Biomarkers in the Era of Precision Oncology

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 47034

Special Issue Editor

Special Issue Information

Dear Colleagues,

Cancer progression and metastasis consist of complex molecular mechanisms that negatively impact immune-related pathways. Even though our molecular and immunological knowledge of cancer have been extensively increased, standard therapies in several types of cancer still rely on chemotherapy and radiotherapy regimens. On the other hand, novel therapeutic modalities, including targeted therapies, vaccinations, and immune checkpoint blockade, have been demonstrated to induce clinical effectiveness in a limited number of patients.

Therefore, combinatorial treatments targeting such molecular and immune pathways are mandatory for an effective cancer therapy. Such treatments rely on prognostic and/or predictive biomarkers that precisely characterize each patients’ molecular and immune landscapes, making their discovery an urgent need.

Precision oncology has already begun to signal a new era in cancer therapy. Nevertheless, we are still far from the discovery of reliable biomarkers for the selection of patients who can benefit from immunotherapeutic or targeted interventions. Although several biomarkers have been described in the literature, including the tumor mutational burden, the number, function and location of tumor-infiltrating lymphocytes, and the expression of programmed death-ligand 1, there remains an unmet need for the discovery of additional biomarkers to promote novel and tailored therapeutic modalities.

In this Special Issue, we aim to highlight the importance of integrating cancer patients’ clinicopathological parameters and immune-related and/or tumor-associated biomarkers which will eventually guide the accurate accrual of patients as well as optimize clinical decision-making. To this end, it is within our priorities to present studies expanding from basic to translational research and clinical trials involving novel “multi-omics” approaches, including genomic, proteomic, transcriptomic and metabolomic analyses of cancerous tissues and liquid biopsies. Such analyses, in conjunction with the acquired clinical information, will create a multi-modal data system that will allow for the definition of favorable personalized therapeutic protocols and avoid over-dosing phenomena, which may lead to ineffective therapies and adverse side effects. I hope that this Special Issue will advance our knowledge of alternative therapeutic modalities for applying precision oncology in the clinical management of cancer, simultaneously proposing the most promising perspectives for the future.

Dr. Constantin N. Baxevanis
Guest Editor

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Keywords

  • cancer
  • precision oncology
  • omics
  • biomarkers
  • high-throughput technologies
  • immunotherapies
  • targeted therapies

Published Papers (20 papers)

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Editorial

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8 pages, 229 KiB  
Editorial
Biomarkers in the Era of Precision Oncology
Cancers 2023, 15(6), 1782; https://doi.org/10.3390/cancers15061782 - 15 Mar 2023
Viewed by 970
Abstract
Cancer heterogeneity provides a formidable obstacle to optimizing clinical protocols to achieve durable clinical responses [...] Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)

Research

Jump to: Editorial, Review, Other

16 pages, 3404 KiB  
Article
Quantitative Evaluation of Stem-like Markers of Human Glioblastoma Using Single-Cell RNA Sequencing Datasets
Cancers 2023, 15(5), 1557; https://doi.org/10.3390/cancers15051557 - 02 Mar 2023
Cited by 2 | Viewed by 1427
Abstract
Targeting glioblastoma (GBM) stem-like cells (GSCs) is a common interest in both the laboratory investigation and clinical treatment of GBM. Most of the currently applied GBM stem-like markers lack validation and comparison with common standards regarding their efficiency and feasibility in various targeting [...] Read more.
Targeting glioblastoma (GBM) stem-like cells (GSCs) is a common interest in both the laboratory investigation and clinical treatment of GBM. Most of the currently applied GBM stem-like markers lack validation and comparison with common standards regarding their efficiency and feasibility in various targeting methods. Using single-cell RNA sequencing datasets from 37 GBM patients, we obtained a large pool of 2173 GBM stem-like marker candidates. To evaluate and select these candidates quantitatively, we characterized the efficiency of the candidate markers in targeting the GBM stem-like cells by their frequencies and significance of being the stem-like cluster markers. This was followed by further selection based on either their differential expression in GBM stem-like cells compared with normal brain cells or their relative expression level compared with other expressed genes. The cellular location of the translated protein was also considered. Different combinations of selection criteria highlight different markers for different application scenarios. By comparing the commonly used GSCs marker CD133 (PROM1) with markers selected by our method regarding their universality, significance, and abundance, we revealed the limitations of CD133 as a GBM stem-like marker. Overall, we propose BCAN, PTPRZ1, SOX4, etc. for laboratory-based assays with samples free of normal cells. For in vivo targeting applications that require high efficiency in targeting the stem-like subtype, the ability to distinguish GSCs from normal brain cells, and a high expression level, we recommend the intracellular marker TUBB3 and the surface markers PTPRS and GPR56. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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15 pages, 1281 KiB  
Article
Implementation of Comprehensive Genomic Profiling in Ovarian Cancer Patients: A Retrospective Analysis
Cancers 2023, 15(1), 218; https://doi.org/10.3390/cancers15010218 - 29 Dec 2022
Cited by 1 | Viewed by 1266
Abstract
Comprehensive genomic profiling (CGP) allows for the detection of driver alterations at high resolution, but the limited number of approved targeted therapies and their high costs have contributed to its limited clinical utilization. We retrospectively compared data of 946 women with ovarian cancer [...] Read more.
Comprehensive genomic profiling (CGP) allows for the detection of driver alterations at high resolution, but the limited number of approved targeted therapies and their high costs have contributed to its limited clinical utilization. We retrospectively compared data of 946 women with ovarian cancer (11.4% were referred to CGP, and 88.6% served as control) to examine whether CGP provides a prognosis benefit. Patient baseline parameters were similar between the groups. Cox regression analysis adjusted for age, disease stage at diagnosis, and recurrence status showed statistically significantly longer median overall survival (mOS) in the CGP group versus the control (73.4 versus 54.5 months, p < 0.001). Fifty-four patients (52.9%) had actionable mutations with potential treatments; twenty-six (48.2%) were treated with matched targeted therapy, showing a trend for longer mOS than the eighty-six women in the CGP group who were not given a suggested treatment (105.5 versus 63.6 months, p = 0.066). None of the genomic alterations predicted metastasis location. CCNE1 amplification and KRAS mutations were associated with shorter mOS. Patients with tumor mutation burden ≥4 mutations/megabase had longer mOS. High loss of heterozygosity was associated with longer mOS (99.0 versus 48.2 months, p = 0.004). CGP testing may provide both prognostic and predictive insights for treatment of patients with ovarian cancer. Prospective studies of larger cohorts are warranted. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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14 pages, 2953 KiB  
Article
Association between Intratumoral CD8+ T Cells with FoxP3+ and CD163+ Cells: A Potential Immune Intrinsic Negative Feedback Mechanism for Acquired Immune Resistance
Cancers 2022, 14(24), 6208; https://doi.org/10.3390/cancers14246208 - 15 Dec 2022
Cited by 2 | Viewed by 1067
Abstract
Acquired immune resistance (AIR) describes a situation in which cancer patients who initially responded clinically to immunotherapies, after a certain period of time, progress with their disease. Considering that AIR represents a feedback response of the tumor against the immune attack generated during [...] Read more.
Acquired immune resistance (AIR) describes a situation in which cancer patients who initially responded clinically to immunotherapies, after a certain period of time, progress with their disease. Considering that AIR represents a feedback response of the tumor against the immune attack generated during the course of immunotherapies, it is conceivable that AIR may also occur before treatment initiation as a mechanism to escape endogenous adaptive antitumor immunity (EAAI). In the present study, we assessed the EAAI in paraffin-embedded breast primary tumor tissue samples and drew correlations with the clinical outcomes. In particular, we analyzed densities of CD8+ cells as elements mediating antitumor cytotoxicity, and of CD163+ and FoxP3+ cells as suppressor elements. We found a direct correlation between the densities of CD8+ cells and of CD163+ and/or FoxP3+ cells in the vast majority of patients’ tumors. Importantly, the vast majority of patients whose tumors were overpopulated by CD8+ cells developed AIR, which was characterized by high intratumoral CD163+ and/or FoxP3+ cell densities and reduced overall survival (OS). We also showed that AIR depends on the levels of CD8+ cell-ratios in the tumor center to the invasive margin. Our data suggest that tumors develop AIR only when under a robust endogenous immune pressure. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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22 pages, 1251 KiB  
Article
Integrated Biomarker Analysis Reveals L1CAM as a Potential Stratification Marker for No Specific Molecular Profile High-Risk Endometrial Carcinoma
Cancers 2022, 14(21), 5429; https://doi.org/10.3390/cancers14215429 - 03 Nov 2022
Cited by 9 | Viewed by 1528
Abstract
Histopathologic assessment of high-risk endometrial cancer (EC) suffers from intersubject variability and poor reproducibility. The pragmatic classification in four molecular subgroups helps to overcome these limits, showing a significant prognostic value. The “no specific molecular profile” (NSMP) is the most heterogeneous EC subgroup, [...] Read more.
Histopathologic assessment of high-risk endometrial cancer (EC) suffers from intersubject variability and poor reproducibility. The pragmatic classification in four molecular subgroups helps to overcome these limits, showing a significant prognostic value. The “no specific molecular profile” (NSMP) is the most heterogeneous EC subgroup, requiring further characterization to better guide its clinical management. DNA sequencing of POLE exonuclease domain and immunohistochemistry for PMS2, MSH6, and p53 were performed in order to stratify a cohort of 94 high-risk EC patients in the four molecular subgroups. Moreover, a panel of seven additional biomarkers was tested. Patients were found to be 16% POLE-mutated, 36% mismatch repair-deficient, 27% p53-abnormal, and 21% NSMP. In the multivariable model, molecular groups confirmed their significant association with disease-specific survival and progression-free survival, with p53-abnormal and NSMP endometrial cancer characterized by poor outcomes. Among the additional evaluated biomarkers, L1CAM was the only one with a significant prognostic value within the NSMP subgroup. NSMP/L1CAM-positive patients experienced the worst outcome and were “early-relapsing” after platinum-based chemotherapy, with a significantly shorter platinum-free interval compared to L1CAM-negative patients. L1CAM appears to be a promising candidate as a prognostic and predictive biomarker in the high-risk NSMP subgroup, which is actually known to lack specific molecular markers. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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17 pages, 7238 KiB  
Article
Increased Density of Growth Differentiation Factor-15+ Immunoreactive M1/M2 Macrophages in Prostate Cancer of Different Gleason Scores Compared with Benign Prostate Hyperplasia
Cancers 2022, 14(19), 4591; https://doi.org/10.3390/cancers14194591 - 22 Sep 2022
Cited by 3 | Viewed by 1856
Abstract
Although growth differentiation factor-15 (GDF-15) is highly expressed in PCa, its role in the development and progression of PCa is unclear. The present study aims to determine the density of GDF-15+ cells and immune cells (M1-/M2 macrophages [MΦ], lymphocytes) in PCa of different [...] Read more.
Although growth differentiation factor-15 (GDF-15) is highly expressed in PCa, its role in the development and progression of PCa is unclear. The present study aims to determine the density of GDF-15+ cells and immune cells (M1-/M2 macrophages [MΦ], lymphocytes) in PCa of different Gleason scores (GS) compared to BPH. Immunohistochemistry and double immunofluorescence were performed on paraffin-embedded human PCa and BPH biopsies with antibodies directed against GDF-15, CD68 (M1 MΦ), CD163 (M2 MΦ), CD4, CD8, CD19 (T /B lymphocytes), or PD-L1. PGP9.5 served as a marker for innervation and neuroendocrine cells. GDF-15+ cell density was higher in all GS than in BPH. CD68+ MΦ density in GS9 and CD163+ MΦ exceeded that in BPH. GDF-15+ cell density correlated significantly positively with CD68+ or CD163+ MΦ density in extratumoral areas. Double immunoreactive GDF-15+/CD68+ cells were found as transepithelial migrating MΦ. Stromal CD68+ MΦ lacked GDF-15+. The area of PGP9.5+ innervation was higher in GS9 than in BPH. PGP9.5+ cells, occasionally copositive for GDF-15+, also occurred in the glandular epithelium. In GS6, but not in BPH, GDF-15+, PD-L1+, and CD68+ cells were found in epithelium within luminal excrescences. The degree of extra-/intra-tumoral GDF-15 increases in M1/M2Φ is proposed to be useful to stratify progredient malignancy of PCa. GDF-15 is a potential target for anti-tumor therapy. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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13 pages, 2276 KiB  
Article
Genetic Analysis Reveals the Prognostic Significance of the DNA Mismatch Repair Gene MSH2 in Advanced Prostate Cancer
Cancers 2022, 14(1), 223; https://doi.org/10.3390/cancers14010223 - 04 Jan 2022
Cited by 6 | Viewed by 1921
Abstract
DNA damage repair is frequently dysregulated in advanced prostate cancer and has been linked to cancer susceptibility and survival outcomes. The aim of this study is to assess the influence of genetic variants in DNA damage repair pathways on the prognosis of prostate [...] Read more.
DNA damage repair is frequently dysregulated in advanced prostate cancer and has been linked to cancer susceptibility and survival outcomes. The aim of this study is to assess the influence of genetic variants in DNA damage repair pathways on the prognosis of prostate cancer. Specifically, 167 single nucleotide polymorphisms (SNPs) in 18 DNA damage repair pathway genes were assessed for association with cancer-specific survival (CSS), overall survival (OS), and progression-free survival (PFS) in a cohort of 630 patients with advanced prostate cancer receiving androgen deprivation therapy. Univariate analysis identified four SNPs associated with CSS, four with OS, and two with PFS. However, only MSH2 rs1400633 C > G showed a significant association upon multivariate analysis and multiple testing adjustments (hazard ratio = 0.75, 95% confidence interval = 0.63–0.90, p = 0.002). Furthermore, rs1400633 risk allele C increased MSH2 expression in the prostate and other tissues, which correlated with more aggressive prostate cancer characteristics. A meta-analysis of 31 gene expression datasets revealed significantly higher MSH2 expression in prostate cancer than in normal tissues (p < 0.001), and this high expression was associated with a poor prognosis of prostate cancer (p = 0.002). In summary, we identified MSH2 rs1400633 as an independent prognostic biomarker for prostate cancer survival, and the association of MSH2 with cancer progression lends relevance to our findings. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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14 pages, 1612 KiB  
Article
Microsatellite Instability, Epstein–Barr Virus, and Programmed Cell Death Ligand 1 as Predictive Markers for Immunotherapy in Gastric Cancer
Cancers 2022, 14(1), 218; https://doi.org/10.3390/cancers14010218 - 03 Jan 2022
Cited by 10 | Viewed by 2064
Abstract
Immunotherapy benefits selected cases of gastric cancer (GC), but the correlation between biomarkers and prognosis is still unclear. Fifty-two patients with GC who underwent immunotherapy were enrolled from June 2016 to December 2020. Their clinical features and biomarkers—microsatellite instability-high (MSI-H), programmed cell death [...] Read more.
Immunotherapy benefits selected cases of gastric cancer (GC), but the correlation between biomarkers and prognosis is still unclear. Fifty-two patients with GC who underwent immunotherapy were enrolled from June 2016 to December 2020. Their clinical features and biomarkers—microsatellite instability-high (MSI-H), programmed cell death ligand 1 (PD-L1) combined positive score (CPS), and Epstein–Barr encoding region (EBER)—were analyzed. Eight patients had MSI-H, five patients had EBER, 29 patients had CPS ≥ 1, and 20 patients had no biomarker. The overall response rates (ORRs) of the MSI-H, EBER, PD-L1 CPS ≥ 1, and all-negative group were 75%, 60%, 44.8%, and 15%, respectively. Compared with that of the all-negative group, progression-free survival (PFS) was better in the MSI-H (p = 0.018), CPS ≥ 5 (p = 0.012), and CPS ≥ 10 (p = 0.006) groups, but not in the EBER (p = 0.2) and CPS ≥ 1 groups (p = 0.35). Ten patients had combined biomarkers, CPS ≥ 1 with either MSI-H or EBER. The ORRs were 66.7% for CPS ≥ 1 and MSI-H and 75% for CPS ≥ 1 and EBER. PFS was better in patients with combined biomarkers (p = 0.01). MSI-H, EBER, and CPS are useful biomarkers for predicting the efficacy of immunotherapy. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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15 pages, 8805 KiB  
Article
Diagnostic and Prognostic Implications of Caspase-1 and PD-L1 Co-Expression Patterns in Myelodysplastic Syndromes
Cancers 2021, 13(22), 5712; https://doi.org/10.3390/cancers13225712 - 15 Nov 2021
Cited by 6 | Viewed by 1776
Abstract
Background: The inflammasome plays an essential role in lower risk MDS and immune subversion, with the up-regulation of immune checkpoint molecules in the progression to higher-risk disease. In this study, we explored the utility of immune-related biomarkers for the diagnosis and prognosis of [...] Read more.
Background: The inflammasome plays an essential role in lower risk MDS and immune subversion, with the up-regulation of immune checkpoint molecules in the progression to higher-risk disease. In this study, we explored the utility of immune-related biomarkers for the diagnosis and prognosis of MDS. Methods: We performed an exploratory, case-control study with 20 randomly selected MDS patients and nine controls with non-inflammatory (n = 3) and inflammatory conditions (n = 6). Patients were stratified in groups of lower (n = 10) and higher risk (n = 10) using IPSS-R. For the exploration of inflammasome and immune checkpoint activities, the expression of caspase-1 (Casp1), programmed cell death protein 1 (PD-1) and its ligand (PD-L1) were assessed in bone marrow samples using immunohistochemistry. Results: In multivariate analysis, we observed significant differences for Casp1 but not PD1/PD-L1 expression in our four conditions (p = 0.003). We found a discordant co-expression of Casp1/PD-L1 in MDS (rho = −0.41, p = 0.07) compared with a concordant co-expression in controls (rho = 0.64, p = 0.06). Neutrophil counts correlated directly with Casp1 (rho = 0.57, p = 0.009) but inversely with PD-L1 expression (rho = −0.58, p = 0.007). Conclusion: We identified characteristic discordant co-expression patterns in lower- (Casp1high/PD-L1low) and higher-risk MDS (Casp1low/PD-L1high), contrasting with concordant patterns in the non-inflammatory (Casp1low/PD-L1low) and inflammatory conditions (Casp1high/PD-L1high). Further validation is warranted in larger, prospective studies. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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30 pages, 16061 KiB  
Article
Immune-Omics Networks of CD27, PD1, and PDL1 in Non-Small Cell Lung Cancer
Cancers 2021, 13(17), 4296; https://doi.org/10.3390/cancers13174296 - 26 Aug 2021
Cited by 13 | Viewed by 3360
Abstract
To date, there are no prognostic/predictive biomarkers to select chemotherapy, immunotherapy, and radiotherapy in individual non-small cell lung cancer (NSCLC) patients. Major immune-checkpoint inhibitors (ICIs) have more DNA copy number variations (CNV) than mutations in The Cancer Genome Atlas (TCGA) NSCLC tumors. Nevertheless, [...] Read more.
To date, there are no prognostic/predictive biomarkers to select chemotherapy, immunotherapy, and radiotherapy in individual non-small cell lung cancer (NSCLC) patients. Major immune-checkpoint inhibitors (ICIs) have more DNA copy number variations (CNV) than mutations in The Cancer Genome Atlas (TCGA) NSCLC tumors. Nevertheless, CNV-mediated dysregulated gene expression in NSCLC is not well understood. Integrated CNV and transcriptional profiles in NSCLC tumors (n = 371) were analyzed using Boolean implication networks for the identification of a multi-omics CD27, PD1, and PDL1 network, containing novel prognostic genes and proliferation genes. A 5-gene (EIF2AK3, F2RL3, FOSL1, SLC25A26, and SPP1) prognostic model was developed and validated for patient stratification (p < 0.02, Kaplan–Meier analyses) in NSCLC tumors (n = 1163). A total of 13 genes (COPA, CSE1L, EIF2B3, LSM3, MCM5, PMPCB, POLR1B, POLR2F, PSMC3, PSMD11, RPL32, RPS18, and SNRPE) had a significant impact on proliferation in 100% of the NSCLC cell lines in both CRISPR-Cas9 (n = 78) and RNA interference (RNAi) assays (n = 92). Multiple identified genes were associated with chemoresponse and radiotherapy response in NSCLC cell lines (n = 117) and patient tumors (n = 966). Repurposing drugs were discovered based on this immune-omics network to improve NSCLC treatment. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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16 pages, 2088 KiB  
Article
PTEN and DNA Ploidy Status by Machine Learning in Prostate Cancer
Cancers 2021, 13(17), 4291; https://doi.org/10.3390/cancers13174291 - 26 Aug 2021
Cited by 4 | Viewed by 3157
Abstract
Machine learning (ML) is expected to improve biomarker assessment. Using convolution neural networks, we developed a fully-automated method for assessing PTEN protein status in immunohistochemically-stained slides using a radical prostatectomy (RP) cohort (n = 253). It was validated according to a predefined [...] Read more.
Machine learning (ML) is expected to improve biomarker assessment. Using convolution neural networks, we developed a fully-automated method for assessing PTEN protein status in immunohistochemically-stained slides using a radical prostatectomy (RP) cohort (n = 253). It was validated according to a predefined protocol in an independent RP cohort (n = 259), alone and by measuring its prognostic value in combination with DNA ploidy status determined by ML-based image cytometry. In the primary analysis, automatically assessed dichotomized PTEN status was associated with time to biochemical recurrence (TTBCR) (hazard ratio (HR) = 3.32, 95% CI 2.05 to 5.38). Patients with both non-diploid tumors and PTEN-low had an HR of 4.63 (95% CI 2.50 to 8.57), while patients with one of these characteristics had an HR of 1.94 (95% CI 1.15 to 3.30), compared to patients with diploid tumors and PTEN-high, in univariable analysis of TTBCR in the validation cohort. Automatic PTEN scoring was strongly predictive of the PTEN status assessed by human experts (area under the curve 0.987 (95% CI 0.968 to 0.994)). This suggests that PTEN status can be accurately assessed using ML, and that the combined marker of automatically assessed PTEN and DNA ploidy status may provide an objective supplement to the existing risk stratification factors in prostate cancer. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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14 pages, 1888 KiB  
Article
TP53 Mutation as a Prognostic and Predictive Marker in Sarcoma: Pooled Analysis of MOSCATO and ProfiLER Precision Medicine Trials
Cancers 2021, 13(13), 3362; https://doi.org/10.3390/cancers13133362 - 05 Jul 2021
Cited by 6 | Viewed by 3088
Abstract
(1) Background: locally resected high-grade sarcomas relapse in 40% of cases. There is no prognostic or predictive genomic marker for response to peri-operative chemotherapy. (2) Methods: MOSCATO and ProfiLER are pan-tumor prospective precision medicine trials for advanced tumors. Molecular analysis in both trials [...] Read more.
(1) Background: locally resected high-grade sarcomas relapse in 40% of cases. There is no prognostic or predictive genomic marker for response to peri-operative chemotherapy. (2) Methods: MOSCATO and ProfiLER are pan-tumor prospective precision medicine trials for advanced tumors. Molecular analysis in both trials comprised targeted next-generation sequencing and comparative genomic hybridization array. We investigated if molecular alterations identified in these trials in sarcomas were associated with disease-free survival (DFS) and response to anthracyclines. (3) Results: this analysis included 215 sarcomas, amongst which 53 leiomyosarcomas, 27 rhabdomyosarcomas, 20 undifferentiated pleomorphic sarcomas, and 17 liposarcomas. The most frequently altered gene was TP53 (46 mutations and eight deletions). There were 149 surgically resected localized sarcomas. Median DFS in TP53 wild type (WT), deleted, and mutated sarcomas was 16, 10, and 10 months, respectively (p = 0.028; deletions: HR = 1.55; 95% CI = 0.75–3.19; mutations: HR = 1.70; 95%CI = 1.13–2.64). In multivariate analysis, TP53 mutations remained associated with shorter DFS (p = 0.027; HR = 2.30; 95%CI = 1.10–4.82). There were 161 localized and advanced sarcomas evaluable for response to anthracyclines. Objective response rates were 35% and 55% in TP53 WT and mutated sarcomas, respectively (OR = 2.24; 95%CI = 1.01–5.03; p = 0.05). In multivariate analysis, TP53 mutations remained associated with increased response (OR = 3.24; 95%CI = 1.30–8.45; p = 0.01). (4) Conclusions: TP53 mutations are associated with shorter DFS and increased response to anthracyclines. Post-validation, these findings could assist in decision-making for peri-operative treatments. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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16 pages, 3837 KiB  
Article
Blockade of HVEM for Prostate Cancer Immunotherapy in Humanized Mice
Cancers 2021, 13(12), 3009; https://doi.org/10.3390/cancers13123009 - 16 Jun 2021
Cited by 17 | Viewed by 3456
Abstract
The herpes virus entry mediator (HVEM) delivers a negative signal to T cells mainly through the B and T lymphocyte attenuator (BTLA) molecule. Thus, HVEM/BTLA may represent a novel immune checkpoint during an anti-tumor immune response. However, a formal demonstration that HVEM can [...] Read more.
The herpes virus entry mediator (HVEM) delivers a negative signal to T cells mainly through the B and T lymphocyte attenuator (BTLA) molecule. Thus, HVEM/BTLA may represent a novel immune checkpoint during an anti-tumor immune response. However, a formal demonstration that HVEM can represent a target for cancer immunotherapy is still lacking. Here, we first showed that HVEM and BTLA mRNA expression levels were associated with a worse progression-free interval in patients with prostate adenocarcinomas, indicating a detrimental role for the HVEM/BTLA immune checkpoint during prostate cancer progression. We then showed that administration of a monoclonal antibody to human HVEM resulted in a twofold reduction in the growth of a prostate cancer cell line in NOD.SCID.gc-null mice reconstituted with human T cells. Using CRISPR/Cas9, we showed that the therapeutic effect of the mAb depended on HVEM expression by the tumor, with no effect on graft vs. host disease or activation of human T cells in the spleen. In contrast, the proliferation and number of tumor-infiltrating leukocytes increased following treatment, and depletion of CD8+ T cells partly alleviated treatment’s efficacy. The expression of genes belonging to various T cell activation pathways was enriched in tumor-infiltrating leukocytes, whereas genes associated with immuno-suppressive pathways were decreased, possibly resulting in modifications of leukocyte adhesion and motility. Finally, we developed a simple in vivo assay in humanized mice to directly demonstrate that HVEM expressed by the tumor is an immune checkpoint for T cell-mediated tumor control. Our results show that targeting HVEM is a promising strategy for prostate cancer immunotherapy. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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Review

Jump to: Editorial, Research, Other

16 pages, 2513 KiB  
Review
The Receptor for Advanced Glycation Endproducts (RAGE) and Its Ligands S100A8/A9 and High Mobility Group Box Protein 1 (HMGB1) Are Key Regulators of Myeloid-Derived Suppressor Cells
Cancers 2023, 15(4), 1026; https://doi.org/10.3390/cancers15041026 - 06 Feb 2023
Cited by 3 | Viewed by 2088
Abstract
Immunotherapies including checkpoint blockade immunotherapy (CBI) and chimeric antigen receptor T cells (CAR-T) have revolutionized cancer treatment for patients with certain cancers. However, these treatments are not effective for all cancers, and even for those cancers that do respond, not all patients benefit. [...] Read more.
Immunotherapies including checkpoint blockade immunotherapy (CBI) and chimeric antigen receptor T cells (CAR-T) have revolutionized cancer treatment for patients with certain cancers. However, these treatments are not effective for all cancers, and even for those cancers that do respond, not all patients benefit. Most cancer patients have elevated levels of myeloid-derived suppressor cells (MDSCs) that are potent inhibitors of antitumor immunity, and clinical and animal studies have demonstrated that neutralization of MDSCs may restore immune reactivity and enhance CBI and CAR-T immunotherapies. MDSCs are homeostatically regulated in that elimination of mature circulating and intratumoral MDSCs results in increased production of MDSCs from bone marrow progenitor cells. Therefore, targeting MDSC development may provide therapeutic benefit. The pro-inflammatory molecules S100A8/A9 and high mobility group box protein 1 (HMGB1) and their receptor RAGE are strongly associated with the initiation and progression of most cancers. This article summarizes the literature demonstrating that these molecules are integrally involved in the early development, accumulation, and suppressive activity of MDSCs, and postulates that S100A8/A9 and HMGB1 serve as early biomarkers of disease and in conjunction with RAGE are potential targets for reducing MDSC levels and enhancing CBI and CAR-T immunotherapies. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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16 pages, 3163 KiB  
Review
T-Cell Repertoire in Tumor Radiation: The Emerging Frontier as a Radiotherapy Biomarker
Cancers 2022, 14(11), 2674; https://doi.org/10.3390/cancers14112674 - 27 May 2022
Cited by 5 | Viewed by 2035
Abstract
Radiotherapy (RT) is a therapeutic modality that aims to eliminate malignant cells through the induction of DNA damage in the irradiated tumor site. In addition to its cytotoxic properties, RT also induces mechanisms that result in the promotion of antitumor immunity both locally [...] Read more.
Radiotherapy (RT) is a therapeutic modality that aims to eliminate malignant cells through the induction of DNA damage in the irradiated tumor site. In addition to its cytotoxic properties, RT also induces mechanisms that result in the promotion of antitumor immunity both locally within the irradiation field but also at distant tumor lesions, a phenomenon that is known as the “abscopal” effect. Because the immune system is capable of sensing the effects of RT, several treatment protocols have been assessing the synergistic role of radiotherapy combined with immunotherapy, collectively referred to as radioimmunotherapy. Herein, we discuss mechanistic insights underlying RT-based immunomodulation, which also enhance our understanding of how RT regulates antitumor T-cell-mediated immunity. Such knowledge is essential for the discovery of predictive biomarkers and for the improvement of clinical trials investigating the efficacy of radio-immunotherapeutic modalities in cancer patients. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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33 pages, 1217 KiB  
Review
Emerging Biomarkers for Immunotherapy in Glioblastoma
Cancers 2022, 14(8), 1940; https://doi.org/10.3390/cancers14081940 - 12 Apr 2022
Cited by 6 | Viewed by 2989
Abstract
Immunotherapy has shown clinical benefits in several solid malignancies—in particular, melanoma and non-small cell lung cancer. However, in other solid tumours such as glioblastoma (GBM), the response to immunotherapy has been more variable, and except for anti-PD-1 for patients with microsatellite instable (MSI)+ [...] Read more.
Immunotherapy has shown clinical benefits in several solid malignancies—in particular, melanoma and non-small cell lung cancer. However, in other solid tumours such as glioblastoma (GBM), the response to immunotherapy has been more variable, and except for anti-PD-1 for patients with microsatellite instable (MSI)+ cancers, no immunotherapy is currently approved for GBM patients. GBM is the most common and most aggressive brain cancer with a very poor prognosis and a median overall survival of 15 months. A few prognostic biomarkers have been identified and are used to some extent, but apart from MSI, no biomarkers are used for patient stratification for treatments other than the standard of care, which was established 15 years ago. Around 25% of new treatments investigated in GBM are immunotherapies. Recent studies indicate that the use of integrated and validated immune correlates predicting the response and guiding treatments could improve the efficacy of immunotherapy in GBM. In this review, we will give an overview of the current status of immunotherapy and biomarkers in use in GBM with the main challenges of treatment in this disease. We will also discuss emerging biomarkers that could be used in future immunotherapy strategies for patient stratification and potentially improved treatment efficacy. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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21 pages, 1291 KiB  
Review
Harnessing Liquid Biopsies to Guide Immune Checkpoint Inhibitor Therapy
Cancers 2022, 14(7), 1669; https://doi.org/10.3390/cancers14071669 - 25 Mar 2022
Cited by 7 | Viewed by 3207
Abstract
Immunotherapy (IO), involving the use of immune checkpoint inhibition, achieves improved response-rates and significant disease-free survival for some cancer patients. Despite these beneficial effects, there is poor predictability of response and substantial rates of innate or acquired resistance, resulting in heterogeneous responses among [...] Read more.
Immunotherapy (IO), involving the use of immune checkpoint inhibition, achieves improved response-rates and significant disease-free survival for some cancer patients. Despite these beneficial effects, there is poor predictability of response and substantial rates of innate or acquired resistance, resulting in heterogeneous responses among patients. In addition, patients can develop life-threatening adverse events, and while these generally occur in patients that also show a tumor response, these outcomes are not always congruent. Therefore, predicting a response to IO is of paramount importance. Traditionally, tumor tissue analysis has been used for this purpose. However, minimally invasive liquid biopsies that monitor changes in blood or other bodily fluid markers are emerging as a promising cost-effective alternative. Traditional biomarkers have limitations mainly due to difficulty in repeatedly obtaining tumor tissue confounded also by the spatial and temporal heterogeneity of tumours. Liquid biopsy has the potential to circumvent tumor heterogeneity and to help identifying patients who may respond to IO, to monitor the treatment dynamically, as well as to unravel the mechanisms of relapse. We present here a review of the current status of molecular markers for the prediction and monitoring of IO response, focusing on the detection of these markers in liquid biopsies. With the emerging improvements in the field of liquid biopsy, this approach has the capacity to identify IO-eligible patients and provide clinically relevant information to assist with their ongoing disease management. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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32 pages, 3055 KiB  
Review
Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets
Cancers 2022, 14(3), 664; https://doi.org/10.3390/cancers14030664 - 28 Jan 2022
Cited by 4 | Viewed by 3759
Abstract
Cancer is the second leading cause of death globally. One of the main hallmarks in cancer is the functional deregulation of crucial molecular pathways via driver genetic events that lead to abnormal gene expression, giving cells a selective growth advantage. Driver events are [...] Read more.
Cancer is the second leading cause of death globally. One of the main hallmarks in cancer is the functional deregulation of crucial molecular pathways via driver genetic events that lead to abnormal gene expression, giving cells a selective growth advantage. Driver events are defined as mutations, fusions and copy number alterations that are causally implicated in oncogenesis. Molecular analysis on tissues that have originated from a wide range of anatomical areas has shown that mutations in different members of several pathways are implicated in different cancer types. In recent decades, significant efforts have been made to incorporate this knowledge into daily medical practice, providing substantial insight towards clinical diagnosis and personalized therapies. However, since there is still a strong need for more effective drug development, a deep understanding of the involved signaling mechanisms and the interconnections between these pathways is highly anticipated. Here, we perform a systemic analysis on cancer patients included in the Pan-Cancer Atlas project, with the aim to select the ten most highly mutated signaling pathways (p53, RTK-RAS, lipids metabolism, PI-3-Kinase/Akt, ubiquitination, b-catenin/Wnt, Notch, cell cycle, homology directed repair (HDR) and splicing) and to provide a detailed description of each pathway, along with the corresponding therapeutic applications currently being developed or applied. The ultimate scope is to review the current knowledge on highly mutated pathways and to address the attractive perspectives arising from ongoing experimental studies for the clinical implementation of personalized medicine. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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9 pages, 718 KiB  
Perspective
Interplay between Tumor Mutational Burden and Mutational Profile and Its Effect on Overall Survival: A Pilot Study of Metastatic Patients Treated with Immune Checkpoint Inhibitors
Cancers 2022, 14(21), 5433; https://doi.org/10.3390/cancers14215433 - 04 Nov 2022
Cited by 4 | Viewed by 1888
Abstract
Purpose: Solid tumors harboring tumor mutational burden (TMB) ≥10 mutations per megabase (mut/Mb) received agnostic approval for pembrolizumab. This work aims to analyze the somatic mutational profile’s influence on the outcomes of patients with TMB-high tumors treated with immune checkpoint inhibitors (ICIs). Methods: [...] Read more.
Purpose: Solid tumors harboring tumor mutational burden (TMB) ≥10 mutations per megabase (mut/Mb) received agnostic approval for pembrolizumab. This work aims to analyze the somatic mutational profile’s influence on the outcomes of patients with TMB-high tumors treated with immune checkpoint inhibitors (ICIs). Methods: This post-hoc analysis evaluated clinical and molecular features of patients with solid tumors treated with ICIs that could be either monoclonal antibody directed against programmed cell death protein-1 or monoclonal antibody directed against programmed cell death ligand 1 (anti-PD-1/anti-PD-L1), monoclonal antibody directed against cytotoxic T lymphocyte-associated antigen (anti-CTLA-4) or a combined treatment regimen including one anti-PD-1/anti-PD-L1 and one anti-CTLA-4 (ICIs combination). We performed OS analysis for TMB thresholds of ≥10, ≥20, and <10 mut/Mb. We assessed OS according to the mutational profile for a TMB ≥ 10 mut/Mb cutoff. For genes correlated with OS at the univariate assessment, we conducted a Cox multivariate analysis adjusted by median TMB, sex, age, microsatellite instability (MSI), and histology. Results: A total of 1661 patients were investigated; 488 with a TMB ≥10 mut/Mb (29.4%). The median OS was 42 months for TMB ≥10 or 20 mut/Mb, and 15 months for TMB <10 mut/Mb (p < 0.005). Among TMB ≥10 mut/Mb patients, mutations in E2F3 or STK11 correlated with worse OS, and mutations in NTRK3, PTPRD, RNF43, TENT5C, TET1, or ZFHX3 with better OS. These associations were confirmed with univariate and multivariate analyses (p < 0.05). Melanoma histology and TMB above the median endowed patients with better OS (p < 0.05), while MSI status, age, and gender did not have a statistically significant effect on OS. Conclusion: Combining TMB and mutation profiles in key cancer genes can better qualify patients for ICI treatment and predict their OS. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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16 pages, 646 KiB  
Systematic Review
Apelin, a Circulating Biomarker in Cancer Evaluation: A Systematic Review
Cancers 2022, 14(19), 4656; https://doi.org/10.3390/cancers14194656 - 25 Sep 2022
Cited by 3 | Viewed by 1295
Abstract
Apelin is a promising biomarker for the detection and prognosis of cancer. This review aims to synthesize current knowledge on associations of circulating apelin with cancer, illustrate knowledge gaps, and discuss future research. Following PRISMA guidelines, CINAHL, EMBASE, and PubMed were searched using [...] Read more.
Apelin is a promising biomarker for the detection and prognosis of cancer. This review aims to synthesize current knowledge on associations of circulating apelin with cancer, illustrate knowledge gaps, and discuss future research. Following PRISMA guidelines, CINAHL, EMBASE, and PubMed were searched using terms “cancer AND apelin” between 2011 and 2021, full text, and English language. Inclusion criteria: measured circulating apelin in adults 18 years or older with cancer, and observational, cross-sectional, longitudinal, case–control, cohort, quasi-experimental, or randomized control trials. Excluded were studies with animal models, tissue samples only, secondary data analyses, systematic reviews, literature reviews, grey literature, and conference abstracts. 16 articles were included. There were significant variations in measurement methods between studies. Comparison of circulating apelin between cases and controls and associations of circulating apelin with clinicopathological characteristics were inconsistent. Variations in results suggest that the relationship between circulating apelin and cancer differs among cancer types. Differences in measurement methods between studies highlight the need for consistency in future research to draw meaningful conclusions. Future research should seek to standardize methods of detecting circulating apelin and examine its associations with specific cancer types to determine what role that circulating apelin may play in cancer development and progression. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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