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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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Liu T, Li M, Cheng W, Yao Q, Xue Y, Wang X, Jin H. A clinical prognostic model for patients with esophageal squamous cell carcinoma based on circulating tumor DNA mutation features. Front Oncol 2023; 12:1025284. [PMID: 36686833 PMCID: PMC9850098 DOI: 10.3389/fonc.2022.1025284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 12/14/2022] [Indexed: 01/07/2023] Open
Abstract
Background Few predictive models have included circulating tumor DNA (ctDNA) indicators to predict prognosis of esophageal squamous cell carcinoma (ESCC) patients. Here, we aimed to explore whether ctDNA can be used as a predictive biomarker in nomogram models to predict the prognosis of patients with ESCC. Methods We included 57 patients who underwent surgery and completed a 5-year follow-up. With next-generation sequencing, a 61-gene panel was used to evaluate plasma cell-free DNA and white blood cell genomic DNA from patients with ESCC. We analyzed the relationship between the mutation features of ctDNA and the prognosis of patients with ESCC, identified candidate risk predictors by Cox analysis, and developed nomogram models to predict the 2- and 5-year disease-free survival (DFS) and overall survival (OS). The area under the curve of the receiver operating characteristic (ROC) curve, concordance index (C-index), calibration plot, and integrated discrimination improvement (IDI) were used to evaluate the performance of the nomogram model. The model was compared with the traditional tumor-nodes-metastasis (TNM) staging system. Results The ROC curve showed that the average mutant allele frequency (MAF) of ctDNA variants and the number of ctDNA variants were potential biomarkers for predicting the prognosis of patients with ESCC. The predictors included in the models were common candidate predictors of ESCC, such as lymph node stage, angiolymphatic invasion, drinking history, and ctDNA characteristics. The calibration curve demonstrated consistency between the observed and predicted results. Moreover, our nomogram models showed clear prognostic superiority over the traditional TNM staging system (based on C-index, 2-year DFS: 0.82 vs. 0.64; 5-year DFS: 0.78 vs. 0.65; 2-year OS: 0.80 vs. 0.66; 5-year OS: 0.77 vs. 0.66; based on IDI, 2-year DFS: 0.33, p <0.001; 5-year DFS: 0.18, p = 0.04; 2-year OS: 0.28, p <0.001; 5-year OS: 0.15, p = 0.04). The comprehensive scores of the nomogram models could be used to stratify patients with ESCC. Conclusions The novel nomogram incorporating ctDNA features may help predict the prognosis of patients with resectable ESCC. This model can potentially be used to guide the postoperative management of ESCC patients in the future, such as adjuvant therapy and follow-up.
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Affiliation(s)
- Tao Liu
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Mengxing Li
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Wen Cheng
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Qianqian Yao
- Department of Medical Science, Shanghai AccuraGen Biotechnology Co., Ltd., Shanghai, China
| | - Yibo Xue
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xiaowei Wang
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China,*Correspondence: Hai Jin, ; Xiaowei Wang,
| | - Hai Jin
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China,*Correspondence: Hai Jin, ; Xiaowei Wang,
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A phase II study to explore biomarkers for the use of mFOLFOX6/XELOX plus bevacizumab as a first-line chemotherapy in patients with metastatic colorectal cancer (WJOG7612GTR). ESMO Open 2022; 7:100592. [PMID: 36502778 PMCID: PMC9808456 DOI: 10.1016/j.esmoop.2022.100592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/07/2022] [Accepted: 08/23/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The purpose of this prospective study was to assess the ability of plasma vascular endothelial growth factor-A short isoforms (pVEGF-Asi) to predict bevacizumab (BV) efficacy and to explore other circulating biomarkers in metastatic colorectal cancer (mCRC) patients treated with modified FOLFOX6/XELOX plus BV (mFOLFOX6/XELOX + BV). PATIENTS AND METHODS Pre-treatment plasma samples were collected from 100 mCRC patients receiving first-line chemotherapy with mFOLFOX6/XELOX + BV. The plasma levels of 11 angiogenesis-associated molecules, including pVEGF-Asi and 22 cancer-associated gene mutations in circulating tumor DNA, were analyzed. For the primary endpoint, we assumed that the hazard ratio (HR) for progression-free survival (PFS) calculated using a Cox proportional hazards model was <1.15, comparing patients with a high versus those with a low pVEGF-Asi level divided according to the median pVEGF-Asi value. RESULTS The median value of pVEGF-Asi was 37 (range 6.5-262) pg/ml. The HR for PFS between the high and low pVEGF-Asi patient groups was 1.3 [95% confidence interval (CI) 0.8-2.1; log rank, P = 0.25], which was larger than the predefined threshold of 1.15. The multivariate analysis demonstrated that PFS was significantly associated with plasma intercellular adhesion molecule-1 (pICAM-1) (≥190.0 versus <190.0 ng/ml; HR 2.1; 95% CI 1.3-3.5), RAS (mutant versus wild; HR 2.5; 95% CI 1.5-4.3), and FBXW7 (mutant versus wild; HR 2.8; 95% CI 1.2-6.8), whereas overall survival was significantly associated with pICAM-1 (HR 2.0; 95% CI 1.1-3.7) and RAS (HR 2.6; 95% CI 1.5-4.6). CONCLUSIONS The addition of BV was unable to compensate for the poor PFS associated with a high pVEGF-Asi level, suggesting that pVEGF-Asi is unlikely to be a good predictive biomarker of the efficacy of mFOLFOX6/XELOX + BV therapy. The clinical significance of circulating ICAM-1, mutant RAS, and mutant FBXW7 levels should be studied further.
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Callesen LB, Hamfjord J, Boysen AK, Pallisgaard N, Guren TK, Kure EH, Spindler KLG. Circulating tumour DNA and its clinical utility in predicting treatment response or survival in patients with metastatic colorectal cancer: a systematic review and meta-analysis. Br J Cancer 2022; 127:500-513. [PMID: 35440666 PMCID: PMC9345951 DOI: 10.1038/s41416-022-01816-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 03/29/2022] [Accepted: 03/31/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND We investigate the current knowledge on circulating tumour DNA (ctDNA) and its clinical utility in predicting outcomes in patients with metastatic colorectal cancer (mCRC). METHODS PubMed, Embase, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials were searched. Last search 16/12/2020. We included studies on patients with mCRC reporting the predictive or prognostic value of ctDNA. We performed separate random-effects meta-analyses to investigate if baseline ctDNA and early changes in ctDNA levels during treatment were associated with survival. The risk of bias was assessed according to the Quality in Prognosis Studies tool. RESULTS Seventy-one studies were included with 6930 patients. Twenty-four studies were included in meta-analyses. High baseline ctDNA level was associated with short progression-free survival (PFS) (HR = 2.2; 95% CI 1.8-2.8; n = 509) and overall survival (OS) (HR = 2.4; 95% CI 1.9-3.1; n = 1336). A small or no early decrease in ctDNA levels during treatment was associated with short PFS (HR = 3.0; 95% CI 2.2-4.2; n = 479) and OS (HR = 2.8; 95% CI 2.1-3.9; n = 583). Results on clonal evolution and lead-time were inconsistent. A majority of included studies (n = 50/71) had high risk of bias in at least one domain. CONCLUSIONS Plasma ctDNA is a strong prognostic biomarker in mCRC. However, true clinical utility is lacking.
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Affiliation(s)
- Louise B Callesen
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.
- Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Julian Hamfjord
- Department of Oncology, Oslo University Hospital, Oslo, Norway
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Anders K Boysen
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Pallisgaard
- Department of Pathology, Zealand University Hospital, Roskilde, Denmark
| | - Tormod K Guren
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Elin H Kure
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Department of Natural Sciences and Environmental Health, Faculty of Technology, Natural Sciences and Maritime Sciences, University of South-Eastern Norway, Campus Bø, Bø, Norway
| | - Karen-Lise G Spindler
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark
- Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Edwards RL, Menteer J, Lestz RM, Baxter-Lowe LA. Cell-free DNA as a solid-organ transplant biomarker: technologies and approaches. Biomark Med 2022; 16:401-415. [PMID: 35195028 DOI: 10.2217/bmm-2021-0968] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
High-quality biomarkers that detect emergent graft damage and/or rejection after solid-organ transplantation offer new opportunities to improve post-transplant monitoring, allow early therapeutic intervention and facilitate personalized patient management. Donor-derived cell-free DNA (DD-cfDNA) is a particularly exciting minimally invasive biomarker because it has the potential to be quantitative, time-sensitive and cost-effective. Increased DD-cfDNA has been associated with graft damage and rejection episodes. Efforts are underway to further improve sensitivity and specificity. This review summarizes the procedures used to process and detect DD-cfDNA, measurement of DD-cfDNA in clinical transplantation, approaches for improving sensitivity and specificity and long-term prospects as a transplant biomarker to supplement traditional organ monitoring and invasive biopsies.
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Affiliation(s)
- Rebecca L Edwards
- Department of Pathology & Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Jondavid Menteer
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.,Division of Cardiology, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Rachel M Lestz
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.,Division of Nephrology, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Lee Ann Baxter-Lowe
- Department of Pathology & Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA
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Croitoru VM, Cazacu IM, Popescu I, Paul D, Dima SO, Croitoru AE, Tanase AD. Clonal Hematopoiesis and Liquid Biopsy in Gastrointestinal Cancers. Front Med (Lausanne) 2022; 8:772166. [PMID: 35127745 PMCID: PMC8814311 DOI: 10.3389/fmed.2021.772166] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 12/02/2021] [Indexed: 02/03/2023] Open
Abstract
The use of blood liquid biopsy is increasingly being incorporated into the clinical setting of gastrointestinal cancers care. Clonal hematopoiesis (CH) occurs naturally as a result of the accumulation of somatic mutations and the clonal proliferation of hematopoietic stem cells with normal aging. The identification of CH-mutations has been described as a source of biological noise in blood liquid biopsy. Incorrect interpretation of CH events as cancer related can have a direct impact on cancer diagnosis and treatment. This review summarizes the current understanding of CH as a form of biological noise in blood liquid biopsy and the reported clinical significance of CH in patients with GI cancers.
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Affiliation(s)
- Vlad M. Croitoru
- Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania
- Department of Medical Oncology, Fundeni Clinical Institute, Bucharest, Romania
| | - Irina M. Cazacu
- Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania
- Department of Medical Oncology, Fundeni Clinical Institute, Bucharest, Romania
| | - Ionut Popescu
- Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania
| | - Doru Paul
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine/New York-Presbyterian, New York, NY, United States
| | - Simona Olimpia Dima
- Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Adina Emilia Croitoru
- Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania
- Department of Medical Oncology, Fundeni Clinical Institute, Bucharest, Romania
- *Correspondence: Adina Emilia Croitoru
| | - Alina Daniela Tanase
- Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania
- Bone Marrow Transplant Unit, Fundeni Clinical Institute, Bucharest, Romania
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Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13184547. [PMID: 34572774 PMCID: PMC8471730 DOI: 10.3390/cancers13184547] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Circulating tumor DNA, or ctDNA, are fragments of tumor DNA that can be detected in the blood of patients with colorectal cancer. Measuring ctDNA levels in the blood has shown the potential to provide important information that can be helpful in the clinical care of patients with colorectal cancer. For example, in patients with colon cancer that has been removed by surgery, measuring ctDNA in the blood can predict the likelihood of cancer recurrence, while in those with metastatic colorectal cancer, measuring ctDNA can inform the clinician whether chemotherapy is effective at earlier timepoints than currently available tests. In this review, we discuss the results from ongoing studies describing the utility of ctDNA measurements across all stages of colorectal cancer. We also discuss the various clinical scenarios that ctDNA may have the most immediate impact in colorectal cancer management. Abstract Emerging data suggest that circulating tumor DNA (ctDNA) can detect colorectal cancer (CRC)-specific signals across both non-metastatic and metastatic settings. With the development of multiple platforms, including tumor-informed and tumor-agnostic ctDNA assays and demonstration of their provocative analytic performance to detect minimal residual disease, there are now ongoing, phase III randomized clinical trials to evaluate their role in the management paradigm of CRC. In this review, we highlight landmark studies that have formed the basis for ongoing studies on the clinically applicability of plasma ctDNA assays in resected, stage I–III CRC and metastatic CRC. We discuss clinical settings by which ctDNA may have the most immediate impact in routine clinical practice. These include the potential for ctDNA to (1) guide surveillance and intensification or de-intensification strategies of adjuvant therapy in resected, stage I–III CRC, (2) predict treatment response to neoadjuvant therapy in locally advanced rectal cancer inclusive of total neoadjuvant therapy (TNT), and (3) predict response to systemic and surgical therapies in metastatic disease. We end by considering clinical variables that can influence our ability to reliably interpret ctDNA dynamics in the clinic.
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Zhao L, Wang Q, Zhao SD, Zhou J, Jiang KW, Ye YJ, Wang S, Shen ZL. Genetic mutations associated with sensitivity to neoadjuvant chemotherapy in metastatic colon cancer: A case report and review of literature. World J Clin Cases 2021; 9:7099-7109. [PMID: 34540965 PMCID: PMC8409210 DOI: 10.12998/wjcc.v9.i24.7099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 05/14/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal liver metastases (CLM) occur in 15%-30% of patients with colorectal cancer (CRC). Advancements in next generation sequencing (NGS) can provide more precise prognoses for cancer patients and help guide clinical treatment. However, the genetic variants that predict high sensitivity to neoadjuvant chemotherapy remain unclear, especially in patients with CLM. The aim of this study was to identify the relevant genetic variants in a single CLM patient and to summarize the current evidence on mutations and single nucleotide polymorphisms (SNPs) that objectively predict sensitivity to neoadjuvant chemotherapy.
CASE SUMMARY A 76-year-old male patient, who was diagnosed as stage IV colon cancer with liver metastases, was found to have APC/TP53/KRAS mutations. He showed a good therapeutic response to 12 courses of oxaliplatin regimens combined with Bevacizumab. Genetic analysis of the patient identified 5 genes with 7 detected SNPs that may be related to a better response to chemotherapy drugs. In addition, a critical literature review was performed based on a standardized appraisal form after selecting the articles. Ultimately, 21 eligible studies were appraised to assess the association between gene mutations and good prognosis. Mutations in KRAS, TP53, SMAD4, and APC were identified as being associated with a poor response to chemotherapy drugs, whereas mutations of CREBBP and POLD1 were associated with longer overall survival.
CONCLUSION NGS can identify precise predictors of response to neoadjuvant chemotherapy, leading to improved outcomes for CRC patients.
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Affiliation(s)
- Long Zhao
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, China
| | - Quan Wang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, China
| | - Shi-Dong Zhao
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, China
| | - Jing Zhou
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, China
| | - Ke-Wei Jiang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, China
| | - Ying-Jiang Ye
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, China
| | - Shan Wang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, China
| | - Zhan-Long Shen
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, China
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9
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Fujii Y, Ono A, Hayes CN, Aikata H, Yamauchi M, Uchikawa S, Kodama K, Teraoka Y, Fujino H, Nakahara T, Murakami E, Miki D, Okamoto W, Kawaoka T, Tsuge M, Imamura M, Chayama K. Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:215. [PMID: 34174931 PMCID: PMC8235843 DOI: 10.1186/s13046-021-02016-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/11/2021] [Indexed: 12/20/2022]
Abstract
Background There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN). Method We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated. Results In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAFmean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAFmean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed. Conclusion Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02016-3.
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Affiliation(s)
- Yasutoshi Fujii
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Kenichiro Kodama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Wataru Okamoto
- Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Masataka Tsuge
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Kazuaki Chayama
- Collaborative Research Laboratory of Medical Innovation, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. .,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan. .,RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
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10
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Petrillo A, Salati M, Trapani D, Ghidini M. Circulating Tumor DNA as a Biomarker for Outcomes Prediction in Colorectal Cancer Patients. Curr Drug Targets 2021; 22:1010-1020. [PMID: 33155906 DOI: 10.2174/1389450121999201103194248] [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: 05/23/2020] [Revised: 08/07/2020] [Accepted: 08/23/2020] [Indexed: 12/24/2022]
Abstract
Circulating tumour DNA (ctDNA) is a novel tool that has been investigated in several types of tumours, including colorectal cancer (CRC). In fact, the techniques based on liquid biopsies are proposed as appealing non-invasive alternatives to tissue biopsy, adding more insights into tumour molecular profile, heterogeneity and for cancer detection and monitoring. Additionally, some analysis showed that in CRC patients, ctDNA seems to act as a biomarker able to predict the outcome (prognostic role) and the response to treatments (predictive role). In particular, in the early stage CRC (stage I-III), it could represent a time marker of adjuvant therapy as well as a marker of minimal residual disease and recurrence risk in addition to the already recognized risk factors. In metastatic CRC, the analysis of molecular tumour profile by ctDNA has shown to have high concordance with the tissue biopsy at diagnosis. Additionally, some studies demonstrated that ctDNA level during the treatment was linked with the early response to treatment and prognosis. Finally, the quantitative analysis of ctDNA and copy number alterations may be useful in order to detect resistance to therapy at the time of progression of disease and to help in finding new therapeutic targets.
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Affiliation(s)
| | - Massimiliano Salati
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Dario Trapani
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - Michele Ghidini
- Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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11
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Zou D, Day R, Cocadiz JA, Parackal S, Mitchell W, Black MA, Lawrence B, Fitzgerald S, Print C, Jackson C, Guilford P. Circulating tumor DNA is a sensitive marker for routine monitoring of treatment response in advanced colorectal cancer. Carcinogenesis 2021; 41:1507-1517. [PMID: 32955091 DOI: 10.1093/carcin/bgaa102] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/08/2020] [Accepted: 09/16/2020] [Indexed: 12/17/2022] Open
Abstract
Accurate assessment of chemotherapy response provides the means to terminate ineffective treatment, trial alternative drug regimens or schedules and reduce dose to minimize toxicity. Here, we have compared circulating tumor DNA (ctDNA) with carcinoembryonic antigen (CEA) for the cycle by cycle assessment of chemotherapy response in 30 patients with metastatic colorectal cancer. CtDNA (quantified using individualized digital droplet PCR (ddPCR) assays) and CEA levels were determined immediately prior to each chemotherapy cycle over time periods ranging from 42-548 days (average of 10 time points/patient). Twenty-nine/thirty (97%) patients had detectable ctDNA compared with 83% whose tumors were CEA-positive (>5 ng/ml) during the monitoring course. Over the course of treatment, 20 disease progression events were detected by computed tomography; ctDNA predicted significantly more of these events than CEA (16 (80%) versus 6 (30%), respectively; P-value = 0.004). When progression was detected by both ctDNA and CEA, the rise in ctDNA occurred significantly earlier than CEA (P-value = 0.046). Partial responses to chemotherapy were also detected more frequently by ctDNA, although this was not significant (P-value = 0.07). In addition, another 28 colorectal cancer patients who underwent potentially curative surgery and showed no evidence of residual disease were monitored with ctDNA for up to 2 years. Clinical relapse was observed in 6/28 (21%) patients. Four out of 6 of these patients showed a significant increase in ctDNA at or prior to relapse. Overall, ctDNA analyses were able to be performed in a clinically relevant timeline and were a more sensitive and responsive measure of tumor burden than CEA.
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Affiliation(s)
- Donghui Zou
- Department of Biochemistry, Cancer Genetics Laboratory, Te Aho Matatū, University of Otago, Dunedin, New Zealand
| | - Robert Day
- Department of Biochemistry, Cancer Genetics Laboratory, Te Aho Matatū, University of Otago, Dunedin, New Zealand
| | - Judy A Cocadiz
- Department of Biochemistry, Cancer Genetics Laboratory, Te Aho Matatū, University of Otago, Dunedin, New Zealand
| | - Sarah Parackal
- Department of Biochemistry, Cancer Genetics Laboratory, Te Aho Matatū, University of Otago, Dunedin, New Zealand
| | - Wilson Mitchell
- Department of Biochemistry, Cancer Genetics Laboratory, Te Aho Matatū, University of Otago, Dunedin, New Zealand
| | - Michael A Black
- Department of Biochemistry, Cancer Genetics Laboratory, Te Aho Matatū, University of Otago, Dunedin, New Zealand
| | - Ben Lawrence
- Discipline of Oncology, The University of Auckland, Auckland, New Zealand
| | - Sandra Fitzgerald
- Department of Molecular Medicine and Pathology, Faculty of Medicine, The University of Auckland, Auckland, New Zealand
| | - Cristin Print
- Department of Molecular Medicine and Pathology, Faculty of Medicine, The University of Auckland, Auckland, New Zealand
| | - Christopher Jackson
- Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Parry Guilford
- Department of Biochemistry, Cancer Genetics Laboratory, Te Aho Matatū, University of Otago, Dunedin, New Zealand
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12
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Abstract
Response evaluation for cancer treatment consists primarily of clinical and radiological assessments. In addition, a limited number of serum biomarkers that assess treatment response are available for a small subset of malignancies. Through recent technological innovations, new methods for measuring tumor burden and treatment response are becoming available. By utilization of highly sensitive techniques, tumor-specific mutations in circulating DNA can be detected and circulating tumor DNA (ctDNA) can be quantified. These so-called liquid biopsies provide both molecular information about the genomic composition of the tumor and opportunities to evaluate tumor response during therapy. Quantification of tumor-specific mutations in plasma correlates well with tumor burden. Moreover, with liquid biopsies, it is also possible to detect mutations causing secondary resistance during treatment. This review focuses on the clinical utility of ctDNA as a response and follow-up marker in patients with non-small cell lung cancer, melanoma, colorectal cancer, and breast cancer. Relevant studies were retrieved from a literature search using PubMed database. An overview of the available literature is provided and the relevance of ctDNA as a response marker in anti-cancer therapy for clinical practice is discussed. We conclude that the use of plasma-derived ctDNA is a promising tool for treatment decision-making based on predictive testing, detection of resistance mechanisms, and monitoring tumor response. Necessary steps for translation to daily practice and future perspectives are discussed.
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13
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Jones RP, Pugh SA, Graham J, Primrose JN, Barriuso J. Circulating tumour DNA as a biomarker in resectable and irresectable stage IV colorectal cancer; a systematic review and meta-analysis. Eur J Cancer 2021; 144:368-381. [PMID: 33422803 DOI: 10.1016/j.ejca.2020.11.025] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/01/2020] [Accepted: 11/15/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND For patients with metastatic colorectal cancer, stratification for treatment (surgery or chemotherapy) is often based on crude clinicopathological characteristics like tumour size and number of lesions. Circulating tumour DNA (ctDNA) acts as a potential biomarker of disease trajectory and biology, allowing better stratification. This study aims to systematically review ctDNA in stage IV colorectal cancer to assess its potential role as a prospective biomarker to guide management decisions. METHODS A literature search was performed to identify studies where the measurement of ctDNA in stage IV colorectal cancer was correlated with a clinical outcome (radiological response, secondary resection rate, PFS, DFS or OS). RESULTS Twenty-eight studies were included, reporting on 2823 patients. Circulating tumour DNA was detectable in between 80% and 90% of patients prior to treatment. Meta-analysis identified a strong correlation between detectable ctDNA after treatment (surgery or chemotherapy) and overall survival (HR 2.2, 95% CI 1.79-2.69, p < 0.00001), as well as progression-free survival (HR 3.15, 95% CI 2.10-4.73, p < 0.00001). ctDNA consistently offered an early marker of long-term prognosis in irresectable disease, with changes after one cycle of systemic therapy demonstrating prognostic value. In resectable disease treated with curative intent, detection of ctDNA offered a lead time over radiological recurrence of 10 months. CONCLUSION Circulating tumour DNA is detectable in the majority of resectable and irresectable patients. The presence of ctDNA is clearly associated with shorter overall survival, with changes in ctDNA an early biomarker of adverse disease behaviour. Prospective trials are essential to test its clinical efficacy.
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Affiliation(s)
- Robert P Jones
- School of Cancer Studies, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Department of Hepatobiliary Surgery, Liverpool University Teaching Hospitals NHS Foundation Trust, Liverpool, UK.
| | | | - Janet Graham
- Beatson West of Scotland Cancer Centre, Glasgow, UK; University of Glasgow, UK
| | | | - Jorge Barriuso
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
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14
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Kobayashi S, Nakamura Y, Taniguchi H, Odegaard JI, Nomura S, Kojima M, Sugimoto M, Konishi M, Gotohda N, Takahashi S, Yoshino T. Impact of Preoperative Circulating Tumor DNA Status on Survival Outcomes After Hepatectomy for Resectable Colorectal Liver Metastases. Ann Surg Oncol 2021; 28:4744-4755. [PMID: 33393041 DOI: 10.1245/s10434-020-09449-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 11/17/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND The optimal perioperative management of patients who undergo hepatectomy for resectable colorectal liver metastases (CRLM) remains unclear due to the lack of reliable methods to stratify the risk of recurrence. METHODS A single-center retrospective study was performed to investigate the impact of preoperative circulating tumor DNA (ctDNA) on survival outcomes of patients who underwent initial hepatectomy for solitary resectable CRLM between January 2005 and December 2017 using the comprehensive genotyping platform Guardant360®. RESULTS Of 212 patients who underwent initial hepatectomy for solitary resectable CRLM, 40 patients for whom pre-hepatectomy plasma was available underwent ctDNA analysis. Among them, 32 (80%) had at least 1 somatic alteration in their ctDNA, while the other 8 (20%) had no detectable ctDNA. Among the patients with undetectable ctDNA, only one had recurrence and none died during a median follow-up period of 39.0 months. The recurrence-free survival was significantly shorter in patients who were positive for ctDNA than in those who were negative for ctDNA [median, 12.5 months vs not reached (NR); HR, 7.6; P = 0.02]. The overall survival also tended to be shorter in patients who were positive for ctDNA than those who were negative for ctDNA (median, 78.1 months vs NR; P = 0.14; HR not available). CONCLUSIONS In patients undergoing hepatectomy for solitary resectable CRLM, the absence of detectable preoperative ctDNA identified patients with a high chance for a cure. Risk stratification according to preoperative ctDNA analysis may be an effective tool that can improve the perioperative management of these patients.
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Affiliation(s)
- Shin Kobayashi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Hiroya Taniguchi
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | | | - Shogo Nomura
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Motohiro Kojima
- Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Motokazu Sugimoto
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masaru Konishi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Naoto Gotohda
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shinichiro Takahashi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
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15
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Holm M, Andersson E, Osterlund E, Ovissi A, Soveri LM, Anttonen AK, Kytölä S, Aittomäki K, Osterlund P, Ristimäki A. Detection of KRAS mutations in liquid biopsies from metastatic colorectal cancer patients using droplet digital PCR, Idylla, and next generation sequencing. PLoS One 2020; 15:e0239819. [PMID: 33237900 PMCID: PMC7688175 DOI: 10.1371/journal.pone.0239819] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 09/15/2020] [Indexed: 12/25/2022] Open
Abstract
Circulating tumor DNA (ctDNA) is released from cancer cells and oncogenic mutations in ctDNA can be measured from plasma samples. Droplet digital PCR (ddPCR) is a sensitive and specific method for the detection of mutations in ctDNA. We analyzed serial plasma samples (n = 80) from ten metastatic colorectal cancer (mCRC) patients with a known KRAS mutation in their primary tumor. The patients were undergoing oncological treatment with bevacizumab in combination with alternating capecitabine and oxaliplatin or irinotecan. Baseline ddPCR KRAS mutation allele frequency (MAF) values ranged from 0% to 63%. The first radiologic response evaluation criteria in solid tumors (RECIST) evaluation was performed 45-63 days after the initiation of treatment, and by this time three patients had an undetectable level of KRAS mutation, one had a MAF value of 0.5%, and one had a MAF value of 3% that had been reduced by 95% from the baseline value. In three of these patients the RECIST assessment was stable disease and in two partial response. In seven patients, ddPCR MAF values increased before radiological disease progression or death, while one patient remained disease-free with an undetectable KRAS mutation level. Next, we analyzed all available plasma samples with the Idylla ctKRAS system (n = 60), and found that the overall degree of agreement between ddPCR and Idylla was almost perfect (kappa value = 0.860). We used next-generation sequencing (NGS) to detect treatment-induced mutations in the last serial plasma sample of each patient, but were unable to find any new mutations when compared to the primary tumor. This study shows that ddPCR and Idylla are equally efficient for the detection of KRAS mutations in the liquid biopsies from mCRC patients and that ctDNA may indicate the disappearance of treatment responsive KRAS positive mCRC clones and serve as an early sign of disease progression.
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Affiliation(s)
- Matilda Holm
- Department of Pathology, Medicum, Faculty of Medicine, University of Helsinki and HUSLAB, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Surgery, Medicum, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Translational Cancer Medicine Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Emma Andersson
- Department of Genetics, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Emerik Osterlund
- Department of Surgery, Medicum, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Ali Ovissi
- Department of Radiology, HUS Diagnostic Center, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland
| | - Leena-Maija Soveri
- Department of Oncology, Clinicum, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Hyvinkää Hospital and Hyvinkää Homecare, Hyvinkää, Finland
| | - Anna-Kaisa Anttonen
- Department of Genetics, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Soili Kytölä
- Department of Genetics, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Kristiina Aittomäki
- Department of Genetics, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Pia Osterlund
- Department of Oncology, Clinicum, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Department of Oncology, Tampere University Hospital, Tampere, Finland
- Faculty of Medicine and Life Sciences, Tampere University, Tampere, Finland
| | - Ari Ristimäki
- Department of Pathology, Medicum, Faculty of Medicine, University of Helsinki and HUSLAB, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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16
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Venniyoor A. Synergism between anti-angiogenic and immune checkpoint inhibitor drugs: A hypothesis. Med Hypotheses 2020; 146:110399. [PMID: 33239232 DOI: 10.1016/j.mehy.2020.110399] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/19/2020] [Accepted: 11/12/2020] [Indexed: 02/08/2023]
Abstract
Hepatocellular cancer (HCC) and renal cell cancer (RCC) are singularly resistant to conventional chemotherapy drugs but therapies targeting the supporting stroma have significantly altered their management. Two recent trials combining anti-angiogenic (AA) agents with immune checkpoint inhibitors (ICIs)- the IMbrave150 and IMmotion151 - have reported impressive progress over targeted agents. It has been suggested that bevacizumab, by improving tissue perfusion, changes the immune suppressive tumour microenvironment to an immune stimulatory one where the ICIs can be more effective. This hypothesis proposes an alternative explanation: That bevacizumab, by increasing tissue hypoxia, amplifies the mutational burden of the tumour by stress-induced mutagenesis, creating a hypermutator profile, which is more vulnerable to the ICI drug, atezolizumab. Additionally, ICIs are known to cause hyperprogression in some tumours, and bevacizumab could provide further benefit by starving these rapidly proliferative tumours of blood supply and nutrients.
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Affiliation(s)
- Ajit Venniyoor
- National Oncology Centre, The Royal Hospital, Muscat, Oman.
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17
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Guan JL, Liu JH, Wang Q, Cong YW, Chen YX, Huang KF, Huang ML, Huang L. Response of human epidermal growth factor receptor 2-positive colorectal cancer to lapatinib monotherapy: A case report. World J Gastrointest Oncol 2020; 12:1065-1072. [PMID: 33005299 PMCID: PMC7509996 DOI: 10.4251/wjgo.v12.i9.1065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 07/16/2020] [Accepted: 08/16/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) amplification is a molecular driver for a subset of colorectal cancers (CRCs) and one of the major causes of anti-epidermal growth factor receptor (EGFR) treatment failure. Compared to dual anti-HER2 treatments, which have been shown to be effective in HER2-positive metastatic CRC patients, single-agent anti-HER2 therapy is rarely used to treat CRC.
CASE SUMMARY Herein, we report a case of RAS/BRAF-wild-type metastatic CRC that was identified as HER2-positive through circulating tumor DNA (ctDNA) testing by next-generation sequencing following the failure of two lines of therapy. Subsequently, the patient was given lapatinib monotherapy that led to a partial response with a progression-free survival of 7.9 mo. Moreover, serial ctDNA detection was used to monitor the efficacy of lapatinib. The aberration of HER2 copy number disappeared when radiographic assessment revealed a partial response. However, a high level of HER2 amplification was detected again at the time of disease progression. Finally, a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutation was identified at the time of tumor progression, which may explain the acquired resistance to lapatinib.
CONCLUSION This is the first case report of HER2-positive RAS/BRAF wild-type metastatic CRC patient responding to lapatinib monotherapy. It highlights that ctDNA testing is an effective and feasible approach to evaluate the efficacy of anti-HER2 therapy.
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Affiliation(s)
- Ji-Lin Guan
- Department of Oncology, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou 510655, Guangdong Province, China
| | - Jian-Hua Liu
- Department of Oncology, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou 510655, Guangdong Province, China
| | - Qing Wang
- The Medical Department, 3D Medicines Inc., Shanghai 201114, China
| | - Yu-Wei Cong
- The Medical Department, 3D Medicines Inc., Shanghai 201114, China
| | - Yao-Xu Chen
- The Medical Department, 3D Medicines Inc., Shanghai 201114, China
| | - Ke-Fei Huang
- The Bioinformatic Department, 3D Medicines Inc., Shanghai 201114, China
| | - Meng-Li Huang
- The Medical Department, 3D Medicines Inc., Shanghai 201114, China
| | - Ling Huang
- Department of Oncology, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou 510655, Guangdong Province, China
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18
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Emerging RAS, BRAF, and EGFR mutations in cell-free DNA of metastatic colorectal patients are associated with both primary and secondary resistance to first-line anti-EGFR therapy. Int J Clin Oncol 2020; 25:1523-1532. [PMID: 32394048 DOI: 10.1007/s10147-020-01691-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/27/2020] [Indexed: 12/17/2022]
Abstract
Oncogenic RAS mutations are negative biomarkers of response to epidermal growth factor receptor (EGFR) blockade. RAS mutations are usually detected in biopsies of primary colorectal tumors. However, the genomic profiles of primary tumors and metastases are not always concordant, and chemotherapeutic agents can alter the tumor molecular landscape. Cell-free DNA (cfDNA) is a novel tool to detect molecular heterogeneity. This study evaluated the clinical utility of cfDNA to predict primary or secondary resistance to EGFR blockade in patients with metastatic colorectal cancer. Thirty metastatic colorectal cancer patients without RAS and BRAF mutations were prospectively enrolled and treated with cytotoxic agents and EGFR blockade as first-line therapy. cfDNA was analyzed for the presence of RAS, BRAF, and EGFR (S492R) point mutations before initiating chemotherapy and every 2 months during chemotherapy. The analysis was performed in 223 plasma samples from all 30 patients. Of the 30 patients, five had RAS mutations in their cfDNA before starting chemotherapy and did not respond. Twenty-four of the remaining 25 patients without cfDNA RAS mutations had a response. Twenty of the 24 responders developed secondary resistance and cfDNA RAS mutations were found in 17 of the 20. cfDNA BRAF mutations were found in seven, and EGFR mutations were found in eight of the 20 patients. Emerging RAS, BRAF, and EGFR mutations occurred in patients with primary and secondary resistance to EGFR blockade. The detection of these mutations in cfDNA is a promising approach to predict treatment response and secondary resistance.
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19
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Reece M, Saluja H, Hollington P, Karapetis CS, Vatandoust S, Young GP, Symonds EL. The Use of Circulating Tumor DNA to Monitor and Predict Response to Treatment in Colorectal Cancer. Front Genet 2019; 10:1118. [PMID: 31824558 PMCID: PMC6881479 DOI: 10.3389/fgene.2019.01118] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 10/16/2019] [Indexed: 12/20/2022] Open
Abstract
Background: Colorectal cancer is one of the most common cancers worldwide and has a high mortality rate following disease recurrence. Treatment efficacy is maximized by providing tailored cancer treatment, ideally involving surgical resection and personalized neoadjuvant and adjuvant therapies, including chemotherapy, radiotherapy and increasingly, targeted therapy. Early detection of recurrence or disease progression results in more treatable disease and is essential to improving survival outcomes. Recent advances in the understanding of tumor genetics have resulted in the discovery of circulating tumor DNA (ctDNA). A growing body of evidence supports the use of these sensitive biomarkers in detecting residual disease and diagnosing recurrence as well as enabling targeted and tumor-specific adjuvant therapies. Methods: A literature search in Pubmed was performed to identify all original articles preceding April 2019 that utilize ctDNA for the purpose of monitoring response to colorectal cancer treatment. Results: Ninety-two clinical studies were included. These studies demonstrate that ctDNA is a reliable measure of tumor burden. Studies show the utility of ctDNA in assessing the adequacy of surgical tumor clearance and changes in ctDNA levels reflect response to systemic treatments. ctDNA can be used in the selection of targeted treatments. The reappearance or increase in ctDNA, as well as the emergence of new mutations, correlates with disease recurrence, progression, and resistance to therapy, with ctDNA measurement allowing more sensitive monitoring than currently used clinical tools. Conclusions: ctDNA shows enormous promise as a sensitive biomarker for monitoring response to many treatment modalities and for targeting therapy. Thus, it is emerging as a new way for guiding treatment decisions-initiating, altering, and ceasing treatments, or prompting investigation into the potential for residual disease. However, many potentially useful ctDNA markers are available and more work is needed to determine which are best suited for specific purposes and for improving specific outcomes.
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Affiliation(s)
- Mifanwy Reece
- Colorectal Surgery, Division of Surgery & Perioperative Medicine, Flinders Medical Centre, Bedford Park, SA, Australia
| | - Hariti Saluja
- Department of Medicine, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.,Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | - Paul Hollington
- Colorectal Surgery, Division of Surgery & Perioperative Medicine, Flinders Medical Centre, Bedford Park, SA, Australia
| | - Christos S Karapetis
- Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.,Department of Medical Oncology, Flinders Medical Centre, Bedford Park, SA, Australia
| | - Sina Vatandoust
- Department of Medical Oncology, Flinders Medical Centre, Bedford Park, SA, Australia
| | - Graeme P Young
- Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | - Erin L Symonds
- Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.,Bowel Health Service, Flinders Medical Centre, Bedford Park, SA, Australia
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20
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Kastrisiou M, Zarkavelis G, Pentheroudakis G, Magklara A. Clinical Application of Next-Generation Sequencing as A Liquid Biopsy Technique in Advanced Colorectal Cancer: A Trick or A Treat? Cancers (Basel) 2019; 11:E1573. [PMID: 31623125 PMCID: PMC6826585 DOI: 10.3390/cancers11101573] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 10/01/2019] [Accepted: 10/13/2019] [Indexed: 12/24/2022] Open
Abstract
Owing to its advantages over prior relevant technologies, massive parallel or next-generation sequencing (NGS) is rapidly evolving, with growing applications in a wide range of human diseases. The burst in actionable molecular alterations in many cancer types advocates for the practicality of using NGS in the clinical setting, as it permits the parallel characterization of multiple genes in a cost- and time-effective way, starting from low-input DNA. In advanced clinical practice, the oncological management of colorectal cancer requires prior knowledge of KRAS, NRAS, and BRAF status, for the design of appropriate therapeutic strategies, with more gene mutations still surfacing as potential biomarkers. Tumor heterogeneity, as well as the need for serial gene profiling due to tumor evolution and the emergence of novel genetic alterations, have promoted the use of liquid biopsies-especially in the form of circulating tumor DNA (ctDNA)-as a promising alternative to tissue molecular analysis. This review discusses recent studies that have used plasma NGS in advanced colorectal cancer and summarizes the clinical applications, as well as the technical challenges involved in adopting this technique in a clinically beneficial oncological practice.
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Affiliation(s)
- Myrto Kastrisiou
- Laboratory of Clinical Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece.
- Department of Medical Oncology, University General Hospital of Ioannina, 45500 Ioannina, Greece.
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45444 Ioannina, Greece.
| | - George Zarkavelis
- Department of Medical Oncology, University General Hospital of Ioannina, 45500 Ioannina, Greece.
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45444 Ioannina, Greece.
| | - George Pentheroudakis
- Department of Medical Oncology, University General Hospital of Ioannina, 45500 Ioannina, Greece.
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45444 Ioannina, Greece.
| | - Angeliki Magklara
- Laboratory of Clinical Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece.
- Department of Biomedical Research, Institute of Molecular Biology & Biotechnology, Foundation for Research & Technology-Hellas, 45110 Ioannina, Greece.
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21
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Amatu A, Schirripa M, Tosi F, Lonardi S, Bencardino K, Bonazzina E, Palmeri L, Patanè DA, Pizzutilo EG, Mussolin B, Bergamo F, Alberti G, Intini R, Procaccio L, Arese M, Marsoni S, Nichelatti M, Zagonel V, Siena S, Bardelli A, Loupakis F, Di Nicolantonio F, Sartore-Bianchi A, Barault L. High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With Regorafenib. Front Oncol 2019; 9:622. [PMID: 31355139 PMCID: PMC6640154 DOI: 10.3389/fonc.2019.00622] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 06/24/2019] [Indexed: 12/12/2022] Open
Abstract
Background: Regorafenib improves progression free survival (PFS) in a subset of metastatic colorectal cancer (mCRC) patients, although no biomarkers of efficacy are available. Circulating methylated DNA (cmDNA) assessed by a five-gene panel was previously associated with outcome in chemotherapy treated mCRC patients. We hypothesized that cmDNA could be used to identify cases most likely to benefit from regorafenib (i.e., patients with PFS longer than 4 months). Methods: Plasma samples from mCRC patients were collected prior to (baseline samples N = 60) and/or during regorafenib treatment (N = 62) for the assessment of cmDNA and total amount of cell free DNA (cfDNA). Results: In almost all patients, treatment with regorafenib increased the total cfDNA, but decreased cmDNA warranting the normalization of cmDNA to the total amount of circulating DNA (i.e., cmDNA/ml). We report that cmDNA/ml dynamics reflects clinical response with an increase in cmDNA/ml associated with higher risk of progression (HR for progression = 1.78 [95%CI: 1.01-3.13], p = 0.028). Taken individually, high baseline cmDNA/ml (above median) was associated with worst prognosis (HR for death = 3.471 [95%CI: 1.83-6.57], p < 0.0001) and also predicted shorter PFS (<16 weeks with PPV 86%). In addition, high cmDNA/ml values during regorafenib treatment predicted with higher accuracy shorter PFS (<16 weeks with a PPV of 96%), therefore associated with increased risk of progression (HR for progression = 2.985; [95%CI: 1.63-5.46; p < 0.0001). Conclusions: Our data highlight the predictive and prognostic value of cmDNA/ml in mCRC patients treated with regorafenib.
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Affiliation(s)
- Alessio Amatu
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Marta Schirripa
- Medical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, Italy
| | - Federica Tosi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Sara Lonardi
- Medical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, Italy
| | - Katia Bencardino
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Erica Bonazzina
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Laura Palmeri
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | | | | | | | - Francesca Bergamo
- Medical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, Italy
| | - Giulia Alberti
- Medical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, Italy.,Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Rossana Intini
- Medical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, Italy
| | - Letizia Procaccio
- Medical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, Italy.,Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Marco Arese
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.,Department of Oncology, University of Turin, Candiolo, Italy
| | - Silvia Marsoni
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.,Department of Precision Oncology, FIRC Institute of Molecular Oncology (IFOM), Milan, Italy
| | - Michele Nichelatti
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Vittorina Zagonel
- Medical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, Italy
| | - Salvatore Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.,Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, Italy
| | - Alberto Bardelli
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.,Department of Oncology, University of Turin, Candiolo, Italy
| | - Fotios Loupakis
- Medical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, Italy
| | - Federica Di Nicolantonio
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.,Department of Oncology, University of Turin, Candiolo, Italy
| | - Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.,Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, Italy
| | - Ludovic Barault
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.,Department of Oncology, University of Turin, Candiolo, Italy
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22
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Cervena K, Vodicka P, Vymetalkova V. Diagnostic and prognostic impact of cell-free DNA in human cancers: Systematic review. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 781:100-129. [PMID: 31416571 DOI: 10.1016/j.mrrev.2019.05.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 05/03/2019] [Accepted: 05/07/2019] [Indexed: 02/06/2023]
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23
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Bach S, Sluiter NR, Beagan JJ, Mekke JM, Ket JCF, van Grieken NCT, Steenbergen RDM, Ylstra B, Kazemier G, Tuynman JB. Circulating Tumor DNA Analysis: Clinical Implications for Colorectal Cancer Patients. A Systematic Review. JNCI Cancer Spectr 2019; 3:pkz042. [PMID: 32328554 PMCID: PMC7050033 DOI: 10.1093/jncics/pkz042] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 05/21/2019] [Accepted: 06/05/2019] [Indexed: 02/06/2023] Open
Abstract
Background Liquid biopsies could improve diagnosis, prognostication, and monitoring of colorectal cancer (CRC). Mutation, chromosomal copy number alteration, and methylation analysis in circulating tumor DNA (ctDNA) from plasma or serum has gained great interest. However, the literature is inconsistent on preferred candidate markers, hampering a clear direction for further studies and clinical translation. This review assessed the potential of ctDNA analysis for clinical utility. Methods A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines was conducted up to December 3, 2018, followed by methodological quality assessment. Primary endpoints were accuracy for detection, prognostication, and monitoring. Results Eighty-four studies were included. For CRC detection, sensitivity was 75% using ctDNA mutation analysis and up to 96% using copy number analysis. Septin 9 (SEPT9) hypermethylation analysis showed sensitivities of 100% and specificities of 97%. Regarding prognostication, ctDNA KRAS mutations were associated with oncological outcome and could predict response to anti-epidermal growth factor receptor therapy. For monitoring, sequential ctDNA KRAS mutation analysis showed promise for detection of relapses or therapy resistance. Conclusions This comprehensive overview of ctDNA candidate markers demonstrates SEPT9 methylation analysis to be promising for CRC detection, and KRAS mutation analysis could assist in prognostication and monitoring. Prospective evaluation of marker panels in clinical decision making should bring ctDNA analysis into practice.
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Affiliation(s)
- Sander Bach
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Vrije Universiteit, Amsterdam, the Netherlands
| | - Nina R Sluiter
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Vrije Universiteit, Amsterdam, the Netherlands
| | - Jamie J Beagan
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Vrije Universiteit, Amsterdam, the Netherlands
| | - Joost M Mekke
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Vrije Universiteit, Amsterdam, the Netherlands
| | - Johannes C F Ket
- Medical Information Specialist/Literature Researcher Medical Library, Amsterdam UMC, Vrije Universiteit Amsterdam, Vrije Universiteit, Amsterdam, the Netherlands
| | - Nicole C T van Grieken
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Vrije Universiteit, Amsterdam, the Netherlands
| | - Renske D M Steenbergen
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Vrije Universiteit, Amsterdam, the Netherlands
| | - Bauke Ylstra
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Vrije Universiteit, Amsterdam, the Netherlands
| | - Geert Kazemier
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Vrije Universiteit, Amsterdam, the Netherlands
| | - Jurriaan B Tuynman
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Vrije Universiteit, Amsterdam, the Netherlands
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24
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Mechanisms of Anticancer Drug Resistance in Hepatoblastoma. Cancers (Basel) 2019; 11:cancers11030407. [PMID: 30909445 PMCID: PMC6468761 DOI: 10.3390/cancers11030407] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 03/12/2019] [Accepted: 03/18/2019] [Indexed: 12/25/2022] Open
Abstract
The most frequent liver tumor in children is hepatoblastoma (HB), which derives from embryonic parenchymal liver cells or hepatoblasts. Hepatocellular carcinoma (HCC), which rarely affects young people, causes one fourth of deaths due to cancer in adults. In contrast, HB usually has better prognosis, but this is still poor in 20% of cases. Although more responsive to chemotherapy than HCC, the failure of pharmacological treatment used before and/or after surgical resection is an important limitation in the management of patients with HB. To advance in the implementation of personalized medicine it is important to select the best combination among available anti-HB drugs, such as platinum derivatives, anthracyclines, etoposide, tyrosine-kinase inhibitors, Vinca alkaloids, 5-fluorouracil, monoclonal antibodies, irinotecan and nitrogen mustards. This requires predicting the sensitivity to these drugs of each tumor at each time because, it should be kept in mind, that cancer chemoresistance is a dynamic process of Darwinian nature. For this goal it is necessary to improve our understanding of the mechanisms of chemoresistance involved in the refractoriness of HB against the pharmacological challenge and how they evolve during treatment. In this review we have summarized the current knowledge on the multifactorial and complex factors responsible for the lack of response of HB to chemotherapy.
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25
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Saini A, Pershad Y, Albadawi H, Kuo M, Alzubaidi S, Naidu S, Knuttinen MG, Oklu R. Liquid Biopsy in Gastrointestinal Cancers. Diagnostics (Basel) 2018; 8:diagnostics8040075. [PMID: 30380690 PMCID: PMC6316210 DOI: 10.3390/diagnostics8040075] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 10/24/2018] [Accepted: 10/24/2018] [Indexed: 12/18/2022] Open
Abstract
Liquid biopsy is the sampling of any biological fluid in an effort to enrich and analyze a tumor's genetic material. Peripheral blood remains the most studied liquid biopsy material, with circulating tumor cells (CTC's) and circulating tumor DNA (ctDNA) allowing the examination and longitudinal monitoring of a tumors genetic landscape. With applications in cancer screening, prognostic stratification, therapy selection and disease surveillance, liquid biopsy represents an exciting new paradigm in the field of cancer diagnostics and offers a less invasive and more comprehensive alternative to conventional tissue biopsy. Here, we examine liquid biopsies in gastrointestinal cancers, specifically colorectal, gastric, and pancreatic cancers, with an emphasis on applications in diagnostics, prognostics and therapeutics.
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Affiliation(s)
- Aman Saini
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - Yash Pershad
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - Hassan Albadawi
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - Malia Kuo
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - Sadeer Alzubaidi
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - Sailendra Naidu
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - M-Grace Knuttinen
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - Rahmi Oklu
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
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26
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Vymetalkova V, Cervena K, Bartu L, Vodicka P. Circulating Cell-Free DNA and Colorectal Cancer: A Systematic Review. Int J Mol Sci 2018; 19:ijms19113356. [PMID: 30373199 PMCID: PMC6274807 DOI: 10.3390/ijms19113356] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/22/2018] [Accepted: 10/24/2018] [Indexed: 02/06/2023] Open
Abstract
There is a strong demand for the identification of new biomarkers in colorectal cancer (CRC) diagnosis. Among all liquid biopsy analysts, cell-free circulating DNA (cfDNA) is probably the most promising tool with respect to the identification of minimal residual diseases, assessment of treatment response and prognosis, and identification of resistance mechanisms. Circulating cell-free tumor DNA (ctDNA) maintains the same genomic signatures that are present in the matching tumor tissue allowing for the quantitative and qualitative evaluation of mutation burdens in body fluids. Thus, ctDNA-based research represents a non-invasive method for cancer detection. Among the numerous possible applications, the diagnostic, predictive, and/or prognostic utility of ctDNA in CRC has attracted intense research during the last few years. In the present review, we will describe the different aspects related to cfDNA research and evidence from studies supporting its potential use in CRC diagnoses and the improvement of therapy efficacy. We believe that ctDNA-based research should be considered as key towards the introduction of personalized medicine and patient benefits.
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Affiliation(s)
- Veronika Vymetalkova
- Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic.
- Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 128 00 Prague, Czech Republic.
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 323 00 Pilsen, Czech Republic.
| | - Klara Cervena
- Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic.
- Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 128 00 Prague, Czech Republic.
| | - Linda Bartu
- Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic.
- Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 128 00 Prague, Czech Republic.
| | - Pavel Vodicka
- Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic.
- Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 128 00 Prague, Czech Republic.
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 323 00 Pilsen, Czech Republic.
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27
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Serial mutational tracking in surgically resected locally advanced colorectal cancer with neoadjuvant chemotherapy. Br J Cancer 2018; 119:419-423. [PMID: 30072744 PMCID: PMC6134007 DOI: 10.1038/s41416-018-0208-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Revised: 07/01/2018] [Accepted: 07/09/2018] [Indexed: 12/11/2022] Open
Abstract
Background We aim to investigate the utility of serial gene mutation tracking for locally advanced CRC in those who underwent curative resection following neoadjuvant chemotherapy. Methods We prospectively collected 10 locally advanced CRC cases for which curative resection was performed following preoperative neoadjuvant chemotherapy. Tissues from the primary tumour, distant metastatic tumours, and blood plasma were obtained during serial treatment. Comprehensive mutation analysis of 47 cancer-associated genes was performed using a pre-designed gene panel and next-generation sequencing. Results All cases showed a partial response to neoadjuvant chemotherapy, and pathological R0 resection was accomplished. In primary tumours, non-synonymous mutations were detected at between 1 and 14 sites before chemotherapy and at between 1 and 2 sites after. Founder mutations were precisely detected in blood plasma and metastatic tumours during longitudinal treatment. Conclusions Serial mutational analysis indicated that subclonal selection occurs during chemotherapy and that plasma can substitute for tumourous tissue in mutational analysis for drug selection and treatment decisions.
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