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Corrias G, Lai E, Ziranu P, Mariani S, Donisi C, Liscia N, Saba G, Pretta A, Persano M, Fanni D, Spanu D, Balconi F, Loi F, Deidda S, Restivo A, Pusceddu V, Puzzoni M, Solinas C, Massa E, Madeddu C, Gerosa C, Zorcolo L, Faa G, Saba L, Scartozzi M. Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging. Cancers (Basel) 2024; 16:1364. [PMID: 38611042 PMCID: PMC11011199 DOI: 10.3390/cancers16071364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 03/24/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
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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Affiliation(s)
- Giuseppe Corrias
- Department of Radiology, University of Cagliari, 09042 Cagliari, Italy;
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Nicole Liscia
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132 Milan, Italy;
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Daniela Fanni
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (D.F.); (C.G.); (G.F.)
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Francesca Balconi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Francesco Loi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Simona Deidda
- Colorectal Surgery Unit, A.O.U. Cagliari, Department of Surgical Science, University of Cagliari, 09042 Cagliari, Italy; (S.D.); (A.R.); (L.Z.)
| | - Angelo Restivo
- Colorectal Surgery Unit, A.O.U. Cagliari, Department of Surgical Science, University of Cagliari, 09042 Cagliari, Italy; (S.D.); (A.R.); (L.Z.)
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Cinzia Solinas
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Elena Massa
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Clelia Madeddu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Clara Gerosa
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (D.F.); (C.G.); (G.F.)
| | - Luigi Zorcolo
- Colorectal Surgery Unit, A.O.U. Cagliari, Department of Surgical Science, University of Cagliari, 09042 Cagliari, Italy; (S.D.); (A.R.); (L.Z.)
| | - Gavino Faa
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (D.F.); (C.G.); (G.F.)
| | - Luca Saba
- Department of Radiology, University of Cagliari, 09042 Cagliari, Italy;
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
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Silva A, Pereira SS, Brandão JR, Brochado P, Monteiro MP, Araújo A, Faria G. Colon tumor CD31 expression is associated with higher disease-free survival in patients with metabolic syndrome. Pathol Res Pract 2022; 240:154182. [PMID: 36327819 DOI: 10.1016/j.prp.2022.154182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/17/2022] [Indexed: 11/07/2022]
Abstract
Metabolic syndrome (MS) is recognized as a risk factor for colon cancer (CC). However, how does the interplay between metabolic dysfunction caused by MS and its individual components affect CC microenvironment and prognosis remains unexplored. Angiogenesis and lymphangiogenesis are fundamental processes for tumor progression and dissemination, ensuring oxygen and nutrient delivery and supporting one of the most important pathways of tumor dissemination, contributing to metastasis. Thus, our aim was to evaluate whether the expression of molecular biomarkers involved in angiogenic and lymphangiogenic processes influenced CC clinicopathological features and prognosis in patients with MS. Clinical and pathological data of 300 patients submitted to CC surgical resection at a single tertiary hospital were retrospectively retrieved from hospital records. Tumor tissue microarrays of archived paraffin-embedded blocks were used to assess CD31, VEGF-A and D2-40 tissue expression by immunohistochemistry. The percentage of stained area was quantified by computerized morphometric analysis. No association between tissue expression of angiogenesis and lymphangiogenesis biomarkers and tumor clinical and pathological characteristics was found. However, in subgroup analysis of patients with MS, dysglycemia was associated with lower D2-40 expression (p = 0.007) and high waist-circumference was associated with higher D2-40 (p = 0.0029) and VEGF-A expression (p = 0.026). In an adjusted Cox proportional hazard model CD31 expression was significantly associated with greater disease-free survival (HR=0.62; 95% CI: 0.41-0.95, p = 0.028). No association was found between D2-40 and VEGF-A expression and CC prognosis. Our data reinforces previous reports that suggest the potential use of CD31 as a CC prognostic biomarker. Additionally, our data further supports the evidence for an interplay between metabolic dysfunction, tumor microenvironment, and vascularization pathways.
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Affiliation(s)
- Ana Silva
- Pharmacy Department, Centro Hospitalar Universitário do Porto (CHUPorto), 4099-001 Porto, Portugal; Department of Endocrine & Metabolic Research, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal; ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal; School of Health, Polytechnic Institute of Porto, Polytechnic of Porto, Porto, Portugal.
| | - Sofia S Pereira
- Department of Endocrine & Metabolic Research, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal; ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
| | - José Ricardo Brandão
- Pathology Department, Centro Hospitalar Universitário do Porto (CHUPorto), 4099-001 Porto, Portugal
| | - Paulo Brochado
- Pathology Department, Centro Hospitalar Universitário do Porto (CHUPorto), 4099-001 Porto, Portugal
| | - Mariana P Monteiro
- Department of Endocrine & Metabolic Research, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal; ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal; Centre for Obesity Research, University College London, London, United Kingdom
| | - António Araújo
- Oncology and Oncobiology Research, Unit for Multidisciplinary Biomedical Research (UMIB), University of Porto, Porto, Portugal; Medical Oncology Department, Centro Hospitalar Universitário do Porto (CHUPorto), 4099-001 Porto, Portugal
| | - Gil Faria
- CINTESIS-Center for Research in Health Technologies and Information Systems, Porto, Portugal; General Surgery, Hospital de Pedro Hispano - Unidade Local de Saúde de Matosinhos, Senhora da Hora, Portugal; Department of Surgery, Faculty of Medicine, University of Porto, Porto, Portugal
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Bignucolo A, Scarabel L, Toffoli G, Cecchin E, De Mattia E. Predicting drug response and toxicity in metastatic colorectal cancer: the role of germline markers. Expert Rev Clin Pharmacol 2022; 15:689-713. [PMID: 35829762 DOI: 10.1080/17512433.2022.2101447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Despite the introduction of targeted agents leading to therapeutic advances, clinical management of patients with metastatic colorectal cancer (mCRC) is still challenged by significant interindividual variability in treatment outcomes, both in terms of toxicity and therapy efficacy. The study of germline genetic variants could help to personalize and optimize therapeutic approaches in mCRC. AREAS COVERED A systematic review of pharmacogenetic studies in mCRC patients published on PubMed between 2011 and 2021, evaluating the role of germline variants as predictive markers of toxicity and efficacy of drugs currently approved for treatment of mCRC, was perfomed. EXPERT OPINION Despite the large amount of pharmacogenetic data published to date, only a few genetic markers (i.e., DPYD and UGT1A1 variants) reached the clinical practice, mainly to prevent the toxic effects of chemotherapy. The large heterogeneity of available studies represents the major limitation in comparing results and identifying potential markers for clinical use, the role of which remains exploratory in most cases. However, the available published findings are an important starting point for future investigations. They highlighted new promising pharmacogenetic markers within the network of inflammatory and immune response signaling. In addition, the emerging role of previously overlooked rare variants has been pointed out.
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Affiliation(s)
- Alessia Bignucolo
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
| | - Lucia Scarabel
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
| | - Erika Cecchin
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
| | - Elena De Mattia
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
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Elamarthi P. Regorafenib: A narrative drug review. CANCER RESEARCH, STATISTICS, AND TREATMENT 2022. [DOI: 10.4103/crst.crst_110_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Prognostic and Predictive Role of CXC Chemokine Receptor 4 in Metastatic Colorectal Cancer Patients. Appl Immunohistochem Mol Morphol 2021; 28:755-760. [PMID: 31985548 DOI: 10.1097/pai.0000000000000828] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. About 30% of patients present with metastatic disease involving predominantly the liver and a similar percentage will develop distant metastases later after removal of the primary tumor. In metastatic CRC, chemotherapies and biological drugs have prolonged survival for up to 30 months. However, there is a great need for biomarkers predictive of response and prognosis to optimize treatments. CXC chemokine receptor 4 (CXCR4) is a chemokine receptor; it binds to CXCL12 and plays a central role in colon cancer cells' growth and dissemination. MATERIALS AND METHODS CXCR4 was evaluated in CRC primary tissues by immunohistochemistry. Formalin-fixed, paraffin-embedded 4-μm tissue sections were immunostained using a biotin-streptavidin-peroxidase method and categorized into 2 semiquantitative classes: (i) absence of staining, ≤50% positive cells (negative/low) and (ii) >50% positive cells (high). Associations between clinic-pathologic variables and CXCR4 expression were evaluated using the χ test. The Kaplan-Meier product-limit method was applied to graph overall survival (OS). OS was defined as the time elapsed from diagnosis to death from any cause. Univariate analysis was carried out using the log-rank test. Cox proportional hazards regression was used to analyze the effect of several risk factors on OS. RESULTS Seventy-eight primary adenocarcinomas were analyzed; 26 were categorized as negative/low and 52 as high. Age, sex, performance status, site of metastases, KRAS mutational status, type of first-line therapy, and a number of therapy lines did not correlate with CXCR4 expression. Although not significant (P=0.0533), high CXCR4 expression was more frequently localized on the right side of the colon. Significant correlations were detected with grading (P=0.0041) and response to first-line anti-epidermal growth factor receptors agents (P<0.0001), bevacizumab (P=0.0029), and chemotherapy alone (P=0.0260). At a median follow-up of 53 months, 77 deaths have been registered. Grading [hazard ratio (HR): 1.42; confidence interval (CI): 0.89-2.28; P<0.0001], KRAS mutational status (HR: 1.73; CI: 1.03-290; P=0.0133), response to first-line chemotherapy (HR: 3.39; CI: 2.10-5.48; P<0.0001), and CXCR4 expression (HR: 3.18; CI: 2.01-5.02; P<0.0001) showed prognostic power at univariate and multivariate analyses. CONCLUSION In the present report, we show that CXCR4 expression on the primary tumor is an independent prognostic factor and correlates with response to first-line chemotherapy in metastatic CRC patients.
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Long Term Survival With Regorafenib: REALITY (Real Life in Italy) Trial - A GISCAD Study. Clin Colorectal Cancer 2021; 20:e253-e262. [PMID: 34429245 DOI: 10.1016/j.clcc.2021.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 07/06/2021] [Accepted: 07/13/2021] [Indexed: 11/20/2022]
Abstract
BACKGROUND Regorafenib is a key agent in metastatic colorectal cancer (mCRC), but no validated factors predicting longer survival are available. PATIENTS AND METHODS REALITY was a retrospective multicenter trial in regorafenib-treated mCRC patients with overall survival (OS) ≥ 6 months. We aimed to assess the association between clinical parameters and outcome to define a panel identifying long term survivors among regorafenib candidates. Primary and secondary endpoints were OS and progression free survival (PFS), respectively. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; independent role of significant variables at univariate analysis: logistic regression). RESULTS Hundred regorafenib-treated mCRC patients with OS ≥ 6 months were enrolled. Median OS was 11.5 m (95%CI:9.60-12.96); median PFS was 4.2 months (95% CI:3.43-43.03). The absence of liver progression and of dose and/or schedule changes during the first 4 cycles (mainly for good tolerability) were independently correlated at multivariate analysis with OS (Exp(b)1.8869, P= .0277and Exp(b)2.2000, P = .0313) and PFS (Exp(b)2.1583, P = .0065 and Exp(b)2.3036, P= .0169). Patients with neither of these variables had a significantly improved OS (n = 14, 20.8 months; 95% CI:12.967-55.267) versus others (n = 86, 10 months; 95% CI:8.367-12.167; HR = 0.4902, P = .0045) and PFS (11.3 months, 95%CI:4.267-35.8 vs. 3.9 months, 95% CI:3.167-43.033; HR = 0.4648, P = .0086). CONCLUSION These 2 factors might allow clinicians to better identify patients more likely to benefit from regorafenib. Toxicity management remains crucial.
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Lai E, Cascinu S, Scartozzi M. Are All Anti-Angiogenic Drugs the Same in the Treatment of Second-Line Metastatic Colorectal Cancer? Expert Opinion on Clinical Practice. Front Oncol 2021; 11:637823. [PMID: 34041019 PMCID: PMC8141840 DOI: 10.3389/fonc.2021.637823] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 04/19/2021] [Indexed: 12/28/2022] Open
Abstract
Targeting tumor-driven angiogenesis is an effective strategy in the management of metastatic colorectal cancer (mCRC); however, the choice of second-line therapy is complicated by the availability of several drugs, the occurrence of resistance and the lack of validated prognostic and predictive biomarkers. This review examines the use of angiogenesis-targeted therapies for the second-line management of mCRC patients. Mechanisms of resistance and anti-placental growth factor agents are discussed, and the role of aflibercept, a recombinant fusion protein consisting of portions of human vascular endothelial growth factor receptor (VEGFR)-1 and VEGFR-2, is highlighted. The novel mechanism of action of aflibercept makes it a useful second-line agent in mCRC patients progressing after oxaliplatin-based chemotherapy, as well as in those with resistance after bevacizumab.
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Affiliation(s)
- Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Stefano Cascinu
- Oncologia Medica, Università Vita-Salute, IRCCS Ospedale San Raffaele, Milano, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
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Conde E, Earl J, Crespo-Toro L, Blanco-Agudo C, Ramos-Muñoz E, Rodríguez-Serrano EM, Martínez Ávila JC, Salinas-Muñoz L, Serrano-Huertas S, Ferreiro R, Rodriguez-Garrote M, Sainz B, Massuti B, Alfonso PG, Benavides M, Aranda E, García-Bermejo ML, Carrato A. Biomarkers Associated with Regorafenib First-Line Treatment Benefits in Metastatic Colorectal Cancer Patients: REFRAME Molecular Study. Cancers (Basel) 2021; 13:cancers13071710. [PMID: 33916610 PMCID: PMC8038427 DOI: 10.3390/cancers13071710] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/27/2021] [Accepted: 03/30/2021] [Indexed: 12/31/2022] Open
Abstract
Simple Summary Biomarkers able to predict response and toxicity upon regorafenib therapy for colorectal cancer (CRC) are critical for treatment choice, particularly relevant in fragile patients. Here, we validated for the first time 18 distinct microRNAs (miRNAs) detected in serum and primary tumor samples, three germline single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) genes, and low levels of Notch 1 expression in the primary tumor as predictive biomarkers of different features. Specifically, these markers were associated with a favorable response to treatment, disease stage, and relapse, as well as the appearance of asthenia. Therefore, these markers can be potentially useful biomarkers for patient stratification and for providing a more personalized and effective therapeutic strategy in fragile patients, while limiting the appearance of adverse effects. Abstract First-line treatment with regorafenib in frail metastatic colorectal cancer (mCRC) patients has shown some benefit. To accurately identify such patients before treatment, we studied blood biomarkers and primary tumor molecules. We unveiled serum microRNAs (miRNAs), single-nucleotide polymorphisms (SNPs) in angiogenic-related genes, and Notch 1 expression as biomarkers associated with response or toxicity. MicroRNA array profiling and genotyping of selected SNPs were performed in the blood of fragile mCRC patients treated with regorafenib. Notch 1 and CRC-associated miRNA expression was also analyzed in tumors. High levels of miR-185-5p in serum, rs7993418 in the vascular endothelial growth factor receptor 1 (VEGFR1) gene, and Notch 1 expression in biopsies were associated with a favorable response to treatment. Serum levels of miR-126-3p and miR-152-3p and tumor expression of miR-92a-1-5p were associated with treatment toxicity, particularly interesting in patients exhibiting comorbidities, and high levels of miR-362-3p were associated with asthenia. Additionally, several miRNAs were associated with the presence of metastasis, local recurrence, and peritoneal metastasis. Besides, miRNAs determined in primary tumors were associated with tumor-node-metastasis (TNM) staging. The rs2305948 and rs699947 SNPs in VEGFR2 and VEGFA, respectively, were markers of poor prognosis correlating with locoregional relapse, a higher N stage, and metastatic shedding. In conclusion, VEGF and VEGFR SNPs, miRNAs, and Notch 1 levels are potential useful biomarkers for the management of advanced CRC under regorafenib treatment.
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Affiliation(s)
- Elisa Conde
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - Julie Earl
- Molecular Epidemiology and Predictive Tumor Markers Group, Alcalá University, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; (J.E.); (R.F.); (M.R.-G.); (A.C.)
- Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain;
| | - Lorena Crespo-Toro
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - Carolina Blanco-Agudo
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - Edurne Ramos-Muñoz
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - E. Macarena Rodríguez-Serrano
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - Jose Carlos Martínez Ávila
- Departamento de Matemática Aplicada y Estadística, Facultad de Ciencias Económicas y Empresariales, Universidad San Pablo CEU, C/Julián Romea, 23, 28003 Madrid, Spain;
| | - Laura Salinas-Muñoz
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - Silvia Serrano-Huertas
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - Reyes Ferreiro
- Molecular Epidemiology and Predictive Tumor Markers Group, Alcalá University, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; (J.E.); (R.F.); (M.R.-G.); (A.C.)
- Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain;
| | - Mercedes Rodriguez-Garrote
- Molecular Epidemiology and Predictive Tumor Markers Group, Alcalá University, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; (J.E.); (R.F.); (M.R.-G.); (A.C.)
- Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain;
| | - Bruno Sainz
- Department of Biochemistry, Ramón y Cajal Health Research Institute (IRYCIS) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Universidad Autónoma de Madrid (UAM), CSIC-UAM, C/Arzobispo Morcillo, 4, 28029 Madrid, Spain;
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer Area 3-IRYCIS, 28034 Madrid, Spain
| | - Bartomeu Massuti
- Oncology Department, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Hospital General Universitario de Alicante, Universidad Miguel Hernández, Pintor Baeza, 11, 03010 Alicante, Spain;
| | - Pilar García Alfonso
- Oncology Department, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital Universitario Gregorio Marañón, Doctor Esquerdo 46, 28028 Madrid, Spain;
| | - Manuel Benavides
- Oncology Department, Hospital Universitario Regional y Virgen de la Victoria, IBIMA, 29010 Málaga, Spain;
| | - Enrique Aranda
- Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain;
- Oncology Department, Instituto Maimonides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofia, University of Córdoba, IMIBIC, Av. Menéndez Pidal, s/n, 14004 Córdoba, Spain
| | - María Laura García-Bermejo
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
- Correspondence: ; Tel.: +34-913-368-075
| | - Alfredo Carrato
- Molecular Epidemiology and Predictive Tumor Markers Group, Alcalá University, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; (J.E.); (R.F.); (M.R.-G.); (A.C.)
- Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain;
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9
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Ottaiano A, Scala S, Santorsola M, Trotta AM, D'Alterio C, Portella L, Clemente O, Nappi A, Zanaletti N, De Stefano A, Avallone A, Granata V, Notariello C, Luce A, Lombardi A, Picone C, Petrillo A, Perri F, Tatangelo F, Di Mauro A, Albino V, Izzo F, Rega D, Pace U, Di Marzo M, Chiodini P, De Feo G, Del Prete P, Botti G, Delrio P, Caraglia M, Nasti G. Aflibercept or bevacizumab in combination with FOLFIRI as second-line treatment of mRAS metastatic colorectal cancer patients: the ARBITRATION study protocol. Ther Adv Med Oncol 2021; 13:1758835921989223. [PMID: 33854566 PMCID: PMC8010802 DOI: 10.1177/1758835921989223] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/31/2020] [Indexed: 11/16/2022] Open
Abstract
Background: The intensive study of predictive factors has strongly ameliorated the therapeutic flow-chart of metastatic colorectal cancer (mCRC) by allowing the selection of patients who benefit from specific therapies. For instance, in mRAS (mutated RAS) mCRC patients, anti-EGFR drugs (cetuximab and panitumumab) are not recommended; in this group of patients, the use of anti-angiogenic drugs (bevacizumab and aflibercept) is predominant. However, at progression to standard bevacizumab-based first-line chemotherapy, still to date, there are no studies to guide oncologists in the choice of the best second-line anti-angiogenic drug (bevacizumab beyond progression versus aflibercept). Methods: ARBITRATION is a prospective, observational study assessing efficacy differences between second-line fluorouracil/irinotecan (FOLFIRI)/bevacizumab versus FOLFIRI/aflibercept at progression to fluoropyrimidines, oxaliplatin and bevacizumab in mRAS mCRC patients. A test power of 80%, a median survival of 9 months from second-line treatment start and a hazard ratio of 0.67 between the two schedules were the basis for statistical design. The final sample will be 220 patients (110 per treatment). The significance will be verified with a two-tailed log-rank test with an alpha value of the I-type error of 5%. Time-to-outcome will be described by Kaplan–Meier curves and prognostic factors studied through multivariable analyses based on the Cox model. Secondary objectives include safety, responses’ duration and progression-free survival. A translational research will be conducted to measure several angiogenic proteins in patients’ serum before starting the therapy in order to evidence any angiogenic factor patterns related to outcome. Discussion: We present a large, prospective, observational study aiming to answer two scientific questions: (1) outcome differences between second-line treatments with FOLFIRI/bevacizumab beyond progression versus FOLFIRI/aflibercept in mRAS mCRC patients, (2) angiogenic factors’ patterns that could associate with efficacy and help oncologists to apply best the therapeutic anti-angiogenic strategies. Trial registration: The ARBITRATION trial (version 0.0, 13 April 2020) has been registered into the clinicaltrials.gov registry on 20 May 2020 with identifier NCT04397601.
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Affiliation(s)
- Alessandro Ottaiano
- Innovative Therapies for Abdominal Metastases Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", via M. Semmola, Naples, Campania 80131, Italy
| | - Stefania Scala
- Functional Genomics, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Mariachiara Santorsola
- Innovative Therapies for Abdominal Metastases Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Anna Maria Trotta
- Functional Genomics, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Crescenzo D'Alterio
- Functional Genomics, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Luigi Portella
- Functional Genomics, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Ottavia Clemente
- Department of Abdominal Oncology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Anna Nappi
- Department of Abdominal Oncology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Nicoletta Zanaletti
- Department of Abdominal Oncology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Alfonso De Stefano
- Department of Abdominal Oncology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Antonio Avallone
- Department of Abdominal Oncology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Vincenza Granata
- Department of Radiology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Carmen Notariello
- Department of Abdominal Oncology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Amalia Luce
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Naples, Italy Biogem Scarl, Institute of Genetic Research, Laboratory of Precision and Molecular Oncology, Ariano Irpino, Italy
| | - Angela Lombardi
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Naples, Italy Biogem Scarl, Institute of Genetic Research, Laboratory of Precision and Molecular Oncology, Ariano Irpino, Italy
| | - Carmine Picone
- Department of Radiology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Antonella Petrillo
- Department of Radiology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Francesco Perri
- Head and Neck Cancer Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Fabiana Tatangelo
- Pathology Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Annabella Di Mauro
- Pathology Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Vittorio Albino
- Hepatobiliary Surgical Oncology Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Francesco Izzo
- Hepatobiliary Surgical Oncology Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Daniela Rega
- Colorectal Cancer Surgery Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Ugo Pace
- Colorectal Cancer Surgery Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Massimiliano Di Marzo
- Colorectal Cancer Surgery Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Paolo Chiodini
- Medical Statistics Unit, University of Campania, Luigi Vanvitelli, Naples, Italy
| | - Gianfranco De Feo
- Scientific Directorate, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Paola Del Prete
- Scientific Directorate, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Gerardo Botti
- Scientific Directorate, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Paolo Delrio
- Colorectal Cancer Surgery Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Naples, Italy Biogem Scarl, Institute of Genetic Research, Laboratory of Precision and Molecular Oncology, Ariano Irpino, Italy
| | - Guglielmo Nasti
- Innovative Therapies for Abdominal Metastases Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
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Tumor Microenvironment in Metastatic Colorectal Cancer: The Arbitrator in Patients' Outcome. Cancers (Basel) 2021; 13:cancers13051130. [PMID: 33800796 PMCID: PMC7961499 DOI: 10.3390/cancers13051130] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Colorectal cancer accounts for approximately 10% of all annually diagnosed cancers worldwide being liver metastasis, the most common cause of death in patients with colorectal cancer. The interplay between tumor and stromal cells in the primary tumor microenvironment and at distant metastases are rising in importance as potential mechanisms of the tumor progression. In this review we discuss the new biomarkers derived from tumor microenvironment and liquid biopsy as emerging prognostic and treatments response markers for metastatic colorectal cancer. We also review the developing new clinical strategies based on tumor microenvironmental cells to tackle metastatic disease in metastatic colorectal cancer patients. Abstract Colorectal cancer (CRC) is one of the most common cancers in western countries. Its mortality rate varies greatly, depending on the stage of the disease. The main cause of CRC mortality is metastasis, which most commonly affects the liver. The role of tumor microenvironment in tumor initiation, progression and metastasis development has been widely studied. In this review we summarize the role of the tumor microenvironment in the liver pre-metastatic niche formation, paying attention to the distant cellular crosstalk mediated by exosomes. Moreover, and based on the prognostic and predictive capacity of alterations in the stromal compartment of tumors, we describe the role of tumor microenvironment cells and related liquid biopsy biomarkers in the delivery of precise medication for metastatic CRC. Finally, we evaluate the different clinical strategies to prevent and treat liver metastatic disease, based on the targeting of the tumor microenvironment. Specifically, targeting angiogenesis pathways and regulating immune response are two important research pipelines that are being widely developed and promise great benefits.
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11
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Lee MS, Cho HJ, Hong JY, Lee J, Park SH, Park JO, Park YS, Lim HY, Kang WK, Cho YB, Kim ST. Clinical and molecular distinctions in patients with refractory colon cancer who benefit from regorafenib treatment. Ther Adv Med Oncol 2020; 12:1758835920965842. [PMID: 33224274 PMCID: PMC7649869 DOI: 10.1177/1758835920965842] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 09/16/2020] [Indexed: 01/01/2023] Open
Abstract
Regorafenib (Stivarga, BAY 73-4506; Bayer Pharma AG, Berlin, Germany) is a novel oral multikinase inhibitor that blocks the activity of several protein kinases. However, few guidelines exist for novel biomarkers to select patients who will likely benefit from regorafenib treatment. Metastatic colorectal cancer (mCRC) patients treated with regorafenib were evaluated in this study. Tumor tissues of these patients were subjected to next-generation sequencing-based cancer panel tests. The relationship between molecular profiling and efficacy of regorafenib was analyzed. Among the 76 mCRC patients, the median age was 58 years (range 22–79 years), and 73.7% received regorafenib as a third-line therapy. The primary tumor locations were the right side (n = 15, 19.8%) and the left side (n = 61, 80.2%). Most patients (97.4%) had received prior anti-angiogenetic agents, and a prior anti-Epidermal Growth Factor Receptor (EGFR) agent had been administered to 32.9%. Of these 76 patients, 65 were evaluated to determine the efficacy of treatment. We observed zero complete responses, seven confirmed partial responses (PR 9.2%), 26 stable disease states (34.2%), and 32 disease progressions (42.1%). The overall confirmed response rate and the disease control rate were 9.2% and 43.4%, respectively. Genomic analysis revealed that APC mutations were significant in patients who demonstrated a tumor response to regorafenib (p < 0.05). Interestingly, FGFR1 amplification was detected in only three of 76 patients (3.9%), and these three patients achieved a PR to regorafenib. The median progression-free survival time was 2.8 months (95% Confidence Interval [CI] 1.6–4.0). Patients with BRAF mutation and/or SMAD4 mutation had significantly worse progression-free survival (PFS) than those without such a mutation. On pathway analysis, Tumor Growth Factor (TGF)-beta pathways were significantly associated with worse PFS. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and TGF-beta pathway were associated with worse PFS after regorafenib. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and the TGF-beta pathway were associated with worse PFS after regorafenib.
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Affiliation(s)
- Min-Sang Lee
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea
| | - Hee Jin Cho
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea Precision Medicine Research Institute, Samsung Medical Center, Gangnam-gu, Seoul, Korea
| | - Jung Yong Hong
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea
| | - Jeeyun Lee
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea
| | - Se Hoon Park
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea
| | - Joon Oh Park
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea
| | - Young Suk Park
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea
| | - Ho Yeong Lim
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea
| | - Won Ki Kang
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea
| | - Yong Beom Cho
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
| | - Seung Tae Kim
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
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12
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De Mattia E, Bignucolo A, Toffoli G, Cecchin E. Genetic Markers of the Host to Predict the Efficacy of Colorectal Cancer Targeted Therapy. Curr Med Chem 2020; 27:4249-4273. [PMID: 31298142 DOI: 10.2174/0929867326666190712151417] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 12/19/2018] [Accepted: 01/30/2019] [Indexed: 12/15/2022]
Abstract
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 therapeutic 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, HIF1α, 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 specifically targeted drug administration.
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Affiliation(s)
- Elena De Mattia
- Clinical and Experimental Pharmacology, "Centro di Riferimento Oncologico"- National Cancer Institute, via Franco Gallini 2, 33081, Aviano (PN), Italy
| | - Alessia Bignucolo
- Clinical and Experimental Pharmacology, "Centro di Riferimento Oncologico"- National Cancer Institute, via Franco Gallini 2, 33081, Aviano (PN), Italy
| | - Giuseppe Toffoli
- Clinical and Experimental Pharmacology, "Centro di Riferimento Oncologico"- National Cancer Institute, via Franco Gallini 2, 33081, Aviano (PN), Italy
| | - Erika Cecchin
- Clinical and Experimental Pharmacology, "Centro di Riferimento Oncologico"- National Cancer Institute, via Franco Gallini 2, 33081, Aviano (PN), Italy
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13
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Ravegnini G, Valori G, Zhang Q, Ricci R, Hrelia P, Angelini S. Pharmacogenetics in the treatment of gastrointestinal stromal tumors - an updated review. Expert Opin Drug Metab Toxicol 2020; 16:797-808. [PMID: 32597248 DOI: 10.1080/17425255.2020.1789589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
INTRODUCTION Gastrointestinal stromal tumors (GIST) are the best example of a targeted therapy in solid tumors. The introduction of tyrosine kinase inhibitors (TKIs) deeply improved the prognosis of this tumor. However, a degree of inter-patient variability is still reported in response rates and pharmacogenetics may play an important role in the final clinical outcome. AREAS COVERED In this review, the authors provide an updated overview of the pharmacogenetic literature analyzing the role of polymorphisms in both GIST treatment efficacy and toxicity. EXPERT OPINION Besides the primary role of somatic DNA in dictating the clinical response to TKIs, several polymorphisms influencing their pharmacokinetics and pharmacodynamics have been identified as being potentially involved. In the last 10 years, many potential biomarkers have been proposed to predict clinical response and toxicity after TKI administration. However, the evidence is still too limited to promote a clinical translation. To date, the somatic mutational status represents the main player in clinical response to TKIs in GIST treatment; however, pharmacogenetics could still explain the degree of inter-patient variability observed in GIST patients. A combination of different theoretical approaches, experimental model systems, and statistical methods is clearly needed, in order to translate pharmacogenetics to clinical practice in the near future.
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Affiliation(s)
- Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna , Bologna, Italy
| | - Giorgia Valori
- Department of Pharmacy and Biotechnology, University of Bologna , Bologna, Italy
| | - Qianqian Zhang
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS , Rome, Italy
| | - Riccardo Ricci
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS , Rome, Italy.,Department of Pathology, Universita Cattolica del Sacro Cuore , Rome, Italy
| | - Patrizia Hrelia
- Department of Pharmacy and Biotechnology, University of Bologna , Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy and Biotechnology, University of Bologna , Bologna, Italy
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14
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From CENTRAL to SENTRAL (SErum aNgiogenesis cenTRAL): Circulating Predictive Biomarkers to Anti-VEGFR Therapy. Cancers (Basel) 2020; 12:cancers12051330. [PMID: 32456056 PMCID: PMC7281010 DOI: 10.3390/cancers12051330] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/16/2020] [Accepted: 05/18/2020] [Indexed: 12/12/2022] Open
Abstract
Background: In the last decade, a series of analyses failed to identify predictive biomarkers of resistance/susceptibility for anti-angiogenic drugs in metastatic colorectal cancer (mCRC). We conducted an exploratory preplanned analysis of serum pro-angiogenic factors (SErum aNgiogenesis-cenTRAL) in 72 mCRC patients enrolled in the phase II CENTRAL (ColorEctalavastiNTRiAlLdh) trial, with the aim to identify potential predictive factors for sensitivity/resistance to first line folinic acid-fluorouracil-irinotecan regimen (FOLFIRI) plus bevacizumab. Methods: First-line FOLFIRI/bevacizumab patients were prospectively assessed for the following circulating pro-angiogenic factors, evaluated with ELISA (enzyme-linked immunosorbent assay)-based technique at baseline and at every cycle: Vascular endothelial growth factor A (VEGF-A), hepatocyte growth factor (HGF), stromal derived factor-1 (SDF-1), placental derived growth factor (PlGF), fibroblast growth factor-2 (FGF-2), monocyte chemotactic protein-3 (MCP-3), interleukin-8 (IL-8). Results: Changes in circulating FGF-2 levels among different blood samples seemed to correlate with clinical outcome. Patients who experienced an increase in FGF-2 levels at the second cycle of chemotherapy compared to baseline, had a median Progression Free Survival (mPFS) of 12.85 vs. 7.57 months (Hazard Ratio—HR: 0.73, 95% Confidence Interval—CI: 0.43-1.27, p = 0.23). Similar results were seen when comparing FGF-2 concentrations between baseline and eight-week time point (mPFS 12.98 vs. 8.00 months, HR: 0.78, 95% CI: 0.46–1.33, p = 0.35). Conclusions: Our pre-planned, prospective analysis suggests that circulating FGF-2 levels’ early increase could be used as a marker to identify patients who are more likely to gain benefit from FOLFIRI/bevacizumab first-line therapy.
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15
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Marin JJG, Serrano MA, Monte MJ, Sanchez-Martin A, Temprano AG, Briz O, Romero MR. Role of Genetic Variations in the Hepatic Handling of Drugs. Int J Mol Sci 2020; 21:E2884. [PMID: 32326111 PMCID: PMC7215464 DOI: 10.3390/ijms21082884] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 04/09/2020] [Accepted: 04/17/2020] [Indexed: 12/18/2022] Open
Abstract
The liver plays a pivotal role in drug handling due to its contribution to the processes of detoxification (phases 0 to 3). In addition, the liver is also an essential organ for the mechanism of action of many families of drugs, such as cholesterol-lowering, antidiabetic, antiviral, anticoagulant, and anticancer agents. Accordingly, the presence of genetic variants affecting a high number of genes expressed in hepatocytes has a critical clinical impact. The present review is not an exhaustive list but a general overview of the most relevant variants of genes involved in detoxification phases. The available information highlights the importance of defining the genomic profile responsible for the hepatic handling of drugs in many ways, such as (i) impaired uptake, (ii) enhanced export, (iii) altered metabolism due to decreased activation of prodrugs or enhanced inactivation of active compounds, and (iv) altered molecular targets located in the liver due to genetic changes or activation/downregulation of alternative/compensatory pathways. In conclusion, the advance in this field of modern pharmacology, which allows one to predict the outcome of the treatments and to develop more effective and selective agents able to overcome the lack of effect associated with the existence of some genetic variants, is required to step forward toward a more personalized medicine.
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Affiliation(s)
- Jose J. G. Marin
- HEVEFARM Group, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.A.S.); (M.J.M.); (A.S.-M.); (A.G.T.); (O.B.); (M.R.R.)
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Arai H, Battaglin F, Wang J, Lo JH, Soni S, Zhang W, Lenz HJ. Molecular insight of regorafenib treatment for colorectal cancer. Cancer Treat Rev 2019; 81:101912. [PMID: 31715423 PMCID: PMC7491975 DOI: 10.1016/j.ctrv.2019.101912] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 12/22/2022]
Abstract
Regorafenib is a multi-targeting kinase inhibitor approved for the treatment of metastatic colorectal cancer patients in refractory to standard chemotherapy. Similarly to sorafenib, this agent was originally developed as a RAF1 inhibitor. However, the kinase inhibitory profile is distinct from sorafenib. A broad-spectrum of kinase inhibition induces wide-range drug sensitivity, irrespective of mutation status of major oncogenes. This agent's main therapeutic effects are anti-angiogenesis and the remodeling of tumor microenvironment through several mechanisms of action. The dual blockade of VEGF receptors and TIE2 can lead to both additive anti-angiogenesis effects and the suggestive unique regulation of vessel stability. Additionally, it inhibits molecular escape pathways to VEGF inhibition (e.g., FGF, PIGF, and PDGF signaling), enabling its continuous antiangiogenic effect even in tumors resistant to VEGF inhibitors. Furthermore, regorafenib has the important effect of enhancing anti-tumor immunity via macrophage modulation. Based on this concept, clinical trials have been recently launched for the development of a combination strategy with immune checkpoint inhibitors. Contrary to regorafenib induced clinical benefits and advances in the novel strategy, currently no predictive biomarkers have been identified. In the present review, we revisit and summarize regorafenib's unique mechanisms of action. The review could highlight molecular insights and provide some perspective for the search of predictive biomarkers used in metastatic colorectal cancer patients treated with regorafenib.
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Affiliation(s)
- Hiroyuki Arai
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States.
| | - Jingyuan Wang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States.
| | - Jae Ho Lo
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States.
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States.
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States.
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17
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Ottaiano A, Capozzi M, Tafuto S, De Stefano A, De Divitiis C, Romano C, Avallone A, Nasti G. Folfiri-Aflibercept vs. Folfiri-Bevacizumab as Second Line Treatment of RAS Mutated Metastatic Colorectal Cancer in Real Practice. Front Oncol 2019; 9:766. [PMID: 31456948 PMCID: PMC6700318 DOI: 10.3389/fonc.2019.00766] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 07/30/2019] [Indexed: 12/18/2022] Open
Abstract
Background: There are no clinical studies comparing the efficacy of bevacizumab vs.aflibercept in association with folfiri in RAS mutated (RAS-M) metastatic colorectal cancer patients (mCRC) pretreated with folfox and bevacizumab. Patients and Methods: Consecutive RAS-M unresectable mCRC patients progressing to first-line folfox/bevacizumab were treated with 12 cycles of folfiri/bevacizumab (arm A) or folfiri/aflibercept (arm B) at Oncologist discretion. Differences in overall survival between the two schedules were analyzed. Responses and toxicities were described with RECIST and NCI-CTC v4.0, respectively. Results: Seventy-four patients were treated from January 2014 to January 2018; 31 with arm A, 43 with arm B. Among clinical factors there was a predominance of more extended disease (>2 metastatic sites) in arm B (26/43 [60.5%] vs. 10/31 [32.2%] arm A; p = 0.0414). Fifty-nine patients were evaluable for response: arm A, 5 PR (Partial Response), 15 SD (Stable Disease), 8 PD (Progressive Disease); arm B, 5 PR, 16 SD, 10 PD. There were no grade 4 toxic events. Duration of first-line chemotherapy was significantly shorter in patients treated in arm B (12 pts <6 months, 16 pts ≥6, and <12, 15 pts ≥12) vs. arm A (1 pts <6 months, 14 pts ≥6, and <12, 16 pts ≥12) (p = 0.0210); these patients were excluded from survival analysis to avoid prognostic interferences. No maintenance treatment with aflibercept was done in arm B while in arm A bevacizumab with or without fluorouracil and folinic acid were allowed. Median OS were 8.9 months in arm A vs. 12.1 months in arm B (+3.2 months; p = 0.9331, HR: 1.02; 95% CI: 0.57–1.84). Six-months survivals were 65% in arm A and 80% in arm B. Conclusions: Folfiri/bevacizumab and folfiri/aflibercept are equally effective second-line therapies in RAS-M mCRC patients. Although not significant, folfiri/aflibercept was associated with a lower risk of death particularly during the 6-months induction phase.
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Affiliation(s)
| | - Monica Capozzi
- Clinical and Experimental Abdominal Oncology of the National Cancer Institute of Naples, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Salvatore Tafuto
- Clinical and Experimental Abdominal Oncology of the National Cancer Institute of Naples, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Alfonso De Stefano
- Clinical and Experimental Abdominal Oncology of the National Cancer Institute of Naples, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Chiara De Divitiis
- Clinical and Experimental Abdominal Oncology of the National Cancer Institute of Naples, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Carmela Romano
- Clinical and Experimental Abdominal Oncology of the National Cancer Institute of Naples, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Antonio Avallone
- Clinical and Experimental Abdominal Oncology of the National Cancer Institute of Naples, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Guglielmo Nasti
- SSD Innovative Therapy for Abdominal Metastases, Naples, Italy
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18
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De Mattia E, Cecchin E, Guardascione M, Foltran L, Di Raimo T, Angelini F, D’Andrea M, Toffoli G. Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma. World J Gastroenterol 2019; 25:3870-3896. [PMID: 31413525 PMCID: PMC6689804 DOI: 10.3748/wjg.v25.i29.3870] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/23/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023] Open
Abstract
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 small-molecule 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 critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.
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Affiliation(s)
- Elena De Mattia
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Erika Cecchin
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Michela Guardascione
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Luisa Foltran
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Tania Di Raimo
- Clinical and Experimental Pharmacology, 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
| | - Francesco Angelini
- Clinical and Experimental Pharmacology, 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
| | - Mario D’Andrea
- Department of Oncology, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Giuseppe Toffoli
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
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19
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Khan K, Rata M, Cunningham D, Koh DM, Tunariu N, Hahne JC, Vlachogiannis G, Hedayat S, Marchetti S, Lampis A, Damavandi MD, Lote H, Rana I, Williams A, Eccles SA, Fontana E, Collins D, Eltahir Z, Rao S, Watkins D, Starling N, Thomas J, Kalaitzaki E, Fotiadis N, Begum R, Bali M, Rugge M, Temple E, Fassan M, Chau I, Braconi C, Valeri N. Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study. Gut 2018; 67:1484-1492. [PMID: 28790159 PMCID: PMC6204951 DOI: 10.1136/gutjnl-2017-314178] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 05/16/2017] [Accepted: 05/23/2017] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection. DESIGN Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies. RESULTS Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07-1.04), p=0.06). CONCLUSIONS Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.
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Affiliation(s)
- Khurum Khan
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, UK
| | - Mihaela Rata
- Division of Radiotherapy and Imaging, Cancer Research UK Imaging Centre, The Institute of Cancer Research and Royal Marsden Hospital, London, UK
| | - David Cunningham
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
| | - Dow-Mu Koh
- Division of Radiotherapy and Imaging, Cancer Research UK Imaging Centre, The Institute of Cancer Research and Royal Marsden Hospital, London, UK
| | - Nina Tunariu
- Division of Radiotherapy and Imaging, Cancer Research UK Imaging Centre, The Institute of Cancer Research and Royal Marsden Hospital, London, UK
| | - Jens C Hahne
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, UK
| | - George Vlachogiannis
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, UK
| | - Somaieh Hedayat
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, UK
| | - Silvia Marchetti
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, UK
| | - Andrea Lampis
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, UK
| | | | - Hazel Lote
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, UK
| | - Isma Rana
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
| | - Anja Williams
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
| | - Suzanne A Eccles
- Division of Cancer Therapeutics, The Institute of Cancer Research, London and Sutton, UK
| | - Elisa Fontana
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
| | - David Collins
- Division of Radiotherapy and Imaging, Cancer Research UK Imaging Centre, The Institute of Cancer Research and Royal Marsden Hospital, London, UK
| | - Zakaria Eltahir
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
| | - Sheela Rao
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
| | - David Watkins
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
| | - Naureen Starling
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
| | - Jan Thomas
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
| | - Eleftheria Kalaitzaki
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
- Department of Statistics, The Royal Marsden NHS Trust, London and Sutton, UK
| | - Nicos Fotiadis
- Division of Radiotherapy and Imaging, Cancer Research UK Imaging Centre, The Institute of Cancer Research and Royal Marsden Hospital, London, UK
| | - Ruwaida Begum
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
| | - Maria Bali
- Division of Radiotherapy and Imaging, Cancer Research UK Imaging Centre, The Institute of Cancer Research and Royal Marsden Hospital, London, UK
| | - Massimo Rugge
- Department of Medicine (DIMED) and Surgical Pathology, University of Padua, Padua, Italy
| | - Eleanor Temple
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
| | - Matteo Fassan
- Department of Medicine (DIMED) and Surgical Pathology, University of Padua, Padua, Italy
| | - Ian Chau
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
| | - Chiara Braconi
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
- Division of Cancer Therapeutics, The Institute of Cancer Research, London and Sutton, UK
| | - Nicola Valeri
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, UK
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20
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Berardi R, Torniai M, Partelli S, Rubini C, Pagliaretta S, Savini A, Polenta V, Santoni M, Giampieri R, Onorati S, Barucca F, Murrone A, Bianchi F, Falconi M. Impact of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) single nucleotide polymorphisms on outcome in gastroenteropancreatic neuroendocrine neoplasms. PLoS One 2018; 13:e0197035. [PMID: 29787601 PMCID: PMC5963762 DOI: 10.1371/journal.pone.0197035] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Accepted: 04/25/2018] [Indexed: 02/06/2023] Open
Abstract
Angiogenesis represents a key event in cancer development, leading to local invasion e metastatization, and might be considered a basic feature in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) with a high expression of angiogenic molecules. We aimed to analyze the prognostic and predictive role of angiogenic factors in GEP-NENs through the analysis of single nucleotide polymorphisms (SNPs) of VEGF-A, VEGFR2 and VEGFR3. The genomic DNA of 58 consecutive patients with GEP-NENs treated at our Institution was extracted from peripheral blood. Two SNPs were identified respectively in VEGF-A (rs2010963G>C, rs699947A>C), VEGFR-2 (rs2305948C>T, rs1870377T>A), and VEGFR-3 (rs307821T>C, rs307826C>A) gene. Gene polymorphisms were determined by Real-Time PCR using TaqMan assays. Median age was 57 years (range 24–79 years); 32 patients were male and 77.5% of NENs were localized in the pancreas. The allele frequency of VEGFR-2 rs2305948T and of VEGF-A rs2010963C showed a trend of higher frequency than in general population (12.1% vs. 8.0% and 34.5% vs. 31.2%, respectively). Three out SNPs (VEGF-A rs699947C, VEGF-A rs2010963GC and VEGFR-3 rs307821C) showed a correlation with an increased risk of disease relapse. Moreover median PFS changes according to the presence of 0–1 SNPs (20.7% of cases; 61.9 months), 2 SNPs (25.9%; 49.2 months) and 3 SNPs (53.4%; 27.8 months) (p = 0.034). Results suggest, for the first time, that specific SNPs in VEGF-A and VEGFR-3 correlate with poor prognosis in GEP-NENs. The identification of this new prognostic factor might be helpful in order to optimize the management of these heterogeneous neoplasms.
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Affiliation(s)
- Rossana Berardi
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
- * E-mail:
| | - Mariangela Torniai
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Stefano Partelli
- Chirurgia del Pancreas, Ospedale San Raffaele IRCCS, Università Vita e Salute, Milano, Italy
| | - Corrado Rubini
- Section of Pathological Anatomy and Histopathology, Deparment of Neuroscience, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Silvia Pagliaretta
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Agnese Savini
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Vanessa Polenta
- Dipartimento di Chirurgia Generale, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Matteo Santoni
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Riccardo Giampieri
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Sofia Onorati
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Federica Barucca
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Alberto Murrone
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Francesca Bianchi
- Clinica di Oncologia Medica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Massimo Falconi
- Section of Pathological Anatomy and Histopathology, Deparment of Neuroscience, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
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Smyth E, Khan K, Valeri N. Translational research and application of basic biology to clinical trial development in GI cancers. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:164. [PMID: 29911112 PMCID: PMC5985276 DOI: 10.21037/atm.2018.05.05] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 04/02/2018] [Indexed: 12/16/2022]
Abstract
Cancers of the gastrointestinal tract have limited available treatments and are often associated with a poor prognosis. Clinical trials and translational work associated with these trials provide the opportunity to increase understanding of the mechanisms of sensitivity and resistance to cytotoxic chemotherapy and targeted therapy in these diseases. In this review we discuss the rationale for intensive translational work within the context of academic clinical trials and the successes and challenges which have been associated with translational work at our institution over the past number of years. We reflect on tissue, plasma and radiological biomarker work including a novel patient derived organoid programme and discuss the iterative application of previous results to next generation trial design.
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Affiliation(s)
- Elizabeth Smyth
- Department of Gastrointestinal Cancer and Lymphoma, Royal Marsden, UK
| | - Khurum Khan
- Department of Gastrointestinal Cancer and Lymphoma, Royal Marsden, UK
| | - Nicola Valeri
- Department of Gastrointestinal Cancer and Lymphoma, Royal Marsden, UK
- Gastrointestinal Cancer Biology and Genomics Team, Institute of Cancer Research, Royal Marsden, UK
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22
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Martinelli E, Sforza V, Cardone C, Capasso A, Nappi A, Martini G, Napolitano S, Rachiglio AM, Normanno N, Cappabianca S, Reginelli A, Bisceglie MD, Latiano TP, Maiello E, Orditura M, De Vita F, Morgillo F, Ciardiello F, Troiani T. Clinical outcome and molecular characterisation of chemorefractory metastatic colorectal cancer patients with long-term efficacy of regorafenib treatment. ESMO Open 2017; 2:e000177. [PMID: 29211816 PMCID: PMC5703385 DOI: 10.1136/esmoopen-2017-000177] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 03/14/2017] [Accepted: 03/15/2017] [Indexed: 12/19/2022] Open
Abstract
Please click here to see linked paper
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Affiliation(s)
- Erika Martinelli
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale 'F. Magrassi e A. Lanzara', Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Vincenzo Sforza
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale 'F. Magrassi e A. Lanzara', Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Claudia Cardone
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale 'F. Magrassi e A. Lanzara', Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Anna Capasso
- Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Anna Nappi
- Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione Giovanni Pascale'-IRCCS, via Mariano Semmola, Napoli, Italy
| | - Giulia Martini
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale 'F. Magrassi e A. Lanzara', Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Stefania Napolitano
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale 'F. Magrassi e A. Lanzara', Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
| | | | - Nicola Normanno
- Cell Biology and Preclinical Models Unit, INT-Fondazione Pascale, Napoli, Italy
| | - Salvatore Cappabianca
- Department of Radiology, Università degli Studi della Campania Luigi Vanvitelli, piazza Miraglia, Napoli, Italy
| | - Alfonso Reginelli
- Department of Radiology, Università degli Studi della Campania Luigi Vanvitelli, piazza Miraglia, Napoli, Italy
| | | | - Tiziana Pia Latiano
- Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Evaristo Maiello
- Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Michele Orditura
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale 'F. Magrassi e A. Lanzara', Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Fernando De Vita
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale 'F. Magrassi e A. Lanzara', Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Floriana Morgillo
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale 'F. Magrassi e A. Lanzara', Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Fortunato Ciardiello
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale 'F. Magrassi e A. Lanzara', Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Teresa Troiani
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale 'F. Magrassi e A. Lanzara', Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
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Off-target effects and clinical outcome in metastatic colorectal cancer patients receiving regorafenib: The TRIBUTE analysis. Sci Rep 2017; 7:45703. [PMID: 28378839 PMCID: PMC5380985 DOI: 10.1038/srep45703] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 02/28/2017] [Indexed: 02/06/2023] Open
Abstract
Regorafenib is an orally administered multikinase inhibitor indicated for the treatment of heavily pretreated metastatic colorectal cancer patients with good performance status, albeit less than 50% treated patients achieve disease stabilisation or better at the first radiological evaluation. In addition to that a particularly broad spectrum of toxicities (experienced as G3 or more NCI CTCAE graded by 50% of patients treated) have led to reconsider its widespread use in the majority of patients. We retrospectively collected data about the magnitude of off-target effects experienced during the first 8-weeks of regorafenib monotherapy and analysed their correlation with overall survival, progression free survival and disease control rate. Our findings suggest that skin rash (Exp (B): 0.52, p = 0.0133) or hypothyroidism (Exp (B): 0.11, p = 0.0349) were significantly correlated with improved overall survival at multivariate regression analysis. It was also demonstrated a statistically significant role of diarrhea as predictor of improved survival but its independent prognostic role was lost at multivariate analysis (Exp (B): 0.63, p = 0.162). This is the first analysis showing a potential correlation between the onset of these forms of side effects and regorafenib efficacy, however sample size limitations and the retrospective nature of our analysis prevent us from drawing definitive conclusions.
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do Espírito Santo GF, Galera BB, Duarte EC, Chen ES, Azis L, Damazo AS, Saba GT, de Sousa Gehrke F, Guerreiro da Silva IDC, Waisberg J. Prognostic significance of vascular endothelial growth factor polymorphisms in colorectal cancer patients. World J Gastrointest Oncol 2017; 9:78-86. [PMID: 28255429 PMCID: PMC5314204 DOI: 10.4251/wjgo.v9.i2.78] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 09/02/2016] [Accepted: 12/14/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the associations of the genetic polymorphisms of vascular endothelial growth factor A (VEGF-A) -1498C>T and -634G>C, with the survival of patients with colorectal cancer (CRC).
METHODS A prospective cohort consisting of 131 Brazilians patients consecutively operated on with a curative intention as a result of sporadic colorectal carcinoma was studied. DNA was extracted from peripheral blood and its amplification and allelic discrimination for each genetic polymorphism was performed using the technique of polymerase chain reaction (PCR) in real-time. The real-time PCR technique was used to identify the VEGF-A -1498C>T (rs833031) and -634G>C (rs2010963) polymorphisms. Genotyping was validated for VEGF-A -1498C>T polymorphism in 129 patients and for VEGF-A -634G>C polymorphism in 118 patients. The analysis of association between categorical variables was performed using logistic regression, survival by Kaplan-Meier method and multivariate analysis by the Cox regression method.
RESULTS In the univariate analysis there was a significant association (OR = 0.32; P = 0.048) between genotype CC of the VEGF-A -1498C>T polymorphism and the presence of CRC liver metastasis. There was no association between VEGF-A -1498C>T polymorphism and VEGF-A -634G>C polymorphism with further clinical or anatomopathologic variables. The genotype CC of the VEGF-A -1498C>T polymorphism was significantly correlated with the 5-year survival (P = 0.032), but not significant difference (P = 0.27) was obtained with the VEGF-A -634G>C polymorphism with the 5-year survival in the univariate analysis. The genotype CT (HR = 2.79) and CC (HR = 4.67) of the polymorphism VEGF-A -1498C>T and the genotype CC (HR = 3.76) of the polymorphism VEGF-A -634C>G acted as an independent prognostic factor for the risk of death in CRC patients.
CONCLUSION The CT and CC genotypes of the VEGF-A -1498C>T and the CC genotype of the VEGF-A -634C>G polymorphisms are prognostic factors of survival in Brazilians patients with sporadic colorectal carcinoma.
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