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1
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Trembath HE, Yeh JJ, Lopez NE. Gastrointestinal Malignancy: Genetic Implications to Clinical Applications. Cancer Treat Res 2024; 192:305-418. [PMID: 39212927 DOI: 10.1007/978-3-031-61238-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.
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Affiliation(s)
- Hannah E Trembath
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Jen Jen Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Nicole E Lopez
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA.
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA.
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Marisi G, Azzali I, Passardi A, Rebuzzi F, Bartolini G, Urbini M, Canale M, Molinari C, Matteucci L, Sullo FG, Debonis SA, Gallio C, Gallo G, Frassineti GL, Ulivi P. Prospective validation of VEGF and eNOS polymorphisms as predictors of first-line bevacizumab efficacy in patients with metastatic colorectal cancer. Sci Rep 2023; 13:12921. [PMID: 37558720 PMCID: PMC10412588 DOI: 10.1038/s41598-023-40220-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 08/07/2023] [Indexed: 08/11/2023] Open
Abstract
Bevacizumab (Bev) plus chemotherapy is a standard first-line treatment in metastatic colorectal cancer (mCRC), however to date no predictive factors of response have been identified. Results of our previous analysis on patients enrolled in a randomized prospective phase III multicenter study (ITACa study) showed a predictive value of Vascular Endothelial Growth Factor (VEGF) polymorphism (VEGF + 936), a 27-nucleotide variable number tandem repeat (VNTR) of the endothelial nitric oxide synthase (eNOS) gene and eNOS + 894 polymorphism. mCRC patients, treated with Bev plus chemotherapy, were included in this prospective validation trial. eNOS + 894G > T was analyzed by Real time PCR, while the eNOS VNTR and VEGF + 936C > T were determined by standard PCR and direct sequencing analysis. These polymorphisms were assessed in relation to progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). These three polymorphisms were not predictive of PFS (p 0.91, 0.59 and 0.09, respectively), and OS (p 0.95, 0.32 and 0.46, respectively). Moreover, the haplotype analyses did not confirm what was found in our previous study; patients bearing a specific haplotype of eNOS had not significantly improved outcomes. This prospective study failed to validate the predictive impact of eNOS and VEGF polymorphisms for response to Bev plus first-line chemotherapy in mCRC patients.
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Affiliation(s)
- Giorgia Marisi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Irene Azzali
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
| | - Francesca Rebuzzi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Giulia Bartolini
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Milena Urbini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Matteo Canale
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Chiara Molinari
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Laura Matteucci
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Francesco Giulio Sullo
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Silvia Angela Debonis
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Chiara Gallio
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Graziana Gallo
- Operative Unit of Pathologic Anatomy, Azienda USL della Romagna, "Bufalini" Hospital, Cesena, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Paola Ulivi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
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Karatza E, Papachristos A, Sivolapenko GB, Gonzalez D. Machine learning-guided covariate selection for time-to-event models developed from a small sample of real-world patients receiving bevacizumab treatment. CPT Pharmacometrics Syst Pharmacol 2022; 11:1328-1340. [PMID: 35851999 PMCID: PMC9574729 DOI: 10.1002/psp4.12848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/28/2022] [Accepted: 07/11/2022] [Indexed: 11/20/2022] Open
Abstract
Therapeutic outcomes in patients with metastatic colorectal cancer (mCRC) receiving bevacizumab treatment are highly variable, and a reliable predictive factor is not available. Progression-free survival (PFS) and overall survival (OS) were recorded from an observational, prospective study after 5 years of follow-up, including 46 patients with mCRC receiving bevacizumab treatment. Three vascular endothelial growth factor (VEGF)-A and two intercellular adhesion molecule-1 genes polymorphisms, age, gender, weight, dosing scheme, and co-treatments were collected. Given the relatively small number of events (37 [80%] for the PFS and 26 [57%] for the OS), to study the effect of these covariates on PFS and OS, a covariate analysis was performed using statistical and supervised machine learning techniques, including Cox regression, penalized Cox regression techniques (least absolute shrinkage and selection operator [LASSO], ridge regression, and elastic net), survival trees, and survival forest. The predictive performance of each method was evaluated in bootstrapped samples, using prediction error curves and the area under the curve of the receiver operating characteristic. The LASSO penalized Cox-regression model showed the best overall performance. Nonlinear mixed effects (NLME) models were developed, and a conventional stepwise covariate search was performed. Then, covariates identified as important by the LASSO model were included in the base NLME models developed for PFS and OS, resulting in improved models as compared to those obtained with the stepwise covariate search. It was shown that having gene polymorphisms in VEGFA (rs699947 and rs1570360) and ICAM1 (rs1799969) are associated with a favorable clinical outcome in patients with mCRC receiving bevacizumab treatment.
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Affiliation(s)
- Eleni Karatza
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of PharmacyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Apostolos Papachristos
- Laboratory of Pharmacokinetics, Department of Pharmacy, School of Health SciencesUniversity of PatrasRion, PatrasGreece
| | - Gregory B. Sivolapenko
- Laboratory of Pharmacokinetics, Department of Pharmacy, School of Health SciencesUniversity of PatrasRion, PatrasGreece
| | - Daniel Gonzalez
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of PharmacyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
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Guleria K, Kaur S, Mahajan D, Sambyal V, Sudan M, Uppal MS. Impact of VEGFA promoter polymorphisms on esophageal cancer risk in North-West Indians: a case-control study. Genes Genomics 2022; 44:923-936. [PMID: 35767183 DOI: 10.1007/s13258-022-01269-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 05/05/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Angiogenesis play a critical role in the development and progression of tumors in solid tumors. Vascular endothelial growth factor (VEGF) is one of the most important endothelial cell mitogen which plays a critical role in normal physiological and tumor angiogenesis. OBJECTIVES The objective of this case-control study was to investigate the association of VEGF-2578C/A, -2549 I/D, and -460T/C promoter polymorphisms with esophageal cancer risk in North-West Indians. METHODS In this study, 200 sporadic esophageal cancer patients and 200 healthy, unrelated, age and gender matched controls were analyzed. The genomic DNA was extracted from blood samples using phenol chloroform method. Genotyping of VEGF- 2549I/D polymorphism was carried out by direct polymerase chain reaction (PCR) whereas VEGF -2578C/A and VEGF-460T/C) polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS AA genotype (p = 0.005) and A allele (p = 0.005) VEGF -2578 C/A, II genotype (p = 0.011) and I allele (p = 0.012) of VEGF - 2549 I/D and CC genotype (p = 0.013) and C allele of VEGF-460T/C polymorphisms were significantly associated with increased risk of esophageal cancer. Stratification of data on the basis of gender showed that VEGF -2578 AA genotype (p = 0.001) and A allele (p = 0.001); VEGF -2549 II genotype (p = 0.002) and I allele (p = 0.002) and VEGF- 460CC genotype (p = 0.001) and C allele (p = 0.002) was significantly associated with increased risk of esophageal cancer in female group. Haplotype analysis revealed that A-2578 I- 2549 C- 460 haplotype was significantly associated with increased risk for esophageal cancer in total samples (p = 0.008) as well as in female group (p = 0.001). CONCLUSIONS The results of present study indicate that VEGF -2578C/A, - 2549I/D and -460T/C polymorphisms were significantly associated with increased risk of esophageal cancer in North-West Indians.
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Affiliation(s)
- Kamlesh Guleria
- Human Cytogenetics Laboratory, Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, 143005, India.
| | - Simranjot Kaur
- Human Cytogenetics Laboratory, Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Deepanshi Mahajan
- Human Cytogenetics Laboratory, Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Vasudha Sambyal
- Human Cytogenetics Laboratory, Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Meena Sudan
- Department of Radiotherapy, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, India
| | - Manjit Singh Uppal
- Department of Surgery, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, India
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Qin W, Zhao B, Wang D, Liu J, Zhou Y, Zhu W, Huang Y, Qiu H, Yuan X. A Genetic Variant in CD274 Is Associated With Prognosis in Metastatic Colorectal Cancer Patients Treated With Bevacizumab-Based Chemotherapy. Front Oncol 2022; 12:922342. [PMID: 35837092 PMCID: PMC9275392 DOI: 10.3389/fonc.2022.922342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 05/23/2022] [Indexed: 12/24/2022] Open
Abstract
Bevacizumab plus chemotherapy is a well-established first-line treatment for metastatic colorectal cancer (mCRC). We investigated whether polymorphisms of genes involved in immune regulation signaling are related to the clinical outcome of mCRC patients treated with bevacizumab-based chemotherapy. In this study, we genotyped 14 single-nucleotide polymorphisms (SNP) in IFN-γ/IFNGRs/JAKs/STATs/PD-L1 pathway by using DNA from blood samples of 141 mCRC patients treated with first-line bevacizumab-based chemotherapy. In the univariate and multivariate analysis, patients with AA genotype of CD274:rs2297136 had a significantly better PFS and OS than patients with AG or GG genotype (10.8 versus 9.8, log-rank P=0.0031; 31.4 versus 20.9, log-rank P=0.0233). Patients with AG/GG genotype of IFNGR1:rs2234711, CT/TT genotype of IFNGR1:rs9376267 also showed longer OS than patients with AA or CC genotype, however, the statistic did not reach significant after adjusted by clinical factors in the multivariate analysis. A nomogram based on the genetic variants and clinic characteristics was developed with a good accuracy to predict patients’ survival. Our result indicates that CD274:rs2297136 is one of the most important predictors for the prognosis of mCRC patients treated with bevacizumab-based chemotherapy, if further validated in larger population.
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Affiliation(s)
- Wan Qin
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Ben Zhao
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Duanrui Wang
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Jiamin Liu
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, China
| | - Yilu Zhou
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom
- Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Wenjun Zhu
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yongbiao Huang
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Qiu
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Hong Qiu, ; Xianglin Yuan,
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Hong Qiu, ; Xianglin Yuan,
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Cevik M, Namal E, Dinc-Sener N, Iner-Koksal U, Ciftci C, Susleyici B. Investigation of Vascular Endothelial Growth Factor Polymorphisms on Risk, Metastasis, Laterality, and Prognosis of Colorectal Cancer in Turkish Subjects. Genet Test Mol Biomarkers 2022; 26:298-306. [PMID: 35593899 DOI: 10.1089/gtmb.2021.0213] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Objectives: Tumor angiogenesis is known to support the spread and invasion of tumor cells, allow distant organ metastasis, resulting in worse prognosis and mortality. Since vascular endothelial growth factor-A (VEGF-A) is the major regulator of angiogenesis, in the present study, the associations of VEGF-A +405G>C and -460C>T polymorphisms with risk, primary tumor location, prognosis, and metastasis of colorectal cancer (CRC) were investigated in Turkish subjects. Material and Methods: A total of 153 subjects consisting of 74 controls and 79 CRC diagnosed patients were included in the study. VEGF-A +405G>C and -460C>T polymorphisms were analyzed using Agena MassARRAY platform. Results: VEGF +405GC+CC genotypes were found to be significantly associated with left colon cancer (unadjusted odds ratio [OR] = 5.208 confidence interval [95% CI]: 1.064-25.496, p = 0.04). VEGF -460TT and CT+TT genotypes were associated with reduced liver metastasis risk (OR = 0.080 95% CI: 0.009-0.689 p = 0.02 and OR = 0.191 95% CI: 0.039-0.925, p = 0.04, respectively). Patients with VEGF +405GG genotype showed longer progression-free survival as a response to bevacizumab treatment (Log rank = 6.92, p = 0.03). Conclusion: According to our results, VEGF +405G>C and -460C>T polymorphisms were found to be associated with CRC prognosis, sidedness, and metastasis. Our findings should be conducted in further studies.
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Affiliation(s)
- Mehtap Cevik
- Department of Molecular Biology, Marmara University Faculty of Science and Letters, Istanbul, Turkey
| | - Esat Namal
- Department of Medical Oncology, Demiroglu Bilim University Faculty of Medicine, Istanbul, Turkey
| | - Nur Dinc-Sener
- Department of Medical Oncology, Demiroglu Bilim University Faculty of Medicine, Istanbul, Turkey
| | | | - Cavlan Ciftci
- Department of Cardiology, Demiroglu Bilim University Faculty of Medicine, Istanbul, Turkey
| | - Belgin Susleyici
- Department of Molecular Biology, Marmara University Faculty of Science and Letters, Istanbul, Turkey
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Kampoli K, Foukas PG, Ntavatzikos A, Arkadopoulos N, Koumarianou A. Interrogating the interplay of angiogenesis and immunity in metastatic colorectal cancer. World J Methodol 2022; 12:43-53. [PMID: 35117981 PMCID: PMC8790311 DOI: 10.5662/wjm.v12.i1.43] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 08/17/2021] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
Colon cancer is the third most common malignancy and the fifth most frequent cause of death from neoplastic disease worldwide. At the time of diagnosis, more than 20% of patients already have metastatic disease. In the last 20 years, the natural course of the disease has changed due to major changes in the management of metastatic disease such as the advent of novel surgical and local therapy approaches as well as the introduction of novel chemotherapy drugs and targeted agents such as anti-epidermal growth factor receptor, anti-BRAF and antiangiogenics. Angiogenesis is a complex biological process of new vessel formation from existing ones and is an integral component of tumor progression supporting cancer cells to grow, proliferate and metastasize. Many molecules are involved in this proangiogenic process, such as vascular endothelial growth factor and its receptors on endothelial cells. A well-standardized methodology that is applied to assess angiogenesis in the tumor microenvironment is microvascular density by using immunohistochemistry with antibodies against endothelial CD31, CD34 and CD105 antigens. Even smaller molecules, such as the microRNAs, which are small non-coding RNAs, are being studied for their usefulness as surrogate biomarkers of angiogenesis and prognosis. In this review, we will discuss recent advances regarding the investigation of angiogenesis, the crosstalk between elements of the immune microenvironment and angiogenesis and how a disorganized tumor vessel network affects the trafficking of CD8+ T cells in the tumor bed. Furthermore, we will present recent data from clinical trials that combine antiangiogenic therapies with immune checkpoint inhibitors in colorectal cancer.
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Affiliation(s)
- Katerina Kampoli
- Hematology Oncology Unit, The Fourth Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Haidari 12462, Athens, Greece
| | - Periklis G Foukas
- The Second Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Haidari 12462, Athens, Greece
| | - Anastasios Ntavatzikos
- Hematology Oncology Unit, The Fourth Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Haidari 12462, Athens, Greece
| | - Nikolaos Arkadopoulos
- The Fourth Surgical Clinic, School of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Haidari 12462, Athens, Greece
| | - Anna Koumarianou
- Hematology Oncology Unit, The Fourth Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Haidari 12462, Athens, Greece
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Genetic Variation in the Vascular Endothelial Growth Factor (VEGFA) Gene at rs13207351 Is Associated with Overall Survival of Patients with Head and Neck Cancer. Cancers (Basel) 2021; 13:cancers13051163. [PMID: 33800431 PMCID: PMC7962814 DOI: 10.3390/cancers13051163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/25/2021] [Accepted: 02/28/2021] [Indexed: 01/10/2023] Open
Abstract
Simple Summary Angiogenesis and apoptosis play a pivotal role in the pathogenesis and clinical course not only of nasopharyngeal cancer (NPC), but also of other subgroups of head and neck cancer (HNC), such as laryngeal cancer. Thus, the aim of this study was to investigate the clinical significance of genetic polymorphisms in four pivotal angiogenesis- and apoptosis-related genes (VEGFA, FAS, EDNRA and NBS1) in HNC patients. Thirty-four genetic variants located in the studied genes were assessed. Two of them (VEGFA rs13207351 and FAS rs2234768) were associated with overall survival for patients with laryngeal cancer and NPC, respectively, with VEGFA rs13207351 showing the most promise for its prognostic value in the subgroup of laryngeal cancer patients. This study suggests that genetic variations in angiogenesis- and apoptosis-related genes may be useful in the management of HNC patients. Abstract Head and neck cancer (HNC) is a significantly heterogeneous disease and includes malignancies arising from different anatomical sites, such as nasopharyngeal cancer (NPC) and laryngeal cancer (LC). In the current study, polymorphisms located in angiogenesis- and apoptosis-related genes (VEGFA, FAS, EDNRA and NBS1) were evaluated regarding their clinical significance in HNC patients. In total, 333 HNC patients were enrolled in this study and 34 variants located on the aforementioned genes were genotyped via Sanger sequencing. LC patients, homozygous A for VEGFA rs13207351, had shorter overall survival (OS) as opposed to homozygous G (Hazard ratio (HR) = 2.06, Wald’s p = 0.017) upon adjustment for age, disease stage, and surgery. Following the dominant model, LC patients carrying the A allele had a marginally significantly higher risk for death (HR = 1.72, p = 0.059). NPC patients heterozygous (CT) for FAS rs2234768 had a marginal but significantly higher risk of death compared to those with homozygosity for the T allele (HR = 2.22, p = 0.056). In conclusion, rs13207351 (VEGFA) and rs2234768 (FAS) polymorphisms seem to have prognostic significance in HNC, with VEGFA rs13207351 showing the most promise in this subgroup of LC patients.
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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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10
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Decorin expression is associated with predictive diffusion MR phenotypes of anti-VEGF efficacy in glioblastoma. Sci Rep 2020; 10:14819. [PMID: 32908231 PMCID: PMC7481206 DOI: 10.1038/s41598-020-71799-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 08/04/2020] [Indexed: 12/13/2022] Open
Abstract
Previous data suggest that apparent diffusion coefficient (ADC) imaging phenotypes predict survival response to anti-VEGF monotherapy in glioblastoma. However, the mechanism by which imaging may predict clinical response is unknown. We hypothesize that decorin (DCN), a proteoglycan implicated in the modulation of the extracellular microenvironment and sequestration of pro-angiogenic signaling, may connect ADC phenotypes to survival benefit to anti-VEGF therapy. Patients undergoing resection for glioblastoma as well as patients included in The Cancer Genome Atlas (TCGA) and IVY Glioblastoma Atlas Project (IVY GAP) databases had pre-operative imaging analyzed to calculate pre-operative ADCL values, the average ADC in the lower distribution using a double Gaussian mixed model. ADCL values were correlated to available RNA expression from these databases as well as from RNA sequencing from patient derived mouse orthotopic xenograft samples. Targeted biopsies were selected based on ADC values and prospectively collected during resection. Surgical specimens were used to evaluate for DCN RNA and protein expression by ADC value. The IVY Glioblastoma Atlas Project Database was used to evaluate DCN localization and relationship with VEGF pathway via in situ hybridization maps and RNA sequencing data. In a cohort of 35 patients with pre-operative ADC imaging and surgical specimens, DCN RNA expression levels were significantly larger in high ADCL tumors (41.6 vs. 1.5; P = 0.0081). In a cohort of 17 patients with prospectively targeted biopsies there was a positive linear correlation between ADCL levels and DCN protein expression between tumors (Pearson R2 = 0.3977; P = 0.0066) and when evaluating different targets within the same tumor (Pearson R2 = 0.3068; P = 0.0139). In situ hybridization data localized DCN expression to areas of microvascular proliferation and immunohistochemical studies localized DCN protein expression to the tunica adventitia of blood vessels within the tumor. DCN expression positively correlated with VEGFR1 & 2 expression and localized to similar areas of tumor. Increased ADCL on diffusion MR imaging is associated with high DCN expression as well as increased survival with anti-VEGF therapy in glioblastoma. DCN may play an important role linking the imaging features on diffusion MR and anti-VEGF treatment efficacy. DCN may serve as a target for further investigation and modulation of anti-angiogenic therapy in GBM.
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11
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Pharmacogenomics, Pharmacokinetics and Circulating Proteins as Biomarkers for Bevacizumab Treatment Optimization in Patients with Cancer: A Review. J Pers Med 2020; 10:jpm10030079. [PMID: 32759686 PMCID: PMC7563856 DOI: 10.3390/jpm10030079] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 07/27/2020] [Accepted: 07/30/2020] [Indexed: 12/19/2022] Open
Abstract
Bevacizumab is a monoclonal antibody that targets VEGF-A and inhibits tumor angiogenesis. Bevacizumab is approved for the treatment of various cancer, including metastatic colorectal cancer (mCRC), ovarian cancer, lung cancer, and others. Thus, it is widely used in oncology, but contrary to other therapeutic classes, there is still a lack of validating predictive factors for treatment outcomes with these agents. In recent years, the research for factors predictive of anti-VEGF treatments and especially bevacizumab response has been one of the most competitive translational research fields. Herein, we review and present the available literature of the clinical use of biomarkers, pharmacogenomics (PG), and therapeutic drug monitoring (TDM) approaches that can be used for the optimization of bevacizumab use in the era of precision medicine.
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12
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Pharmacogenetics in Model-Based Optimization of Bevacizumab Therapy for Metastatic Colorectal Cancer. Int J Mol Sci 2020; 21:ijms21113753. [PMID: 32466535 PMCID: PMC7311957 DOI: 10.3390/ijms21113753] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/19/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023] Open
Abstract
Vascular endothelial growth factor A (VEGF-A) and intercellular adhesion molecule 1 (ICAM-1) are significant regulators of angiogenesis, an important biological process involved in carcinogenesis. Bevacizumab, an anti-VEGF monoclonal antibody (MAB), is approved for the treatment of metastatic Colorectal cancer (mCRC), however clinical outcomes are highly variable. In the present study, we developed a pharmacokinetic (PK), a simplified quasi-steady state (QSS) and a pharmacokinetic/pharmacodynamic (PK/PD) model to identify potential sources of variability. A total of 46 mCRC patients, who received bevacizumab in combination with chemotherapy were studied. VEGF-A (rs2010963, rs1570360, rs699947) and ICAM-1 (rs5498, rs1799969) genes’ polymorphisms, age, gender, weight, and dosing scheme were investigated as possible co-variates of the model’s parameters. Polymorphisms, trough, and peak levels of bevacizumab, and free VEGF-A were determined in whole blood and serum. Data were analyzed using nonlinear mixed-effects modeling. The two-compartment PK model showed that clearance (CL) was significantly lower in patients with mutant ICAM-1 rs1799969 (p < 0.0001), inter-compartmental clearance (Q) was significantly higher with mutant VEGF-A rs1570360 (p < 0.0001), and lower in patients with mutant VEGF-A rs699947 (p < 0.0001). The binding QSS model also showed that mutant ICAM-1 rs1799969 was associated with a lower CL (p = 0.0177). Mutant VEGF-A rs699947 was associated with a lower free VEGF-A levels, prior to the next dose (p = 0.000445). The above results were confirmed by the PK/PD model. Findings of the present study indicated that variants of the genes regulating angiogenesis might affect PK and PD characteristics of bevacizumab, possibly influencing the clinical outcomes.
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13
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Papachristos A, Kemos P, Katsila T, Panoilia E, Patrinos GP, Kalofonos H, Sivolapenko GB. VEGF-A and ICAM-1 Gene Polymorphisms as Predictors of Clinical Outcome to First-Line Bevacizumab-Based Treatment in Metastatic Colorectal Cancer. Int J Mol Sci 2019; 20:ijms20225791. [PMID: 31752122 PMCID: PMC6888109 DOI: 10.3390/ijms20225791] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 11/10/2019] [Accepted: 11/13/2019] [Indexed: 12/11/2022] Open
Abstract
Bevacizumab is used to treat metastatic colorectal cancer (mCRC). However, there are still no available predictors of clinical outcomes. We investigated selected single nucleotide polymorphisms (SNPs) in the genes involved in VEGF-dependent and -independent angiogenesis pathways and other major intracellular signaling pathways involved in the pathogenesis of mCRC as an attempt to find predictors of clinical outcome. Forty-six patients treated with first-line bevacizumab-based chemotherapy were included in this study with a 5 year follow up. Genomic DNA was isolated from whole blood for the analysis of VEGF-A (rs2010963, 1570360, rs699947), ICAM-1 (rs5498, rs1799969) SNPs and from tumor tissue for the detection of genomic variants in KRAS, NRAS, BRAF genes. PCR and next generation sequencing were used for the analysis. The endpoints of the study were progression-free survival (PFS) and overall survival (OS). The VEGF-A rs699947 A/A allele was associated with increased PFS (p = 0.006) and OS (p = 0.043). The ICAM-1 rs1799969 G/A allele was associated with prolonged OS (p = 0.036). Finally, BRAF wild type was associated with increased OS (p = 0.027). We identified VEGF-A and ICAM-1 variants in angiogenesis and other major intracellular signaling pathways, such as BRAF, that can predict clinical outcome upon bevacizumab administration. These identified biomarkers could be used to select patients with mCRC who may achieve long-term responses and benefit from bevacizumab-based therapies.
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Affiliation(s)
- Apostolos Papachristos
- Laboratory of Pharmacokinetics, Department of Pharmacy, School of Health Sciences, University of Patras, Patra 26504, Greece; (A.P.); (E.P.)
- Division of Cancer, University College London Hospital NHS Foundation Trust, London NW12BU, UK
| | - Polychronis Kemos
- Centre for Immunobiology, Blizard institute, Queen Mary University of London, London E12AT, UK;
| | - Theodora Katsila
- Laboratory of Pharmacogenomics and Individualized Therapy, Department of Pharmacy, School of Health Sciences, University of Patras, Patra 26504, Greece; (T.K.); (G.P.P.)
- Institute of Chemical Biology, National Hellenic Research Centre, Athens 11635, Greece
| | - Eirini Panoilia
- Laboratory of Pharmacokinetics, Department of Pharmacy, School of Health Sciences, University of Patras, Patra 26504, Greece; (A.P.); (E.P.)
| | - George P. Patrinos
- Laboratory of Pharmacogenomics and Individualized Therapy, Department of Pharmacy, School of Health Sciences, University of Patras, Patra 26504, Greece; (T.K.); (G.P.P.)
| | - Haralabos Kalofonos
- Division of Medical Oncology, University Hospital of Patras, Patra 26504, Greece;
| | - Gregory B. Sivolapenko
- Laboratory of Pharmacokinetics, Department of Pharmacy, School of Health Sciences, University of Patras, Patra 26504, Greece; (A.P.); (E.P.)
- Correspondence: ; Tel.: +30-26-1096-2324
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14
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Giulia M, Teresa T, Claudia C, Paolo VP, Davide C, Floriana M, Fortunato C, Erika M. Anti-angiogenic Treatment in Metastatic Colorectal Cancer: Current Issues and Future Aims. CURRENT CANCER THERAPY REVIEWS 2019. [DOI: 10.2174/1573394714666181119145327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
:
Blocking angiogenesis represents a fundamental process in Colorectal Cancer (CRC)
treatment. VEGF (vascular endothelial growth factor) pathway is implicated in various processes
that regulate tumor vascularization and proliferation. In the last years, great efforts have been
made thanks to the discovery of targeted drugs that block VEGF and its receptors conferring a
benefit in a variety of tumors, including CRC. To date, four drugs have been approved for the
treatment of metastatic CRC (mCRC): bevacizumab, aflibercept, ramucirumab and regorafenib.
Unfortunately, patients relapse due to the appearance of resistance. The VEGF family, its role in
the angiogenesis and complex heterogeneity of mechanisms that escape tumor blockade are not
completely understood and there is a lack of biomarkers of response to anti-angiogenic drugs. We
describe the principal mechanisms of resistance to anti-VEGF therapy and discuss potential biomarkers
to be investigated in the near future.
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Affiliation(s)
- Martini Giulia
- Medical Oncology, Department of Clinical and Experimental Medicine F. Magrassi, Università degli Studi della Campania L. Vanvitelli, Naples, Italy
| | - Troiani Teresa
- Medical Oncology, Department of Clinical and Experimental Medicine F. Magrassi, Università degli Studi della Campania L. Vanvitelli, Naples, Italy
| | - Cardone Claudia
- Medical Oncology, Department of Clinical and Experimental Medicine F. Magrassi, Università degli Studi della Campania L. Vanvitelli, Naples, Italy
| | - Vitiello Pietro Paolo
- Medical Oncology, Department of Clinical and Experimental Medicine F. Magrassi, Università degli Studi della Campania L. Vanvitelli, Naples, Italy
| | - Ciardiello Davide
- Medical Oncology, Department of Clinical and Experimental Medicine F. Magrassi, Università degli Studi della Campania L. Vanvitelli, Naples, Italy
| | - Morgillo Floriana
- Medical Oncology, Department of Clinical and Experimental Medicine F. Magrassi, Università degli Studi della Campania L. Vanvitelli, Naples, Italy
| | - Ciardiello Fortunato
- Medical Oncology, Department of Clinical and Experimental Medicine F. Magrassi, Università degli Studi della Campania L. Vanvitelli, Naples, Italy
| | - Martinelli Erika
- Medical Oncology, Department of Clinical and Experimental Medicine F. Magrassi, Università degli Studi della Campania L. Vanvitelli, Naples, Italy
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15
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Parikh AR, Lee FC, Yau L, Koh H, Knost J, Mitchell EP, Bosanac I, Choong N, Scappaticci F, Mancao C, Lenz HJ. MAVERICC, a Randomized, Biomarker-stratified, Phase II Study of mFOLFOX6-Bevacizumab versus FOLFIRI-Bevacizumab as First-line Chemotherapy in Metastatic Colorectal Cancer. Clin Cancer Res 2018; 25:2988-2995. [DOI: 10.1158/1078-0432.ccr-18-1221] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 07/10/2018] [Accepted: 09/12/2018] [Indexed: 01/13/2023]
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16
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Varol U, Yildiz I, Salman T, Karabulut B, Uslu R. Markers to Predict the Efficacy of Bevacizumab in the Treatment of Metastatic Colorectal Cancer. TUMORI JOURNAL 2018. [DOI: 10.1177/1636.17888] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Umut Varol
- Medical Oncology Clinic, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir
| | - Ibrahim Yildiz
- Medical Oncology Clinic, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir
| | - Tarik Salman
- Medical Oncology Clinic, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir
| | - Bulent Karabulut
- Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Izmir, Turkey
| | - Ruchan Uslu
- Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Izmir, Turkey
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17
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"Vessels in the Storm": Searching for Prognostic and Predictive Angiogenic Factors in Colorectal Cancer. Int J Mol Sci 2018; 19:ijms19010299. [PMID: 29351242 PMCID: PMC5796244 DOI: 10.3390/ijms19010299] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 01/08/2018] [Accepted: 01/11/2018] [Indexed: 12/22/2022] Open
Abstract
High expectations are placed upon anti-angiogenic compounds for metastatic colorectal cancer (mCRC), the first malignancy for which such type of treatment has been approved. Indeed, clinical trials have confirmed that targeting the formation of new vessels can improve in many cases clinical outcomes of mCRC patients. However, current anti-angiogenic drugs are far from obtaining the desirable or expected curative results. Many are the factors probably involved in such disappointing results, but particular attention is currently focused on the validation of biomarkers able to improve the direction of treatment protocols. Because clinical studies have clearly demonstrated that serum or tissue concentration of some angiogenic factors is associated with the evolution of the disease of mCRC patients, they are currently explored as potential biomarkers of prognosis and of tumor response to therapy. However, the complex biology underlying CRC -induced angiogenesis is a hurdle in finding rapid solutions. The aim of this review was to explore molecular mechanisms that determine the formation of tumor-associated vessels during CRC progression, and to discuss the potential role of angiogenic factors as diagnostic, prognostic and predictive biomarkers in CRC.
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18
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Noonan SA, Morrissey ME, Martin P, Biniecka M, Ó'Meachair S, Maguire A, Tosetto M, Nolan B, Hyland J, Sheahan K, O'Donoghue D, Mulcahy H, Fennelly D, O'Sullivan J. Tumour vasculature immaturity, oxidative damage and systemic inflammation stratify survival of colorectal cancer patients on bevacizumab treatment. Oncotarget 2018. [PMID: 29535825 PMCID: PMC5828217 DOI: 10.18632/oncotarget.24276] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Despite treatment of patients with metastatic colorectal cancer (mCRC) with bevacizumab plus chemotherapy, response rates are modest and there are no biomarkers available that will predict response. The aim of this study was to assess if markers associated with three interconnected cancer-associated biological processes, specifically angiogenesis, inflammation and oxidative damage, could stratify the survival outcome of this cohort. Levels of angiogenesis, inflammation and oxidative damage markers were assessed in pre-bevacizumab resected tumour and serum samples of mCRC patients by dual immunofluorescence, immunohistochemistry and ELISA. This study identified that specific markers of angiogenesis, inflammation and oxidative damage stratify survival of patients on this anti-angiogenic treatment. Biomarkers of immature tumour vasculature (% IMM, p=0.026, n=80), high levels of oxidative damage in the tumour epithelium (intensity of 8-oxo-dG in nuclear and cytoplasmic compartments, p=0.042 and 0.038 respectively, n=75) and lower systemic pro-inflammatory cytokines (IL6 and IL8, p=0.053 and 0.049 respectively, n=61) significantly stratify with median overall survival (OS). In summary, screening for a panel of biomarkers for high levels of immature tumour vasculature, high levels of oxidative DNA damage and low levels of systemic pro-inflammatory cytokines may be beneficial in predicting enhanced survival outcome following bevacizumab treatment for mCRC.
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Affiliation(s)
- Sinead A Noonan
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Maria E Morrissey
- Trinity Translational Medicine Institute (TTMI), Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Petra Martin
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Monika Biniecka
- Education and Research Centre, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Shane Ó'Meachair
- Centre for Health Decision Science (CHeDS), School of Computer Science and Statistics, Trinity College Dublin, Dublin, Ireland
| | - Aoife Maguire
- Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | - Miriam Tosetto
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Blathnaid Nolan
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - John Hyland
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Kieran Sheahan
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Diarmuid O'Donoghue
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Hugh Mulcahy
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - David Fennelly
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Jacintha O'Sullivan
- Trinity Translational Medicine Institute (TTMI), Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin, Ireland
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19
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Cui W, Li F, Yuan Q, Chen G, Chen C, Yu B. Role of VEGFA gene polymorphisms in colorectal cancer patients who treated with bevacizumab. Oncotarget 2017; 8:105472-105478. [PMID: 29285265 PMCID: PMC5739652 DOI: 10.18632/oncotarget.22295] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 08/26/2017] [Indexed: 01/05/2023] Open
Abstract
Objectives This study aimed to explore the effects of vascular endothelial growth factor A (VEGFA) gene polymorphisms (rs699947 and rs833061) on Bevacizumab (BEV) treatment in colorectal cancer (CRC) patients. Methods 125 CRC cases receiving BEV plus FOLFIRI treatment were recruited in this study. VEGFA polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Correlation of VEGFA gene polymorphisms with the response rate and progression free survival (PFS) was evaluated. Multivariate analyses were performed to estimate the effects of VEGFA polymorphisms on the therapeutic effects of BEV treatment in CRC patients. Results Rs699947 variants did not show significant association with BEV treatment. For rs833061 analysis, TT and TC genotype carriers had significantly higher ORR (objective response rate) than CC carriers (P=0.048 and P=0.021, respectively). Moreover, TT carriers underwent a well DCR (disease control rate) compared to CC carriers (P=0.002). PFS time also showed obvious correlation with rs833061 polymorphism (log rank test, P=0.002). Multivariate analyses demonstrated that TT and TC genotypes of rs833061 polymorphism were significantly correlated with enhanced therapeutic effects and prolonged PFS in CRC patients. Conclusion VEGFA rs833061 polymorphism is significantly associated with the therapeutic efficiency of bevacizumab in CRC patients.
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Affiliation(s)
- Wei Cui
- Department of General Surgery, The Military General Hospital of Beijing PLA, Beijing 100700, China
| | - Feng Li
- Department of Health, The Military General Hospital of Beijing PLA, Beijing 100700, China
| | - Qiang Yuan
- Department of General Surgery, The Military General Hospital of Beijing PLA, Beijing 100700, China
| | - Gang Chen
- Department of General Surgery, The Military General Hospital of Beijing PLA, Beijing 100700, China
| | - Cailing Chen
- Department of General Surgery, The Military General Hospital of Beijing PLA, Beijing 100700, China
| | - Bo Yu
- Department of General Surgery, The Military General Hospital of Beijing PLA, Beijing 100700, China
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20
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Riechelmann R, Grothey A. Antiangiogenic therapy for refractory colorectal cancer: current options and future strategies. Ther Adv Med Oncol 2017; 9:106-126. [PMID: 28203302 PMCID: PMC5298403 DOI: 10.1177/1758834016676703] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Even though significant improvements in the treatment of colorectal cancer (CRC) have been made in recent years, survival rates for metastatic colorectal cancer (mCRC) are poor. Effective treatment options for metastatic colorectal cancer remain limited, and new therapeutic strategies are desperately needed. Several tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) that target angiogenesis, a critical process for facilitating tumor cell growth, invasion, and metastasis, are either approved or in clinical development for the treatment of mCRC. Many of these agents have shown efficacy in mCRC, both as single agents and in combination with standard chemotherapy regimens. However, there is a need for predictive markers of response to identify those patients most likely to benefit from antiangiogenic therapy, and, to date, no markers of this type have been validated in patients. Additionally, because antiangiogenic agents typically cause cytostatic as opposed to cytotoxic antitumor effects, it is important to determine the best strategies for evaluating therapeutic response in mCRC to ensure maximum clinical benefit. In this review, we summarize the efficacy and tolerability of approved and investigational antiangiogenic agents for the treatment of mCRC. We also discuss potential markers of response to antiangiogenic agents and how these markers, along with appropriate endpoint selection, can improve clinical trial design.
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Affiliation(s)
- Rachel Riechelmann
- Instituto do Cancer do Estado de São Paulo, Av. Doutor Arnaldo 251, 5° Andar, CEP 01246-000, São Paulo, SP, Brazil
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21
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Abstract
In the last 20 years, improvements in metastatic colorectal cancer treatment lead to a radical raise of outcomes with median survival reaching now more than 30 months. Despite that, the identification of predictive and/or prognostic biomarker still represents a challenging issue, and until today, although clinician and researchers might face with a deeper knowledge of biological mechanisms related to colorectal cancer, many pieces of evidence underline the heterogeneity and the dynamism of such disease. In the present review, we describe the road leading to the discovery of RAS mutations, BRAF V600E mutation, and microsatellite instability role in colorectal cancer; second, we discuss some of the possible major pitfalls of biomarker research, and lastly, we give new suggestions for future research in this field.
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22
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Nie XJ, Liu WM, Zhang L. Association of VEGF Gene Polymorphisms with the Risk and Prognosis of Cutaneous Squamous Cell Carcinoma. Med Sci Monit 2016; 22:3658-3665. [PMID: 27729640 PMCID: PMC5074797 DOI: 10.12659/msm.896710] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Cutaneous squamous cell carcinoma (cSCC) is the second most common type of non-melanoma skin cancer (NMSC) globally. The aims of this study were to further systematically clarify the potential association of rs833061 (-460 C>T) and rs1570360 (-1154 G>A), two SNPs of VEGF, with the risk of cSCC and the prognostic impacts on cSCC patients. MATERIAL AND METHODS This hospital-based case-control study analyzed peripheral venous blood collected from 100 cSCC patients and 124 healthy controls, and gathered personal information on patients. Genotypes of the VEGF gene -460C>T and -1154G>A polymorphism were detected using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. Different distributions of allele frequencies and genotype in the case and control group were measured, comparing different genotype differences in the survival of patients with cSCC. RESULTS Distributions of allele frequencies and genotype of -460 C>T in the case and control group were statistically different; the TT + CT genotype was significantly correlated with a decrease risk of cSCC (OR=0.36, 95% CI=0.21-0.63, P<0.001). There was no difference in the distribution of allele frequencies and genotype of -1154 G>A between control and case groups. For -1154460C>T, the CC genotype was an adverse factor, associated with a significant decrease in the survival status of cSCC patients (P<0.001). For VEGF-1154 G>A, the AA genotype was significantly correlated with the reduced overall survival in cSCC patients, with the mean survival time of 23.88 months (P=0.009). CONCLUSIONS The VEGF gene -460 C>T polymorphism and -1154 G>A polymorphism may serve as potential genetic markers for the risk and prognosis of cSCC.
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Affiliation(s)
- Xiao-Juan Nie
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China (mainland)
| | - Wen-Min Liu
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China (mainland)
| | - Li Zhang
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China (mainland)
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23
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Roh SA, Park IJ, Yoon YS, Kwon YH, Chung JH, Kim TW, Cho DH, Lim BH, Kim SK, Kim SY, Kim YS, Kim JC. Feasibility of novel PPP1R15A and proposed ANXA11 single nucleotide polymorphisms as predictive markers for bevacizumab regimen in metastatic colorectal cancer. J Cancer Res Clin Oncol 2016; 142:1705-1714. [PMID: 27177629 DOI: 10.1007/s00432-016-2177-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 05/02/2016] [Indexed: 12/26/2022]
Abstract
PURPOSE Bevacizumab improves survival in patients with metastatic colorectal cancer (mCRC) under chemotherapy, but few predictive markers have been identified. METHODS To investigate chemosensitive single nucleotide polymorphisms (SNPs) of mCRC, we performed exome sequencing and RNA sequencing in 19 patients. A clinical association analysis was performed with the other 116 patients who had received chemotherapy to bevacizumab regimens. In vivo biodistribution studies and [(18)F]FDG-PET imaging were performed on mice bearing human colorectal cancer (HCT116 and SW480) xenografts after injection of bevacizumab with 5-FU, leucovorin, and irinotecan (FOLFIRI). RESULTS PPP1R15A rs557806 showed the most significant association with FRB-driven tumor IR in exome sequencing and the highest correlation (r = 0.74) with drug responses in RNA sequencing. Patients homozygous for the reference alleles (GG) of PPP1R15A rs557806 exhibited greater disease control rate and a tendency toward greater objective response rate (ORR) than those with homozygous or heterozygous substitution alleles (GC and CC; P = 0.027 and 0.073, respectively). In xenografted mice, HCT116 clones transfected with the G allele at PPP1R15A rs557806 were more sensitive to bevacizumab regimens than those with the C allele. Tumor volume of xenografts with the G allele was significantly lower than that of xenografts with the C allele (P = 0.004, day 13). [(18)F]FDG uptake decreased to 75 % in HCT116 xenograft-bearing mice with the G allele, whereas [(18)F]FDG uptake was 42 % in mice xenografts with the C allele (P = 0.032). ANXA11 rs1049550, a predictive biomarker of SNP described in our previous study, was validated using the xenograft model. Tumor volume and [(18)F]FDG uptake analyses showed that tumors in the SW480 xenografts expressing the substitution allele (T) at ANXA11 rs1049550 were more susceptible to FOLFIRI plus bevacizumab-induced suppression than those expressing the reference allele (C) (P = 0.001 and 0.026, respectively). CONCLUSION ANXA11 rs1049550 and PPP1R15A rs557806 may improve the identification of mCRC patients sensitive to bevacizumab regimens, and further validation is required in large cohorts.
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Affiliation(s)
- Seon Ae Roh
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
- Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea
| | - In Ja Park
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Yong Sik Yoon
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
- Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea
| | - Yi Hong Kwon
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea
- Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea
| | - Jin Hwa Chung
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea
| | - Tae Won Kim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong Hyung Cho
- Graduate School of East-West Medical Science, Kyung Hee University, Suwon, Gyeonggi-do, Korea
| | - Byung Ho Lim
- Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea
| | - Seon Kyu Kim
- Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea
| | - Seon Young Kim
- Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea
| | - Yong Sung Kim
- Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
| | - Jin Cheon Kim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.
- Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
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Cidon EU, Alonso P, Masters B. Markers of Response to Antiangiogenic Therapies in Colorectal Cancer: Where Are We Now and What Should Be Next? Clin Med Insights Oncol 2016; 10:41-55. [PMID: 27147901 PMCID: PMC4849423 DOI: 10.4137/cmo.s34542] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/15/2016] [Accepted: 03/13/2016] [Indexed: 12/17/2022] Open
Abstract
Despite advances in the treatment of colorectal cancer (CRC), it remains the second most common cause of cancer-related death in the Western world. Angiogenesis is a complex process that involves the formation of new blood vessels from preexisting vessels. It is essential for promoting cancer survival, growth, and dissemination. The inhibition of angiogenesis has been shown to prevent tumor progression experimentally, and several chemotherapeutic targets of tumor angiogenesis have been identified. These include anti-vascular endothelial growth factor (VEGF) treatments, such as bevacizumab (a VEGF-specific binding antibody) and anti-VEGF receptor tyrosine kinase inhibitors, although antiangiogenic therapy has been shown to be effective in the treatment of several cancers, including CRC. However, it is also associated with its own side effects and financial costs. Therefore, the identification of biomarkers that are able to identify patients who are more likely to benefit from antiangiogenic treatment is very important. This article intends to be a concise summary of the potential biomarkers that can predict or prognosticate the benefit of antiangiogenic treatments in CRC, and also what we can expect in the near future.
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Affiliation(s)
- E. Una Cidon
- Department of Medical Oncology, Royal Bournemouth Hospital NHS Foundation Trust, Bournemouth, UK
| | - P. Alonso
- Department of Clinical Oncology, Clinical University Hospital, Valladolid, Spain
| | - B. Masters
- Department of Oncology, Nottingham City Hospital, Nottingham, UK
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Liu J, Fan L, Wang H, Sun G. Autophagy, a double-edged sword in anti-angiogenesis therapy. Med Oncol 2015; 33:10. [PMID: 26715036 DOI: 10.1007/s12032-015-0721-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 12/12/2015] [Indexed: 12/24/2022]
Abstract
Autophagy is a highly conservative cell behavior to keep the intracellular homeostasis and is frequently activated when cells encounter disgusting conditions, such as nutrition or growth factor deprive, hypoxia and cytotoxic agents. However, the precise role of autophagy under various conditions may be opposite, differ from protect cells survival to promote cells death, and the mechanism of this conditional-dependent role is still unclear. Anti-angiogenesis agents, such as bevacizumab, sorafenib and sunitinib, could reduce tumor microvascular density and increase tumor hypoxia, thus up-regulating autophagy activation of tumor cells, but the function of autophagy induced by anti-angiogenesis agents is still divergent and is considered to play a cytoprotective role in most cases. In this review, we mainly discuss the relationship between anti-angiogenesis therapy-induced hypoxia and autophagy, and pay special attention on the exact role of anti-angiogenesis agents induced autophagy in the process of anti-angiogenesis treatment.
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Affiliation(s)
- Jiatao Liu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China.,Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China
| | - Lulu Fan
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China
| | - Guoping Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China.
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Ulivi P, Scarpi E, Passardi A, Marisi G, Calistri D, Zoli W, Del Re M, Frassineti GL, Tassinari D, Tamberi S, Vertogen B, Amadori D. eNOS polymorphisms as predictors of efficacy of bevacizumab-based chemotherapy in metastatic colorectal cancer: data from a randomized clinical trial. J Transl Med 2015; 13:258. [PMID: 26259598 PMCID: PMC4531503 DOI: 10.1186/s12967-015-0619-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 07/27/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Bevacizumab plus chemotherapy is a widely used therapeutic option for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of bevacizumab efficacy have not yet been identified. We analyzed vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) polymorphisms in relation to response to bevacizumab. METHODS Two hundred and thirty-seven patients with mCRC enrolled onto the phase III prospective multicentre randomized "Italian Trial in Advanced Colorectal Cancer (ITACa)" trial were evaluated. One hundred fourteen patients received chemotherapy plus bevacizumab (CT + B) and 123 received chemotherapy (CT) alone. Five single nucleotide polymorphisms (SNPs) (-2578, -1498, -1154, -634 and +936) for VEGF and 2 SNPs (-786, +894) and one variable number tandem repeat in intron 4 for eNOS were analyzed for each patient. The polymorphisms were assessed in relation to progression-free survival (PFS), objective response rate (ORR) and overall survival (OS). RESULTS VEGF 936C/T, eNOS +894 G/T and VNTR were significantly correlated with outcome in CT + B patients, but not in CT-only patients. In particular, patients with a specific haplotype combination of the 2 eNOS polymorphisms (defined eNOS Haplo1/Haplo1 and eNOS Haplo 2/Haplo2) showed significantly longer PFS (15.0 vs 9.1 months, P = 0.001) and OS (34.5 vs 20.5 months P = 0.002), and a higher ORR (71 vs 45.9%, P = 0.013) than those with the other genotypes, respectively. CONCLUSIONS Specific eNOS polymorphisms may be capable of identifying a subset of mCRC patients who are more responsive to bevacizumab-based chemotherapy. If confirmed, these results would permit individually tailored treatment with bevacizumab.
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Affiliation(s)
- Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014, Meldola, Italy.
| | - Emanuela Scarpi
- Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola, Italy.
| | | | - Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014, Meldola, Italy.
| | - Daniele Calistri
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014, Meldola, Italy.
| | - Wainer Zoli
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014, Meldola, Italy.
| | - Marzia Del Re
- Department of Clinical and Experimental Medicine, Pisa University Hospital, Pisa, Italy.
| | | | - Davide Tassinari
- Department of Oncology, Per gli Infermi Hospital, Rimini, Italy.
| | | | | | - Dino Amadori
- Department of Medical Oncology, IRST IRCCS, Meldola, Italy.
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Association between Polymorphisms in Vascular Endothelial Growth Factor Gene and Response to Chemotherapies in Colorectal Cancer: A Meta-Analysis. PLoS One 2015; 10:e0126619. [PMID: 25955730 PMCID: PMC4425504 DOI: 10.1371/journal.pone.0126619] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Accepted: 04/06/2015] [Indexed: 12/16/2022] Open
Abstract
Background Some studies have investigated the effects of polymorphisms in the vascular endothelial growth factor (VEGF) gene on responsiveness to chemotherapy for colorectal cancer (CRC) and have shown inconclusive results. Methods Eligible studies that assessed the associations between polymorphisms in the VEGF gene and response to chemotherapy in CRC were searched in the PubMed, Embase and Medline databases until November 2014. Odds ratios (OR) and 95% confidence intervals (CIs) were used to evaluate the associations, using Review Manager software, version 5.3. Stratified analysis was also conducted. Results In the overall analysis, a significant association with responsiveness to chemotherapy in CRC was identified in CC vs. CA of the VEGF -2578 C/A polymorphism (OR = 1.40, 95% CI 1.00-1.97, P = 0.05) and in CC+CT vs. TT of the VEGF -460 C/T polymorphism (OR = 0.71, 95% CI 0.53-0.96, P = 0.02). In subgroup analysis, a significant association was found in excluding anti-angiogenic agent subgroup in three comparison models of the VEGF -2578 C/A polymorphism and another three genetic models of the VEGF -460 C/T C/A polymorphism. Conclusions CC vs. CA of the VEGF -2578 C/A polymorphism and CC+CT vs. TT of the VEGF -460 C/T polymorphism might be predictive factors of responsiveness to chemotherapy in CRC. However, single-nucleotide polymorphisms in the VEGF gene lacked sufficient predictive ability to determine whether patients with CRC should add anti-angiogenic agents to their chemotherapy regimens.
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De Mattia E, Cecchin E, Toffoli G. Pharmacogenomics of intrinsic and acquired pharmacoresistance in colorectal cancer: Toward targeted personalized therapy. Drug Resist Updat 2015; 20:39-70. [DOI: 10.1016/j.drup.2015.05.003] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 05/11/2015] [Accepted: 05/14/2015] [Indexed: 02/07/2023]
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Sibertin-Blanc C, Mancini J, Fabre A, Lagarde A, Del Grande J, Levy N, Seitz JF, Olschwang S, Dahan L. Vascular Endothelial Growth Factor A c.*237C>T polymorphism is associated with bevacizumab efficacy and related hypertension in metastatic colorectal cancer. Dig Liver Dis 2015; 47:331-7. [PMID: 25617075 DOI: 10.1016/j.dld.2014.12.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 11/25/2014] [Accepted: 12/21/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND No predictive marker has been yet identified for bevacizumab which is widely used in metastatic colorectal cancer. AIMS Evaluate impact of single nucleotide polymorphisms involved in Vascular Endothelial Growth Factor pathway on efficacy and tolerance of bevacizumab. METHODS We retrospectively included patients who were treated with bevacizumab-based chemotherapy for metastatic colorectal cancer, and for whom a deoxyribonucleic acid sample was available. Ten polymorphisms in Vascular Endothelial Growth Factor-A, his receptors and hypoxia inducible factor-1α were genotyped on germ line DNA using real-time polymerase chain reaction TaqMan(®). RESULTS 89 patients were included. The CC genotype for rs3025039 (Vascular Endothelial Growth Factor-A c.*237C>T) was associated with a significantly better time to treatment failure (14.2 months) as compared to the CT and TT genotypes (6.0 months) in univariate (p = 0.004) and multivariate (p = 0.022; HR = 0.57; 95% CI [0.35-0.92]) analysis. Patients with at least one T allele showed worse overall survival and progression-free survival as compared to homozygous CC patients in univariate analysis (respectively p = 0.016 and p = 0.044). There was significantly more severe hypertension for the CC genotype (29.5%) compared to CT and TT genotypes (7.1%) (p = 0.022) in multivariate analysis. CONCLUSIONS In this retrospective study, the rs3025039 polymorphism was significantly associated with time to treatment failure and hypertension in patients treated with bevacizumab-based chemotherapy.
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Affiliation(s)
- Camille Sibertin-Blanc
- Department of Digestive Oncology, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; UMR S-910 INSERM, Medical Genetics and Functional Genomics, Aix-Marseille University, Marseille, France.
| | - Julien Mancini
- Department of Biostatistics, Assistance Publique Hôpitaux de Marseille, Marseille, France; UMR_S912, Economic & Social Sciences, Health Systems & Medical Informatics, SESSTIM, Aix Marseille Université, Inserm, IRD, Marseille, France
| | - Aurélie Fabre
- UMR S-910 INSERM, Medical Genetics and Functional Genomics, Aix-Marseille University, Marseille, France; Department of Medical Genetics, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France
| | - Arnaud Lagarde
- UMR S-910 INSERM, Medical Genetics and Functional Genomics, Aix-Marseille University, Marseille, France; Department of Medical Genetics, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France
| | - Jean Del Grande
- Department of Pathology, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France
| | - Nicolas Levy
- UMR S-910 INSERM, Medical Genetics and Functional Genomics, Aix-Marseille University, Marseille, France; Department of Medical Genetics, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France
| | - Jean-François Seitz
- Department of Digestive Oncology, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; UMR S-910 INSERM, Medical Genetics and Functional Genomics, Aix-Marseille University, Marseille, France
| | - Sylviane Olschwang
- UMR S-910 INSERM, Medical Genetics and Functional Genomics, Aix-Marseille University, Marseille, France; Department of Medical Genetics, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France
| | - Laetitia Dahan
- Department of Digestive Oncology, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; UMR S-910 INSERM, Medical Genetics and Functional Genomics, Aix-Marseille University, Marseille, France
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Prognostic factors for survival with bevacizumab-based therapy in colorectal cancer patients: a systematic review and pooled analysis of 11,585 patients. Med Oncol 2015; 32:456. [DOI: 10.1007/s12032-014-0456-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 12/12/2014] [Indexed: 12/21/2022]
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Yoon YS, Kim JC. Recent applications of chemosensitivity tests for colorectal cancer treatment. World J Gastroenterol 2014; 20:16398-16408. [PMID: 25469008 PMCID: PMC4248183 DOI: 10.3748/wjg.v20.i44.16398] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 07/08/2014] [Accepted: 08/13/2014] [Indexed: 02/06/2023] Open
Abstract
The evaluation of therapeutic efficacy is necessary to predict the outcome of patients with metastatic colorectal cancer (CRC). In these patients, there is a critical need for predictive chemosensitivity assays and biomarkers to optimize efficacy and minimize toxicity. The introduction of targeted agents has improved the progression-free survival and overall survival of patients with metastatic disease. However, approximately 50% of patients do not show a positive response to chemotherapy and the selection of patients likely to respond to a specific regimen remains challenging. Cell culture-based chemosensitivity tests use autologous viable tumor cells to evaluate susceptibility to specific agents in vitro and predict their direct effects. Adenosine triphosphate-based assays and methyl thiazolyl-diphenyl-tetrazolium bromide-based assays are used widely as sensitivity tests because of their short assay period, technical simplicity, and the requirement of small amount of specimen. Among protein- and gene-based chemosensitivity assays, assessment of KRAS mutation status predicts the response to epidermal growth factor receptor-targeted therapy in CRC patients. The validation of predictive and prognostic markers enables the selection of therapeutic regimens with optimal efficacy and minimal toxicity for each patient, which has been termed personalized treatment. This review summarizes currently available predictive and prognostic chemosensitivity tests for metastatic CRC.
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Sohn BS, Park SJ, Kim JE, Kim KP, Hong YS, Suh C, Kim YS, Kim SY, Im SA, Kim SY, Kim JH, Ahn JB, Park YS, Kim TW. Single-nucleotide polymorphisms in the vascular endothelial growth factor pathway and outcomes of patients treated with first-line cytotoxic chemotherapy combined with bevacizumab for advanced colorectal cancer. Oncology 2014; 87:280-92. [PMID: 25139485 DOI: 10.1159/000365593] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 06/30/2014] [Indexed: 01/13/2023]
Abstract
OBJECTIVE The aim of this study was to evaluate the association between the efficacy of first-line cytotoxic chemotherapy plus bevacizumab and single-nucleotide polymorphisms (SNPs) of angiogenic genes in patients with advanced colorectal cancer (CRC). METHODS DNA was extracted from blood samples of 125 patients, and 12 SNPs were evaluated for association with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS The vascular endothelial growth factor A (VEGFA) rs833061 T/T was associated with superior ORR compared to its alternative genotypes (75.9 vs. 50.8%; p = 0.008), and the interleukin 8 rs4073 A/A genotype tended to be associated with poor ORR (45.0 vs. 66.0%; p = 0.067). The median PFS and OS were superior in patients with the fms-related tyrosine kinase 1 (FLT1) rs9513070 A/A genotype (8.7 vs. 6.6 months; p = 0.001 and 26.4 vs. 16.1 months; p = 0.038, respectively). The kinase insert domain receptor rs1531289 G/G genotype tended to be associated with improved PFS (8.0 vs. 7.1 months; p = 0.069). In haplotype analysis, the FLT1 rs9513070/rs9554320/rs9582036 GCA haplotype was associated with inferior PFS and OS (p = 0.004 and p = 0.041, respectively). CONCLUSION The VEGFA rs833061 SNP is associated with the ORR, and the FLT1 rs9513070 SNP and FLT1 GCA haplotypes are associated with PFS and OS in advanced CRC patients treated with cytotoxic chemotherapy plus bevacizumab.
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Affiliation(s)
- Byeong Seok Sohn
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Marisi G, Passardi A, Calistri D, Zoli W, Amadori D, Ulivi P. Discrepancies between VEGF -1154 G>A polymorphism analysis performed in peripheral blood samples and FFPE tissue. Int J Mol Sci 2014; 15:13333-43. [PMID: 25079441 PMCID: PMC4159797 DOI: 10.3390/ijms150813333] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 07/02/2014] [Accepted: 07/23/2014] [Indexed: 01/01/2023] Open
Abstract
Single nucleotide polymorphisms (SNPs) may be associated with the response or toxicity to different types of treatment. Although SNP analysis is usually performed on DNA from peripheral blood, formalin fixed paraffin-embedded (FFPE) tissue is often used for retrospective studies. We analyzed VEGF (-2578C>A, -1498C>T, -1154G>A, -634C>G, +936C>T) and eNOS (+894G>T, -786T>C, VNTR (variable number of tandem repeats) 27bp intron 4) polymorphisms by direct sequencing or Real Time PCR in 237 patients with advanced colorectal cancer. Peripheral blood was used for 153 patients, whereas only FFPE tumor tissue was available for 84 patients. All SNP frequencies were in Hardy-Weinberg Equilibrium (HWE), with the exception of VEGF -1154, which was only in HWE in peripheral blood specimens. We therefore analyzed this SNP in DNA extracted from FFPE tumor tissue compared to FFPE healthy tissue and peripheral blood from 20 patients. Numerous heterozygous patients in peripheral blood DNA were homozygous for the A-allele in both tumor and healthy FFPE tissues. Our findings indicate that, although FFPE tissue might be a suitable specimen for genotyping, VEGF -1154 does not give reliable results on this type of material. As other SNPs may also have this limitation, genotype concordance should first be confirmed by comparing results obtained from FFPE and fresh sample analyses.
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Affiliation(s)
- Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy.
| | - Alessandro Passardi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy.
| | - Daniele Calistri
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy.
| | - Wainer Zoli
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy.
| | - Dino Amadori
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy.
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy.
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The role of antiangiogenic agents in the treatment of patients with advanced colorectal cancer according to K-RAS status. Angiogenesis 2014; 17:805-21. [PMID: 24793846 DOI: 10.1007/s10456-014-9433-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2012] [Accepted: 04/21/2014] [Indexed: 12/30/2022]
Abstract
Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide. Recently, it has been found that about 40 % of patients with CRC have mutations in the K-RAS gene. Several clinical trials have showed that patients with metastatic colorectal cancer (mCRC) who present tumour-promoting mutations in signalling pathways involving the epidermal growth factor receptor (EGFR), which includes activating K-RAS mutations, do not respond to anti-EGFR drugs such as panitumumab and cetuximab. Hence, K-RAS status is now considered an important negative predictive factor for response to anti-EGFR drugs. Moreover, K-RAS status seems to have also a prognostic role in CRC, but this fact is somewhat controversial. Activity of antiangiogenic agents seems not to be influenced by K-RAS gene status. Tumour angiogenesis has attracted interest in attempts to improve the management of mCRC. The vascular endothelial growth factor (VEGF) pathway is fundamental to the regulation of angiogenesis, and research has focused on developing agents that selectively target it. In this way, the anti-VEGF antibody bevacizumab in combination with chemotherapy has provided important clinical benefits in terms of response rate, progression-free survival and overall survival to patients with mCRC. Efficacy data of bevacizumab in K-RAS wild-type patients seem to be comparable with the efficacy data observed with anti-EGFR therapies in a cross-trial comparison. Although there is a lack of prospective and randomized data in this setting, the combination of chemotherapy plus antiangiogenic agents could be considered as an effective alternative for the treatment of mCRC with independence of K-RAS gene status. Here, we review the available data we have in the literature of the use of antiangiogenic strategies in the treatment of mCRC nowadays.
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Luo HY, Xu RH. Predictive and prognostic biomarkers with therapeutic targets in advanced colorectal cancer. World J Gastroenterol 2014; 20:3858-3874. [PMID: 24744578 PMCID: PMC3983442 DOI: 10.3748/wjg.v20.i14.3858] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/11/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common human malignant diseases and the second leading cause of cancer-related deaths worldwide. The treatment of advanced CRC has improved significantly in recent years. With the emergence of two targeted antibodies, cetuximab (Erbitux), an anti-epidermal growth factor receptor monoclonal antibody and bevacizumab (Avastin), a vascular endothelial growth factor monoclonal antibody, the treatment of metastatic CRC has entered the era of personalized therapy. Predictive and prognostic biomarkers have, and will continue to, facilitate the selection of suitable patients and the personalization of treatment for metastatic CRC (mCRC). In this review, we will focus primarily on the important progresses made in the personalized treatment of mCRC and discuss the potentially novel predictive and prognostic biomarkers for improved selection of patients for anti-cancer treatment in the future.
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Renal carcinoma pharmacogenomics and predictors of response: Steps toward treatment individualization. Urol Oncol 2014; 33:179-86. [PMID: 24495452 DOI: 10.1016/j.urolonc.2013.09.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Revised: 09/10/2013] [Accepted: 09/13/2013] [Indexed: 02/07/2023]
Abstract
Molecular knowledge has deeply affected the treatment and outcome of kidney cancer in recent years, and several therapeutic options have become available. However, there are no validated biomarkers to select the best drug for each patient. Already published studies and ongoing investigations could change this scenario in the near future. Regarding antiangiogenic drugs, several works on single nucleotide polymorphisms have achieved promising results, with some SNPs predicting resistance to sunitinib and pazopanib being validated. If more evidence is gained, it could prompt prospective studies exploring a molecularly driven selection of treatment. Another relevant line of investigation for antiangiogenic drugs is the cytokines and antiangiogenic factors. Different studies have found that cytokines and antiangiogenic factors are able to predict the outcome of patients treated with sunitinib, pazopanib, or sorafenib. Issues regarding the thresholds of normality and the best time for assessment are pending, but the communicated results are encouraging. Less evidence is available for mammalian target of rapamycin inhibitors but recent data support a key role of the phosphoinositide 3-kinase/Akt pathway in clear cell renal cell carcinoma and points toward poor response to angiogenic drugs when the pathway is activated. Whether modern phosphoinositide 3-kinase inhibitors could be the best option for these patients is a question that should be addressed. Additionally, a new class of immunomodulators, like anti-programmed death 1 drugs, has demonstrated to achieve long-lasting stabilizations even in some patients with no radiological response or early progression. This is a singular situation where the identification of reliable predictors of efficacy will be key in the development of these drugs in renal cell carcinoma. Finally, germline mutations of the c-Met gene have been proposed as the first predictor of response to targeted therapies in papillary renal cell carcinoma. As a conclusion, translational research will be a cornerstone to move a next step forward in kidney cancer.
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Abstract
Currently approved treatments for metastatic renal cell carcinoma (RCC) include vascular endothelial growth factor (VEGF)-blocking agents, mammalian target of rapamycin (mTOR) inhibitors, and cytokine therapy. In the near future, we are likely to add immune checkpoint blocking agents to this list. As we develop treatment platforms around each therapeutic class, determining which drug is best for a particular patient becomes increasingly important. At this point, we do not have validated predictive biomarkers for patients with RCC. Here, we discuss the logistical challenges surrounding biomarker development, summarize the current crop of biomarker candidates, and explore potential avenues for the development of more effective predictive tools for patients with advanced RCC.
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Affiliation(s)
- Jesus Garcia-Donas
- Genitourinary Tumors Programme Centro Integral Oncologico Clara Campal CIOCC, Madrid, Spain
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Koutras AK, Kotoula V, Papadimitriou C, Dionysopoulos D, Zagouri F, Kalofonos HP, Kourea HP, Skarlos DV, Samantas E, Papadopoulou K, Kosmidis P, Pectasides D, Fountzilas G. Vascular endothelial growth factor polymorphisms and clinical outcome in patients with metastatic breast cancer treated with weekly docetaxel. THE PHARMACOGENOMICS JOURNAL 2013; 14:248-55. [PMID: 24061601 DOI: 10.1038/tpj.2013.36] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 05/25/2013] [Revised: 08/03/2013] [Accepted: 08/15/2013] [Indexed: 11/09/2022]
Abstract
The aim of the study was to evaluate the association of vascular endothelial growth factor (VEGF) genotypes with treatment efficacy in a phase II trial. This study evaluated weekly docetaxel, as first-line treatment for metastatic breast cancer. Existing data from in vitro and animal model experiments suggest that docetaxel at low doses has anti-angiogenic activity. DNA was extracted from blood samples of 86 patients participating in the trial. Genotyping was performed for selected single-nucleotide polymorphisms (SNPs; VEGF-2578, -1498, -1154, and +936). Moreover, due to the highly polymorphic nature of the studied areas, we were able to analyze additional registered SNPs. All candidate genotypes were evaluated for associations with overall survival (OS), progression-free survival (PFS) and response rate. The VEGF-1154 GG genotype was more frequent in patients not responding to treatment compared with responders (42.9% vs 0.0%, P=0.048). Moreover, the VEGF-2578 AA genotype was associated with longer PFS compared with CC (hazard ratio (HR)=0.40; 95% confidence interval (CI) 0.17-0.98; pairwise P=0.0457). Patients with the VEGF-1190 GG genotype demonstrated shorter PFS compared with those with the alternative genotypes (GA and AA) combined (HR=3.85; 95% CI: 1.20-12.50; P=0.0224). In addition, the VEGF-2551/-2534 homozygous del18bp and VEGF-2430/-2425 homozygous ins1bp genotypes were associated with worse PFS compared with no deletion and no insertion, respectively (HR=2.49; 95% CI: 1.02-6.07; pairwise P=0.0442 and HR=2.57; 95% CI: 1.05-6.27; pairwise P=0.0385, respectively). Furthermore, patients with the VEGF-1498 CC genotype exhibited longer median OS compared with those with the alternatives genotypes (CT and TT) combined (HR=0.27; 95% CI: 0.08-0.89; P=0.0311). In multivariate analysis, the VEGF-2578 AA genotype retained its significance (P=0.0220) for PFS. Our results support the association of specific VEGF genotypes with clinical outcome in patients with metastatic breast cancer treated with a potentially anti-angiogenic regimen, such as weekly docetaxel. However, current results should be validated prospectively in larger cohorts.
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Affiliation(s)
- A K Koutras
- Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece
| | - V Kotoula
- Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
| | - C Papadimitriou
- Department of Clinical Therapeutics, 'Alexandra' Hospital, University of Athens School of Medicine, Athens, Greece
| | - D Dionysopoulos
- Department of Medical Oncology, 'Papageorgiou' Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
| | - F Zagouri
- Department of Clinical Therapeutics, 'Alexandra' Hospital, University of Athens School of Medicine, Athens, Greece
| | - H P Kalofonos
- Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece
| | - H P Kourea
- Department of Pathology, University Hospital of Patras, Patras, Greece
| | - D V Skarlos
- Second Department of Medical Oncology, 'Metropolitan' Hospital, Piraeus, Greece
| | - E Samantas
- Third Department of Medical Oncology, 'Agii Anargiri' Cancer Hospital, Athens, Greece
| | - K Papadopoulou
- Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
| | - P Kosmidis
- Second Department of Medical Oncology, Hygeia Hospital, Athens, Greece
| | - D Pectasides
- Oncology Section, Second Department of Internal Medicine, 'Hippokration' Hospital, Athens, Greece
| | - G Fountzilas
- Department of Medical Oncology, 'Papageorgiou' Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
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39
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Moorcraft SY, Smyth EC, Cunningham D. The role of personalized medicine in metastatic colorectal cancer: an evolving landscape. Therap Adv Gastroenterol 2013; 6:381-95. [PMID: 24003339 PMCID: PMC3756633 DOI: 10.1177/1756283x13491797] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Advances in the treatment of metastatic colorectal cancer have led to an improvement in survival from 12 months with fluorouracil monotherapy to approximately 2 years. This is partly as a result of the addition of irinotecan and oxaliplatin, but is also due to the use of monoclonal antibodies against the epidermal growth factor receptor (EGFR) and antiangiogenic drugs such as bevacizumab. However, there are significant molecular differences between tumours which can affect both prognosis and response to treatment. Personalized medicine aims to tailor treatment according to the characteristics of the individual patient and is now a clinical reality as testing for KRAS mutations to guide treatment with the anti-EGFR monoclonal antibodies cetuximab and panitumumab is now part of routine clinical practice. However, not all patients who are KRAS wild type respond to anti-EGFR therapy and a validated biomarker for antiangiogenic therapy is still lacking. Therefore, other biomarkers are needed to assist with predicting response to both existing drugs as well as to drugs currently under investigation. This review summarizes the molecular biology of colorectal cancer, focusing on the genetic features that are currently most clinically relevant. Current and emerging biomarkers are reviewed along with their roles in selecting patients for targeted treatment with currently licensed therapies and drugs being evaluated in clinical trials. The value of predictive biomarkers of chemosensitivity and potential future treatment strategies are also discussed.
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40
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Kline CLB, El-Deiry WS. Personalizing colon cancer therapeutics: targeting old and new mechanisms of action. Pharmaceuticals (Basel) 2013; 6:988-1038. [PMID: 24276379 PMCID: PMC3817731 DOI: 10.3390/ph6080988] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 07/30/2013] [Accepted: 08/16/2013] [Indexed: 12/17/2022] Open
Abstract
The use of pharmaceuticals for colon cancer treatment has been increasingly personalized, in part due to the development of new molecular tools. In this review, we discuss the old and new colon cancer chemotherapeutics, and the parameters that have been shown to be predictive of efficacy and safety of these chemotherapeutics. In addition, we discuss how alternate pharmaceuticals have been developed in light of a potential lack of response or resistance to a particular chemotherapeutic.
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Affiliation(s)
- Christina Leah B Kline
- Hematology/Oncology Division, Penn State Hershey Medical Center, Hershey, PA 17033, USA.
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41
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Silvestri A, Pin E, Huijbers A, Pellicani R, Parasido EM, Pierobon M, Petricoin E, Liotta L, Belluco C. Individualized therapy for metastatic colorectal cancer. J Intern Med 2013; 274:1-24. [PMID: 23527888 DOI: 10.1111/joim.12070] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Systemic therapeutic efficacy is central to determining the outcome of patients with metastatic colorectal cancer (CRC). In these patients, there is a critical need for predictive biomarkers to optimize efficacy whilst minimizing toxicity. The integration of a new generation of molecularly targeted drugs into the treatment of CRC, coupled with the development of sophisticated technologies for individual tumours as well as patient molecular profiling, underlines the potential for personalized medicine. In this review, we focus on the latest progress made within the genomic and proteomic fields, concerning predictive biomarkers for individualized therapy in metastatic CRC.
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Affiliation(s)
- A Silvestri
- Division of Experimental Oncology 2, CRO-IRCCS, National Cancer Institute, Aviano, Italy
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Custodio A, Barriuso J, de Castro J, Martínez-Marín V, Moreno V, Rodríguez-Salas N, Feliu J. Molecular markers to predict outcome to antiangiogenic therapies in colorectal cancer: current evidence and future perspectives. Cancer Treat Rev 2013; 39:908-24. [PMID: 23510598 DOI: 10.1016/j.ctrv.2013.02.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2012] [Revised: 02/08/2013] [Accepted: 02/08/2013] [Indexed: 12/13/2022]
Abstract
Angiogenesis is a universal requirement for the growth of solid tumours beyond the limits of oxygen diffusion from the existing vasculature. The expression and function of proangiogenic and antiangiogenic factors are altered in solid malignancies to drive net neoangiogenesis. Vascular endothelial growth factor (VEGF) has been confirmed in several clinical trials as an important therapeutic target in colorectal cancer (CRC) treatment. However, given that the efficacy of antiangiogenic agents appears to be limited to a subset of patients, the identification of who will obtain the greater benefit from this therapy or suffer from specific toxicities and when or for how long they should be administered in the treatment algorithm are major open questions for clinicians and challenges for present and future research. Current evidence indicates some predictive value for particular circulating measures, such as an increase in VEGF, a decrease in vascular endothelial growth factor receptor 2 (VEGFR-2) or circulating endothelial cells, tissue biomarkers, microvessel density, KRAS and BRAF gene mutations or polymorphisms affecting components of the VEGF pathway. Many questions relating to these and other surrogate biomarkers, however, remain unanswered and their clinical usefulness has yet to be proven. This review will focus on the present status of knowledge and future perspectives for developing molecular tools to foresee and monitor antiangiogenic therapy activity in CRC patients.
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Affiliation(s)
- Ana Custodio
- Medical Oncology Department, IDiPAZ, RTICC (RD06/0020/1022), La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain.
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43
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Fakih M. The evolving role of VEGF-targeted therapies in the treatment of metastatic colorectal cancer. Expert Rev Anticancer Ther 2013; 13:427-38. [PMID: 23432698 DOI: 10.1586/era.13.20] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Therapies that target angiogenesis and the VEGF pathway are a component of treatment for patients with metastatic colorectal cancer (mCRC). Bevacizumab is a humanized monoclonal antibody that binds to VEGFA. Chemotherapy plus bevacizumab has led to improved outcomes for mCRC patients. Despite these benefits, progressive disease invariably ensues. Multiple members of the VEGF family can potentially contribute to tumor angiogenesis and/or evasion of antiangiogenic therapy if one pathway should be inhibited. Aflibercept, a new biological agent, is a multiple angiogenic factor trap that prevents not only VEGFA, but also VEGFB and PlGF from activating their native receptors. Key clinical data for bevacizumab and aflibercept for treatment of mCRC, clinical evidence for use of these agents beyond progression, and the search for angiogenic biomarkers to better define patients most likely to benefit from these interventions will be reviewed.
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Affiliation(s)
- Marwan Fakih
- Medical Oncology, City of Hope, 1500 Duarte Rd, Duarte, CA 91010, USA.
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44
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Lambrechts D, Lenz HJ, de Haas S, Carmeliet P, Scherer SJ. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol 2013; 31:1219-30. [PMID: 23401453 DOI: 10.1200/jco.2012.46.2762] [Citation(s) in RCA: 274] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Bevacizumab is the first antiangiogenic therapy proven to slow metastatic disease progression in patients with cancer. Although it has changed clinical practice, some patients do not respond or gradually develop resistance, resulting in rather modest gains in terms of overall survival. A major challenge is to develop robust biomarkers that can guide selection of patients for whom bevacizumab therapy is most beneficial. Here, we discuss recent progress in finding such markers, including the first results from randomized phase III clinical trials evaluating the efficacy of bevacizumab in combination with comprehensive biomarker analyses. In particular, these studies suggest that circulating levels of short vascular endothelial growth factor A (VEGF-A) isoforms, expression of neuropilin-1 and VEGF receptor 1 in tumors or plasma, and genetic variants in VEGFA or its receptors are strong biomarker candidates. The current challenge is to expand this first set of markers and to validate it and implement it into clinical practice. A first prospective biomarker study known as MERiDiAN, which will treat patients stratified for circulating levels of short VEGF-A isoforms with bevacizumab and paclitaxel, is planned and will hopefully provide us with new directions on how to treat patients more efficiently.
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45
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Hagan S, Orr MCM, Doyle B. Targeted therapies in colorectal cancer-an integrative view by PPPM. EPMA J 2013; 4:3. [PMID: 23356214 PMCID: PMC3584939 DOI: 10.1186/1878-5085-4-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Accepted: 12/26/2012] [Indexed: 12/12/2022]
Abstract
In developed countries, colorectal cancer (CRC) is the third most common malignancy, but it is the second most frequent cause of cancer-related death. Clinicians are still faced with numerous challenges in the treatment of this disease, and future approaches which target the molecular features of the disorder will be critical for success in this disease setting. Genetic analyses of many solid tumours have shown that up to 100 protein-encoding genes are mutated. Within CRC, numerous genetic alterations have been identified in a number of pathways. Therefore, understanding the molecular pathology of CRC may present information on potential routes for treatment and may also provide valuable prognostic information. This will be particularly pertinent for molecularly targeted treatments, such as anti-vascular endothelial growth factor therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy. KRAS and BRAF mutations have been shown to predict response to anti-EGFR therapy. As EGFR can also signal via the phosphatidylinositol 3-kinase (PI3K) kinase pathway, there is considerable interest in the potential roles of members of this pathway (such as PI3K and PTEN) in predicting treatment response. Therefore, a combined approach of new techniques that allow identification of these biomarkers alongside interdisciplinary approaches to the treatment of advanced CRC will aid in the treatment decision-making process and may also serve to guide future therapeutic approaches.
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Affiliation(s)
- Suzanne Hagan
- Department of Life Sciences Glasgow, Caledonian University, Glasgow, G4 0BA, UK
| | - Maria C M Orr
- Personalised Healthcare and Biomarkers, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
| | - Brendan Doyle
- Department of Histopathology, Trinity College, St. James's Hospital, Dublin, 8, Ireland
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Schneider BP, Gray RJ, Radovich M, Shen F, Vance G, Li L, Jiang G, Miller KD, Gralow JR, Dickler MN, Cobleigh MA, Perez EA, Shenkier TN, Vang Nielsen K, Müller S, Thor A, Sledge GW, Sparano JA, Davidson NE, Badve SS. Prognostic and predictive value of tumor vascular endothelial growth factor gene amplification in metastatic breast cancer treated with paclitaxel with and without bevacizumab; results from ECOG 2100 trial. Clin Cancer Res 2013; 19:1281-9. [PMID: 23340303 DOI: 10.1158/1078-0432.ccr-12-3029] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PURPOSE Clinically validated biomarkers for anti-angiogenesis agents are not available. We have previously reported associations between candidate VEGFA single-nucleotide polymorphisms (SNP) and overall survival (OS) in E2100. The associations between tumor VEGFA amplification and outcome are evaluated here. EXPERIMENTAL DESIGN E2100 was a phase III trial comparing paclitaxel with or without bevacizumab for patients with metastatic breast cancer. FISH to assess gene amplification status for VEGFA was conducted on paraffin-embedded tumors from 363 patients in E2100. Evaluation for association between amplification status and outcomes was conducted. RESULTS Estrogen receptor (ER)+ or progesterone receptor (PR)+ tumors were less likely to have VEGFA amplification than ER/PR- tumors (P = 0.020). VEGFA amplification was associated with worse OS (20.2 vs. 25.3 months; P = 0.013) in univariate analysis with a trend for worse OS in multivariate analysis (P = 0.08). There was a significant interaction between VEGFA amplification, hormone receptor status, and study arm. Patients with VEGFA amplification and triple-negative breast cancers (TNBC) or HER2 amplification had inferior OS (P = 0.047); amplification did not affect OS for those who were ER+ or PR+ and HER2-. Those who received bevacizumab with VEGFA amplification had inferior progression-free survival (PFS; P = 0.010) and OS (P = 0.042); no association was seen in the control arm. Test for interaction between study arm and VEGFA amplification with OS was not significant. CONCLUSION VEGFA amplification in univariate analysis was associated with poor outcomes; this was particularly prominent in HER2+ or TNBCs. Additional studies are necessary to confirm the trend for poor OS seen on multivariate analysis for patients treated with bevacizumab.
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Affiliation(s)
- Bryan P Schneider
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana 46202, USA.
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Kämmerer PW, Koch FP, Schiegnitz E, Kumar VV, Berres M, Toyoshima T, Al-Nawas B, Brieger J. Associations between single-nucleotide polymorphisms of the VEGF gene and long-term prognosis of oral squamous cell carcinoma. J Oral Pathol Med 2012; 42:374-81. [DOI: 10.1111/jop.12026] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2012] [Indexed: 12/23/2022]
Affiliation(s)
- P. W. Kämmerer
- Harvard Medical School; Boston MA USA
- Department of Oral, Maxillofacial and Plastic Surgery; University Medical Centre; Mainz Germany
- M.R. Ambedkar Dental College and Hospital; Bangalore India
| | - F. P. Koch
- Department of Oral, Maxillofacial and Plastic Surgery; University Medical Centre; Mainz Germany
| | - E. Schiegnitz
- Department of Oral, Maxillofacial and Plastic Surgery; University Medical Centre; Mainz Germany
| | - V. V. Kumar
- Department of Oral, Maxillofacial and Plastic Surgery; University Medical Centre; Mainz Germany
- M.R. Ambedkar Dental College and Hospital; Bangalore India
| | - M. Berres
- Institute of Medical Biostatistics; Epidemiology and Informatics (IMBEI); University Medical Centre; Mainz Germany
| | - T. Toyoshima
- Department of Oral and Maxillofacial Surgery; Kyushu University; Fukuoka Japan
| | - B. Al-Nawas
- Department of Oral, Maxillofacial and Plastic Surgery; University Medical Centre; Mainz Germany
| | - J. Brieger
- Department of Otorhinolaryngology; Johannes Gutenberg-University; Mainz Germany
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Morita S, Uehara K, Nakayama G, Shibata T, Oguri T, Inada-Inoue M, Shimokata T, Sugishita M, Mitsuma A, Ando Y. Association between bevacizumab-related hypertension and vascular endothelial growth factor (VEGF) gene polymorphisms in Japanese patients with metastatic colorectal cancer. Cancer Chemother Pharmacol 2012; 71:405-11. [DOI: 10.1007/s00280-012-2028-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Accepted: 11/05/2012] [Indexed: 10/27/2022]
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49
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Schneider BP, Shen F, Miller KD. Pharmacogenetic biomarkers for the prediction of response to antiangiogenic treatment. Lancet Oncol 2012; 13:e427-36. [PMID: 23026828 PMCID: PMC3730288 DOI: 10.1016/s1470-2045(12)70275-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Antiangiogenic treatments have shown activity across multiple tumour types and in various settings. Despite having been approved on the basis of efficacy, the therapeutic index varies substantially in different settings for many of these agents. A major limitation is the current inability to personalise treatment a priori according to findings on measurement of a predictive biomarker. The roles of germline single-nucleotide polymorphisms have been investigated as potential biomarkers for antiangiogenic treatments. The rationale is founded on the understanding that the drugs target the vasculature rather than the tumour, which could mean that much of the variability is regulated by the host. Several single-nucleotide polymorphisms have been associated with differential outcomes and toxic effects in clinical trials. In this Review we provide an overview of available data with particular attention paid to the pitfalls and strengths of potential biomarkers. We also highlight continuing work and plans for confirmatory studies.
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Affiliation(s)
- Bryan P Schneider
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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