RESUMO
Despite continued research, pancreatic ductal adenocarcinoma (PDAC) remains one of the main causes of cancer death. Interest is growing in the role of the tumour suppressors breast cancer 1 (BRCA1) and BRCA2-typically associated with breast and ovarian cancer-in the pathogenesis of PDAC. Indeed, both germline and sporadic mutations in BRCA1/2 have been found to play a role in the development of PDAC. However, data regarding BRCA1/2-mutant PDAC are lacking. In this review, we aim to outline the specific landscape of BRCA-mutant PDAC, focusing on heritability, clinical features, differences between BRCA1 and 2 mutations and between germline and sporadic alterations, as well as established therapeutic strategies and those that are still under evaluation.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Mutação , Medicina de PrecisãoRESUMO
BACKGROUND: The data from randomised trials suggested that primary tumour sidedness could represent a prognostic and predictive factor in colorectal cancer (CRC) patients, particularly during treatment with anti-epidermal growth factor receptor (EGFR) therapy. However, an in-deep molecular selection might overcome the predictive role of primary tumour location in this setting. METHODS: We conducted a retrospective analysis in which tumour samples from RAS/BRAF wild-type (WT) metastatic CRC patients treated with second-third-line irinotecan/cetuximab were analysed for EGFR gene copy number (GCN) and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Median follow-up duration was 14.3 months. RESULTS: Eighty-eight patients were included in the study, 27.3% had right-sided CRC, 72.7% had left-sided CRC; 36.4% had EGFR GCN<2.12 tumour, 63.6% had EGFR GCN⩾2.12 tumour; 50% had EGFR promoter-methylated tumour. Right-sided colorectal cancer (RSCRC) were associated with reduced overall response rate (ORR) (4.2% for RSCRC vs 35.9% for left sided colorectal cancer (LSCRC), P=0.0030), shorter progression-free survival (PFS) (3.0 vs 6.75 months, P<0.0001) and shorter overall survival (OS) (8 vs 13.6 months, P<0.0001). EGFR GCN<2.12 tumours were associated with reduced ORR (6.2% for EGFR GCN<2.12 vs 39.3% for EGFR GCN⩾2.12 tumours, P=0.0009), shorter PFS (3.5 vs 6.5 months, P=0.0006) and shorter OS (8.5 vs 14.0 months, P<0.0001). Epidermal growth factor receptor-methylated tumours were associated with reduced ORR (9.1% for methylated vs 45.5% for unmethylated, P=0.0001), shorter PFS (3 vs 7.67 months, P<0.0001) and shorter OS (8 vs 17 months, P<0.0001). At multivariate analysis, EGFR GCN and EGFR promoter methylation maintained their independent role for ORR (respectively P=0.0082 and 0.0025), PFS (respectively P=0.0048 and<0.0001) and OS (respectively P=0.0001 and<0.0001). CONCLUSIONS: In our study, an accurate molecular selection based on an all RAS and BRAF analysis along with EGFR GCN and EGFR promoter methylation status seems to be more relevant than primary tumour sidedness in the prediction of clinical outcome during cetuximab/irinotecan therapy. However, these data need to be validated with future prospective and translational studies.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Metilação de DNA , Dosagem de Genes , Genes erbB-1 , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab/administração & dosagem , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , DNA de Neoplasias/análise , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Genes ras/genética , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Metástase Neoplásica , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas B-raf/genética , Retratamento , Estudos Retrospectivos , Taxa de SobrevidaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Continuidade da Assistência ao Paciente , Medicina de Precisão/métodos , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Humanos , Terapia de Alvo Molecular/métodos , Metástase Neoplásica , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Hormone receptor (HR)-positive/HER2-positive breast cancer represents a distinct subtype expressing estrogen and progesterone receptors with an overexpression of HER2. Approximately 14% of female breast cancer cases are HER2-positive, with the majority being HR-positive. These tumors show a cross-talk between the hormonal and HER2 pathways; the interaction has implications for the treatment options for the disease. In this review, we analyze the biology of HR-positive/HER2-positive breast cancer and summarize the evidence concerning the standard of care options both in neoadjuvant/adjuvant settings and in advanced disease. Additionally, we focus on new trials and drugs for HR-positive/HER2-positive breast cancer and the new entity: HER2-low breast cancer.
RESUMO
BACKGROUND: Preclinical and clinical data indicate that p53 expression might modulate the activity of the epidermal growth factor receptor (EGFR), influencing response/resistance to anti-EGFR monoclonal antibodies. However, the association between p53 status and clinical outcome has not been clarified yet. OBJECTIVE: In our study, we evaluated the role of p53 expression in patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) receiving irinotecan/cetuximab in an exploratory and a validation cohort. PATIENTS AND METHODS: p53 expression was analysed in patients with RAS/BRAF wild-type mCRC receiving second-line or third-line irinotecan/cetuximab. Survival distribution was assessed by the Kaplan-Meier method, while the log-rank test was used for survival comparison. RESULTS: Among 120 patients with RAS/BRAF wild-type mCRC included in our analysis, 52 (59%) and 19 (59%) patients showed p53 overexpression in the exploratory and validation cohort, respectively. In the exploratory cohort, low p53 expression was correlated with better median progression-free survival (hazard ratio 0.39; p < 0.0001), median overall survival (hazard ratio: 0.23; p < 0.0001) and response rate (p < 0.0001). These results were confirmed by data of the validation cohort where we observed better median progression-free survival (hazard ratio: 0.48; p = 0.0399), median overall survival (hazard ratio: 0.26; p = 0.0027) and response rate (p =0.0007) in patients with p53 normal expression mCRC. CONCLUSIONS: In our study, p53 overexpression was associated with anti-EGFR treatment resistance in patients with RAS/BRAF WT mCRC, as confirmed in a validation cohort. Larger studies are needed to validate the role of p53 and investigate EGFR cross-talk in these patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Irinotecano/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cetuximab/farmacologia , Feminino , Humanos , Irinotecano/farmacologia , Masculino , Pessoa de Meia-Idade , Metástase NeoplásicaRESUMO
INTRODUCTION: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated and the role of antidiabetic medications such as metformin has also been investigated. The objective of this study was to examine the association between insulin use and overall survival (OS) in patients with advanced PDAC and DM2. METHODS: We retrospectively collected data from 164 patients, including an exploratory cohort of 96 patients from Medical Oncology Unit, University Hospital and University of Cagliari, Italy, and a validation cohort of 68 patients from Medical Oncology of Modena University Hospital. Patients had metastatic disease and received a first-line gemcitabine-based chemotherapy and, subsequently, a second-line fluoropyrimidines-based chemotherapy. We performed univariate analysis to evaluate correlation between long-term diabetes and overall survival. Then we performed multivariate analysis, adjusting for sex, metastatic sites, Eastern Cooperative Oncology Group Performance Status, Ca19.9 levels, N/L ratio, and lactate dehydrogenase levels at diagnosis, to confirm the independence of the variable. RESULTS: In the exploratory cohort, DM2 was significantly associated with higher median OS at univariate analysis (16 vs 10 months; p = 0.004). This result was confirmed by validation cohort (11 months vs 6 months; p = 0.01). In multivariate analysis, insulin-treated patients compared with non diabetic patients showed a significantly increased survival of 4.6 months (p = 0.03). CONCLUSIONS: Patients with insulin-treated metastatic PDAC showed better OS than non diabetic patients, as demonstrated by both cohorts. The correlation between OS and insulin-treated DM2 should be investigated further through a prospective clinical trial.
Assuntos
Carcinoma Ductal Pancreático/complicações , Carcinoma Ductal Pancreático/mortalidade , Diabetes Mellitus Tipo 2/complicações , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/epidemiologia , Carcinoma Ductal Pancreático/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/patologia , Prognóstico , Vigilância em Saúde Pública , Estudos Retrospectivos , Análise de Sobrevida , Neoplasias PancreáticasRESUMO
The listing of the author names and affiliations, which previously read.
RESUMO
BACKGROUND: Sorafenib represents one of the therapeutic strongholds for advanced hepatocellular carcinoma (HCC), but unfortunately, predictive factors are lacking. We previously reported that the VEGF single nucleotide polymorphisms (SNPs) rs2010963 and rs4604006 might correlate with clinical outcomes in sorafenib-treated HCC patients. OBJECTIVE: The objective of the ALICE-2 study is to define a prognostic angiogenesis profile to better identify HCC patients who are more likely to benefit from sorafenib treatment. PATIENTS AND METHODS: From 2008 to 2015, all consecutive HCC patients receiving sorafenib according to the Italian label were tested for specific HIF-1α, VEGF, and VEGFR SNPs. Results from angiogenesis genotyping were then correlated with clinical outcome parameters. RESULTS: Globally, a total of 210 patients were enrolled. At multivariate analysis rs12434438 of HIF1α, rs2010963 of VEGF-A, and rs4604006 of VEGF-C were confirmed as independent predictive factors. At the combined analysis of significant SNPs, the presence of two favourable alleles of rs2010963 and rs4604006 of VEGF compared to only one or to none favourable alleles, was able to identify three separate patients populations with different time-to-progression (TTP) (10.8 vs. 5.6 vs. 3.7 months, respectively; p < 0.0001) and overall survival (OS) (19.0 vs. 13.5 vs. 7.5 months, respectively; p < 0.0001). Furthermore, the presence of the GG genotype of rs12434438 (HIF-1α) seemed able to select a population with a particularly poor outcome, independently from the clinical effect of the two VEGF SNPs (TTP: 2.6 months, HR: 0.54, p = 0.0374; OS: 6.6 months, p = 0.0061, HR: 0.43). CONCLUSIONS: Our findings show that polymorphism analysis of HIF-1α, VEGF, and VEGFR genes may represent a prognostic panel to better identify HCC patients who are more likely to benefit from sorafenib treatment.
Assuntos
Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/genética , Feminino , Genótipo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Estudos Retrospectivos , Sorafenibe/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Metastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients. METHODS: A review of clinical trials, retrospective studies and case reports was performed regarding molecular biomarkers with therapeutic implications. RESULTS: RAS wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of RAS status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for BRAFV600E mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (POLE-1) mutant patients. Data are still lacking on NTRK, RET, MGMT, and TGF-ß, which require further research. CONCLUSION: Several molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients.
RESUMO
BACKGROUND: In the last decade, a series of analyses failed to identify predictive biomarkers of resistance/susceptibility for anti-angiogenic drugs in metastatic colorectal cancer (mCRC). We conducted an exploratory preplanned analysis of serum pro-angiogenic factors (SErum aNgiogenesis-cenTRAL) in 72 mCRC patients enrolled in the phase II CENTRAL (ColorEctalavastiNTRiAlLdh) trial, with the aim to identify potential predictive factors for sensitivity/resistance to first line folinic acid-fluorouracil-irinotecan regimen (FOLFIRI) plus bevacizumab. METHODS: First-line FOLFIRI/bevacizumab patients were prospectively assessed for the following circulating pro-angiogenic factors, evaluated with ELISA (enzyme-linked immunosorbent assay)-based technique at baseline and at every cycle: Vascular endothelial growth factor A (VEGF-A), hepatocyte growth factor (HGF), stromal derived factor-1 (SDF-1), placental derived growth factor (PlGF), fibroblast growth factor-2 (FGF-2), monocyte chemotactic protein-3 (MCP-3), interleukin-8 (IL-8). RESULTS: Changes in circulating FGF-2 levels among different blood samples seemed to correlate with clinical outcome. Patients who experienced an increase in FGF-2 levels at the second cycle of chemotherapy compared to baseline, had a median Progression Free Survival (mPFS) of 12.85 vs. 7.57 months (Hazard Ratio-HR: 0.73, 95% Confidence Interval-CI: 0.43-1.27, p = 0.23). Similar results were seen when comparing FGF-2 concentrations between baseline and eight-week time point (mPFS 12.98 vs. 8.00 months, HR: 0.78, 95% CI: 0.46-1.33, p = 0.35). CONCLUSIONS: Our pre-planned, prospective analysis suggests that circulating FGF-2 levels' early increase could be used as a marker to identify patients who are more likely to gain benefit from FOLFIRI/bevacizumab first-line therapy.
RESUMO
Pancreatic ductal adenocarcinoma (PDAC) is associated with poor survival. Of all newly diagnosed patients, only about 20% can benefit from a potentially curative surgical resection, the remaining 80% presenting with unresectable locally advanced (LAPC) or metastatic (MPC) disease. Currently, there are limited therapeutic options for LAPC and MPC patients. Furthermore, despite intensive research efforts to better understand the molecular bases of PDAC and the biological relevance of its tumor microenvironment, treatments still largely consist of classical cytotoxic chemotherapy agents. Several studies of genetic and epigenetic sequencing have demonstrated the existence of 4 molecular PDAC subtypes, with heterogeneous genetic characteristics and different biological behaviour: squamous, pancreatic progenitor, immunogenic and aberrantly differentiated endocrine exocrine (ADEX). These distinct subtypes derive from alterations at multiple levels. Apart from the DNA repair pathway, however, none of these has so far been validated as a clinically relevant therapeutic target. Also, PDAC is unique from an immunological perspective and many studies have recently tried to elucidate the role of intratumoral effector T-cells, RAS oncogene, immunosuppressive leukocytes and desmoplastic reaction in maintaining the immunological homeostasis of this disease. However, there still remains much to be learned about the mechanisms whereby the pancreatic immune microenvironment promotes immune escape of cancer cells. Furthermore, while therapies targeting the stroma as well as immunotherapies hold promise for the future, these are not yet standard of care. This review aims to outline the state-of-the-art of LAPC and MPC treatment, highlighting data on the target therapies failure and current ongoing clinical trials on new promising therapeutic strategies.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Ensaios Clínicos como Assunto , Humanos , Terapia de Alvo Molecular , Mutação , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
INTRODUCTION: BRAF mutant colorectal cancer (BRAF MT CRC) is a unique category of colorectal tumour with peculiar molecular, pathological and clinical features and poor prognosis; despite recent research, BRAF mutation predictive value and standard treatment of BRAF MT CRC still have to be defined. In this review, we focused on this challenging topic. Areas covered: The potential use of BRAF mutational status among recent additional prognostic and predictive indicators and current treatment strategy in use in these patients is discussed. Moreover, implications and characteristics of new BRAF mutations other than BRAFV600E are analyzed. An in-deep outlook on the immediate future for clinical and translational research in this subgroup of patients is also presented, such as combination therapy with agents targeting the RAS/RAF/MEK/ERK pathway and standard chemotherapy in order to overcome resistance. We performed a research on Pubmed typing 'BRAF mutation', 'colorectal cancer', 'predictive and prognostic value', 'targeted therapy', 'BRAF inhibition'. Expert commentary: BRAFV600E mutation represents a strong, independent negative prognostic factor in II-III stage MSS CRC and mCRC. The best treatment still has to be identified; currently, in good performance status patients, an intensive-chemotherapy-combination remains the standard of care. Further investigations are warranted to explore new horizons to change BRAF MT mCRC outcomes.
Assuntos
Neoplasias Colorretais , Sistema de Sinalização das MAP Quinases , Glicoproteínas de Membrana , Mutação de Sentido Incorreto , Sulfotransferases , Substituição de Aminoácidos , Animais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Prognóstico , Sulfotransferases/antagonistas & inibidores , Sulfotransferases/genética , Sulfotransferases/metabolismoRESUMO
Chronic inflammation following infections, autoimmune diseases or exposure to environmental irritants plays a crucial role in tumor development and influences the host immune response to neoplastic cells. The presence of an anti-tumor immune infiltrate is often associated with better outcomes in gastro-intestinal primary cancers, particularly in those with high microsatellite instability (MSI-H). Immunotherapeutic drugs inhibiting the PD-1 and PD-L1 pathway showed promising results in the treatment of these patients in the metastatic setting. The aim of this review is to resume the role tumor infiltrating lymphocytes (TILs) play in gastrointestinal tumors, underlining their potential value as a prognostic and predictive biomarker. TILs assessment could identify subsets of patients with high extent of TILs and better prognosis, that could be spared from adjuvant systemic treatments. Immune infiltration parameters might be additional predictors of a greater benefit from the immunotherapy with the immune checkpoint blockade.
Assuntos
Neoplasias Gastrointestinais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Animais , Biomarcadores Tumorais/análise , Neoplasias Gastrointestinais/química , Neoplasias Gastrointestinais/terapia , Humanos , Imunoterapia , PrognósticoRESUMO
The cancer anorexia-cachexia syndrome (CACS) is considered a multifactorial syndrome that leads a general decline of the cancer patient conditions, prognosis and survival, and characterized by progressive loss of body mass and functional impairment, due to marked energy metabolism imbalance and immunological disorders. It is the cause of death in almost one out of five advanced cancer patients. CACS is also accompanied with loss of quality of life, reduced response and tolerance to anticancer therapies and affected outcome. This condition arises by acute-chronic inflammation, hypercatabolism and resulting in an increased energy expenditure, anorexia and negative caloric balance. Although the international scientific community has reached some important findings in last years regarding CACS, a precise definition agreement for CACS in order to a precise patients assessment is still lacking. In light of the advances in pathogenesis and evaluation of CACS, as well as those reached in the therapy, this review aims to draft a list of key points that could be useful for the oncologist to recognize the different signs and symptoms of this syndrome, in order to evaluate and stage the cancer patients in attempt to target an early multimodal pharmacological-nutritional treatment strategy to improve his outcome and his quality of life.
Assuntos
Caquexia , Anorexia , Humanos , Neoplasias , Oncologistas , Qualidade de VidaRESUMO
The risk and mechanism of chemotherapy-induced cardiotoxicity (CTX) vary depending on the type and intensity of the anticancer regimen. Myriad chemotherapeutic drugs produce adverse cardiovascular effects such as arterial hypertension, heart failure, and thromboembolic events. Among the numerous classes of these drugs, anthracyclines have been studied most extensively because of their overt cardiovascular effects and the high associated incidence of heart failure. However, CTX might also be caused by other types of chemotherapeutic agents, including alkylating agents (cyclophosphamide, ifosfamide), platinum agents, antimetabolites (5-fluorouracil, capecitabine), antibiotics (mitoxantrone, mitomycin, bleomycin), and antimicrotubule agents (taxanes). Here, we review the incidence, clinical impact, and potential mechanisms of CTX associated with nonanthracycline chemotherapy used for cancer patients. The published data support a marked increase in CTX risk, particularly with certain drugs such as 5-fluorouracil and cisplatin. Each anticancer regimen is associated with distinct modes of heart damage, both symptomatic and asymptomatic. However, the underlying mechanisms of CTX have been established only in a few cases, and only few nonanthracycline chemotherapeutics (mitoxantrone, mitomycin, ifosfamide) act through a recognizable mechanism and show a predictable dose dependence. Lastly, nonanthracycline chemotherapy can induce both chronic lesions, such as systolic dysfunction, and acute lesions, such as the ischemia that occurs within hours or days after treatment. An increased understanding of the incidence, mechanisms, and potential therapeutic targets of CTX induced by various nonanthracycline chemotherapeutic agents is clearly required.
Assuntos
Antibacterianos/efeitos adversos , Antineoplásicos Alquilantes/efeitos adversos , Cardiotoxicidade/fisiopatologia , Neoplasias/tratamento farmacológico , Antraciclinas/efeitos adversos , Cardiotoxicidade/etiologia , Fluoruracila/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Humanos , Estresse Oxidativo/efeitos dos fármacos , Platina/efeitos adversos , Volume Sistólico , Taxoides/efeitos adversos , Disfunção Ventricular Esquerda/induzido quimicamenteRESUMO
The risk and mechanism of chemotherapy-induced cardiotoxicity (CTX) vary depending on the type and intensity of the anticancer regimen. Myriad chemotherapeutic drugs produce adverse cardiovascular effects such as arterial hypertension, heart failure, and thromboembolic events. Among the numerous classes of these drugs, anthracyclines have been studied most extensively because of their overt cardiovascular effects and the high associated incidence of heart failure. However, CTX might also be caused by other types of chemotherapeutic agents, including alkylating agents (cyclophosphamide, ifosfamide), platinum agents, antimetabolites (5-fluorouracil, capecitabine), antibiotics (mitoxantrone, mitomycin, bleomycin), and antimicrotubule agents (taxanes). Here, we review the incidence, clinical impact, and potential mechanisms of CTX associated with nonanthracycline chemotherapy used for cancer patients. The published data support a marked increase in CTX risk, particularly with certain drugs such as 5-fluorouracil and cisplatin. Each anticancer regimen is associated with distinct modes of heart damage, both symptomatic and asymptomatic. However, the underlying mechanisms of CTX have been established only in a few cases, and only few nonanthracycline chemotherapeutics (mitoxantrone, mitomycin, ifosfamide) act through a recognizable mechanism and show a predictable dose dependence. Lastly, nonanthracycline chemotherapy can induce both chronic lesions, such as systolic dysfunction, and acute lesions, such as the ischemia that occurs within hours or days after treatment. An increased understanding of the incidence, mechanisms, and potential therapeutic targets of CTX induced by various nonanthracycline chemotherapeutic agents is clearly required.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Coração/efeitos dos fármacos , Coração/fisiopatologia , Cardiotoxicidade/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Humanos , Neoplasias/tratamento farmacológicoRESUMO
The encouraging results in immunotherapy for melanoma also led the way for translational and clinical research about immune-related mechanisms possibly relevant for gastrointestinal tumours. It is in fact now evident that the immune checkpoint modulation and in particular cell-mediated immune-response through programmed cell death-1 (PD-1) and the cytotoxic T-lymphocyte antigen-4 (CTLA4) receptors along with the regulatory T cells activity all have a relevant role in gastrointestinal cancers as well. This review aims to explore the state of the art of immunotherapy for gastrointestinal tumours, deepening recent scientific evidence regarding anti PD-1/PDL-1 and anti CTLA4 monoclonal antibodies, peptide based vaccine, DNA based vaccine, and pulsed dendritic cells, either alone or in combination with other antineoplastic medical therapy and locoregional treatments. Considering the non-negligible toxicity profile deriving from such a treatment approach, predictive biomarkers of response to immunotherapy in gastrointestinal cancer are also urgently needed in order to better select the patients' group with the highest likelihood of benefit.
Assuntos
Neoplasias Gastrointestinais/imunologia , Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , HumanosRESUMO
Although the number of therapeutic options targeting tumour angiogenesis is becoming increasingly relevant, the question of the optimal choice for second-line anti-angiogenic inhibition in combination with chemotherapy for metastatic colorectal cancer patients remains largely unanswered. In fact the lack of head to head comparison between consolidated options such as bevacizumab and new treatment alternatives such as aflibercept and ramucirumab makes the selection in the clinical practice challenging, particularly when the patient has already received an anti-angiogenic-based combination up-front. In the following pages we described the biological scenario validating second-line angiogenesis inhibition in colorectal cancer along with potential mechanism of resistance. We also critically described the available evidence recommending the use of the bevacizumab, aflibercept and ramucirumab in this setting with the final aim to guide the choice in the clinical practice.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Bevacizumab/uso terapêutico , Quimioterapia Adjuvante/métodos , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/patologia , Humanos , Metástase Neoplásica , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , RamucirumabRESUMO
Regorafenib monotherapy is a potential option for metastatic colorectal cancer patients. However, the lack of predictive factors and the severe toxicities related to treatment have made its use in clinical practice challenging. Polymorphisms of VEGF and its receptor (VEGFR) genes might regulate angiogenesis and thus potentially influence outcome during anti-angiogenesis treatment such as regorafenib. Aim of our study was to evaluate the role of VEGF and VEGFR genotyping in determining clinical outcome for colorectal cancer patients receiving regorafenib. We retrospectively collected clinical data and samples (tumour or blood) of 138 metastatic colorectal cancer patients treated with regorafenib. We analysed the correlation of different VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs) with patients' progression-free survival (PFS) and overall survival (OS). Results from angiogenesis genotyping showed that only VEGF-A rs2010963 maintained an independent correlation with PFS and OS. Among clinical factors only ECOG PS was independently correlated with OS, whereas no correlation with PFS was evident. Grouping together those results allowed further patients stratification into 3 prognostic groups: favourable, intermediate and unfavourable. VEGF-A rs2010963 genotyping may represent an important tool for a more accurate selection of optimal candidates for regorafenib therapy.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Receptores de Fatores de Crescimento de Fibroblastos/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Inibidores da Angiogênese/farmacologia , Neoplasias Colorretais/genética , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Variantes Farmacogenômicos , Compostos de Fenilureia/farmacologia , Polimorfismo de Nucleotídeo Único , Piridinas/farmacologia , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
Several clinical series have demonstrated a notably low overall survival for colorectal cancer patients diagnosed with a BRAF-mutant tumor. A potentially interesting predictive role has also been suggested for BRAF-mutant colorectal cancer receiving anti-EGFR monoclonal antibodies. Although a global consensus exists in indicating BRAF as a prognostic factor with a possible predictive activity, the clinical use of BRAF mutational status in colorectal tumors is still controversial. This article reviews the current knowledge on the use and implications of BRAF mutational status in colorectal tumors, in order to define its present role in the clinical practice. Also suggested are possible treatment strategies in this prognostically challenging group of patients. Finally, a comprehensive outlook on future developments for specifically directed anti-BRAF therapy is illustrated.