RESUMO
BACKGROUND: Immunotherapy has determined unprecedented long-term responses in several hematological and solid tumors. In the MOUSEION-03 study, we conducted a meta-analysis to determine the possibility of achieving complete remissions (CR) with immunotherapy or immuno-oncology combinations in cancer patients. METHODS: The primary endpoint was to assess the incidence of CR in cancer patients receiving immune checkpoint inhibitors (ICIs) alone or in combination with other agents versus control treatments. The pooled odds ratio (OR) and 95% confidence interval (CI) for CR rate were extracted. RESULTS: A total of 12,130 potentially relevant trials were identified; 5 phase II and 80 phase III randomized studies (37 monotherapies and 48 combinations) and 49,425 cancer patients were included. The most frequent types of malignancies were non-small cell lung cancer (n = 14,249; 29%), urothelial cancer (n = 6536; 13%), renal cell carcinoma (n = 5743; 12%), and melanoma (n = 2904; 6%). In patients treated with immunotherapy (as monotherapy or in combination with other anticancer agents), the pooled OR was 1.67 (1.52-1.84). The highest OR was registered by immune-based combinations with two ICIs (3.56, 95% CI 1.28-9.90). CONCLUSIONS: To the best of the authors' knowledge, no comprehensive meta-analysis on the use of ICIs and ICI-based combinations in solid tumors to systematically investigate the probability to achieve CR has been published so far. Although CR is not a common event in several cancer patients receiving immunotherapy, the MOUSEION-03 suggests that the use of ICIs may significantly increase the chance of achieving CR in comparison with control treatments.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Renais , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Antineoplásicos/uso terapêutico , Imunoterapia/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC. METHODS: Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study. RESULTS: Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD. CONCLUSIONS: Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting.
Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Masculino , Feminino , Humanos , Carcinoma de Células de Transição/patologia , Cisplatino/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMO
Triple-negative breast cancer (TNBC) is associated with a poor prognosis, due to its aggressive behaviour and lack of effective targeted therapies. Immunocheckpoint inhibitors, such as anti-programmed cell death 1 (PD-1) and anti-PD-ligand(L)1 agents, are in course of investigation in TNBC, used alone or in combination with other systemic or local approaches. However, the high cost of these drugs and the lack of validated predictive biomarkers support the development of strategies aimed to overcome resistance and optimize the efficacy of these approaches. Tumor-Associated Macrophages (TAMs) derive from peripheral blood monocytes recruited into the TNBC microenvironment and, in response to several stimuli, undergo M1 (classical) or M2 (alternative) activation. In TNBC, TAMs promote tumor growth and progression by several mechanisms that include the secretion of inhibitory cytokines, the reduction of effector functions of Tumor Infiltrating Lymphocytes (TILs) and the promotion of Regulatory T cell (Treg). Interestingly, TAMs have been shown to directly and indirectly modulate PD-1/PD-L1 expression in tumor environment. On this scenario, several TAM-centered strategies have been proposed, such as the suppression of TAM recruitment, the depletion of their number, the switch of M2 TAMs into antitumor M1 phenotype and the inhibition of TAM-associated molecules. In this review, we will illustrate the activity of TAMs and associated molecules in TNBC, focusing on their role in modulating the expression of PD-1/PD-L1 and on the emerging TAM-tailored strategies for TNBC patients.
Assuntos
Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Linfócitos do Interstício Tumoral/fisiologia , Macrófagos/fisiologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/terapia , Animais , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Humanos , Imunomodulação , Prognóstico , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologiaRESUMO
Aims: To capture the complex relationships between risk factors and cancer incidences in the US and predict future cancer burden. Materials & methods: Two artificial neural network (ANN) algorithms were adopted: a multilayer feed-forward network (MLFFNN) and a nonlinear autoregressive network with eXogenous inputs (NARX). Data on the incidence of the four most common tumors (breast, colorectal, lung and prostate) from 1992 to 2016 (available from National Cancer Institute online datasets) were used for training and validation, and data until 2050 were predicted. Results: The rapid decreasing trend of prostate cancer incidence started in 2010 will continue until 2018-2019; it will then slow down and reach a plateau after 2050, with several differences among ethnicities. The incidence of breast cancer will reach a plateau in 2030, whereas colorectal cancer incidence will reach a minimum value of 35 per 100,000 in 2030. As for lung cancer, the incidence will decrease from 50 per 100,000 (2017) to 31 per 100,000 in 2030 and 26 per 100,000 in 2050. Conclusion: This up-to-date prediction of cancer burden in the US could be a crucial resource for planning and evaluation of cancer-control programs.
Assuntos
Neoplasias/epidemiologia , História do Século XX , História do Século XXI , Humanos , Incidência , Neoplasias/história , Redes Neurais de Computação , Vigilância em Saúde Pública , Estados Unidos/epidemiologiaRESUMO
Prostate cancer is the most frequent malignancy in the worldwide male population; it is also one of the most common among all the leading cancer-related death causes. In the last two decades, the therapeutic scenario of metastatic castration-resistant prostate cancer has been enriched by the use of chemotherapy and androgen receptor signaling inhibitors (ARSI) and, more recently, by immunotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors. At the same time, several trials have shown the survival benefits related to the administration of novel ARSIs among patients with non-castration-resistant metastatic disease along with nonmetastatic castration-resistant cancer too. Consequently, the therapeutic course of this malignancy has been radically expanded, ensuring survival benefits never seen before. Among the more recently emerging agents, the so-called "antibody-drug conjugates" (ADCs) are noteworthy because of their clinical practice changing outcomes obtained in the management of other malignancies (including breast cancer). The ADCs are novel compounds consisting of cytotoxic agents (also known as the payload) linked to specific antibodies able to recognize antigens expressed over cancer cells' surfaces. As for prostate cancer, researchers are focusing on STEAP1, TROP2, PSMA, CD46 and B7-H3 as optimal antigens which may be targeted by ADCs. In this paper, we review the pivotal trials that have currently changed the therapeutic approach to prostate cancer, both in the nonmetastatic castration-resistant and metastatic settings. Therefore, we focus on recently published and ongoing trials designed to investigate the clinical activity of ADCs against prostate malignancy, characterizing these agents. Lastly, we briefly discuss some ADCs-related issues with corresponding strategies to overwhelm them, along with future perspectives for these promising novel compounds.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Imunoconjugados/farmacologia , Masculino , Terapia de Alvo Molecular , Prognóstico , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/etiologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Padrão de Cuidado , Resultado do TratamentoRESUMO
BACKGROUND: Breast cancer (BC) is the second most common type of cancer worldwide. Among targeted therapies for Hormone Receptor-positive (HR+) and Human Epidermal growth factor Receptor 2-negative (HER2-) BC, the Cyclin-Dependent Kinases (CDK4/6) are targeted by inhibitors such as Ribociclib (Rib); however, resistance to CDK4/6 inhibitors frequently develops. The aim of this work is to assess in vitro activity of Rib and Everolimus (Eve) in HR+HER2- MCF-7 and HR-HER2-BT-549 BC cell lines. METHODS: HR+HER2- MCF-7 and HR-HER2- BT-549 BC cell lines were treated with increasing concentration of Rib and Eve (up to 80 µg/mL) for 48-72 h. Subsequently, HR+HER2- MCF-7 cells were silenced for Retinoblastoma (Rb) gene, and thus, the effect of Rib in sequential or concurrent schedule with Eve for the treatment of both Rb wild type or Rb knock-down MCF-7 in vitro was evaluated. Cell viability of HR+HER2- MCF-7cells treated with sequential and concurrent dosing schedule was analyzed by MTT assay. Moreover, cell cycle phases, cell death and senescence were evaluated by cytofluorimetric analysis after treatment with Rib or Eve alone or in combination. RESULTS: The sequential treatment didn't produce a significant increase of cytotoxicity, compared to Rib alone. Instead, the cotreatment synergized to increase the cytotoxicity compared to Rib alone. The cotreatment reduced the percentage of cells in S and G2/M phases and induced apoptosis. Rib triggered senescence and Eve completely reversed this effect in Rb wild type BC cells. Rib also showed Rb-independent effects as shown by results in Rb knock-down MCF-7. CONCLUSION: Overall, the Rib/Eve concurrent therapy augmented the in vitro cytotoxic effect, compared to Rib/Eve sequential therapy or single treatments.
Assuntos
Aminopiridinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Everolimo/uso terapêutico , Células MCF-7/metabolismo , Purinas/uso terapêutico , Receptor ErbB-2/metabolismo , Aminopiridinas/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Everolimo/farmacologia , Feminino , Humanos , Purinas/farmacologiaRESUMO
One of the most attractive cancer-related genes under investigation is BAP1. Reasons of this growing interest are related to the wide spectrum of pathways directly or indirectly modulated by this gene and shared by several solid tumors. Programmed cell-death, cell metabolisms, immune cells development, ferroptosis and defects in DNA damage response are only some of the multitude of processes depending on BAP1. Loss of this gene seems to occur in different times of tumor history. Moreover, times of BAP1 loss strongly diverge among primary tumors suggesting the presence of several and different triggering factors. Regardless of when it happens, BAP1 loss usually results in prognosis worsening and in the acquisition of more aggressive clinical features by cancer cells.
Assuntos
Neoplasias/etiologia , Neoplasias/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Animais , Biomarcadores Tumorais , Suscetibilidade a Doenças , Meio Ambiente , Regulação Neoplásica da Expressão Gênica , Interação Gene-Ambiente , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/diagnóstico , Neoplasias/terapia , PrognósticoRESUMO
Obesity is a well-known risk factor for renal cell carcinoma (RCC) development. However, the RCC-obesity link has not been fully addressed when considering a comprehensive scenario starting from pathogenetic aspects through pathological issues up to the outcome of medical treatment. We therefore conducted an electronic PubMed search using keywords "obesity", "body mass index", "overweight", "renal cell carcinoma/kidney cancer", "medical treatment", "targeted therapy", and "immunotherapy/immune checkpoint inhibitors". The selected data supported a crosstalk between adipose tissue (adipocytes and other white adipose tissue cells) and cancer cells inducing several signaling pathways that finally stimulated angiogenesis, survival, and cellular proliferation. Accurate sampling of renal sinus fat correlated with a prognostic value. Retrospective clinical evidence in metastatic RCC patients with higher body mass index (BMI) and treated with targeted therapies and/or immune checkpoint inhibitors showed advantageous survival outcomes. Therefore, obesity may influence the course of RCC patients, although the interplay between obesity/BMI and RCC warrants a large prospective confirmation. We are therefore still far from determining a clear role of obesity as a prognostic/predictive factor in metastatic RCC patients undergoing targeted therapy and immunotherapy.
Assuntos
Carcinoma de Células Renais/complicações , Neoplasias Renais/complicações , Obesidade/complicações , Animais , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Humanos , Imunoterapia , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Terapia de Alvo Molecular , Obesidade/patologia , Prognóstico , Resultado do TratamentoRESUMO
PURPOSE: Recent development in anticancer therapies for breast carcinoma allowed an improvement in patients' survival, notwithstanding a parallel increase of cardiovascular morbidity. Cardiotoxicity of anticancer therapies represents a relevant problem due to its insidious onset and potentially irreversible cardiac damage. The aim of the present study was to test whether 2D speckle tracking analysis can help in predicting overt systolic dysfunction. METHODS: A "real world" cohort of 69 patients with breast carcinoma undergoing adjuvant and/or neo-adjuvant chemotherapy was tested 2D-speckle tracking analysis before the beginning of chemotherapy and every 3 months for 1 year. Clinical data, 12-lead ECGs, and lab tests were collected according to the same visit protocol. RESULTS: Over 1-year follow-up, 19 patients (27 %) developed cardiac dysfunction according to the CREC criteria, with an average onset time from enrolment of 6.8 months. A global longitudinal strain (GLS) threshold ≥-16 % at 3 months from chemotherapy was able to predict subsequent systolic dysfunction development with high sensitivity (80 %) and specificity (90 %) and a negative predictive value of 92 %. After the introduction of cardioprotective drugs, left ventricular ejection fraction (LVEF) progressively recovered, while alterations of GLS persisted at 1-year follow-up. CONCLUSIONS: Strain imaging with 2D speckle tracking allows the identification of patients at low-risk for chemotherapy-related systolic dysfunction and can help optimizing resources allocations and improving follow-up quality. GLS can also provide a more accurate prognostic index of resolved systolic dysfunction when compared to standard LVEF.
Assuntos
Neoplasias da Mama/complicações , Cardiotoxicidade/diagnóstico , Ecocardiografia Doppler em Cores/métodos , Idoso , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos ProspectivosRESUMO
BACKGROUND: There is a growing body of evidence that immune response plays a large role in cancer outcome. The neutrophil to lymphocyte ratio (NLR) has been used as a simple parameter of systemic inflammation in several tumors. The purpose was to investigate the association between pre-treatment NLR, disease-free survival and overall survival in patients with early triple negative breast cancer (TNBC). METHODS: We reviewed the records of patients with stage I-III TNBC at our Institution from 2006 to 2012. The association between pre-treatment NLR and survival was analyzed. The difference among variables was calculated by chi-square test. DFS and OS were estimated using Kaplan-Meier method. Cox analysis was performed to analyze clinical parameters for their prognostic relevance. RESULTS: A total of 90 patients were eligible. There was no significant correlation among pre-treatment NLR and various clinical pathological factors. Patients with NLR higher than 3 showed significantly lower DFS (p = 0.002) and OS (p = 0.009) than patients with NLR equal or lower than 3. The Cox proportional multivariate hazard model revealed that higher pre-treatment NLR was independently correlated with poor DFS and OS, with hazard ratio 5.15 (95% confidence interval [CI] 1.11-23.88, p = 0.03) and 6.16 (95% CI 1.54-24.66, p = 0.01) respectively. CONCLUSION: Our study suggests that pre-treatment NLR may be associated with DFS and OS patients with early TNBC. Further validation and a feasibility study are required before it can be considered for clinical use.
Assuntos
Carcinoma Ductal de Mama/imunologia , Linfócitos/imunologia , Neutrófilos/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Adulto , Idoso , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/secundário , Carcinoma Ductal de Mama/terapia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Contagem de Linfócitos , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapiaRESUMO
Extracellular vesicles (EVs) are small lipid particles secreted by almost all human cells into the extracellular space. They perform the essential function of cell-to-cell communication, and their role in promoting breast cancer progression has been well demonstrated. It is known that EVs released by triple-negative and highly aggressive MDA-MB-231 breast cancer cells treated with paclitaxel, a microtubule-targeting agent (MTA), promoted chemoresistance in EV-recipient cells. Here, we studied the RNA content of EVs produced by the same MDA-MB-231 breast cancer cells treated with another MTA, eribulin mesylate. In particular, we analyzed the expression of different RNA species, including mRNAs, lncRNAs, miRNAs, snoRNAs, piRNAs and tRNA fragments by RNA-seq. Then, we performed differential expression analysis, weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, and miRNA-target identification. Our findings demonstrate the possible involvement of EVs from eribulin-treated cells in the spread of chemoresistance, prompting the design of strategies that selectively target tumor EVs.
Assuntos
Neoplasias da Mama , Vesículas Extracelulares , Cetonas , MicroRNAs , Policetídeos de Poliéter , Humanos , Feminino , Neoplasias da Mama/patologia , MicroRNAs/genética , Furanos , Vesículas Extracelulares/metabolismoRESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) remains a clinically challenging subtype due to its aggressive nature and limited treatment options post-neoadjuvant failure. Historically, capecitabine has been the cornerstone of adjuvant therapy for TNBC patients not achieving a pathological complete response (pCR). However, the integration of new modalities such as immunotherapy and PARP inhibitors has prompted a re-evaluation of traditional post-neoadjuvant approaches. METHODS: This review synthesizes data from pivotal clinical trials and meta-analyses to evaluate the efficacy of emerging therapies in the post-neoadjuvant setting. We focus on the role of immune checkpoint inhibitors (ICIs), PARP inhibitors (PARPis), and antibody-drug conjugates (ADCs) alongside or in place of capecitabine in TNBC treatment paradigms. RESULTS: The addition of ICIs like pembrolizumab to neoadjuvant regimens has shown increased pCR rates and improved event-free survival, posing new questions about optimal post-neoadjuvant therapies. Similarly, PARPis have demonstrated efficacy in BRCA-mutated TNBC populations, with significant improvements in disease-free survival (DFS) and overall survival (OS). Emerging studies on ADCs further complicate the adjuvant landscape, offering potentially efficacious alternatives to capecitabine, especially in patients with residual disease after neoadjuvant therapy. DISCUSSION: The challenge remains to integrate these new treatments into clinical practice effectively, considering factors such as drug resistance, patient-specific characteristics, and socio-economic barriers. This review discusses the implications of these therapies and suggests a future direction focused on personalized medicine approaches in TNBC. CONCLUSIONS: As the treatment landscape for TNBC evolves, the role of capecitabine is being critically examined. While it remains a viable option for certain patient groups, the introduction of ICIs, PARPis, and ADCs offers promising alternatives that could redefine adjuvant therapy standards. Ongoing and future trials will be pivotal in determining the optimal therapeutic strategies for TNBC patients with residual disease post-neoadjuvant therapy.
Assuntos
Capecitabina , Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Capecitabina/uso terapêutico , Terapia Neoadjuvante/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Feminino , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêuticoRESUMO
BACKGROUND: About 20% of patients with renal cell carcinoma present with non-clear cell histology (nccRCC), encompassing various histological types. While surgery remains pivotal for localized-stage nccRCC, the role of cytoreductive nephrectomy (CN) in metastatic nccRCC is contentious. Limited data exist on the role of CN in metastatic nccRCC under current standard of care. OBJECTIVE: This retrospective study focused on the impact of upfront CN on metastatic nccRCC outcomes with first-line immune checkpoint inhibitor (IO) combinations or tyrosine kinase inhibitor (TKI) monotherapy. METHODS: The study included 221 patients with nccRCC and synchronous metastatic disease, treated with IO combinations or TKI monotherapy in the first line. Baseline clinical characteristics, systemic therapy, and treatment outcomes were analyzed. The primary objective was to assess clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Statistical analysis involved the Fisher exact test, Pearson's correlation coefficient, analysis of variance, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. RESULTS: Median OS for patients undergoing upfront CN was 36.8 (95% confidence interval [CI] 24.9-71.3) versus 20.8 (95% CI 12.6-24.8) months for those without CN (p = 0.005). Upfront CN was significantly associated with OS in the multivariate Cox regression analysis (hazard ratio 0.47 [95% CI 0.31-0.72], p < 0.001). In patients without CN, the median OS and PFS was 24.5 (95% CI 18.1-40.5) and 13.0 months (95% CI 6.6-23.5) for patients treated with IO+TKI versus 7.5 (95% CI 4.3-22.4) and 4.9 months (95% CI 3.0-8.1) for those receiving the IO+IO combination (p = 0.059 and p = 0.032, respectively). CONCLUSIONS: Our study demonstrates the survival benefits of upfront CN compared with systemic therapy without CN. The study suggests that the use of IO+TKI combination or, eventually, TKI monotherapy might be a better choice than IO+IO combination for patients who are not candidates for CN regardless of IO eligibility. Prospective trials are needed to validate these findings and refine the role of CN in current mRCC management.
Assuntos
Carcinoma de Células Renais , Procedimentos Cirúrgicos de Citorredução , Imunoterapia , Neoplasias Renais , Nefrectomia , Inibidores de Proteínas Quinases , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Estudos Retrospectivos , Masculino , Feminino , Nefrectomia/métodos , Pessoa de Meia-Idade , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Procedimentos Cirúrgicos de Citorredução/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Imunoterapia/métodos , Idoso , Adulto , Metástase Neoplásica , Idoso de 80 Anos ou maisRESUMO
The treatment of castration-sensitive prostate cancer (CSPC) has been revolutionized by the advent of apalutamide and enzalutamide in this setting; however, a direct comparison between these agents is still missing. In the current paper, we performed both Number Needed to Treat (NNT) and Number Needed to Harm (NNH) analyses aimed to compare clinical outcomes in CSPC patients treated with apalutamide or enzalutamide; data from 3323 CSPC patients enrolled in the ARCHES, ENZAMET and TITAN phase III studies were included. According to our results, apalutamide showed better results in terms of overall survival (OS) and safety in patients with CSPC, while better outcomes were observed with enzalutamide in the low-volume subgroup.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Tioidantoínas/uso terapêutico , CastraçãoRESUMO
INTRODUCTION: The androgen/androgen receptor (AR) axis represents a key driver of treatment resistance in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT) and targeted agents, and a deeper comprehension of resistance mechanisms is fundamental to adopt effective therapeutic strategies. AREAS COVERED: We review the mechanisms of primary or secondary resistance to hormone therapy (HT) in PCa, especially focusing on available data and emerging evidence. EXPERT OPINION: First- and second-generation HT resistance has been associated with several AR-dependent and AR-independent mechanisms, ranging from the amplification of the AR gene locus to somatic AR mutations and the intratumoral synthesis of androgens from adrenal steroids and cholesterol. As reported in the current review, the development of novel and effective treatments is needed to personalize anticancer therapies in this setting and to finally improve clinical outcomes in patients with HT-resistant disease.
Assuntos
Antineoplásicos , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Androgênios/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antagonistas de Androgênios/uso terapêutico , Receptores Androgênicos , Antineoplásicos/uso terapêutico , Resultado do Tratamento , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
This multicenter phase II trial was designed to evaluate the activity of lapatinib in metastatic breast cancer patients with HER2-negative primary tumors and HER2-positive circulating tumor cells (CTCs). In this study MBC patients with HER2-negative primary tumors and HER2-positive CTCs previously treated with at least a first-line therapy for metastatic disease received lapatinib 1500 mg/day. The CellSearch System® was used for CTCs isolation and bio-characterization. HER2 status was assessed on CTCs by immunofluorescence. A case was defined as CTCs positive if ≥2 CTC/7.5 ml of blood were isolated and HER2-positive if ≥50% of CTCs were HER2-positive. 139 HER2-negative patients were screened, 96 patients were positive for CTCs (mean number of CTCs: 85; median number of CTCs: 19; range 2-1637). Seven of the 96 patients (7%) had ≥50% HER2-positive CTCs and were eligible for treatment with lapatinib. No objective tumor responses occurred in this population. In one patient, disease stabilization lasting 254 days (8.5 months) was observed. From the findings of this study, we concluded that a subset of patients with a HER2-negative primary tumor presents HER2-positive CTCs during disease progression, although the HER2 shift rate seems to be lower than previously reported. Despite the lack of objective response, the durable disease stabilization observed in one patient cannot rule out the hypothesis that lapatinib may have some activity in this patient population. However, considering that only 1/139 screened patients may potentially have derived benefit from this approach, future trials designed according to the presented strategy cannot be recommended.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Células Neoplásicas Circulantes/metabolismo , Quinazolinas/uso terapêutico , Receptor ErbB-2/metabolismo , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/metabolismo , Carcinoma Lobular/secundário , Feminino , Humanos , Lapatinib , Pessoa de Meia-Idade , Quinazolinas/farmacologia , Resultado do TratamentoRESUMO
INTRODUCTION: Substantial paradigm shifts have been recently registered in metastatic renal cell carcinoma (mRCC), with combination therapies including immunotherapy showing unprecedented results. We performed number needed to treat (NNT) and number needed to harm (NNH) analyses to evaluate these approaches in mRCC. AREAS COVERED: Clinical data of mRCC patients enrolled in four phase III trials were collected. The rates at 6, 12, 18, and 24 months for overall survival (OS), duration of response (DoR), and progression-free survival (PFS) were considered. At 6 months, the number of patients that should be treated to prevent one death with sunitinib was 20 for both pembrolizumab-lenvatinib or axitinib, 14 for nivolumab-cabozantinib, and 50 for nivolumab-ipilimumab. NNT was 100 (at 6 months) or >100 (at 12 and 18 months) for nivolumab-ipilimumab. The combinations reported peculiar and not superimposable safety profiles at the NNH analysis. EXPERT OPINION: Although our results should be interpreted with caution, the analysis provides useful insight into the increasingly compelling interpretation of clinical trials. Immune combinations present clinically meaningful differences in terms of efficacy, with some treatments reporting different results at the NNT and the NNH analyses.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renais , Neoplasias Renais , Anilidas/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Axitinibe/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Ipilimumab/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Nivolumabe/efeitos adversos , Números Necessários para Tratar , Compostos de Fenilureia/efeitos adversos , Piridinas/efeitos adversos , Quinolinas/efeitos adversosRESUMO
The primary endpoint of MOUSEION-01 was to assess overall survival (OS) in male and female patients receiving immune checkpoint inhibitors versus control treatments, calculating the pooled OS Hazard Ratio (HR) and 95 % Confidence Interval (CI) in both groups. 37 randomized phase III studies and 22646 patients (16382 men and 6264 women) were included. In patients treated with immunotherapy (as monotherapy or in combination with other agents), the pooled OS HR was 0.78 (0.75-0.82) and 0.77 (95 % CI, 0.72-0.83) in male and female subjects, respectively. The pooled HR for OS in male patients treated with single-agent immunotherapy versus control was 0.77 (95 % CI, 0.70-0.85), while this benefit was smaller in female patients (HR, 0.81; 95 % CI, 0.73-0.9). Our findings highlight that high-quality trials accounting for potential confounders are needed before being able to suggest a real effect of the patient's gender on immune checkpoint inhibitors efficacy in different settings.