Genetic biomarkers for hepatocellular cancer risk in a caucasian population

AIMTo uncover novel genetic markers that could contribute to predicting hepatocellular carcinoma (HCC) susceptibility in Caucasians.METHODSThe present retrospective case-control study compared genotype frequencies between a cohort of HCC cases and two, independent, HCC-free, age/sex-matched control groups. The HCC cohort comprised 192 homogeneous patients that had undergone orthotopic liver transplantation. The first control group comprised 167 patients that were matched to the HCC cohort for the percentage of hepatitis B (HBV) and/or hepatitis C (HCV) infections. A second control group included 192 virus-free, healthy individuals that were used to evaluate the generalizability of the identified predictive markers. All cases and controls were Caucasian. The three study populations were characterized with a panel of 31 markers derived from 21 genes that encoded key proteins involved in hepatocarcinogenesis-related pathways. The study end-point was to assess the association between genetic variants and HCC onset.RESULTSFive genetic markers were identified as risk factors for HCC in high-risk patients infected with HBV/HCV. According to a dominant model, reduced HCC risk was associated with three polymorphisms: ERCC1 rs3212986 (OR = 0.46, 95% CI: 0.30-0.71, P = 0.0005), GST-P1 rs1138272 (OR = 0.41, 95% CI: 0.21-0.81, P = 0.0097), and CYP17A1 rs743572 (OR = 0.50, 95% CI: 0.31-0.79, P = 0.0032). Conversely, according to a recessive model, increased HCC risk was associated with two polymorphisms: XRCC3 rs1799794 (OR = 3.70, 95% CI: 1.02-13.39, P = 0.0461) and ABCB1 rs1128503 (OR = 2.06, 95% CI: 1.18-3.61, P = 0.0111). These associations remained significant in a subgroup analysis, where patients were stratified according to viral status (HBV-or HCV-positive serology). Two variants exhibited a serology-specific effect: ABCB1 rs1128503 (OR = 4.18, 95% CI: 1.55-11.29, P = 0.0048) showed an effect in the HBV-positive subgroup; and ERCC1 rs3212986 (OR = 0.33, 95% CI: 0.18-0.60, P = 0.0003) showed an effect in the HCV-positive subgroup. Among the five markers identified, ERCC1 rs3212986 (OR = 0.43, P < 0.0001) and CYP17A1 rs743572 (OR = 0.73, P = 0.0310) had a different distribution in patients with HCC compared to healthy individuals. With a recursive partitioning approach, we also demonstrated that significant gene-gene interactions between ERCC1 rs3212986, CYP17A1 rs743572, GST-P1 rs1138272, and the previously described UGT1A7*3 predictive marker, played a role in the complex trait of HCC susceptibility.CONCLUSIONWe identified five polymorphisms and interactions that contributed crucially to predicting HCC risk. These findings represented an important step towards improving HCC diagnosis and management

IL15RA and SMAD3 Genetic Variants Predict Overall Survival in Metastatic Colorectal Cancer Patients Treated with FOLFIRI Therapy: A New Paradigm

Simple SummaryThere is an increasing scientific interest in the study of the interaction between the immune system and drugs in cancer that can affect the efficacy of an anti-cancer treatment. This study was undertaken to better understand if the genetic characteristic of a cancer patient's immune system can predict the tumor response to the treatment and the duration of survival. The topic was studied on 335 metastatic colorectal cancer patients treated with a first-line chemotherapy (FOLFIRI regimen, irinotecan-5-fluorouracil-leucovorin). The research highlighted two markers, IL15RA-rs7910212 and SMAD3-rs7179840, significantly associated with the patient's survival. When considering IL15RA-rs7910212 and SMAD3-rs7179840 in combination with other two genetic markers previously investigated (NR1I2-rs1054190, VDR-rs7299460), we built up a highly predictive genetic score of survival. The herein identified markers must be further validated, but still represent good candidates to understand how much a patient with a metastatic colorectal cancer can benefit from a chemotherapy with FOLFIRI regimen.A new paradigm in cancer chemotherapy derives from the interaction between chemotherapeutics, including irinotecan and 5-fluorouracil (5-FU), and the immune system. The patient's immune response can modulate chemotherapy effectiveness, and, on the other hand, chemotherapeutic agents can foster tumor cell immunogenicity. On these grounds, the analysis of the cancer patients' immunogenetic characteristics and their effect on survival after chemotherapy represent a new frontier. This study aims to identify genetic determinants in the immuno-related pathways predictive of overall survival (OS) after FOLFIRI (irinotecan, 5-FU, leucovorin) therapy. Two independent cohorts comprising a total of 335 patients with metastatic colorectal cancer (mCRC) homogeneously treated with first-line FOLFIRI were included in the study. The prognostic effect of 192 tagging genetic polymorphisms in 34 immune-related genes was evaluated using the bead array technology. The IL15RA rs7910212-C allele was associated with worse OS in both discovery (HR: 1.57, p = 0.0327, Bootstrap p-value = 0.0280) and replication (HR: 1.71, p = 0.0411) cohorts. Conversely, SMAD3 rs7179840-C allele was associated with better OS in both discovery (HR: 0.65, p = 0.0202, Bootstrap p-value = 0.0203) and replication (HR: 0.61, p = 0.0216) cohorts. A genetic prognostic score was generated integrating IL15RA-rs7910212 and SMAD3-rs7179840 markers with inflammation-related prognostic polymorphisms we previously identified in the same study population (i.e., PXR [NR1I2]-rs1054190, VDR-rs7299460). The calculated genetic score successfully discriminated patients with different survival probabilities (p < 0.0001 log-rank test). These findings provide new insight on the prognostic value of genetic determinants, such as IL15RA and SMAD3 markers, and could offer a new decision tool to improve the clinical management of patients with mCRC receiving FOLFIRI

Uso di marcatori farmacogenetici per migliorare la sicurezza e l'efficacia dei trattamenti antiblastici all'interno dello studio di implementazione delle linee guida PGx PREPARE

Despite the scientific and clinical advances in pharmacogenomics (PGx) to date, its application in clinical practice is still limited, although numerous studies and implementation programs have been launched in recent years. The Experimental and Clinical Pharmacology of Centro di Riferimento Oncologico (CRO) has been investigating and supporting the use of pharmacogenetic markers in oncology for over 20 years to improve patient outcomes in terms of both toxicity and efficacy. However, there are still several obstacles to overcome in order to recognize the clinical utility of PGx. The U-PGx consortium (Ubiquitous Pharmacogenomics), which includes CRO Experimental and Clinical Pharmacology, was formed with the aim of filling these gaps by designing a prospective randomized controlled clinical trial called PREPARE: "PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions", funded by a grant from the Horizon 2020 program of European Commission (Grant Agreement N°668353). Our structure has been particularly involved in the design of this project and represents a national reference point for the implementation of this new model of personalized medicine in a unique program for its multi-gene, multi-drug and multi-ethnic approach in different European health contexts. This aspect is particularly relevant in oncology treatments, where drugs such as fluoropyrimidines and irinotecan have a narrow therapeutic index and the patient is exposed to toxic effects that are sometimes severe or even fatal. Therefore, the use of PGx guidelines in cancer clinical practice can be a powerful tool to improve and personalize cancer therapies. The main objective of this work was to implement PGx guidelines in the clinical practice of cancer patients in order to personalize their therapy. Specifically, our work focused on the implementation of clinical recommendations related to genetic variants in the DPYD, UGT1A and CYP2D6 genes following the prescription of fluoropyrimidines, irinotecan and tamoxifen, respectively. The secondary objective of this work was to demonstrate that PGx testing prior to administration of therapy has a positive impact on cancer patient outcomes in terms of toxicity and efficacy. Following this implementation project, a PGx diagnostic procedure was developed at our institute and integrated into the patient's clinical journey. Through the U-PGx experience, which has allowed health professionals to increase their awareness of PGx, requests from oncologists for PGx analysis prior to treatment have increased exponentially. A preliminary analysis of a subset of 563 patients showed that in the control arm, patients with actionable genotype had a higher risk of developing G ≥ 3 toxicity than patients with non-actionable genotype (p = 0.0317). This difference was not significant in the study arm in which patients received genotype-based dose reduction from the start of therapy (p = 0.746). Treatment discontinuation due to adverse events was also examined. This showed that patients with actionable genotype in the control arm discontinued therapy at a higher rate than wild-type patients (p = 0.0002). This trend was not significant in the study arm (p= 0.9999). Evaluation of treatment delays due to toxicity revealed a significant difference between patients with actionable and non-actionable genotype in the control arm (p = 0.0018). In the study arm, this difference did not reach statistical significance (p = 0.5492). Interesting data emerged from the evaluation of the Relative Dose Intensity (RDI) of patients with actionable genotype included in both arms. Patients with actionable genotype in the control arm had similar DI to patients with actionable genotype in the study arm who received PGx-based dose reduction prior to initiation of therapy (p = 0.3571). These data suggest that PGx approach is an easily implementable model in clinical oncology practice and improves patient outcome.Despite the scientific and clinical advances in pharmacogenomics (PGx) to date, its application in clinical practice is still limited, although numerous studies and implementation programs have been launched in recent years. The Experimental and Clinical Pharmacology of Centro di Riferimento Oncologico (CRO) has been investigating and supporting the use of pharmacogenetic markers in oncology for over 20 years to improve patient outcomes in terms of both toxicity and efficacy. However, there are still several obstacles to overcome in order to recognize the clinical utility of PGx. The U-PGx consortium (Ubiquitous Pharmacogenomics), which includes CRO Experimental and Clinical Pharmacology, was formed with the aim of filling these gaps by designing a prospective randomized controlled clinical trial called PREPARE: "PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions", funded by a grant from the Horizon 2020 program of European Commission (Grant Agreement N°668353). Our structure has been particularly involved in the design of this project and represents a national reference point for the implementation of this new model of personalized medicine in a unique program for its multi-gene, multi-drug and multi-ethnic approach in different European health contexts. This aspect is particularly relevant in oncology treatments, where drugs such as fluoropyrimidines and irinotecan have a narrow therapeutic index and the patient is exposed to toxic effects that are sometimes severe or even fatal. Therefore, the use of PGx guidelines in cancer clinical practice can be a powerful tool to improve and personalize cancer therapies. The main objective of this work was to implement PGx guidelines in the clinical practice of cancer patients in order to personalize their therapy. Specifically, our work focused on the implementation of clinical recommendations related to genetic variants in the DPYD, UGT1A and CYP2D6 genes following the prescription of fluoropyrimidines, irinotecan and tamoxifen, respectively. The secondary objective of this work was to demonstrate that PGx testing prior to administration of therapy has a positive impact on cancer patient outcomes in terms of toxicity and efficacy. Following this implementation project, a PGx diagnostic procedure was developed at our institute and integrated into the patient's clinical journey. Through the U-PGx experience, which has allowed health professionals to increase their awareness of PGx, requests from oncologists for PGx analysis prior to treatment have increased exponentially. A preliminary analysis of a subset of 563 patients showed that in the control arm, patients with actionable genotype had a higher risk of developing G ≥ 3 toxicity than patients with non-actionable genotype (p = 0.0317). This difference was not significant in the study arm in which patients received genotype-based dose reduction from the start of therapy (p = 0.746). Treatment discontinuation due to adverse events was also examined. This showed that patients with actionable genotype in the control arm discontinued therapy at a higher rate than wild-type patients (p = 0.0002). This trend was not significant in the study arm (p= 0.9999). Evaluation of treatment delays due to toxicity revealed a significant difference between patients with actionable and non-actionable genotype in the control arm (p = 0.0018). In the study arm, this difference did not reach statistical significance (p = 0.5492). Interesting data emerged from the evaluation of the Relative Dose Intensity (RDI) of patients with actionable genotype included in both arms. Patients with actionable genotype in the control arm had similar DI to patients with actionable genotype in the study arm who received PGx-based dose reduction prior to initiation of therapy (p = 0.3571). These data suggest that PGx approach is an easily implementable model in clinical oncology practice and improves patient outcome

Genetic markers of the host to predict the efficacy of colorectal cancer targeted therapy

The introduction of anti-EGFR (cetuximab and panitumumab) and antiangiogenic (bevacizumab, regorafeninb, ramucirumab, and aflibercept) agents in the therapeutic armamentarium of the metastatic colorectal cancer (CRC) has significantly improved the therapy efficacy and patients survival. However, despite the great improvements achieved in the patients life expectation, the high inter-individual heterogeneity in the response to the targeted agents still represent an issue for the management of advanced CRC patients. Even if the role of tumor genetic mutations as predictive markers of drug efficacy has been well-established, the contribution of the host genetic markers is still controversial. Promising results regard the germ-line immune-profile, inflammation and tumor microenvironment. Inherent variations in KRAS 3'UTR region as well as EGF/ EGFR genes were investigated as markers of cetuximab effectiveness. More recently interesting data in the field of anti-EGFR agents were generated also for germ-line variants in genes involved in inflammation (e.g. COX-2, LIFR, IGF1 signaling), immune system (e,g, FCGRs, IL-1RA), and other players of the RAS signaling, including the Hippo pathway related genes (e.g. Rassf, YAP, TAZ). Host genetic variants in VEGF-dependent (i.e., EGF, IGF-1, HIF1\u3b1, eNOS, iNOS) and -independent (i.e., EMT cascade, EGFL7) pathways, with specific attention on inflammation and immune system-related factors (e.g., IL-8, CXCR-1/2, CXCR4-CXCL12 axis, TLRs, GADD34, PPP1R15A, ANXA11, MKNK1), were investigated as predictive markers of bevacizumab outcome, generating some promising results. In this review we aimed to summarize the most recent literature data regarding the potential role of common and rare inhered variants in predicting which CRC patients will benefit more from a specific targeted drug administration

Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment

The use of targeted agents in the treatment of metastatic colorectal cancer (CRC) has improved patient outcomes. Anti-epidermal growth factor receptor (anti-EGFR) agents (cetuximab and panitumumab) and antiangiogenic molecules (bevacizumab, regorafeninb, ramucirumab, and aflibercept) have been successfully integrated into clinical practice. Other drugs have been designed to target additional deregulated pathways in CRC, such as MAPK (mitogen-activated protein kinase)/PI3K-AKT (phosphatidylinositol-3-kinase-AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin), HER-2 and 3 ( human epidermal growth factor receptor-2 and -3), and BRAF. A major issue with targeted treatment is early identification of patients with primary or secondary drug resistance. Pharmacogenomic research has demonstrated its value in this field, highlighting some tumor mutations that could discriminate responders from non-responders. The tumor genetic profile of the RAS/RAF pathway is needed before treatment with anti-EGFR agents; mutations in EGFR pathway genes have also been explored in relation to antiangiogenic molecules although further data are required prior to their integration into clinical practice. The introduction of immunotherapy has paved the way for a new generation of predictive markers, including genome-wide assessment of the tumor landscape. Furthermore, the development of next generation sequencing technology and non-invasive approaches to analyze circulating tumor DNA will make real-time monitoring of the tumor pharmacogenomic markers possible in the clinical routine, rendering precision medicine available to every patient

Pharmacogenetics Role of Genetic Variants in Immune-Related Factors: A Systematic Review Focusing on mCRC

Pharmacogenetics plays a key role in personalized cancer treatment. Currently, the clinically available pharmacogenetic markers for metastatic colorectal cancer (mCRC) are in genes related to drug metabolism, such as DPYD for fluoropyrimidines and UGT1A1 for irinotecan. Recently, the impact of host variability in inflammatory and immune-response genes on treatment response has gained considerable attention, opening innovative perspectives for optimizing tailored mCRC therapy. A literature review was performed on the predictive role of immune-related germline genetic biomarkers on pharmacological outcomes in patients with mCRC. Particularly, that for efficacy and toxicity was reported and the potential role for clinical management of patients was discussed. Most of the available data regard therapy effectiveness, while the impact on toxicity remains limited. Several studies focused on the effects of polymorphisms in genes related to antibody-dependent cellular cytotoxicity (FCGR2A, FCGR3A) and yielded promising but inconclusive results on cetuximab efficacy. The remaining published data are sparse and mainly hypothesis-generating but suggest potentially interesting topics for future pharmacogenetic studies, including innovative gene&ndash;drug interactions in a clinical context. Besides the tumor immune escape pathway, genetic markers belonging to cytokines/interleukins (IL-8 and its receptors) and angiogenic mediators (IGF1) seem to be the best investigated and hopefully most promising to be translated into clinical practice after validation

Wind Turbine Emulator for experimental microgrids

This paper presents the “hardware in the loop” wind turbine emulator installed at the PrInCE Lab microgrid of the Polytechnic University of Bari. The emulator consists of a four-quadrant 60-kVA AC/AC converter that behaves as a controlled current source for the microgrid. The control of the power converter is performed by a local microcontroller, which enables the emulation of different kinds of horizontal as well as vertical axis wind turbines. The emulator includes also an HMI software that allows the user to directly interact with the emulator, providing him the ability to choose the wind turbine model and wind speed to adopt for testing purpose

Evaluation of Concomitant Use of Anticancer Drugs and Herbal Products: From Interactions to Synergic Activity

CAM is used by about 40% of cancer patients in Western Countries, with peaks of 80% for breast cancer patients. Cancer patients use CAM to boost immune function, to control cancer symptoms and treatment-related side effects, and to improve health-related quality of life (HR-QoL) and survival. Unfortunately, self-prescription of natural remedies in cancer patients can lead to unexpected toxicities and can reduce the effectiveness of cancer therapy. Although CAM usually refers to all the &ldquo;natural or organic&rdquo; products/methods that are generally considered less toxic, there are concerns about drug interactions, especially in patients participating in clinical trials with experimental agents. Despite the claims of the promising and potential benefits made by prescribers, many CAMs lack clear scientific evidence of their safety and efficacy. Given the widespread use of CAM&mdash;both clearly declared and overt&mdash;in this review, we focused on the most important known data on the risk of interactions between biologics and oncology drugs with the goal of opening up CAM in accordance with the meaning of integrative medicine