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1.
Front Oncol ; 12: 852583, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35530345

RESUMO

Background: Rechallenge with EGFR inhibitors represents a promising strategy for patients with RAS wild type (WT) colorectal cancer (CRC) but definitive selection criteria are lacking. Recently, the RAS WT status on circulating tumor DNA (ct-DNA) emerged as a potential watershed for this strategy. Our study explored the liquid biopsy-driven cetuximab rechallenge in a RAS and BRAF WT selected population. Methods: CRC patients with RAS and BRAF WT both on tumor tissue and on ct-DNA at baseline receiving rechallenge with cetuximab were eligible for our analysis. Ct-DNA was analyzed for RAS-BRAF mutations with pyro-sequencing and nucleotide sequencing assays. Real-time PCR and droplet digital PCR were performed to confirm the RAS-BRAF mutational status. Results: A total of 26 patients were included in our analysis. In the global population, RR was 25.0%, median overall survival (mOS) was 5.0 months, and median progression-free survival (mPFS) was 3.5 months. Previous response to anti-EGFR was associated with improved mPFS (5.0 vs. 2.0 months, HR: 0.26, p = 0.048); anti-EGFR free interval > 14 months and anti-EGFR free interval > 16 months were associated with improved mPFS (respectively 7.0 vs. 3.0 months, HR: 0.27, p = 0.013 and not reached vs. 3.0 months, HR: 0.20, p = 0.002) and with improved mOS (respectively 13.0 vs. 5.0 months, HR: 0.27, p = 0.013 and 13.0 vs. 5.0 months, HR: 0.20, p = 0.002). Previous lines >2 were correlated with improved mPFS (4.0 vs. 1.0 month, HR: 0.05, p = 0.041) and with improved mOS (7.0 vs. 1.0 month, HR: 0.045, p = 0.034). In a multiple logistic regression model, only the anti-EGFR free interval was confirmed to be a significant predictor for mOS and mPFS. Conclusions: Liquid biopsy-driven cetuximab rechallenge was confirmed to be effective. The clinical outcome was consistent with available results from phase II studies. In addition to the molecular selection through the analysis of ct-DNA for RAS, the long anti-EGFR free interval is confirmed as a prospective selection criterion for this therapeutic option.

2.
Crit Rev Oncol Hematol ; 173: 103674, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35364261

RESUMO

PURPOSE: This study aimed to clarify the current knowledge on the use of immunotherapy in patients with advanced gastric(G)/gastroesophageal(GEJ) cancers. MATERIALS AND METHODS: A meta-analysis was done to evaluate the efficacy of immune checkpoint inhibitors(ICIs) in G/GEJ cancer both in the unselected population and in that stratified for combined positive score (CPS)≥ 1 and ≥ 10 patients. RESULTS: In the unselected population the result showed 21%(P < 0.00001), and 29%(P < 0.00001) reduction of death and progression risk for patients treated with ICIs compared without ICIs, while in CPS≥ 1 and≥ 10 populations, the result showed a death reduction of 19%(P = 0.001) and 33%(P < 0.00001) respectively, and, and 23% (P < 0.00001) and 43% (P < 0.00001) progression risk reduction respectively, for patients treated with and without ICIs. CONCLUSION: overall survival(OS) and progression free survival(PFS) data obtained in our meta-analysis, are in favor to use ICIs in association with standard first line chemotherapy for G/GEJ cancer patients regardless to CPS status.


Assuntos
Neoplasias Esofágicas , Neoplasias Gástricas , Neoplasias Esofágicas/tratamento farmacológico , Junção Esofagogástrica , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Gástricas/tratamento farmacológico
3.
Epigenomics ; 14(9): 507-517, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35473355

RESUMO

Background: Predictive biomarkers for advanced hepatocellular carcinoma are lacking. EZH2 drives sorafenib resistance through H3K27me3 and is counteracted by SETD2, which catalyzes H3K36me3. The authors tested the predictive power of circulating H3K27me3 and H3K36me3 in advanced hepatocellular carcinoma patients treated with sorafenib. Methods: A total of 80 plasma samples were tested for histone variants by ELISA. Changes from baseline to best response or progressive disease were correlated with patient survival. Results: A higher EZH2/SETD2 ratio predicted worse prognosis in this setting. H3K27me3 and H3K36me3 decreased from baseline to best response. The H3K27me3/H3K36me3 ratio increased from baseline to progressive disease. Higher ratios at best response were associated with shorter progression-free survival. Conclusion: The authors suggest that circulating H3K27me3/H3K36me3 ratio level acts as a predictive biomarker for sorafenib treatment outcomes in patients with advanced hepatocellular carcinoma.


Hepatocellular carcinoma (HCC) is responsible for approximately 10% of all cancer-related deaths worldwide. It is caused mainly by dysmetabolic syndrome, which is the presence of multiple risk factors: abdominal obesity, high blood pressure, hypercholesterolemia and diabetes. The authors aimed to identify new and predictive factors for sorafenib treatment outcomes in advanced HCC patients. The authors enrolled 85 patients who received sorafenib at two Italian oncological institutions, testing their blood for the following epigenetic biomarkers: H3, H3.1 variant, H3K27me3 and H3K36me3. The authors found that H3K27me3 and H3K36me3 decreased from baseline to maximum tumor shrinkage, H3K27me3/H3K36me3 ratio increased from baseline to progressive disease and higher ratios were associated with shorter progression-free survival. The authors suggest that circulating H3K27me3/H3K36me3 ratio level acts as a predictive biomarker for sorafenib treatment outcomes in patients with advanced HCC, and its role warrants further investigation in different HCC therapeutic strategies.

4.
Eur J Cancer ; 168: 34-40, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35436675

RESUMO

BACKGROUND: Encorafenib plus cetuximab is efficient in anti-EGFR-naïve patients with BRAFV600E mutated (BRAFm) metastatic colorectal cancer (mCRC). No data are available concerning the efficacy of BRAF inhibitors associated with anti-EGFRs (B + E) in patients previously treated with an anti-EGFR agent. METHODS: We retrospectively collected a series of patients with BRAFm mCRC treated with B + E after previous anti-EGFR treatment, in 14 centers. Progression-free survival (PFS) and overall survival (OS) were calculated from the start of treatment, and we reported objective response and disease control rates (ORR, DCR; RECIST V1.1). RESULTS: Twenty-five BRAFm mCRC patients were enrolled. Prior to B + E treatment, 4/10/11 patients were treated with 1/2/> 2 previous treatment lines. Ten patients received previous panitumumab, 14 cetuximab, 1 both. Immediate progression with previous anti-EGFR was reported for 7 patients. Anti-BRAF was encorafenib for 21 patients, dabrafenib for 4 patients, with cetuximab for 24 patients and panitumumab for 1 patient. ORR was 40% (10 patients) and DCR was 80% (20 patients). Median PFS and OS were 4.8 months (95% CI, 4.01-7.95) and 10.1 months (95% CI, 7.75-NR). DCR amongst patients with previous primary resistance to anti-EGFR (N = 7) was 100%. Two patients discontinued B + E due to drug-related adverse event. CONCLUSIONS: Though in a limited retrospective series of patients, these results show the efficacy of the combination of anti-BRAF and anti-EGFRs in BRAFm mCRC patients previously treated with an anti-EGFR. The use of this combination should thus not be ruled out in this population with limited therapeutic options.

5.
Br J Cancer ; 2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35177798

RESUMO

BACKGROUND: Biliary tract cancers (BTC) are rare but highly aggressive tumours with poor prognosis, usually detected at advanced stages. Herein, we aimed at identifying BTC-specific DNA methylation alterations. METHODS: Study design included statistical power and sample size estimation. A genome-wide methylation study of an explorative cohort (50 BTC and ten matched non-tumoral tissue samples) has been performed. BTC-specific altered CpG islands were validated in over 180 samples (174 BTCs and 13 non-tumoral controls). The final biomarkers, selected by a machine-learning approach, were validated in independent tissue (18 BTCs, 14 matched non-tumoral samples) and bile (24 BTCs, five non-tumoral samples) replication series, using droplet digital PCR. RESULTS: We identified and successfully validated BTC-specific DNA methylation alterations in over 200 BTC samples. The two-biomarker panel, selected by an in-house algorithm, showed an AUC > 0.97. The best-performing biomarker (chr2:176993479-176995557), associated with HOXD8, a pivotal gene in cancer-related pathways, achieved 100% sensitivity and specificity in a new series of tissue and bile samples. CONCLUSIONS: We identified a novel fully efficient BTC biomarker, associated with HOXD8 gene, detectable both in tissue and bile by a standardised assay ready-to-use in clinical trials also including samples from non-invasive matrices.

6.
J Chemother ; : 1-7, 2022 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-35156913

RESUMO

Biliary tract cancer's (BTC) treatment main stone for advanced stages is constituted by chemotherapy. Surgical centralization and physicians' confidence in the use of new technologies and molecular analysis turned out to be of interest and potentially influencing survival. After applying a random-effect model, the relationship between each clinical variable on the main outcome was investigated through multilevel mixed-effects logistic regression. The risk-standardized outcomes were calculated for each centre involved. In the unadjusted cohort the median survival was 8.6 months (95%C.I.: 7.8-9.3) with a 9-month survival rate of 48.3% (95%C.I.: 45.0-51.5). A substantial heterogeneity across hospitals was found (I2: 70.3%). In multilevel mixed effect logistic regression, male, being treated for gallbladder cancer, higher ECOG, increased NLR, CEA and Ca 19.9 and low value of haemoglobin showed to increase the odds for 9-month mortality. The model estimated that the residual variance observed in 9-month mortality was attributable for the 2.6% to the treating hospital. Through a multilevel mixed effect model, average risk-standardized mortality within 9 months was 50.1%. As noticeable, all hospital's risk-standardized mortality falls within 95%C.I., thus all participating centres provided similar outcomes when adjusted for patient case-mix. Heterogenicity between hospital did not affect the outcome in term of overall survival.

7.
J Chemother ; 34(2): 123-132, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34313188

RESUMO

Advanced biliary tract cancer (aBTC) comprises a heterogeneous group of rare malignancies with dismal prognosis. Given the scarcity of prospective evidence, the aim of this study was to derive clinically useful insights and prognostic factors from a large, real-world series of aBTC. Clinicopathologic variables and treatment outcomes were retrospectively collected involving 940 patients diagnosed with aBTC between 2001 and 2017, and treated with first-line chemotherapy (CT1) at 14 Italian medical oncology institutions. Median overall survival (OS) was 10.3 months (CI95% 9.5-11.1). CT1 with gemcitabine-Platinum salts doublets achieved OS of 11.7 months vs 7.5 with gemcitabine alone (HR 0.67, p < 0.001). However, a clear temporal trend towards improved OS could not be demonstrated. Radical surgery of recurrent disease achieved a relapse-free survival of 5.9 months. A substantial minority (44.5%) of patients were able to receive a second-line chemotherapy, which achieved a response rate of 7.6%, and disease control in 30% of patients with no significant differences between combination regimens and monotherapies. In a large retrospective series of real-world aBTC, outcomes of standard CT1 closely resembled those of the registrational trials. A limited set of easily retrievable independent prognostic factors was defined. Further research is needed on second-line regimens.


Assuntos
Neoplasias do Sistema Biliar , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Resultado do Tratamento
8.
Cancer Immunol Immunother ; 71(4): 865-874, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34462870

RESUMO

BACKGROUND: The prognostic relevance of early immune-related adverse events (irAEs) in patients affected by non-small cell lung cancer (NSCLC) upon immunotherapy is not fully understood. METHODS: The Leading to Treatment Discontinuation cohort included 24 patients experiencing severe irAEs after one of two administrations of single anti-PD-1/PD-L1 in any line setting for metastatic NSCLC between November 2015 and June 2019. The control cohort was composed of 526 patients treated with single anti-PD-1/PD-L1 in any line setting with no severe irAE reported. The primary end points were median progression-free survival, overall survival, objective response rate, risk of progression of disease and risk of death. The correlation of clinic pathological features with early severe irAEs represented the secondary end point. RESULTS: Median PFS was 9.3 and 8.4 months, median OS was 12.0 months and 14.2 months at a median follow-up of 18.1 and 22.6 months in the LTD cohort and in the control cohort, respectively. The ORR was 40% (95% CI 17.2-78.8) in the LTD cohort and 32.7% (95% CI 27.8-38.2) in the control cohort. The risk of disease progression was higher in the LTD cohort (HR 2.52 [95% 1.10-5.78], P = .0288). CONCLUSIONS: We found no survival benefit in LTD cohort compared to the control cohort. However, early and severe irAEs might underly an immune anti-tumor activation. We identified a significant association with first-line immune checkpoints inhibitors treatment and good PS. Further studies on risk prediction and management of serious and early irAEs in NSCLC patients are needed.


Assuntos
Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/patologia , Receptor de Morte Celular Programada 1 , Estudos Retrospectivos
9.
Hum Cell ; 35(1): 310-319, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34719006

RESUMO

DNA methylation alterations are early events during tumourigenesis, affecting genes involved in the crosstalk between cells and surroundings in colorectal cancer (CRC). Among these genes, GRIA4, Glutamate Ionotropic Receptor AMPA Type Subunit 4, displays hypermethylation in the promoter region, and is an early diagnostic biomarker. It is well known that methylation can also affect alternative transcription. The purpose of this study is to evaluate the expression, at transcript and protein level, of GRIA4 main isoforms (the canonical one and a short variant) in 23 CRC and matched normal samples, of which we previously verified the methylation status. We further predicted miRNA/transcript target interactions as a possible post-transcriptional regulation using bioinformatics tools. As expected, downregulation of both variants has been observed in tumours. Interestingly, in contrast to what observed at transcriptional level, the GluR4 protein short isoform displayed higher expression than the canonical one either in normal or tumoural tissues. This may be explained by miRNA specifically targeting the canonical isoform. Our study is the first one that shows the expression of both isoforms in colon tissues. To note, the evident expression of the short isoform suggests a functional role in intestinal cell biology.


Assuntos
Colo/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Metilação de DNA , Regulação Neoplásica da Expressão Gênica/genética , Expressão Gênica/genética , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Humanos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
10.
J Immunother Cancer ; 9(11)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34815354

RESUMO

BACKGROUND: No standard therapies beyond first line are established for advanced squamous cell anal carcinoma (aSCAC). Earlier preliminary data suggest activity of epidermal growth factor receptor (EGFR) inhibition and programmed cell death ligand (PD-(L))1 blockade in patients with previously treated disease. Aim of this study was to explore activity and safety of avelumab with/without cetuximab in patients with aSCAC. METHODS: In this open-label, non-comparative, 'pick the winner', multicenter randomized phase II trial (NCT03944252), patients with aSCAC progressing after one or more lines of treatment were randomized 1:1 to the anti-PD-L1 agent avelumab alone (arm A) or combined with cetuximab (arm B). Overall response rate (ORR) was the primary endpoint. With one-sided α error set at 0.05 and power of 80%, at least 4 responses out of 27 patients per arm had to be observed to declare the study positive. Secondary endpoints were progression free survival (PFS), overall survival (OS), and safety. RESULTS: Thirty patients per arm were enrolled. Three patients in arm A and five in arm B achieved partial response: primary endpoint was reached in combination arm. ORR was 10% (95% CI 2.1 to 26.5) and 17% (95% CI 5.6 to 34.7) in arms A and B; disease control rate was 50% (95% CI 31.3 to 68.7) in arm A and 57 (95% CI 37.4-74.5) in arm B. At a median follow-up of 26.7 months (IQR 26.5-26.9), median PFS was 2.0 months (95% CI 1.8 to 4.0) in arm A and 3.9 (95% CI 2.1 to 5.6) in arm B. Median OS was 13.9 months (95% CI 7.7 to 19.4) in arm A and 7.8 (95% CI 6.2 to 11.2) in arm B. Acceptable safety profile was observed in both arms. CONCLUSIONS: CARACAS study met its primary endpoint in arm B, documenting promising activity of dual EGFR and PD-L1 blockade in aSCAC.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Cetuximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cetuximab/farmacologia , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica
11.
Expert Opin Ther Targets ; 25(11): 987-1005, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34806517

RESUMO

INTRODUCTION: Despite available treatment options, pancreatic ductal adenocarcinoma (PDAC) is frequently lethal. Recent immunotherapy strategies have failed to yield any notable impact. Therefore, research is focussed on unearthing new drug targets and therapeutic strategies to tackle this malignancy and attain more positive outcomes for patients. AREAS COVERED: In this perspective article, we evaluate the main resistance mechanisms to immune checkpoint inhibitors (ICIs) and the approaches to circumvent them. We also offer an assessment of concluded and ongoing trials of PDAC immunotherapy. Literature research was performed on Pubmed accessible through keywords such as: 'pancreatic ductal adenocarcinoma,' 'immunotherapy,' 'immunotherapy resistance,' 'immune escape,' 'biomarkers.' Papers published between 2000 and 2021 were selected. EXPERT OPINION: The tumor microenvironment is a critical variable of treatment resistance because of its role as a physical barrier and inhibitory immune signaling. Promising therapeutic strategies appear to be a combination of immunotherapeutics with other targeted treatments. Going forward, predictive biomarkers are required to improve patient selection. Biomarker-driven trials could enhance approaches for assessing the role of immunotherapy in PDAC.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/patologia , Humanos , Imunoterapia , Neoplasias Pancreáticas/patologia , Microambiente Tumoral
12.
Front Oncol ; 11: 736104, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660299

RESUMO

BACKGROUND: KRAS mutations in metastatic colorectal cancer (mCRC) define a subset of tumors that have primary resistance to anti-EGFR-based therapy. Data concerning whether different KRAS mutations may also have a prognostic value are lacking. Furthermore, novel KRAS G12C inhibitors are currently in development. The aim of our analysis was to compare response rates in patients treated with first-line chemotherapy doublet + Bevacizumab among different KRAS variants. Secondary end-points were progression free survival (PFS) and overall survival (OS). METHODS: Patients with KRAS mutated mCRC treated with either FOLFIRI/FOLFOX/XELOX + Bevacizumab were eligible for enrollment. Patients whose tumor harbored NRAS mutations or that coexpressed also BRAF mutations were excluded from this retrospective analysis. Patients' individual data were collected from patients' records. Propensity score matching (nearest method, 1:2 ratio) was used to define the two different groups of patients for comparison (KRAS G12C mutated vs other KRAS variants). Eastern Cooperative Oncology Group Performance Status (ECOG PS), sex, metastatic site of involvement, synchronous vs metachronous metastatic disease, tumor sidedness, mucinous histology, primary tumor surgery, more than two lines of treatment for metastatic disease, and radical surgery of metastases were used as matching factors. Response rate (RR) was calculated by RECIST 1.1 criteria. Both progression free-survival and overall survival were calculated by Kaplan-Meier method. Categorical variables were compared by Fisher exact test for binomial variables and by chi-square test for all other instances. The level of statistical significance p was set at 0.05 for all tests. RESULTS: A total of 120 patients were assessed in the final analysis. Out of the 120 patients, 15 (12%) were KRAS G12C mutated. In the whole cohort of patients, 59/120 (49%) had partial response (PR), 42/120 (35%) had stable disease (SD), and 19/120 (16%) had progressive disease (PD) as the best response. In KRAS G12C patients, 4/15 (27%) had PR, 6/15 (40%) had SD, and the remaining 5/15 (33%) had PD as the best response. In patients with other KRAS mutations, 55/105 (52%) had PR, 37/105 (35%) had SD, and the remaining 13/105 (12%) had PD as the best response. The difference in RR between the two groups of patients was statistically significant (p=0.017). On the other hand, no difference in PFS (p=0.76) and OS (p=0.56) was observed. After matching procedures, the difference in response rates between KRAS G12C mutated patients vs the matched cohort of patients with other KRAS mutations remained statistically significant (p=0.016). KRAS G12C mutations were not associated with differences in sites of metastatic involvement, sex, and ECOG PS. On the other hand, synchronous vs metachronous metastatic disease (p=0.039), age > 75 years (p=0.043), and mucinous histology (p=0.008) were more frequent in G12C mutated tumors. CONCLUSIONS: In our cohort of patients, it was observed that KRAS G12C mutations are associated with worse response rates compared to other KRAS variants when treated with standard chemotherapy doublet + Bevacizumab. On the other hand, both PFS and OS were not significantly different. Based on these findings, we believe that new treatment options focused on KRAS G12C inhibition should be tested mainly in first-line setting and in addition to standard chemotherapy doublet + Bevacizumab for mCRC patients, as they might "fill the gap" in response rates that was seen in our study.

13.
Expert Rev Gastroenterol Hepatol ; 15(12): 1367-1383, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34669536

RESUMO

INTRODUCTION: Biliary tract cancer represents a heterogeneous group of malignancies characterized by dismal prognosis and scarce therapeutic options. AREA COVERED: In the last years, a growing interest in BTC pathology has emerged, thus highlighting a significant heterogeneity of the pathways underlying the carcinogenesis process, from both a molecular and genomic point of view. A better understanding of these differences is mandatory to deepen the behavior of this complex disease, as well as to identify new targetable target mutations, with the aim to improve the survival outcomes. The authors decided to provide a comprehensive overview of the recent highlights on BTCs, with a special focus on the genetic, epigenetic and molecular alterations, which may have an interesting clinical application in the next future. EXPERT OPINION: In the last years, the efforts resulted from international collaborations have led to the identification of new promising targets for precision medicine approaches in the BTC setting. Further investigations and prospective trials are needed, but the hope is that these new knowledge in cooperation with the new technologies and procedures, including bio-molecular and genomic analysis as well radiomic studies, will enrich the therapeutic armamentarium thus improving the survival outcomes in a such lethal and complex disease.


Assuntos
Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Neoplasias dos Ductos Biliares/terapia , Colangiocarcinoma/terapia , Epigenômica , Humanos , Terapia de Alvo Molecular , Prognóstico
14.
Semin Oncol ; 48(3): 208-225, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34620502

RESUMO

In the recent years characterized by the cancer immunotherapy revolution, attention has turned to how to potentially boost and/or generate an efficient anti-tumor immune response in breast cancer (BC). Clinical activity of immune checkpoint blockade (ICB) targeting PD-1 or PD-L1 in BC has been more evident in the triple negative subtype and in earlier lines of the treatment. Remarkably, some responders to single agent ICB have achieved durable responses with metastatic disease, possibly as a result of treatment-induced immunological memory. However, most BC are immunologically quiescent and current research efforts developing ICB combinations are attempting to convert "cold" into "hot" tumors by manipulating the tumor microenvironment, expanding anti-tumor T cells improving efficient antigen presentation, and suppressing pro-tumor inhibitory cells. The aim of this review is to summarize existing data on the efficacy of immune checkpoint blockers as single agents and combination strategies in all BC subtypes, highlighting the BC subgroups that benefit most from ICB.


Assuntos
Neoplasias da Mama , Inibidores de Checkpoint Imunológico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Microambiente Tumoral
15.
Hepatol Res ; 51(12): 1229-1241, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34591334

RESUMO

BACKGROUND: Advanced Hepatocarcinoma (HCC) is an important health problem worldwide. Recently, the REFLECT trial demonstrated the non-inferiority of Lenvatinib compared to Sorafenib in I line setting, thus leading to the approval of new first-line standard of care, along with Sorafenib. AIMS AND METHODS: With aim to evaluate the optimal choice between Sorafenib and Lenvatinib as primary treatment in clinical practice, we performed a multicentric analysis with the propensity score matching on 184 HCC patients. RESULTS: The median overall survival (OS) were 15.2 and 10.5 months for Lenvatinib and Sorafenib arm, respectively. The median progression-free survival (PFS) was 7.0 and 4.5 months for Lenvatinib and Sorafenib arm, respectively. Patients treated with Lenvatinib showed a 36% reduction of death risk (p = 0.0156), a 29% reduction of progression risk (p = 0.0446), a higher response rate (p < 0.00001) and a higher disease control rate (p = 0.002). Sorafenib showed to be correlated with more hand-foot skin reaction and Lenvatinib with more hypertension and fatigue. We highlighted the prognostic role of Barcelona Clinic Liver Cancer (BCLC) stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), bilirubin, alkaline phosphatase and eosinophils for Sorafenib. Conversely, albumin, aspartate aminotransferase (AST), alkaline phosphatase and Neutrophil-Lymphocyte Ratio (NLR) resulted prognostic in Lenvatinib arm. Finally, we highlighted the positive predictive role of albumin > Normal Value (NV), ECOG > 0, NLR < 3, absence of Hepatitis C Virus positivity, and presence of portal vein thrombosis in favor of Lenvatinib arm. Eosinophil < 50 and ECOG > 0 negatively predicted the response to Sorafenib. CONCLUSION: SLenvatinib showed to better perform in a real-word setting compared to Sorafenib. More researches are needed to validate the predictor factors of response to Lenvatinib rather than Sorafenib.

16.
Expert Rev Anticancer Ther ; 21(11): 1253-1264, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34551663

RESUMO

INTRODUCTION: In the past, targeted therapies have not shown positive results as they have been used without adequate molecular selection of patients with biliary tract cancer (BTC). This has led to an expansion of research on characteristics and molecular selection to identify new effective strategies in this setting. Improved knowledge of the molecular biology of these neoplasms has highlighted their extraordinary heterogeneity and has made it possible to identify targetable gene alterations, including fibroblast growth factor receptor (FGFR) 2 gene fusions, and isocitrate dehydrogenase (IDH) mutations. The FDA recently approved ivosidenib and pemigatinib for the treatment of BTCs. AREAS COVERED: We review data in the literature regarding targeted therapies for the treatment of BTCs, as well as on the prospects deriving from the extraordinary molecular heterogeneity of these neoplasms. EXPERT OPINION: At present, it is essential to evaluate the expression of the genetic alterations expressed by these neoplasms to offer patients an increasingly personalized therapeutic approach. Studies are needed to better define the limits and potentials of targeted therapies and their role in the therapeutic algorithm to improve the poor prognosis of these patients.


Assuntos
Antineoplásicos , Neoplasias do Sistema Biliar , Colangiocarcinoma , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/genética , Colangiocarcinoma/tratamento farmacológico , Humanos , Terapia de Alvo Molecular/métodos
17.
Cancer Sci ; 112(12): 4819-4833, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34534382

RESUMO

Biliary tract cancers (BTCs) consist of a group of highly heterogeneous malignancies that are characterized by genomic differences among tumors from different anatomic sites. The current treatment for BTC includes surgery, chemotherapy, target therapy, and immunotherapy. Although surgery remains the primary option for localized disease, representing the only potential curative treatment, a high risk of recurrence cannot be neglected. Chemotherapy has been considered the standard of care for both advanced and metastatic disease and in adjuvant settings. However, drug resistance is a major obstacle associated with chemotherapy. The development of genetic testing technologies, including next-generation sequencing, has opened the door for the identification of drug targets and candidate molecules. A series of preclinical studies has demonstrated the role of gene mutations, abnormal signaling pathways, and immunosuppression in the pathogenesis of BTC, laying the foundation for the application of targeted therapy and immunotherapy. A variety of molecularly targeted agents, including pemigatinib, have shown promising survival benefits in patients with advanced disease. The rapidly evolving role of multimodal therapy represents the subject of this review.


Assuntos
Neoplasias do Sistema Biliar/terapia , Terapia Combinada/métodos , Redes Reguladoras de Genes , Antineoplásicos/farmacologia , Neoplasias do Sistema Biliar/genética , Ensaios Clínicos como Assunto , Procedimentos Cirúrgicos do Sistema Digestório , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Medicina de Precisão , Radioterapia
18.
Clin Colorectal Cancer ; 20(4): e253-e262, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34429245

RESUMO

BACKGROUND: Regorafenib is a key agent in metastatic colorectal cancer (mCRC), but no validated factors predicting longer survival are available. PATIENTS AND METHODS: REALITY was a retrospective multicenter trial in regorafenib-treated mCRC patients with overall survival (OS) ≥ 6 months. We aimed to assess the association between clinical parameters and outcome to define a panel identifying long term survivors among regorafenib candidates. Primary and secondary endpoints were OS and progression free survival (PFS), respectively. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; independent role of significant variables at univariate analysis: logistic regression). RESULTS: Hundred regorafenib-treated mCRC patients with OS ≥ 6 months were enrolled. Median OS was 11.5 m (95%CI:9.60-12.96); median PFS was 4.2 months (95% CI:3.43-43.03). The absence of liver progression and of dose and/or schedule changes during the first 4 cycles (mainly for good tolerability) were independently correlated at multivariate analysis with OS (Exp(b)1.8869, P= .0277and Exp(b)2.2000, P = .0313) and PFS (Exp(b)2.1583, P = .0065 and Exp(b)2.3036, P= .0169). Patients with neither of these variables had a significantly improved OS (n = 14, 20.8 months; 95% CI:12.967-55.267) versus others (n = 86, 10 months; 95% CI:8.367-12.167; HR = 0.4902, P = .0045) and PFS (11.3 months, 95%CI:4.267-35.8 vs. 3.9 months, 95% CI:3.167-43.033; HR = 0.4648, P = .0086). CONCLUSION: These 2 factors might allow clinicians to better identify patients more likely to benefit from regorafenib. Toxicity management remains crucial.


Assuntos
Neoplasias Colorretais , Neoplasias Colorretais/tratamento farmacológico , Humanos , Compostos de Fenilureia , Piridinas , Estudos Retrospectivos
19.
Acta Oncol ; 60(10): 1317-1324, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34282710

RESUMO

BACKGROUND: Standard treatment of advanced biliary tract cancer (aBTC) is represented by first-line chemotherapy (CT1). However, some patients do not gain any benefit from CT1, contributing to the overall dismal prognosis of aBTC. The present study aimed to devise a prognostic model in aBTC patients receiving CT1. METHODS: A large panel of clinical, laboratory, and pathology variables, available before the start of CT1, were retrospectively assessed in a multi-centric cohort to determine their prognostic value on univariate and multivariate regression analysis. The variables that showed a significant correlation with overall survival (OS) were computed in a three-tier prognostic score. External validation of the prognostication performance was carried out. RESULTS: Clinical histories of 935 patients (median OS 10.3 months), with diagnosis dates ranging from 2001 to 2017, were retrieved from 14 institutions. According to multivariate analysis, Eastern Cooperative Oncology Group performance status, carbohydrate antigen 19.9, albumin levels, and neutrophil/lymphocyte ratio were strongly associated with OS (p <0.01). The prognostic score could generate a highly significant stratification (all between-group p values ≤0.001) into groups of favorable (comprising 51.5% of the sample), intermediate (39.2%), and poor prognosis (9.3%): median OS was 12.7 (CI95% 11.0-14.4), 7.1 (CI95% 5.8-8.4), and 3.2 months (CI95% 1.7-4.7), respectively. This OS gradient was replicated in the validation set (129 patients), with median OS of 12.7 (CI95% 11.0-14.3), 7.5 (CI95% 6.1-8.9), and 1.4 months (CI95% 0.1-2.7), respectively (all between-group p values ≤0.05). CONCLUSION: A prognostic score, derived from a limited set of easily-retrievable variables, efficiently stratified a large population of unselected aBTC patients undergoing CT1. This tool could be useful to clinicians, to ascertain the potential benefit from CT1 at the start of treatment.


Assuntos
Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Biliar/tratamento farmacológico , Humanos , Linfócitos , Prognóstico , Estudos Retrospectivos
20.
Br J Cancer ; 125(10): 1321-1332, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34262146

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 Precisão
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