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The challenge of molecular selection in liver-limited metastatic colorectal cancer for surgical resection: a systematic review and meta-analysis in the context of current and future approaches

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Oncology Research 2024年第9期32卷 1407-1422页

作者： ROSSANA RONCATO JERRY POLESEL FEDERICA TOSI ELENA PERUZZI erika BRUGUGNOLI CLAUDIA LAURIA PANTANO MARIA FURFARO FILIPPO DI GIROLAMO ALESSANDRO NANI ARIANNA PANI NOEMI MILAN ELENA DE MATTIA ANDREA SARTORE-BIANCHI erika cecchin Experimental and Clinical Pharmacology Unit Centro di Riferimento Oncologico di Aviano(CRO)IRCCSAviano33081Italy Department of Medicine(DMED) University of UdineUdine33100Italy Unit of Cancer Epidemiology Centro di Riferimento Oncologico di Aviano(CRO)IRCCSAviano33081Italy Department of Oncology and Hemato-Oncology Universitàdegli Studi di MilanoMilan20122Italy Department of Hematology Oncologyand Molecular MedicineGrande Ospedale Metropolitano NiguardaMilan20122Italy Oncology Pharmacy Unit IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino AmadoriMeldola47014Italy Pharmacy Unit Fondazione IRCCS Istituto Tumori di MilanoMilan20122Italy Department of Pharmacy Ca’Foncello Treviso Regional HospitalPiazzale Ospedale 1Treviso31100Italy Department of Medical Surgical and Health Sciences University of TriesteTrieste34127Italy Hospital Pharmacy Cattinara HospitalAzienda Sanitaria Universitaria Giuliano IsontinaTrieste34148Italy Department of Oncology and Onco-Hematology Postgraduate School of Clinical Pharmacology and ToxicologyUniversity of MilanMilan20122Italy

Objectives:Treatment of metastatic colorectal cancer(mCRC)includes resection of liver metastases(LM),however,no validated biomarker identifies patients most likely to benefit from this *** meta-analysis aimed to assess the impact of the most relevant molecular alterations in cancer-related genes of CRC(i.e.,RAS,BRAF,SMAD4,PIK3CA)as prognostic markers of survival and disease recurrence in patients with mCRC surgically treated by LM ***:A systematic literature review was performed to identify studies reporting data regarding survival and/or recurrence in patients that underwent complete liver resection for CRC LM,stratified according to RAS,BRAF,PIK3CA,and SMAD4 mutational *** ratios(HRs)from multivariate analyses were pooled in the meta-analysis and various adjustment strategies for confounding factors were *** search was conducted in numerous databases,including MEDLINE(PubMed),Embase,Cumulative Index to Nursing and Allied Health Literature(CINAHL)(EBSCO host),and WHO Global Index Medicus,through March 18th,***-analyses,editorials,letters to the editor,case reports,studies on other primary cancers,studies with primary metastatic sites other than the liver,studies lacking specific oncological outcome variables or genetic data,non-English language studies,and studies omitting residual disease data from liver metastasectomy were *** remaining 47 studies were summarized in a descriptive table which outlines the key characteristics of each study and final results were graphically ***:RAS mutation status was negatively associated with overall survival(OS)(HR,1.68;95%CI,1.54–1.84)and recurrence free survival(RFS)(HR,1.46;95%CI,1.33–1.61).A negative association was also found for BRAF regarding OS(HR,2.64;95%CI,2.15–3.24)and RFS(HR,1.89;95%CI,1.32–2.73)and SMAD4 regarding OS(HR,1.93;95%CI,1.56–2.38)and RFS(HR,1.95;95%CI,1.31–2.91).For PIK3CA only three studies were eligible and no significant associati

关键词： Metastasectomy Liver metastases RAS BRAF SMAD4 PIK3CA Colorectal

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The use of pharmacogenetics to increase the safety of colorectal cancer patients treated with fluoropyrimidines

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Cancer Drug Resistance 2019年第1期2卷 116-130页

作者： Elena De Mattia Rossana Roncato Chiara Dalle Fratte Fabrizio Ecca Giuseppe Toffoli erika cecchin Experimental and Clinical Pharmacology Unit Centro di Riferimento Oncologico di Aviano(CRO)IRCCSAviano 33081Italy

Fluoropyrimidines(FP)are given in the combination treatment of the advanced disease or as monotherapy in the neo-adjuvant and adjuvant treatment of colorectal cancerand other solid tumors including breast,head and neck and gastric *** present a narrow therapeutic index with 10 to 26% of patients experiencing acute severe or life-threatening *** the high number of patients receiving FP-based therapies,and the significant effects of toxicities on their quality of life,the prevention of FP-related adverse events is of major clinical *** genetic variants in the rate limiting enzyme dihydropyrimidine dehydrogenase(DPYD)gene are related to the occurrence of extremely severe,early onset toxicity in FP treated *** pre-treatment diagnostic test of 4 DPYD genetic polymorphisms is suggested by the currently available pharmacogenetic *** prospective implementation projects are ongoing to support the introduction of up-front genotyping of the patients in clinical *** pharmacogenetic studies tried to assess the predictive role of other polymorphisms in genes involved in the FP pharmacokinetics/pharmacodynamic pathways,TYMS and MTHFR,but no additional clinically validated genetic markers of toxicity are available to *** development of next-generation sequencing platforms opens new possibilities to highlight previously unreported genetic ***,the investigation of the genetic variation in the patients immunological system,a pivotal target in cancer treatment,could bring notable advances in the *** review will describe the most recent literature on the use of pharmacogenetics to increase the safety of a treatment based on FP administration in colorectal cancer patients.

关键词： Fluoropyrimidines pharmacogenetics colorectal cancer toxicity DPYD TYMS MTHFR

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Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

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World Journal of Gastroenterology 2019年第29期25卷 3870-3896页

作者： Elena De Mattia erika cecchin Michela Guardascione Luisa Foltran Tania Di Raimo Francesco Angelini Mario D’Andrea Giuseppe Toffoli Clinical and Experimental Pharmacology Centro di Riferimento Oncologico di Aviano (CRO) IRCCS Aviano (PN) 33081 Italy Department of Medical Oncology Centro di Riferimento Oncologico di Aviano (CRO) IRCCS Aviano (PN) 33081 Italy Medical Oncology and Anatomic Pathology Unit “San Filippo Neri Hospital” Rome 00135 Italy Department of Oncology “San Filippo Neri Hospital” Rome 00135 Italy

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other smallmolecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c- MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and

关键词： Hepatocellular carcinoma Pharmacogenetics Genetic markers Sorafenib Regorafenib Immune checkpoint inhibitors Cytochromes UDP glucuronosyltransferase 1A

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Genetic biomarkers for hepatocellular cancer risk in a caucasian population

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World Journal of Gastroenterology 2017年第36期23卷 6674-6684页

作者： Elena De Mattia erika cecchin Jerry Polesel Alessia Bignucolo Rossana Roncato Francesco Lupo Marina Crovatto Angela Buonadonna Claudio Tiribelli Giuseppe Toffoli Clinical and Experimental Phar-macology “Centro di Riferimento Oncologico”-National Cancer Institute Unit of Cancer Epidemiology “Centro di Riferimento Oncologico”-National Cancer Institute General Surgery 2U and Liver Transplantation Center A.O.U.Cittàdella Salute e della Scienza di TorinoUniversity of Torino Cytogenetics and Molecular Biology Unit Santa Maria degli Angeli Hospital Pordenone Medical Oncology Unit “Centro di Riferimento Oncologico”-National Cancer Institute Fondazione Italiana Fegato AREA Science Park

AIM To uncover novel genetic markers that could contribute to predicting hepatocellular carcinoma(HCC)susceptibility in Caucasians. METHODS The present retrospective case-control study compared genotype frequencies between a cohort of HCC cases and two,independent,HCC-free,age/sex-matched control *** HCC cohort comprised 192 homogeneous patients that had undergone orthotopic liver *** first control group comprised167 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 included192 virus-free,healthy individuals that were used to evaluate the generalizability of the identified predictive *** cases and controls were *** three study populations were characterized with a panel of 31 markers derived from 21 genes that encoded key proteins involved in hepatocarcinogenesis-related *** study end-point was to assess the association between genetic variants and HCC onset. RESULTS Five genetic markers were identified as risk factors for HCC in high-risk patients infected with HBV/*** to a dominant model,reduced HCC risk was associated with three polymorphisms:ERCC1rs3212986(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 *** the five markers identified,E

关键词： ERCC1 XRCC3 GST-P1 CYP17A1 MDR-1 Polymorphisms Hepatocellular carcinoma risk Early diagnosis Antiviral therapy Hepatitis B viral/hepatitis C viral

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