Hepatocellular carcinoma (HCC) is the typical inflammation-induced neoplasia. It often prospers where a chronic liver disease persists, thus leading a strong rationale for immune therapy. Several ...immune-based treatments, including immune checkpoint inhibitors (ICI), cytokines, adoptive cell transfer, and vaccines, have been tested in the treatment of HCC. In this review, we summarize the role of the ICI in HCC patients in various sets of treatment. As for advanced HCC, the anti-Programmed cell Death protein 1 (PD1) antibodies and the anti-Cytotoxic T-Lymphocyte Antigen
(CTLA-4) antibodies have been examined in patients with enthusiastic results in phase I-II-III studies. Overall, this led the Food and Drug Administration (FDA) to approve pembrolizumab, nivolumab, and nivolumab + ipilimumab in the second-line setting. The anti- Programmed Death-Ligand 1 (PDL-1) antibodies have also been evaluated. Thanks to the results obtained from phase III IMbrave study, atezolizumab + bevacizumab is now the standard of care in the first-line advanced setting of HCC. As for localized HCC, the putative immunological effect of locoregional therapies led to evaluate the combination strategy with ICI. This way, chemoembolization, ablation with radiofrequency, and radioembolization combined with ICI are currently under study. Likewise, the study of adjuvant immunotherapy following surgical resection is underway. In addition, the different ICI has been studied in combination with other ICI as well as with multikinase inhibitors and anti-angiogenesis monoclonal antibody. The evidence available suggests that combining systemic therapies and locoregional treatments with ICI may represent an effective strategy in this context.
Immune checkpoint inhibitors (ICIs) showed efficacy in metastatic colorectal cancer (mCRC) with mismatch-repair deficiency or high microsatellite instability (dMMR-MSI-H). Unfortunately, a patient's ...subgroup did not benefit from immunotherapy. Caudal-related homeobox transcription factor 2 (CDX-2) would seem to influence immunotherapy's sensitivity, promoting the chemokine (C-X-C motif) ligand 14 (CXCL14) expression. Therefore, we investigated CDX-2 role as a prognostic-predictive marker in patients with mCRC MSI-H. We retrospectively collected data from 14 MSI-H mCRC patients treated with ICIs between 2019 and 2021. The primary endpoint was the 12-month progression-free-survival (PFS) rate. The secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and disease control rate (DCR). The PFS rate at 12 months was 81% in CDX-2 positive patients vs 0% in CDX-2 negative patients (p = 0.0011). The median PFS was not reached (NR) in the CDX-2 positive group versus 2.07 months (95%CI 2.07-10.8) in CDX-2 negative patients (p = 0.0011). Median OS was NR in CDX-2-positive patients versus 2.17 months (95% Confidence Interval CI 2.17-18.7) in CDX2-negative patients (p = 0.026). All CDX-2-positive patients achieved a disease response, one of them a complete response. Among CDX-2-negative patients, one achieved stable disease, while the other progressed rapidly (ORR: 100% vs 0%, p = 0.0005; DCR: 100% vs 50%, p = 0.02). Twelve patients received 1st-line pembrolizumab (11 CDX-2 positive and 1 CDX-2 negative) not reaching median PFS, while two patients (1 CDX-2 positive and 1 CDX-2 negative) received 3rd-line pembrolizumab reaching a median PFS of 10.8 months (95% CI, 10.8-12.1; p = 0.036). Although our study reports results on a small population, the prognostic role of CDX-2 in CRC seems confirmed and could drive a promising predictive role in defining the population more sensitive to immunotherapy treatment. Modulating the CDX-2/CXCL14 axis in CDX-2-negative patients could help overcome primary resistance to immunotherapy.
The transmembrane glycoprotein CD44, the major hyaluronan (HA) receptor, has been proven to regulate cell growth, survival, differentiation, and migration. It is therefore widely considered to be ...involved in carcinogenesis. Its role as a new therapeutic target in solid tumors is under evaluation in clinical trials. The prognostic value remains controversial. Here, we aimed to investigate the correlation between CD44 expression and the clinicopathological features and survival in metastatic colorectal cancer (mCRC) patients.
Data from 65 mCRC patients of the Medical Oncology Unit, University Hospital and University of Cagliari were retrospectively collected from 2008 to 2021. Immunohistochemical analysis was performed at the Pathology Division, University Hospital of Cagliari on 3 μm thick sections obtained from paraffin blocks. The intensity of immunohistochemical staining was subclassified into four groups: score 0 if negative or weak membrane staining in less than 10% of tumor cells; score 1+ if weak membrane staining in at least 10% of tumor cells or moderate membrane staining in less than 10% of tumor cells; score 2+ if moderate membrane staining in at least 10% of tumor cells or intensive membrane staining in less than 10% of tumor cells; score 3+ if intense membrane staining in at least 10% of tumor cells. Based on this score, we distinguished patients into low CD44 expression (score 0, 1+, 2+) and high CD44 expression (score 3+). Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; association between categorical variables: Fisher's exact test).
Patients' median age was 66 years (range 49-85). Regarding CD44 expression, score was 0 in 18 patients, 1+ in 15 patients, 2+ in 18 patients, and 3+ in 14 patients. Median overall survival (mOS) was 28.1 months (95%CI: 21.3-101). CD44 overexpression (3+) was correlated with poor prognosis (
= 0.0011; HR = 0.2), with a mOS of 14.5 months (95%CI 11.7 to 35.9) versus 30.7 months (95%CI 27.8 to 101) in lower CD44 expression. Higher CD44 expression was associated with clinically poor prognostic features: age ≥ 70 years (
= 0.0166); inoperable disease (
= 0.0008); stage IV at diagnosis (
= 0.0241); BRAF mutated (
= 0.0111), high-grade tumor (
= 0.0084).
CD44 markedly correlated with aggressive tumor behavior and contributed to the earlier progression of disease, thus suggesting its role as a novel prognostic marker and potential therapeutic target for mCRC patients.
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.
A review of clinical trials, retrospective ...studies and case reports was performed regarding molecular biomarkers with therapeutic implications.
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
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
mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (
) mutant patients. Data are still lacking on
, and TGF-β, which require further research.
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.
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.
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Background: Aging inevitably leads to an accumulation of senescent cells, and immune system cells aren't an exception. They can contribute to a pro-inflammatory state and be involved in the ...immune escape of cancer cells through a boosted PD-L1 expression. Immunocheckpoint inhibitors (ICIs) represent the standard of care in several cancer histotypes, and immune-related adverse events (irAEs) seem to be associated with better outcomes. ICIs represent a valid therapeutic agent in elderly patients too. However, there is a lack of data on irAEs and outcomes correlation in this subgroup of patients. This retrospective-prospective study aims to evaluate the relationship between thyroid dysfunction and progression-free survival (PFS) and overall survival (OS) in elderly patients undergoing ICIs. Methods: From January 2019 to January 2023, we retrospectively collected data from 65 elderly patients under treatment with ICIs at the Medical Oncology Unit of the University Hospital and University of Cagliari, Italy. All patients were affected by stage IV disease. The primary endpoint was PFS and the secondary endpoint was overall survival OS. Statistical analyses were performed using the MedCalc Statistical Software Version 20.216. Results: The median age was 76 (± 5,5); 15.38% were female, whereas 84.62% were male. The histologies were: melanoma (26.9%), lung cancer (48.0%), kidney cancer (15.3%), and colorectal cancer (9.8%). Compared to those without thyroid dysfunction during immunotherapy treatment, individuals with thyroid irAE had, at univariate analysis, longer median PFS (68 versus 26 months, p = 0.02, CI 95% 18.0-68.0, HR 0.29 0.10-0.83) and longer median OS (59 versus 39 months, p = 0.04, CI 95% 25.0-90.0 HR 0.50 0.25-0.99). Conclusions: In an era where biomarkers for immunotherapeutic agents are lacking, thyroid dysfunction irAE could be a predictive factor of better PFS and OS in elderly patients affected by cancer of various histology.
This study aimed to clarify the current knowledge on the use of immunotherapy in patients with advanced gastric(G)/gastroesophageal(GEJ) cancers.
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.
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.
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
•Advanced gastric (aG) and gastroesophageal junction (GEJ) cancers remain a poor prognosis disease.•Immune checkpoint inhibitors (ICIs) in first line could represent an attractive strategy for aG and GEJ cancer.•It’s necessary to find a combined positive score range to select patients that could benefit from ICIs.
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•Advanced hepatocellular carcinoma remains a disease with poor prognosis.•Immunotherapy is an attractive strategy for advanced hepatocellular carcinoma.•Interaction between ...immunotherapy and tumour microenvironment is crucial.
Advanced hepatocellular carcinoma (HCC) is the most frequent liver cancer. Immunotherapy has been explored in this disease in order to improve survival outcomes. Nowadays, scientific research is focusing especially on immune checkpoint inhibitors, in particular anti-PD1, anti-PD-L1 and anti-CTLA4 monoclonal antibodies (mAbs), as single-agent or in combination with other immunotherapy agents, target therapies, anti-vascular endothelial growth factor (VEGF) and other agents targeting specific molecular pathways. Other immunotherapy strategies have been assessed or are under investigation in advanced HCC, namely cytokines, adoptive cell therapy, oncolytic virus, cancer vaccines. Each treatment presents specific efficacy and toxicity profiles, strictly related to their mechanism of action and to advanced HCC tumour microenvironment (TME). The aim of this review is to outline the state-of-the-art of immunotherapy in advanced HCC treatment, highlighting data on already investigated treatment strategies, safety and toxicity (including HBV/HCV-related HCC), and ongoing clinical trials focusing on new promising therapeutic weapons.
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Background: Due to the inconsistent data on curative resection of isolated lung metastases (LM) from colorectal cancer (CRC) and the lack of specific recommendations, the therapeutic approaches ...for metastatic liver disease are mostly applied to LM treatment, despite differences in their biological behavior. Like Fong's criteria in CRC liver metastases, our study proposed a score associated with clinical outcomes in patients (pts) undergoing CRC lung metastasectomy, aiming to better pts' selection for surgery and the most appropriate therapeutic strategy. Methods: We retrospectively collected data from 260 pts (aged 18-85) who underwent CRC lung metastasectomy with curative intent from December 2002 to January 2022 at four Italian Centers: the Division of Thoracic Surgery at “A. Businco Cancer Center” in Cagliari, the Division of Thoracic Surgery at “Città della Salute e della Scienza” in Tourin, the Department of Thoracic Surgery at “IRCCS Azienda Ospedaliero-Universitaria” in Boulogne, and the Medical Oncology Unit of the University Hospital of Cagliari. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; association between categorical variables: Fisher's exact test). Results: We analyzed the impact of different clinicopathological features on overall survival (OS). At the univariate analysis: higher baseline CEA levels (p = 0.0001), disease-free survival less than or equal to 12 months (m) (p = 0.0043), LM size larger than 2 cm (p = 0.0187), multiple resectable nodules (p = 0.0083), and positive nodal status of the primary tumor (p = 0.0011) were associated with poorer prognosis. In a Cox regression model, these five characteristics retained their independent role for OS (p < 0.0001) and were chosen as criteria to be assigned one point each for clinical risk score. The 5-year survival rate in pts with 0 points was 88%, while no pts with a 5-points score survived at 2 years. Based on the 0-2 versus 3-5 score range, we obtained a significant difference in median OS: 101.7 m (95%CI 64.6 - 101.7) vs. 39.5 m (95%CI 27.3 - 87.5) respectively (p < 0.0001) stratifying pts into good and poor prognosis. Conclusions: The Meta-Lung Score appeared to be an exciting prognostic tool in selecting CRC pts’ candidates for radical surgical treatment when LM were diagnosed. Whether early surgery should be considered in pts with a score 0-2, the same choice should be taken with caution in pts with a score 3-5, for whom early chemotherapy would allow better assessment of tumor biology and appropriate selection for surgery.Table: see text
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.
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.
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.
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