New therapeutic targets in pancreatic cancer Lai, Eleonora; Puzzoni, Marco; Ziranu, Pina ...
Cancer treatment reviews,
December 2019, 2019-Dec, 2019-12-00, 20191201, Letnik:
81
Journal Article
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•Pancreatic cancer has disappointing response to cytotoxic drugs and poor prognosis.•To date, no targetable driver genes have been recognized for pancreatic cancer therapy.•The genomic ...characterization should be the base for clinical trials development.•In clinical trials, drug combination strategy seems the most interesting approach.
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.
Immune checkpoint inhibitors have reshaped the prognostic of several tumor types, including metastatic colorectal tumors with microsatellite instability (MSI). However, 90-95% of metastatic ...colorectal tumors are microsatellite stable (MSS) in which immunotherapy has failed to demonstrate meaningful clinical results. MSS colorectal tumors are considered immune-cold tumors. Several factors have been proposed to account for this lack of response to immune checkpoint blockade including low levels of tumor infiltrating lymphocytes, low tumor mutational burden, a high rate of WNT/β-catenin pathway mutations, and liver metastases which have been associated with immunosuppression. However, studies with novel combinations based on immune checkpoint inhibitors are showing promising activity in MSS colorectal cancer. Here, we review the underlying biological facts that preclude immunotherapy activity, and detail the different immune checkpoint inhibitor combinations evaluated, along with novel immune-based therapies, to overcome innate mechanisms of resistance in MSS colorectal cancer.
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.
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.
Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a ...milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical outcomes. Nevertheless, not all patients respond to treatment and some develop resistance. Therefore, the identification of predictive factors able to predict response to angiogenesis pathway blockade is required in order to identify the best candidates to receive these agents. Unfortunately, no predictive biomarkers have been prospectively validated to date. Over the years, research has focused on biologic factors such as genetic polymorphisms, circulating biomarkers, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and microRNA. Moreover, research efforts have evaluated the potential correlation of molecular biomarkers with imaging techniques used for tumor assessment as well as the application of imaging tools in clinical practice. In addition to functional imaging, radiomics, a relatively newer technique, shows real promise in the setting of correlating molecular medicine to radiological phenotypes.
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Background: Anti-angiogenic drugs represent a cornerstone of metastatic colorectal cancer (mCRC) patients (pts) treatment. Currently, no prognostic/predictive biomarkers were validated to ...identify who is more likely to benefit from these agents. We performed at our Centre a retrospective research to assess potential prognostic/predictive factors in this population. Methods: We retrospectively collected laboratory, radiological and clinical data of mCRC pts receiving anti-angiogenic agents at the Medical Oncology Unit of Cagliari University Hospital (2018- 09/2023) in order to assess their correlation with overall survival (OS) and progression free survival (PFS) from the treatment start. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; cut-off: ROC curves). Results: Globally, 32 mCRC pts were included in our research (19 male, 13 female; 12 RAS wild-type, 21 left-sided primary). 10 received anti-angiogenic drugs in the 1st-line, 12 in the 2nd-line (bevacizumab and aflibercept) and 10 in 1st-2nd line. Median OS was 34.8 months (m) (95%CI:24.7-41.6). We observed a statistically significant improve in OS (34.8 months m versus vs 8.2 m) in pts with higher monocyte count (>0.3x10
3
/μL; 95%CI 26.5-39.5 vs 95%CI 8.2-24.7, p=0.0103, HR 0.01), lower alcalin phosphatase (ALP; <136 U/l; p=0.0001, HR=0.0001; 95%CI 12-39.5 vs 95% CI 8.2-10.4), lactate dehydrogenasis (LDH; <365 U/l; p<0,0001, HR=0.0000006; 95%CI 24.7-39.5 vs 95% CI 8.2-10.4) and platelet to lymphocyte ratio (PLR; ≤253; p<0.0001, HR= 0.00000062; 95%CI 24.7-39.5 vs 95% CI 8.2-10.4). Median PFS was 14.9 m (95% CI 9.5-18.5). The same factors were significantly related to PFS, which was 18.3 m vs 2.7 m for higher monocyte count (95%CI 11.4-22.1 vs 95%CI 2.7-14, p=0.0386, HR=0.05), lower LDH (95%CI 11.4-22.1 vs 95%CI 2.7-8.9, p=0.0024, HR=0.004), lower PLR (95%CI 11.4-22.1 vs 95%CI 2.7-8.9, p=0.0024, HR=0.004) and 18.3 m vs 8.9 m for lower ALP (95%CI 11.4-23.3, p=0.0369, HR=0.04). Furthermore pts not developing bleeding during treatment showed a significant benefit in OS (39.5 m 95%CI 26.5-41.6 vs 8.2 m 95%CI 8.2-12, p< 0.0001, HR 0.000001761) and improved PFS (17.9 m 95%CI 9.9-18.4 vs 2.4 m 95%CI 2.4-2.7; p<0.0001). Conclusions: Our findings showed a promising prognostic role of baseline monocytes, ALP, LDH and PLR and absence of bleeding occurrence in mCRC patients receiving anti-angiogenic drugs, even if in a limited population. Further larger prospective studies are encouraged for confirmation.
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Background: In the last decade several studies have shown an increase in the incidence of early-onset PDAC (EO-PDAC), conventionally defined as cancer that occurs in adults between the ages of 18 ...and 49. Clinical and prognostic data on this setting are limited and conflicting. The aim of our study was to evaluate the clinical, and prognostic differences in a large group of patients with early onset mPDAC. Methods: We retrospectively collected data from 368 patients affected with metastatic pancreatic ductal adenocarcinoma, from 3 different Italian Institutions. All patients had one or more metastatic sites, and received first-line chemotherapy. The main objective of the study was to evaluate the median overall survival in EO-PDAC patients compared to late onset PDAC (LO-PDAC), while secondary endpoint was evaluations of mPFS. Statistical analysis was performed with the MedCalc package. Results: 30 (8,1%) patients were early onset and 338 (91,9%) were late onset; median age was 46 (±5) and 68 (±8), respectively. M/F ratios were 1:1 in both group. In the overall population mOS was significantly lower in EO-PDAC patients: 10,0 versus 15,0 months ( p = 0,03). Furthermore, mPFS was significantly lower in EO-PDAC patients: 5,0 versus 8,0 months ( p = 0,04). ORR obtained from 244 pts were: 11% in EO-PDAC and 24,7% in LO-PDAC. Conclusions: The results of our work, although limited by the retrospective nature of the study, showed a worse prognosis for patients with early onset PDAC compared to late onsets. Further investigations will be needed to better understand this growing group of patients from a molecular and therapeutic point of view.
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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: Glucose and other metabolites (lactates and glutamine) in the tumor microenvironment (TME) may alter the activity of the immune system cells. Cancer cells consume glucose and its ...decrease in the TME affects the function of tumour-infiltrating lymphocytes (TILs). Moreover, tumor-infiltrated immunosuppressive cells and vascular endothelial cells also deplete nutrients, in the TME, enhancing an immunosuppressive environment. On the basis of the results coming from our previous works regarding lymphocytes to monocytes ratio (LMr) and diabetes, suggesting a role for each of them as predictors of better outcomes, in this study we evaluate both of them in order to establish a possible role of them as outcomes predictive factors. Methods: Data from 228 patients (pts) were collected retrospectively from 2016 to 2021: 175 from the Medical Oncology Unit of University Hospital of Cagliari; 53 from the Medical Oncology Unit, AOU Ospedali Riuniti di Ancona. All pts had stage IV disease and received gemcitabine plus nab-paclitaxel 1st line chemotherapy. Statistical analysis was performed with the MedCalc package. We aimed to evaluate the correlation between treated DM2 and lymphocytes to monocytes ratio (LMr) ≥ 4 with outcomes. Survival distribution was assessed by Kaplan-Meier curves. Multivariate analysis was performed taking into consideration the following prognostic factors: sex, ECOG-PS, LMr, NLr, LDH, Ca19.9, and metastatic sites. Results: Median age was 68 (±9), 123/228 (54%) were male, 94/232 (40,6%) were affected by DM2 (insulin or metfomin-treated) and 138 (59,4%) pts were not affected by DM2. 52/228 (23%) pts had a LMr ≥ 4, 176/228 (77%) pts had a LMr < 4. In multivariate analysis, DM2 and LM ratio ≥ 4 were found to be independent factors associated with higher overall survival. Therefore, we divided the pts into 3 groups: co-presence DM2 and LM ≥ 4 (DM+LM+); absence of DM2 and LM ≥ 4 (DM-LM-); presence of DM2 or LM ≥ 4 (DM+LM- or DM-LM+). DM+LM+ demonstrated statistically significantly higher median OS than DM+LM-/DM-LM+ and DM-LM- (not reached versus 21 versus 9 months, respectively, p < 0.0001). Furthermore, DM+LM+ showed a statistically significant better median PFS than DM+LM-/DM-LM+ and DM-LM- (11 versus 9 versus 6 months, respectively, p = 0,0036). Conclusions: Results showed a correlation between pts with DM2/LMr ≥ 4 and better outcomes. This may suggest the presence of a link between glucose metabolism and lymphocytes activation. Antidiabetic medications could promote the inhibition of Warburg effect in tumor cells, and, consequently, provide a better glucose intake to extracellular microenvironment, and immune cells, including T lymphocytes. This process leads to a higher activity of T-cells and a better treatment response. Further studies are warranted.
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Background: Despite the most recent therapeutic achievements, pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and response to treatments. Among the most investigated ...prognostic biomarkers, the lymphocyte to monocyte ratio (LMr) is gaining increasing interest in literature, mostly in hematological malignancies, breast cancer, bladder cancer, non-small cell lung cancer, colorectal cancer, and resected pancreatic adenocarcinoma. In these settings, a higher LMr allows identifying a subset of patients with a better prognosis. Our study aimed to evaluate the role of the LMr as a prognostic factor in patients affected by metastatic PDAC and to find a cut-off value able to identify a subset of patients with better prognosis and possibly susceptible to other therapeutic options. Methods: Data from 228 patients were collected retrospectively from 2014 to 2021. 175 from the Department of Medical Oncology of the University Hospital of Cagliari and 53 from the Oncology Clinic - University Hospital of Ospedali Riuniti of Ancona. All patients had metastatic PDAC and blood samples were collected before starting first-line chemotherapy. The cut-off value for LMr was calculated according to the ROC curves at 6, 12, and 18 months. Kaplan-Meier curves were then obtained for the evaluation of survivals. Finally, multivariate analysis was performed, taking into consideration the following prognostic factors: sex, ECOG-PS, NL ratio, metastatic sites, Ca19.9 and LDH. Results: The median age was 68 y.o. (range 39-84 y.o.), 123 (54%) were males. Cut off value obtained for LMR, was 4. 156 (68,4%) patients had an LMr < 4 and 72 (31,6%) patients had an LMR ≥ 4. Patients with a ratio ≥ 4 showed a statistically significant difference in terms of median overall survival compared to patients with a ratio < 4 (23 months versus 11 months, p < 0.0001). First-line median progression-free survival was also different in patients with a value greater than or equal to 4 (11 months versus 6 months, p = 0.005), suggesting a better treatment response in the first group of patients. Finally, multivariate analysis showed that LMR ≥ 4 is an independent prognostic factor for OS ( p = 0.0005). Conclusions: The results of our study show that the lymphocyte to monocyte ratio could be an important prognostic factor in patients with metastatic pancreatic ductal adenocarcinoma, although the limitations of a retrospective study should be considered. Furthermore, these findings suggest the active role of the immune response in limiting disease progression, indicating a group of patients who could benefit most from a target or combined immunotherapy treatment.
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