cell inflamed. These inflamed NEPC cases were enriched in IFN gamma signaling and PD-1 signaling compared with other NEPC tumors. Comparison of NEPC with SCLC revealed that NEPC had poor immune content and less mutations compared with SCLC, but expression of checkpoint genes PD-L1 and CTLA-4 was comparable between NEPC and SCLC. CONCLUSIONS: NEPC is characterized by a relatively immune-depleted tumor immune microenvironment compared with other primary and metastatic prostate adenocarcinoma except in a minority of cases. These findings may inform development of immunotherapy strategies for patients with advanced prostate cancer.
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Carcinoma Neuroendócrino , Tumores Neuroendócrinos , Neoplasias da Próstata , Masculino , Humanos , Estudos Retrospectivos , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Neoplasias da Próstata/patologia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/terapia , Tumores Neuroendócrinos/metabolismo , Carcinoma Neuroendócrino/patologia , Microambiente Tumoral/genéticaRESUMO
Ovarian cancer is a highly lethal gynecological malignancy. Drug resistance rapidly occurs, and different therapeutic approaches are needed. So far, no biomarkers have been discovered to predict early response to therapies in the case of multi-treated ovarian cancer patients. The aim of our investigation was to identify a protein panel and the molecular pathways involved in chemotherapy response through a combination of studying proteomics and network enrichment analysis by considering a subset of samples from a clinical setting. Differential mass spectrometry studies were performed on 14 serum samples from patients with heavily pretreated platinum-resistant ovarian cancer who received the FOLFOX-4 regimen as a salvage therapy. The serum was analyzed at baseline time (T0) before FOLFOX-4 treatment, and before the second cycle of treatment (T1), with the aim of understanding if it was possible, after a first treatment cycle, to detect significant proteome changes that could be associated with patients responses to therapy. A total of 291 shared expressed proteins was identified and 12 proteins were finally selected between patients who attained partial response or no-response to chemotherapy when both response to therapy and time dependence (T0, T1) were considered in the statistical analysis. The protein panel included APOL1, GSN, GFI1, LCATL, MNA, LYVE1, ROR1, SHBG, SOD3, TEC, VPS18, and ZNF573. Using a bioinformatics network enrichment approach and metanalysis study, relationships between serum and cellular proteins were identified. An analysis of protein networks was conducted and identified at least three biological processes with functional and therapeutic significance in ovarian cancer, including lipoproteins metabolic process, structural component modulation in relation to cellular apoptosis and autophagy, and cellular oxidative stress response. Five proteins were almost independent from the network (LYVE1, ROR1, TEC, GFI1, and ZNF573). All proteins were associated with response to drug-resistant ovarian cancer resistant and were mechanistically connected to the pathways associated with cancer arrest. These results can be the basis for extending a biomarker discovery process to a clinical trial, as an early predictive tool of chemo-response to FOLFOX-4 of heavily treated ovarian cancer patients and for supporting the oncologist to continue or to interrupt the therapy.
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BACKGROUND: Immunotherapy has not achieved improvement of survival in prostate cancer patients. Myeloid-derived suppressor cells (MDSCs) in tumor microenvironment can hamper its efficacy. Some preclinical studies explored the role of MDSCs in prostate cancer development. We aimed to verify the availability of studies exploring the prognostic effect of circulating MDSCs in prostate cancer patients. METHODS: We systematically selected studies for a meta-analysis, which compares survival between prostate cancer patients with high vs low circulating MDSC levels. We extracted or calculated hazard ratios (HRs) and relative 95% confidence intervals (CIs) in terms of overall survival (OS) from selected studies. We calculated the pooled HR and relative 95% CIs and estimated publication bias. RESULTS: Among 133 studies retrieved from search on Pubmed, 5 eligible studies (236 prostate cancer patients) met inclusion criteria. High circulating MDSC levels are associated with a worse OS (HR = 2.19; 95%CI = 1.51-3.17). Heterogeneity was not significant (I2 = 0%; p = 0.64). Publication bias was also not significant (Egger's test, p = 0.09). CONCLUSIONS: High levels of circulating MDSCs induce a worse OS in prostate cancer patients than in those with low levels. This finding supports the importance of MDSC detection and targeting also in prostate cancer patients.
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Células Supressoras Mieloides , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/patologia , Células Supressoras Mieloides/patologia , Prognóstico , Imunoterapia , Microambiente TumoralRESUMO
Simple summary: Low-grade serous ovarian cancer (LGSOC) represents an uncommon histotype of serous ovarian cancer (accounting for approximately 5% of all ovarian cancer) with a distinct behavior compared to its high-grade serous counterpart, characterized by a better prognosis and low response rate to chemotherapeutic agents. Similar to high-grade serous ovarian cancer, cytoreductive surgery is considered crucial for patient survival. This retrospective study aimed to analyze the outcomes of women affected by advanced stages (III-IV FIGO) of LGSOC from two high-volume oncological centers for ovarian neoplasm. In particular, we sought to evaluate the impact on survival outcomes of optimal cytoreductive surgery [i.e., residual disease (RD) <10 mm at the end of surgery]. The results of our work confirm the role of complete cytoreduction (i.e., no evidence of disease after surgery) in the survival of patients and even the positive prognostic role of a minimal RD (i.e., <10 mm), whenever complete cytoreduction cannot be achieved. Background: Low-grade serous ovarian cancer (LGSOC) is a rare entity with different behavior compared to high-grade serous (HGSOC). Because of its general low chemosensitivity, complete cytoreductive surgery with no residual disease is crucial in advanced stage LGSOC. We evaluated the impact of optimal cytoreduction on survival outcome both at first diagnosis and at recurrence. Methods: We retrospectively studied consecutive patients diagnosed with advanced LGSOCs who underwent cytoreductive surgery in two oncological centers from January 1994 to December 2018. Survival curves were estimated by the Kaplan-Meier method, and 95% confidence intervals (95% CI) were estimated using the Greenwood formula. Results: A total of 92 patients were included (median age was 47 years, IQR 35-64). The median overall survival (OS) was 142.3 months in patients with no residual disease (RD), 86.4 months for RD 1-10 mm and 35.2 months for RD >10 mm (p = 0.002). Progression-free survival (PFS) was inversely related to RD after primary cytoreductive surgery (RD = 0 vs RD = 1-10 mm vs RD >10 mm, p = 0.002). On multivariate analysis, RD 1-10 mm (HR = 2.30, 95% CI 1.30-4.06, p = 0.004), RD >10 mm (HR = 3.89, 95% CI 1.92-7.88, p = 0.0004), FIGO stage IV (p = 0.001), and neoadjuvant chemotherapy (NACT) (p = 0.010) were independent predictors of PFS. RD >10 mm (HR = 3.13, 95% CI 1.52-6.46, p = 0.004), FIGO stage IV (p <0.0001) and NACT (p = 0.030) were significantly associated with a lower OS. Conclusions: Optimal cytoreductive surgery improves survival outcomes in advanced stage LGSOC s . When complete debulking is impossible, a RD <10 mm confers better OS compared to an RD >10 mm in this setting of patients.