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Kasprzak A, Geltz A. The State-of-the-Art Mechanisms and Antitumor Effects of Somatostatin in Colorectal Cancer: A Review. Biomedicines 2024; 12:578. [PMID: 38540191 PMCID: PMC10968376 DOI: 10.3390/biomedicines12030578] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 03/02/2024] [Accepted: 03/03/2024] [Indexed: 01/03/2025] Open
Abstract
Somatostatin, a somatotropin release inhibiting factor (SST, SRIF), is a widely distributed multifunctional cyclic peptide and acts through a transmembrane G protein-coupled receptor (SST1-SST5). Over the past decades, research has begun to reveal the molecular mechanisms underlying the anticancer activity of this hormonal peptide. Among gastrointestinal tract (GIT) tumors, direct and indirect antitumor effects of SST have been documented best in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and less well in non-endocrine cancers, including sporadic colorectal cancer (CRC). In the latter, the signaling pathways involved in the antitumor function of SST are primarily MAPK/ERK/AKT and Wnt/β-catenin. Direct (involving the MAPK pathway) and indirect (VEGF production) antiangiogenic effects of SST in CRC have also been described. The anti-inflammatory role of SST in CRC is emphasized, but detailed molecular mechanisms are still being explored. The role of SST in tumor genome/tumor microenvironment (TME)/host's gut microbiome interactions is only partially known. The results of SST analogues (SSAs)' treatment of sporadic CRC in monotherapy in vivo are not spectacular. The current review aims to present the state-of-the-art mechanisms and antitumor activity of endogenous SST and its synthetic analogues in CRC, with particular emphasis on sporadic CRC.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznań, Poland;
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2
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Isanejad A, Nazari S, Gharib B, Motlagh AG. Comparison of the effects of high-intensity interval and moderate-intensity continuous training on inflammatory markers, cardiorespiratory fitness, and quality of life in breast cancer patients. JOURNAL OF SPORT AND HEALTH SCIENCE 2023; 12:674-689. [PMID: 37423313 PMCID: PMC10658315 DOI: 10.1016/j.jshs.2023.07.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/14/2023] [Accepted: 05/08/2023] [Indexed: 07/11/2023]
Abstract
BACKGROUND As the effectiveness of breast cancer treatment has improved, a growing number of long-term breast cancer survivors are seeking help for unique health problems. These patients may be at increased risk of cardiovascular disease due to the side effects of treatment. The positive impact of most types of exercise has been repeatedly reported in people with cancer, but the most effective exercise approaches for maximum beneficial adaptations remain controversial. Thus, this study aimed to compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on inflammatory indices, adipokines, metabolic markers, body composition, cardiorespiratory fitness, and quality of life in breast cancer patients during adjuvant endocrine therapy. METHODS Thirty non-metastatic breast cancer patients during adjuvant endocrine therapy who had been treated with chemotherapy and/or radiotherapy were recruited from Iran and randomized to HIIT, MICT, or control groups for a supervised exercise intervention that took place 3 times a week for 12 weeks. The training intensity was determined based on the peak oxygen uptake (VO2peak), and the volume of training was matched in HIIT and MICT based on the VO2peak. Body composition, functional capacity, cardiorespiratory fitness, metabolic indices, sex hormones, adipokines, and inflammatory markers were assessed before and after the intervention. RESULTS The VO2peak increased by 16.8% in the HIIT group in comparison to baseline values (mean difference = 3.61 mL/kg/min). HIIT significantly improved the VO2peak compared to control (mean difference = 3.609 mL/kg/min) and MICT (mean differences = 2.974 mL/kg/min) groups. Both HIIT (mean difference = 9.172 mg/dL) and MICT (mean difference = 7.879 mg/dL) interventions significantly increased high-density lipoprotein cholesterol levels compared to the control group. The analysis of covariance showed that physical well-being significantly improved in MICT compared to control group (mean difference = 3.268). HIIT significantly improved the social well-being compared to the control group (mean difference = 4.412). Emotional well-being subscale was significantly improved in both MICT (mean difference = 4.248) and HIIT (mean difference = 4.412) compared to the control group. Functional well-being scores significantly increased in HIIT group compared with control group (mean difference = 3.35) . Significant increase were also observed in total functional assessment of cancer therapy-General scores in both HIIT (mean difference = 14.204) and MICT groups (mean difference = 10.036) compared with control group. The serum level of suppressor of cytokine signaling 3 increased significantly (mean difference = 0.09 pg/mL) in the HIIT group compared to the baseline. There were no significant differences between groups for body weight, body mass index, fasting blood glucose, insulin resistance, sex hormone binding globulin, total cholesterol, low-density lipoprotein cholesterol, adipokines, interleukin-6, tumor necrosis factor-α, or interleukin-10. CONCLUSION HIIT can be used as a safe, feasible, and time-efficient intervention to improve cardiovascular fitness in breast cancer patients. Both HIIT and MICT modalities enhance quality of life. Further large-scale studies will help determine whether these promising results translate into improved clinical and oncological outcomes.
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Affiliation(s)
- Amin Isanejad
- Immunoregulation Research Center, Shahed University, Tehran 1417953836, Iran; Department of Exercise Physiology, Sport Sciences Research Institute, Tehran 1587958711, Iran.
| | - Somayeh Nazari
- Department of Physical Education and Sport Sciences, Faculty of Human Sciences, Shahed University, Tehran 1417953836, Iran
| | - Behroz Gharib
- Oncology Department, Naft Hospital, Tehran 1136774114, Iran
| | - Ali Ghanbari Motlagh
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran 1516745811, Iran
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Becerra‐Tomás N, Balducci K, Abar L, Aune D, Cariolou M, Greenwood DC, Markozannes G, Nanu N, Vieira R, Giovannucci EL, Gunter MJ, Jackson AA, Kampman E, Lund V, Allen K, Brockton NT, Croker H, Katsikioti D, McGinley‐Gieser D, Mitrou P, Wiseman M, Cross AJ, Riboli E, Clinton SK, McTiernan A, Norat T, Tsilidis KK, Chan DSM. Postdiagnosis dietary factors, supplement use and breast cancer prognosis: Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis. Int J Cancer 2023; 152:616-634. [PMID: 36279902 PMCID: PMC10092903 DOI: 10.1002/ijc.34321] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 09/20/2022] [Accepted: 09/23/2022] [Indexed: 02/01/2023]
Abstract
Little is known about how diet might influence breast cancer prognosis. The current systematic reviews and meta-analyses summarise the evidence on postdiagnosis dietary factors and breast cancer outcomes from randomised controlled trials and longitudinal observational studies. PubMed and Embase were searched through 31st October 2021. Random-effects linear dose-response meta-analysis was conducted when at least three studies with sufficient information were available. The quality of the evidence was evaluated by an independent Expert Panel. We identified 108 publications. No meta-analysis was conducted for dietary patterns, vegetables, wholegrains, fish, meat, and supplements due to few studies, often with insufficient data. Meta-analysis was only possible for all-cause mortality with dairy, isoflavone, carbohydrate, dietary fibre, alcohol intake and serum 25-hydroxyvitamin D (25(OH)D), and for breast cancer-specific mortality with fruit, dairy, carbohydrate, protein, dietary fat, fibre, alcohol intake and serum 25(OH)D. The results, with few exceptions, were generally null. There was limited-suggestive evidence that predefined dietary patterns may reduce the risk of all-cause and other causes of death; that isoflavone intake reduces the risk of all-cause mortality (relative risk (RR) per 2 mg/day: 0.96, 95% confidence interval (CI): 0.92-1.02), breast cancer-specific mortality (RR for high vs low: 0.83, 95% CI: 0.64-1.07), and recurrence (RR for high vs low: 0.75, 95% CI: 0.61-0.92); that dietary fibre intake decreases all-cause mortality (RR per 10 g/day: 0.87, 95% CI: 0.80-0.94); and that serum 25(OH)D is inversely associated with all-cause and breast cancer-specific mortality (RR per 10 nmol/L: 0.93, 95% CI: 0.89-0.97 and 0.94, 95% CI: 0.90-0.99, respectively). The remaining associations were graded as limited-no conclusion.
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Affiliation(s)
- Nerea Becerra‐Tomás
- Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK
| | - Katia Balducci
- Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK
| | - Leila Abar
- Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK
| | - Dagfinn Aune
- Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK
- Department of NutritionBjørknes University CollegeOsloNorway
- Department of EndocrinologyMorbid Obesity and Preventive Medicine, Oslo University HospitalOsloNorway
- Unit of Cardiovascular and Nutritional EpidemiologyInstitute of Environmental Medicine, Karolinska InstitutetStockholmSweden
| | - Margarita Cariolou
- Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK
| | - Darren C. Greenwood
- Leeds Institute for Data Analytics, Faculty of Medicine and HealthUniversity of LeedsLeedsUK
| | - Georgios Markozannes
- Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK
- Department of Hygiene and EpidemiologyUniversity of Ioannina Medical SchoolIoanninaGreece
| | - Neesha Nanu
- Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK
| | - Rita Vieira
- Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK
| | - Edward L. Giovannucci
- Department of EpidemiologyHarvard T.H. Chan School of Public HealthBostonMassachusettsUSA
- Department of NutritionHarvard T.H. Chan School of Public HealthBostonMassachusettsUSA
| | - Marc J. Gunter
- Nutrition and Metabolism SectionInternational Agency for Research on CancerLyonFrance
| | - Alan A. Jackson
- Faculty of Medicine, School of Human Development and HealthUniversity of SouthamptonSouthamptonUK
- National Institute of Health Research Cancer and Nutrition CollaborationSouthamptonUK
| | - Ellen Kampman
- Division of Human Nutrition and HealthWageningen University & ResearchWageningenThe Netherlands
| | - Vivien Lund
- World Cancer Research Fund InternationalLondonUK
| | - Kate Allen
- World Cancer Research Fund InternationalLondonUK
| | | | - Helen Croker
- World Cancer Research Fund InternationalLondonUK
| | | | | | | | | | - Amanda J. Cross
- Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK
| | - Steven K. Clinton
- Division of Medical Oncology, The Department of Internal MedicineCollege of Medicine and Ohio State University Comprehensive Cancer Center, Ohio State UniversityColumbusOhioUSA
| | - Anne McTiernan
- Division of Public Health SciencesFred Hutchinson Cancer Research CenterSeattleWashingtonUSA
| | - Teresa Norat
- Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK
- World Cancer Research Fund InternationalLondonUK
| | - Konstantinos K. Tsilidis
- Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK
- Department of Hygiene and EpidemiologyUniversity of Ioannina Medical SchoolIoanninaGreece
| | - Doris S. M. Chan
- Department of Epidemiology and Biostatistics, School of Public HealthImperial College LondonLondonUK
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Chan DS, Vieira R, Abar L, Aune D, Balducci K, Cariolou M, Greenwood DC, Markozannes G, Nanu N, Becerra‐Tomás N, Giovannucci EL, Gunter MJ, Jackson AA, Kampman E, Lund V, Allen K, Brockton NT, Croker H, Katsikioti D, McGinley‐Gieser D, Mitrou P, Wiseman M, Cross AJ, Riboli E, Clinton SK, McTiernan A, Norat T, Tsilidis KK. Postdiagnosis body fatness, weight change and breast cancer prognosis: Global Cancer Update Program (CUP global) systematic literature review and meta-analysis. Int J Cancer 2023; 152:572-599. [PMID: 36279884 PMCID: PMC10092239 DOI: 10.1002/ijc.34322] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 07/29/2022] [Accepted: 09/05/2022] [Indexed: 02/01/2023]
Abstract
Previous evidence on postdiagnosis body fatness and mortality after breast cancer was graded as limited-suggestive. To evaluate the evidence on body mass index (BMI), waist circumference, waist-hip-ratio and weight change in relation to breast cancer prognosis, an updated systematic review was conducted. PubMed and Embase were searched for relevant studies published up to 31 October, 2021. Random-effects meta-analyses were conducted to estimate summary relative risks (RRs). The evidence was judged by an independent Expert Panel using pre-defined grading criteria. One randomized controlled trial and 225 observational studies were reviewed (220 publications). There was strong evidence (likelihood of causality: probable) that higher postdiagnosis BMI was associated with increased all-cause mortality (64 studies, 32 507 deaths), breast cancer-specific mortality (39 studies, 14 106 deaths) and second primary breast cancer (11 studies, 5248 events). The respective summary RRs and 95% confidence intervals per 5 kg/m2 BMI were 1.07 (1.05-1.10), 1.10 (1.06-1.14) and 1.14 (1.04-1.26), with high between-study heterogeneity (I2 = 56%, 60%, 66%), but generally consistent positive associations. Positive associations were also observed for waist circumference, waist-hip-ratio and all-cause and breast cancer-specific mortality. There was limited-suggestive evidence that postdiagnosis BMI was associated with higher risk of recurrence, nonbreast cancer deaths and cardiovascular deaths. The evidence for postdiagnosis (unexplained) weight or BMI change and all outcomes was graded as limited-no conclusion. The RCT showed potential beneficial effect of intentional weight loss on disease-free-survival, but more intervention trials and well-designed observational studies in diverse populations are needed to elucidate the impact of body composition and their changes on breast cancer outcomes.
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Affiliation(s)
- Doris S.M. Chan
- Department of Epidemiology and BiostatisticsSchool of Public Health, Imperial College LondonLondonUK
| | - Rita Vieira
- Department of Epidemiology and BiostatisticsSchool of Public Health, Imperial College LondonLondonUK
| | - Leila Abar
- Department of Epidemiology and BiostatisticsSchool of Public Health, Imperial College LondonLondonUK
| | - Dagfinn Aune
- Department of Epidemiology and BiostatisticsSchool of Public Health, Imperial College LondonLondonUK
- Department of NutritionBjørknes University CollegeOsloNorway
- Department of Endocrinology, Morbid Obesity and Preventive MedicineOslo University HospitalOsloNorway
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska InstitutetStockholmSweden
| | - Katia Balducci
- Department of Epidemiology and BiostatisticsSchool of Public Health, Imperial College LondonLondonUK
| | - Margarita Cariolou
- Department of Epidemiology and BiostatisticsSchool of Public Health, Imperial College LondonLondonUK
| | - Darren C. Greenwood
- Leeds Institute for Data Analytics, Faculty of Medicine and HealthUniversity of LeedsLeedsUK
| | - Georgios Markozannes
- Department of Epidemiology and BiostatisticsSchool of Public Health, Imperial College LondonLondonUK
- Department of Hygiene and EpidemiologyUniversity of Ioannina Medical SchoolIoanninaGreece
| | - Neesha Nanu
- Department of Epidemiology and BiostatisticsSchool of Public Health, Imperial College LondonLondonUK
| | - Nerea Becerra‐Tomás
- Department of Epidemiology and BiostatisticsSchool of Public Health, Imperial College LondonLondonUK
| | - Edward L. Giovannucci
- Department of EpidemiologyHarvard T.H. Chan School of Public HealthBostonMassachusettsUSA
- Department of Nutrition, Harvard T. H. Chan School of Public HealthBostonMassachusettsUSA
| | - Marc J. Gunter
- Nutrition and Metabolism Section, International Agency for Research on CancerLyonFrance
| | - Alan A. Jackson
- Faculty of Medicine, School of Human Development and HealthUniversity of SouthamptonSouthamptonUK
- National Institute of Health Research Cancer and Nutrition CollaborationSouthamptonUK
| | - Ellen Kampman
- Division of Human Nutrition and HealthWageningen University & ResearchWageningenThe Netherlands
| | - Vivien Lund
- World Cancer Research Fund InternationalLondonUK
| | - Kate Allen
- World Cancer Research Fund InternationalLondonUK
| | | | - Helen Croker
- World Cancer Research Fund InternationalLondonUK
| | | | | | | | | | - Amanda J. Cross
- Department of Epidemiology and BiostatisticsSchool of Public Health, Imperial College LondonLondonUK
| | - Elio Riboli
- Department of Epidemiology and BiostatisticsSchool of Public Health, Imperial College LondonLondonUK
| | - Steven K. Clinton
- Division of Medical Oncology, The Department of Internal MedicineCollege of Medicine and Ohio State University Comprehensive Cancer Center, Ohio State UniversityColumbusOhioUSA
| | - Anne McTiernan
- Division of Public Health SciencesFred Hutchinson Cancer Research CenterSeattleWashingtonUSA
| | - Teresa Norat
- Department of Epidemiology and BiostatisticsSchool of Public Health, Imperial College LondonLondonUK
- World Cancer Research Fund InternationalLondonUK
| | - Konstantinos K. Tsilidis
- Department of Epidemiology and BiostatisticsSchool of Public Health, Imperial College LondonLondonUK
- Department of Hygiene and EpidemiologyUniversity of Ioannina Medical SchoolIoanninaGreece
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Di Magno L, Di Pastena F, Bordone R, Coni S, Canettieri G. The Mechanism of Action of Biguanides: New Answers to a Complex Question. Cancers (Basel) 2022; 14:cancers14133220. [PMID: 35804992 PMCID: PMC9265089 DOI: 10.3390/cancers14133220] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/20/2022] [Accepted: 06/23/2022] [Indexed: 01/27/2023] Open
Abstract
Biguanides are a family of antidiabetic drugs with documented anticancer properties in preclinical and clinical settings. Despite intensive investigation, how they exert their therapeutic effects is still debated. Many studies support the hypothesis that biguanides inhibit mitochondrial complex I, inducing energy stress and activating compensatory responses mediated by energy sensors. However, a major concern related to this “complex” model is that the therapeutic concentrations of biguanides found in the blood and tissues are much lower than the doses required to inhibit complex I, suggesting the involvement of additional mechanisms. This comprehensive review illustrates the current knowledge of pharmacokinetics, receptors, sensors, intracellular alterations, and the mechanism of action of biguanides in diabetes and cancer. The conditions of usage and variables affecting the response to these drugs, the effect on the immune system and microbiota, as well as the results from the most relevant clinical trials in cancer are also discussed.
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Affiliation(s)
- Laura Di Magno
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.D.M.); (F.D.P.); (R.B.); (S.C.)
| | - Fiorella Di Pastena
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.D.M.); (F.D.P.); (R.B.); (S.C.)
| | - Rosa Bordone
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.D.M.); (F.D.P.); (R.B.); (S.C.)
| | - Sonia Coni
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.D.M.); (F.D.P.); (R.B.); (S.C.)
| | - Gianluca Canettieri
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.D.M.); (F.D.P.); (R.B.); (S.C.)
- Istituto Pasteur—Fondazione Cenci—Bolognetti, 00161 Rome, Italy
- Correspondence:
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Spiliopoulou M, Karavassili F, Triandafillidis DP, Valmas A, Fili S, Kosinas C, Barlos K, Barlos KK, Morin M, Reinle-Schmitt ML, Gozzo F, Margiolaki I. New perspectives in macromolecular powder diffraction using single-photon-counting strip detectors: high-resolution structure of the pharmaceutical peptide octreotide. ACTA CRYSTALLOGRAPHICA A-FOUNDATION AND ADVANCES 2021; 77:186-195. [PMID: 33944797 DOI: 10.1107/s2053273321001698] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 02/11/2021] [Indexed: 11/10/2022]
Abstract
Advances in instrumentation, as well as the development of powerful crystallographic software have significantly facilitated the collection of high-resolution diffraction data and have made X-ray powder diffraction (XRPD) particularly useful for the extraction of structural information; this is true even for complex molecules, especially when combined with synchrotron radiation. In this study, in-line with past instrumental profile studies, an improved data collection strategy exploiting the MYTHEN II detector system together with significant beam focusing and tailored data collection options was introduced and optimized for protein samples at the Material Science beamline at the Swiss Light Source. Polycrystalline precipitates of octreotide, a somatostatin analog of particular pharmaceutical interest, were examined with this novel approach. XRPD experiments resulted in high angular and d-spacing (1.87 Å) resolution data, from which electron-density maps of enhanced quality were extracted, revealing the molecule's structural properties. Since microcrystalline precipitates represent a viable alternative for administration of therapeutic macromolecules, XRPD has been acknowledged as the most applicable tool for examining a wide spectrum of physicochemical properties of such materials and performing studies ranging from phase identification to complete structural characterization.
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Affiliation(s)
- Maria Spiliopoulou
- Department of Biology, Section of Genetics, Cell Biology and Development, University of Patras, Patras, GR-26500, Greece
| | - Fotini Karavassili
- Department of Biology, Section of Genetics, Cell Biology and Development, University of Patras, Patras, GR-26500, Greece
| | | | - Alexandros Valmas
- Department of Biology, Section of Genetics, Cell Biology and Development, University of Patras, Patras, GR-26500, Greece
| | - Stavroula Fili
- Department of Biology, Section of Genetics, Cell Biology and Development, University of Patras, Patras, GR-26500, Greece
| | - Christos Kosinas
- Department of Biology, Section of Genetics, Cell Biology and Development, University of Patras, Patras, GR-26500, Greece
| | | | | | - Mickael Morin
- Excelsus Structural Solutions (Swiss) AG, Park Innovaare, Villigen, 5234, Switzerland
| | | | - Fabia Gozzo
- Excelsus Structural Solutions (Swiss) AG, Park Innovaare, Villigen, 5234, Switzerland
| | - Irene Margiolaki
- Department of Biology, Section of Genetics, Cell Biology and Development, University of Patras, Patras, GR-26500, Greece
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Kim H, Giovannucci E. Vitamin D Status and Cancer Incidence, Survival, and Mortality. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1268:39-52. [DOI: 10.1007/978-3-030-46227-7_3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Dowling RJO, Kalinsky K, Hayes DF, Bidard FC, Cescon DW, Chandarlapaty S, Deasy JO, Dowsett M, Gray RJ, Henry NL, Meric-Bernstam F, Perlmutter J, Sledge GW, Bratman SV, Carey LA, Chang MC, DeMichele A, Ennis M, Jerzak KJ, Korde LA, Lohmann AE, Mamounas EP, Parulekar WR, Regan MM, Schramek D, Stambolic V, Thorat MA, Whelan TJ, Wolff AC, Woodgett JR, Sparano JA, Goodwin PJ. Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 1: Late Recurrence: Current Understanding, Clinical Considerations. JNCI Cancer Spectr 2019; 3:pkz050. [PMID: 32337479 PMCID: PMC7049988 DOI: 10.1093/jncics/pkz050] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 06/20/2019] [Accepted: 07/10/2019] [Indexed: 12/12/2022] Open
Abstract
Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor-positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor-positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.
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Affiliation(s)
- Ryan J O Dowling
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Kevin Kalinsky
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | - Daniel F Hayes
- University of Michigan Rogel Cancer Center and the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | | | - David W Cescon
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Division of Medical Oncology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Sarat Chandarlapaty
- Human Oncology and Pathogenesis Program, and Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill-Cornell Medical College, New York, NY
| | - Joseph O Deasy
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mitch Dowsett
- Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, The Royal Marsden NHS Foundation Trust, Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK
| | - Robert J Gray
- Department of Biostatistics, Dana-Farber Cancer Institute, Boston, MA
- Harvard T.H. Chan School of Public Health, Boston, MA
| | - N Lynn Henry
- University of Utah, Huntsman Cancer Institute, Salt Lake City, UT
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - George W Sledge
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Scott V Bratman
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network Toronto, ON, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Lisa A Carey
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Martin C Chang
- University of Vermont Medical Center, Larner College of Medicine, Burlington, VT
| | - Angela DeMichele
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
| | | | - Katarzyna J Jerzak
- Division of Medical Oncology and Hematology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Larissa A Korde
- Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD
| | - Ana Elisa Lohmann
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Sinai Health System, Toronto, ON, Canada
- Department of Medicine, University of Toronto, Toronto, ON, Canada
| | | | - Wendy R Parulekar
- Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada
| | - Meredith M Regan
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Daniel Schramek
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Sinai Health System, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Vuk Stambolic
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Mangesh A Thorat
- Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Timothy J Whelan
- McMaster University and Juravinski Cancer Centre, Hamilton, ON, Canada
| | - Antonio C Wolff
- The Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | - Jim R Woodgett
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Sinai Health System, Toronto, ON, Canada
| | - Joseph A Sparano
- Departments of Medicine and Medical Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Albert Einstein Cancer Center, New York, NY
| | - Pamela J Goodwin
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Sinai Health System, Toronto, ON, Canada
- Department of Medicine, University of Toronto, Toronto, ON, Canada
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9
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Fili S, Valmas A, Spiliopoulou M, Kontou P, Fitch A, Beckers D, Degen T, Barlos K, Barlos KK, Karavassili F, Margiolaki I. Revisiting the structure of a synthetic somatostatin analogue for peptide drug design. ACTA CRYSTALLOGRAPHICA SECTION B-STRUCTURAL SCIENCE CRYSTAL ENGINEERING AND MATERIALS 2019; 75:611-620. [DOI: 10.1107/s2052520619006012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/30/2019] [Indexed: 11/10/2022]
Abstract
Natural or artificially manufactured peptides attract scientific interest worldwide owing to their wide array of pharmaceutical and biological activities. X-ray structural studies are used to provide a precise extraction of information, which can be used to enable a better understanding of the function and physicochemical characteristics of peptides. Although it is vulnerable to disassociation, one of the most vital human peptide hormones, somatostatin, plays a regulatory role in the endocrine system as well as in the release of numerous secondary hormones. This study reports the successful crystallization and complete structural model of octreotide, a stable octapeptide analogue of somatostatin. Common obstacles in crystallographic studies arising from the intrinsic difficulties of obtaining a suitable single-crystal specimen were efficiently overcome as polycrystalline material was employed for synchrotron and laboratory X-ray powder diffraction (XPD) measurements. Data collection and preliminary analysis led to the identification of unit-cell symmetry [orthorhombic, P212121, a = 18.5453 (15), b = 30.1766 (25), c = 39.798 (4) Å], a process which was later followed by complete structure characterization and refinement, underlying the efficacy of the suggested (XPD) approach.
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10
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Abstract
Early preclinical and population data suggested a role for the type I insulin-like growth factor receptor (IGF1R) in the regulation of breast cancer growth and survival. To target this pathway, multiple monoclonal antibodies and tyrosine kinase inhibitors were developed and tested in clinical trials. While some of the early clinical trials suggested a benefit for these drugs, none of the attempts showed improved outcomes when compared to conventional therapy. This failure of the IGF1R inhibitors was pronounced in breast cancer; multiple trials testing IGF1R inhibition in estrogen receptor-positive breast cancer were conducted, none showed benefit. This review will evaluate the rationale for IGF1R inhibition, discuss results of the clinical trials and suggest a path forward.
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Affiliation(s)
- Douglas Yee
- Masonic Cancer CenterUniversity of Minnesota, Minneapolis, Minnesota, USA
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11
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A reappraisal on metformin. Regul Toxicol Pharmacol 2018; 92:324-332. [DOI: 10.1016/j.yrtph.2017.12.023] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 12/23/2017] [Accepted: 12/27/2017] [Indexed: 12/14/2022]
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12
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Yerushalmi R, Dong B, Chapman JW, Goss PE, Pollak MN, Burnell MJ, Levine MN, Bramwell VHC, Pritchard KI, Whelan TJ, Ingle JN, Shepherd LE, Parulekar WR, Han L, Ding K, Gelmon KA. Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials. Ann Oncol 2018; 28:1560-1568. [PMID: 28379421 DOI: 10.1093/annonc/mdx152] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Indexed: 12/12/2022] Open
Abstract
Background We hypothesized that increased baseline BMI and BMI change would negatively impact clinical outcomes with adjuvant breast cancer systemic therapy. Methods Data from chemotherapy trials MA.5 and MA.21; endocrine therapy MA.12, MA.14 and MA.27; and trastuzumab HERA/MA.24 were analyzed. The primary objective was to examine the effect of BMI change on breast cancer-free interval (BCFI) landmarked at 5 years; secondary objectives included BMI changes at 1 and 3 years; BMI changes on disease-specific survival (DSS) and overall survival (OS); and effects of baseline BMI. Stratified analyses included trial therapy and composite trial stratification factors. Results In pre-/peri-/early post-menopausal chemotherapy trials (N = 2793), baseline BMI did not impact any endpoint and increased BMI from baseline did not significantly affect BCFI (P = 0.85) after 5 years although it was associated with worse BCFI (P = 0.03) and DSS (P = 0.07) after 1 year. BMI increase by 3 and 5 years was associated with better DSS (P = 0.01; 0.01) and OS (P = 0.003; 0.05). In pre-menopausal endocrine therapy trial MA.12 (N = 672), patients with higher baseline BMI had worse BCFI (P = 0.02) after 1 year, worse DSS (P = 0.05; 0.004) after 1 and 5 years and worse OS (P = 0.01) after 5 years. Increased BMI did not impact BCFI (P = 0.90) after 5 years, although it was associated with worse BCFI (P = 0.01) after 1 year. In post-menopausal endocrine therapy trials MA.14 and MA.27 (N = 8236), baseline BMI did not significantly impact outcome for any endpoint. BMI change did not impact BCFI or DSS after 1 or 3 years, although a mean increased BMI of 0.3 was associated with better OS (P = 0.02) after 1 year. With the administration of trastuzumab (N = 1395) baseline BMI and BMI change did not significantly impact outcomes. Conclusions Higher baseline BMI and BMI increases negatively affected outcomes only in pre-/peri-/early post-menopausal trial patients. Otherwise, BMI increases similar to those expected in healthy women either did not impact outcome or were associated with better outcomes. Clinical Trials numbers CAN-NCIC-MA5; National Cancer Institute (NCI)-V90-0027; MA.12-NCT00002542; MA.14-NCT00002864; MA.21-NCT00014222; HERA, NCT00045032;CAN-NCIC-MA24; MA-27-NCT00066573.
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Affiliation(s)
- R Yerushalmi
- Department of Medical Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva and Tel-Aviv University, Tel Aviv, Israel
| | - B Dong
- Canadian Cancer Trials Group (CCTG; Formerly, NCIC Clinical Trials Group), Queen's University, Kingston, Canada
| | - J W Chapman
- Canadian Cancer Trials Group (CCTG; Formerly, NCIC Clinical Trials Group), Queen's University, Kingston, Canada
| | - P E Goss
- Massachusetts General Hospital Cancer Center, Boston, USA
| | - M N Pollak
- Department of Medical Oncology, Jewish General Hospital, McGill University, Montreal
| | - M J Burnell
- Department of Medical Oncology, Saint John Regional Hospital, Saint John
| | - M N Levine
- Department of Oncology, McMaster University, Juravinski Cancer Center, Hamilton, Ontario
| | - V H C Bramwell
- Department of Medical Oncology, Tom Baker Cancer Centre, Alberta Health Services and University of Calgary, Calgary
| | - K I Pritchard
- Department of Medical Oncology, Sunnybrook Odette Cancer Centre and the University of Toronto, Toronto, Canada
| | - T J Whelan
- Department of Oncology, Juravinski Cancer Center, McMaster University, Hamilton, Ontario
| | - J N Ingle
- Department of Oncology, Mayo Clinic, Rochester, USA
| | - L E Shepherd
- Canadian Cancer Trials Group (CCTG; Formerly, NCIC Clinical Trials Group), Queen's University, Kingston, Canada
| | - W R Parulekar
- Canadian Cancer Trials Group (CCTG; Formerly, NCIC Clinical Trials Group), Queen's University, Kingston, Canada
| | - L Han
- Canadian Cancer Trials Group (CCTG; Formerly, NCIC Clinical Trials Group), Queen's University, Kingston, Canada
| | - K Ding
- Canadian Cancer Trials Group (CCTG; Formerly, NCIC Clinical Trials Group), Queen's University, Kingston, Canada
| | - K A Gelmon
- Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, Canada
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13
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Christopoulos PF, Corthay A, Koutsilieris M. Aiming for the Insulin-like Growth Factor-1 system in breast cancer therapeutics. Cancer Treat Rev 2017; 63:79-95. [PMID: 29253837 DOI: 10.1016/j.ctrv.2017.11.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 11/29/2017] [Accepted: 11/30/2017] [Indexed: 12/23/2022]
Abstract
Despite the major discoveries occurred in oncology the recent years, breast malignancies remain one of the most common causes of cancer-related deaths for women in developed countries. Development of HER2-targeting drugs has been considered a breakthrough in anti-cancer approaches and alluded to the potential of targeting growth factors in breast cancer (BrCa) therapeutics. More than twenty-five years have passed since the Insulin-like Growth Factor-1 (IGF-1) system was initially recognized as a potential target candidate in BrCa therapy. To date, a growing body of studies have implicated the IGF-1 signaling with the BrCa biology. Despite the promising experimental evidence, the impression from clinical trials is rather disappointing. Several reasons may account for this and the last word regarding the efficacy of this system as a target candidate in BrCa therapeutics is probably not written yet. Herein, we provide the theoretical basis, as well as, a comprehensive overview of the current literature, regarding the different strategies targeting the various components of the IGF-1/IGF-1R axis in several pathophysiological aspects of BrCa, including the tumor micro-environment and cancer stemness. In addition, we review the rationale for targeting the IGF-1 system in the different BrCa molecular subtypes and in treatment resistant breast tumors with a focus on both the molecular mechanisms and on the clinical perspectives of such approaches in specific population subgroups. We also discuss the future challenges, as well as, the development of novel molecules and strategies targeting the system and suggest potential improvements in the field.
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Affiliation(s)
- Panagiotis F Christopoulos
- Department of Experimental Physiology, Medical School, National & Kapodistrian University of Athens, Athens, Greece; Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway; Department of Medical Biology, Faculty of Health Sciences, UiT the Arctic University of Norway, Tromsø, Norway.
| | - Alexandre Corthay
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Michael Koutsilieris
- Department of Experimental Physiology, Medical School, National & Kapodistrian University of Athens, Athens, Greece
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14
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Hussain I, Ali I, Rahman H, Ghani SS. Novel contribution of chromatography in the development and analyses of metformin hydrochloride in biological and environmental samples. J LIQ CHROMATOGR R T 2017. [DOI: 10.1080/10826076.2017.1334216] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Iqbal Hussain
- Department of General Studies, Jubail Industrial College, Jubail Industrial City, Saudi Arabia
| | - Imran Ali
- Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi, India
| | - Habibur Rahman
- Department of General Studies, Jubail Industrial College, Jubail Industrial City, Saudi Arabia
| | - Syed Sauban Ghani
- Department of General Studies, Jubail Industrial College, Jubail Industrial City, Saudi Arabia
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Abstract
Obesity rates are increasing in the developed and developing world; this has implications for breast cancer risk and outcome. Areas covered: Recent advances relating to the association of obesity with breast cancer are reviewed. Expert commentary: Obesity has been associated with increased risk of postmenopausal hormone receptor positive and premenopausal triple negative breast cancer and with poor prognosis of most types of breast cancer. Obese individuals may present with breast cancer at a more advanced stage and their breast cancer may differ biologically from cancers diagnosed in nonobese women. A picture of a complex, multifactorial biology underlying the obesity-cancer link is emerging, with the identification of obesity-associated tissue and systemic changes that are cancer promoting, enhancing proliferation, invasion and metastasis. Intervention research to ascertain effects of weight loss and of pharmacologic interventions that reverse the metabolic changes of obesity is needed.
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Affiliation(s)
- Pamela J Goodwin
- a Department of Medicine, Lunenfeld-Tanenbaum Research Institute , Mount Sinai Hospital, University of Toronto , Toronto , Canada
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16
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Clinical studies in humans targeting the various components of the IGF system show lack of efficacy in the treatment of cancer. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2016; 772:105-122. [PMID: 28528684 DOI: 10.1016/j.mrrev.2016.09.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Revised: 09/15/2016] [Accepted: 09/16/2016] [Indexed: 01/28/2023]
Abstract
The insulin-like growth factors (IGFs) system regulates cell growth, differentiation and energy metabolism and plays crucial role in the regulation of key aspects of tumor biology, such as cancer cell growth, survival, transformation and invasion. The current focus for cancer therapeutic approaches have shifted from the conventional treatments towards the targeted therapies and the IGF system has gained a great interest as anti-cancer therapy. The proliferative, anti-apoptotic and transformation effects of IGFs are mainly triggered by the ligation of the type I IGF receptor (IGF-IR). Thus, aiming at developing novel and effective cancer therapies, different strategies have been employed to target IGF system in human malignancies, including but not limited to ligand or receptor neutralizing antibodies and IGF-IR signaling inhibitors. In this review, we have focused on the clinical studies that have been conducted targeting the various components of the IGF system for the treatment of different types of cancer, providing a description and the challenges of each targeting strategy and the degree of success.
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17
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Dieli-Conwright CM, Lee K, Kiwata JL. Reducing the Risk of Breast Cancer Recurrence: an Evaluation of the Effects and Mechanisms of Diet and Exercise. CURRENT BREAST CANCER REPORTS 2016; 8:139-150. [PMID: 27909546 PMCID: PMC5112289 DOI: 10.1007/s12609-016-0218-3] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
With recent medical advances in diagnosis and treatment, the increasing numbers of long-term survivors of breast cancer is considerable and has resulted in the expansion of scientific research to include examination of lifestyle modifications as means of prevention of recurrence, new breast cancer events, and mortality. The objective of this report is to review randomized controlled trials (RCTs) including diet and/or exercise interventions on breast cancer recurrence in women with a history of breast cancer as well as pertinent recent epidemiologic evidence. Implicated biologic mechanisms are discussed to elucidate the impact of diet and exercise on disease recurrence.
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Affiliation(s)
- Christina M Dieli-Conwright
- Division of Biokinesiology and Physical Therapy, University of Southern California, 1540 E. Alcazar St., CHP-155, Los Angeles, CA 90033 USA
| | - Kyuwan Lee
- Division of Biokinesiology and Physical Therapy, University of Southern California, 1540 E. Alcazar St., CHP-155, Los Angeles, CA 90033 USA
| | - Jacqueline L Kiwata
- Division of Biokinesiology and Physical Therapy, University of Southern California, 1540 E. Alcazar St., CHP-155, Los Angeles, CA 90033 USA
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18
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Chapman JAW, Sgroi DC, Goss PE, Zarella E, Binns S, Zhang Y, Schnabel CA, Erlander MG, Pritchard KI, Han L, Badovinac-Crnjevic T, Shepherd LE, Pollak MN. Relapse-free survival of statistically standardized continuous RT-PCR estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2): NCIC CTG MA.14. Breast Cancer Res Treat 2016; 157:101-8. [PMID: 27116182 DOI: 10.1007/s10549-016-3806-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 04/19/2016] [Indexed: 11/29/2022]
Abstract
Recent ASCO/CAP guidelines focus on decision making associated with the presence/absence of continuous breast biomarkers. Statistical standardization (SS) is demonstrated as a method to evaluate the effects of continuous RT-PCR biomarker expression levels on breast cancer outcomes. MA.14 allocated 667 postmenopausal patients to tamoxifen based on locally determined ER/PR. Of 299 available patient tumor samples, 292 passed internal quality control. All tumors were centrally assessed by RT-PCR ER/PR/HER2 with each biomarker's z-scores categorized: ≥1.0 standard deviation (SD) below mean; <1.0 SD below mean; ≤1.0 SD above mean; >1.0 SD above mean. Log-rank statistics tested univariate differences in breast cancer relapse-free survival (RFS). Continuous SS-ER/PR/HER2 were assessed in multivariate Cox step-wise forward regression, adding a factor if p ≤ 0.05. Sensitivity analyses examined an external HER2+ cut-point of 1.32. Patients whose tumors were tested were representative of the MA.14 population (p values = 0.18-0.90). At 9.8 years median follow-up, SS-ER did not univariately impact RFS (p = 0.31). SS-PR values above the mean (z ≥ 0.0) had the best univariate RFS (p = 0.03). SS-HER2 also univariately impacted RFS (p = 0.004) with lowest (z-scores ≤ -1.0) and highest (z-scores > 1.0) having shortest RFS. Multivariate stratified/unstratified Cox models indicated patients with T1 tumors (p = 0.02/p = 0.0002) and higher SS-PR (p = 0.02/p = 0.01) had longer RFS; node-negative patients had better RFS (in unstratified analysis, p < 0.0001). Local ER/PR status did not impact RFS (p > 0.05). Patients with SS HER2+ ≥ 1.32 had worse RFS (univariate, p = 0.05; multivariate, p = 0.06). We demonstrated that higher SS-PR, and SS HER2 levels, measured by RT-PCR impacted breast cancer RFS outcomes. Evaluation in other trials may provide support for this methodology.
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Affiliation(s)
- Judith-Anne W Chapman
- Canadian Cancer Trials Group (Formerly, NCIC Clinical Trials Group), Queen's University, 10 Stuart St, Kingston, ON, Canada.
| | - Dennis C Sgroi
- Massachusetts General Hospital, Harvard University, Boston, MA, USA
| | - Paul E Goss
- Massachusetts General Hospital, Harvard University, Boston, MA, USA
| | | | - Shemeica Binns
- Massachusetts General Hospital, Harvard University, Boston, MA, USA
| | - Yi Zhang
- bioTheranostics Inc, San Diego, CA, USA
| | | | | | | | - Lei Han
- Canadian Cancer Trials Group (Formerly, NCIC Clinical Trials Group), Queen's University, 10 Stuart St, Kingston, ON, Canada
| | | | - Lois E Shepherd
- Canadian Cancer Trials Group (Formerly, NCIC Clinical Trials Group), Queen's University, 10 Stuart St, Kingston, ON, Canada
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Lack of cortistatin or somatostatin differentially influences DMBA-induced mammary gland tumorigenesis in mice in an obesity-dependent mode. Breast Cancer Res 2016; 18:29. [PMID: 26956474 PMCID: PMC4782371 DOI: 10.1186/s13058-016-0689-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 02/19/2016] [Indexed: 01/08/2023] Open
Abstract
Background Somatostatin (SST) and cortistatin (CORT), two structurally and functionally related peptides, share a family of widespread receptors (sst1-5) to exert apparently similar biological actions, including endocrine/metabolic regulation and suppression of tumor cell proliferation. However, despite their therapeutic potential, attempts to apply SST-analogs to treat breast cancer have yielded unsatisfactory results. Actually, the specific roles of SST and CORT in mammary gland tumorigenesis (MGT), particularly in relation to metabolic dysregulation (i.e. obesity), remain unknown. Methods The role of endogenous SST and CORT in carcinogen-induced MGT was investigated under normal (lean) and obesity conditions. To that end, SST- and CORT-knockout (KO) mice and their respective littermate-controls, fed low-fat (LF) or high-fat (HF) diets, were treated with 7,12-dimethyl-benza-anthracene (DMBA) once a week (wk) for 3 wk, and MGT was monitored for 25 wk. Additionally, we examined the effect of SST or CORT removal in the development of the mammary gland. Results Lack of SST did not alter DMBA-induced MGT incidence under lean conditions; conversely, lack of endogenous CORT severely aggravated DMBA-induced MGT in LF-fed mice. These differences were not attributable to altered mammary gland development. HF-diet modestly increased the sensitivity to DMBA-induced carcinogenesis in control mice, whereas, as observed in LF-fed CORT-KO, HF-fed CORT-KO mice exhibited aggravated tumor incidence, discarding a major influence of obesity on these CORT actions. In marked contrast, HF-fed SST-KO mice exhibited much higher tumor incidence than LF-fed SST-KO mice, which could be associated with higher mammary complexity. Conclusions Endogenous SST and CORT distinctly impact on DMBA-induced MGT, in a manner that is strongly dependent on the metabolic/endocrine milieu (lean vs. obese status). Importantly, CORT, rather than SST, could represent a major inhibitor of MGT under normal/lean-conditions, whereas both neuropeptides would similarly influence MGT under obesity conditions. The mechanisms mediating these different effects likely involve mammary development and hormones, but the precise underlying factors are still to be fully elucidated. However, our findings comprise suggestive evidence that CORT-like molecules, rather than classic SST-analogs, may help to identify novel tools for the medical treatment of breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0689-1) contains supplementary material, which is available to authorized users.
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20
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Sgroi DC, Chapman JAW, Badovinac-Crnjevic T, Zarella E, Binns S, Zhang Y, Schnabel CA, Erlander MG, Pritchard KI, Han L, Shepherd LE, Goss PE, Pollak M. Assessment of the prognostic and predictive utility of the Breast Cancer Index (BCI): an NCIC CTG MA.14 study. Breast Cancer Res 2016; 18:1. [PMID: 26728744 PMCID: PMC4700696 DOI: 10.1186/s13058-015-0660-6] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 12/09/2015] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Biomarkers that can be used to accurately assess the residual risk of disease recurrence in women with hormone receptor-positive breast cancer are clinically valuable. We evaluated the prognostic value of the Breast Cancer Index (BCI), a continuous risk index based on a combination of HOXB13:IL17BR and molecular grade index, in women with early breast cancer treated with either tamoxifen alone or tamoxifen plus octreotide in the NCIC MA.14 phase III clinical trial (ClinicalTrials.gov Identifier NCT00002864; registered 1 November 1999). METHODS Gene expression analysis of BCI by real-time polymerase chain reaction was performed blinded to outcome on RNA extracted from archived formalin-fixed, paraffin-embedded tumor samples of 299 patients with both lymph node-negative (LN-) and lymph node-positive (LN+) disease enrolled in the MA.14 trial. Our primary objective was to determine the prognostic performance of BCI based on relapse-free survival (RFS). MA.14 patients experienced similar RFS on both treatment arms. Association of gene expression data with RFS was evaluated in univariate analysis with a stratified log-rank test statistic, depicted with a Kaplan-Meier plot and an adjusted Cox survivor plot. In the multivariate assessment, we used stratified Cox regression. The prognostic performance of an emerging, optimized linear BCI model was also assessed in a post hoc analysis. RESULTS Of 299 samples, 292 were assessed successfully for BCI for 146 patients accrued in each MA.14 treatment arm. BCI risk groups had a significant univariate association with RFS (stratified log-rank p = 0.005, unstratified log-rank p = 0.007). Adjusted 10-year RFS in BCI low-, intermediate-, and high-risk groups was 87.5 %, 83.9 %, and 74.7 %, respectively. BCI had a significant prognostic effect [hazard ratio (HR) 2.34, 95 % confidence interval (CI) 1.33-4.11; p = 0.004], although not a predictive effect, on RFS in stratified multivariate analysis, adjusted for pathological tumor stage (HR 2.22, 95 % CI 1.22-4.07; p = 0.01). In the post hoc multivariate analysis, higher linear BCI was associated with shorter RFS (p = 0.002). CONCLUSIONS BCI had a strong prognostic effect on RFS in patients with early-stage breast cancer treated with tamoxifen alone or with tamoxifen and octreotide. BCI was prognostic in both LN- and LN+ patients. This retrospective study is an independent validation of the prognostic performance of BCI in a prospective trial.
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Affiliation(s)
- Dennis C Sgroi
- Molecular Pathology Unit, Pathology Research Center, Massachusetts General Hospital, MGH East, Molecular Pathology, Research, 149 13th Street, Charlestown, MA, 02129, USA. .,Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA. .,Department of Pathology, Harvard Medical School, Boston, MA, USA.
| | | | - T Badovinac-Crnjevic
- Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.
| | - Elizabeth Zarella
- Molecular Pathology Unit, Pathology Research Center, Massachusetts General Hospital, MGH East, Molecular Pathology, Research, 149 13th Street, Charlestown, MA, 02129, USA. .,Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA. .,Department of Pathology, Harvard Medical School, Boston, MA, USA.
| | - Shemeica Binns
- Molecular Pathology Unit, Pathology Research Center, Massachusetts General Hospital, MGH East, Molecular Pathology, Research, 149 13th Street, Charlestown, MA, 02129, USA. .,Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA. .,Department of Pathology, Harvard Medical School, Boston, MA, USA.
| | - Yi Zhang
- bioTheranostics, Inc., San Diego, CA, USA.
| | | | | | | | - Lei Han
- NCIC Clinical Trials Group, Queen's University, Kingston, ON, Canada.
| | - Lois E Shepherd
- NCIC Clinical Trials Group, Queen's University, Kingston, ON, Canada.
| | - Paul E Goss
- Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.
| | - Michael Pollak
- Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada.
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Chapman JAW, Costantino JP, Dong B, Margolese RG, Pritchard KI, Shepherd LE, Gelmon KA, Wolmark N, Pollak MN. Octreotide LAR and tamoxifen versus tamoxifen in phase III randomize early breast cancer trials: NCIC CTG MA.14 and NSABP B-29. Breast Cancer Res Treat 2015; 153:353-60. [PMID: 26276354 DOI: 10.1007/s10549-015-3547-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 08/11/2015] [Indexed: 11/25/2022]
Abstract
NCIC CTG MA.14 and NSABP B-29 trials examined the addition of Octreotide LAR (OCT) to 5 years of tamoxifen (TAM). Gallbladder toxicity led to B-29 discontinuation of OCT, and MA.14 OCT administration shortened to 2 years. Median follow-up was 9.8 years for 667 MA.14 patients and 6.8 years for 893 B-29 patients. The primary endpoint was disease-free survival (DFS), defined as time from randomization to time of breast cancer recurrence; second primary cancer other than squamous or basal cell skin carcinoma, cervical carcinoma in situ, or lobular breast carcinoma in situ; or death. The primary statistical test was a univariable pooled stratified log-rank test; multivariable assessment was with Cox regression. For MA.14, 97% of patients were ≥50 years; for B-29, 62%. MA.14 patients were 53% lymph node negative (LN-) while B-29 were 100% LN-; 33% of MA.14 patients received adjuvant chemotherapy, 2% concurrently, while B-29 had 53% concurrent chemotherapy. MA.14 patients were 90% hormone receptor positive; B-29, 100%. MA.14 patients experienced 5-year DFS of 80% with TAM, 76% with TAM + OCT; B-29 patients had 5-year DFS of 88% for both arms. Pooled univariable TAM + OCT to TAM hazard ratio (HR) was 0.99 (95% CI 0.81-1.20; p = 0.69): for MA.14, HR = 0.94 (0.73-1.20; p = 0.50); for B-29, HR = 1.09 (0.80-1.50; p = 0.59). Multivariable pooled HR = 0.98 (0.81-1.20; p = 0.84). Older patients (p < 0.001), with higher T stage (p < 0.001), and LN + (p < 0.001) had shorter DFS. Addition of OCT to TAM did not significantly improve DFS; gallbladder toxicity shortened the additional administration of OCT. This does not negate targeting the insulin-IGF-I receptor family with less toxic therapeutics.
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Affiliation(s)
- Judith-Anne W Chapman
- NCIC Clinical Trials Group, Queen's University, 10 Stuart Street, Kingston, ON, K7L 3N6, Canada,
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Valdivieso M, Corn BW, Dancey JE, Wickerham DL, Horvath LE, Perez EA, Urton A, Cronin WM, Field E, Lackey E, Blanke CD. The Globalization of Cooperative Groups. Semin Oncol 2015; 42:693-712. [PMID: 26433551 DOI: 10.1053/j.seminoncol.2015.07.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The National Cancer Institute (NCI)-supported adult cooperative oncology research groups (now officially Network groups) have a longstanding history of participating in international collaborations throughout the world. Most frequently, the US-based cooperative groups work reciprocally with the Canadian national adult cancer clinical trial group, NCIC CTG (previously the National Cancer Institute of Canada Clinical Trials Group). Thus, Canada is the largest contributor to cooperative groups based in the United States, and vice versa. Although international collaborations have many benefits, they are most frequently utilized to enhance patient accrual to large phase III trials originating in the United States or Canada. Within the cooperative group setting, adequate attention has not been given to the study of cancers that are unique to countries outside the United States and Canada, such as those frequently associated with infections in Latin America, Asia, and Africa. Global collaborations are limited by a number of barriers, some of which are unique to the countries involved, while others are related to financial support and to US policies that restrict drug distribution outside the United States. This article serves to detail the cooperative group experience in international research and describe how international collaboration in cancer clinical trials is a promising and important area that requires greater consideration in the future.
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Affiliation(s)
- Manuel Valdivieso
- Division of Hematology/Oncology, University of Michigan; and SWOG, Executive Officer, Quality Assurance and International Initiatives, Ann Arbor, MI.
| | - Benjamin W Corn
- Institute of Radiotherapy, Tel Aviv Medical Center, Tel Aviv, Israel; and Department of Radiation Oncology, Jefferson Medical College, Philadelphia, PA
| | - Janet E Dancey
- Director, NCIC Clinical Trials Group; Scientific Director Canadian Cancer Clinical Trials Network; Program Leader, High Impact Clinical Trials, Ontario Institute for Cancer Research; Professor of Oncology, Queen's University, Kingston, Ontario, Canada
| | - D Lawrence Wickerham
- Deputy Chairman, NRG Oncology, Pittsburgh, PA; Department of Human Oncology, Pittsburgh Campus, Drexel University School of Medicine; Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA
| | - L Elise Horvath
- Executive Officer, Alliance for Clinical Trials in Oncology, Chicago, IL
| | - Edith A Perez
- Deputy Director at Large, Mayo Clinic Cancer Center; Group Vice Chair, Alliance for Clinical Trials in Oncology; Hematology/Oncology and Cancer Biology Mayo Clinic, Jacksonville, FL
| | - Alison Urton
- Group Administrator, NCIC Clinical Trials Group, Queen's University, Kingston, Ontario, Canada
| | - Walter M Cronin
- Associate Director, NRG Oncology Statistics and Data Management Center (SDMC); Associate Director, Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA
| | - Erica Field
- Project Specialist III, RTOG, Philadelphia, PA
| | - Evonne Lackey
- Coordinating Center Manager, SWOG Statistical Center, Seattle, WA
| | - Charles D Blanke
- Chair, SWOG; Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University and Knight Cancer Institute, Portland, OR
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Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 2015; 16:839-47. [DOI: 10.1016/s1470-2045(15)00027-3] [Citation(s) in RCA: 310] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 04/01/2015] [Accepted: 04/02/2015] [Indexed: 02/06/2023]
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Leporati P, Fonte R, de Martinis L, Zambelli A, Magri F, Pavesi L, Rotondi M, Chiovato L. A male patient with acromegaly and breast cancer: treating acromegaly to control tumor progression. BMC Cancer 2015; 15:397. [PMID: 25962899 PMCID: PMC4436112 DOI: 10.1186/s12885-015-1400-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 04/29/2015] [Indexed: 12/04/2022] Open
Abstract
Background Acromegaly is a rare disease associated with an increased risk of developing cancer. Case presentation We report the case of a 72-year-old man who was diagnosed with acromegaly (IGF-1 770 ng/ml) and breast cancer. Four years before he suffered from a colon-rectal cancer. Pituitary surgery and octreotide-LAR treatment failed to control acromegaly. Normalization of IGF-1 (97 ng/ml) was obtained with pegvisomant therapy. Four years after breast cancer surgery, 2 pulmonary metastases were detected at chest CT. The patient was started on anastrozole, but, contrary to medical advice, he stopped pegvisomant treatment (IGF-I 453 ng/ml). Four months later, chest CT revealed an increase in size of the metastatic lesion of the left lung. The patient was shifted from anastrozole to tamoxifen and was restarted on pegvisomant, with normalization of serum IGF-1 levels (90 ng/ml). Four months later, a reduction in size of the metastatic lesion of the left lung was detected by CT. Subsequent CT scans throughout a 24-month follow-up showed a further reduction in size and then a stabilization of the metastasis. Conclusions This is the first report of a male patient with acromegaly and breast cancer. The clinical course of breast cancer was closely related to the metabolic control of acromegaly. The rapid progression of metastatic lesion was temporally related to stopping pegvisomant treatment and paralleled a rise in serum IGF-1 levels. Normalization of IGF-1 after re-starting pegvisomant impressively reduced the progression of metastatic breast lesions. Control of acromegaly is mandatory in acromegalic patients with cancer.
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Affiliation(s)
- Paola Leporati
- Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri I.R.C.C.S., Laboratory for Endocrine Disruptors, Chair of Endocrinology, University of Pavia, 27100, Pavia, Italy.
| | - Rodolfo Fonte
- Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri I.R.C.C.S., Laboratory for Endocrine Disruptors, Chair of Endocrinology, University of Pavia, 27100, Pavia, Italy.
| | - Luca de Martinis
- Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri I.R.C.C.S., Laboratory for Endocrine Disruptors, Chair of Endocrinology, University of Pavia, 27100, Pavia, Italy.
| | - Alberto Zambelli
- Unit of Medical Oncology, Fondazione Salvatore Maugeri I.R.C.C.S., 27100, Pavia, Italy.
| | - Flavia Magri
- Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri I.R.C.C.S., Laboratory for Endocrine Disruptors, Chair of Endocrinology, University of Pavia, 27100, Pavia, Italy.
| | - Lorenzo Pavesi
- Unit of Medical Oncology, Fondazione Salvatore Maugeri I.R.C.C.S., 27100, Pavia, Italy.
| | - Mario Rotondi
- Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri I.R.C.C.S., Laboratory for Endocrine Disruptors, Chair of Endocrinology, University of Pavia, 27100, Pavia, Italy.
| | - Luca Chiovato
- Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri I.R.C.C.S., Laboratory for Endocrine Disruptors, Chair of Endocrinology, University of Pavia, 27100, Pavia, Italy.
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Prognostic associations of 25 hydroxy vitamin D in NCIC CTG MA.21, a phase III adjuvant randomized clinical trial of three chemotherapy regimens in high-risk breast cancer. Breast Cancer Res Treat 2015; 150:605-11. [PMID: 25833209 DOI: 10.1007/s10549-015-3355-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 03/23/2015] [Indexed: 10/23/2022]
Abstract
Low vitamin D levels have been associated with poor breast cancer outcomes in observational studies. We examined the association of vitamin D blood levels with relapse-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS) in the MA.21 randomized clinical trial. Fasting blood was collected pre-chemotherapy in 934/2104 (44.4 %) of subjects; 25 hydroxy vitamin D was measured (radioimmunoassay, Diasorin) in one batch. Vitamin D was assessed as a transformed continuous factor, and categorically (quartiles and clinical classifications). Univariate and multivariate prognostic analyses (adjusted for treatment, stratification factors, and baseline imbalances) were performed using Cox models. Most patients were young (median 47.8 years), white (91.6 %) and premenopausal (69.4 %) with grade III (52 %), HER2 negative or missing (89.5 %), ER positive (61.9 %), T1-2 (89.4 %), N + (72.7 %) breast cancer. Compared to the full population, those with vitamin D levels were more likely to be white, PS 1 or 2, to have undergone mastectomy, and to have an ER + tumor. Mean vitamin D was 69.7 nmol/L (27.9 ng/ml) and did not vary by tumor subtype. The majority (80.5 %) had levels >50 nmol/L (20 ng/ml), considered adequate by Institute of Medicine. Continuous vitamin D was not multivariately associated with RFS, BCSS, or OS (p = 0.36, 0.26, 0.33, respectively); categorical vitamin D was also not associated with outcome. Vitamin D associations with RFS did not differ within ER/HER2 subgroups. There was no evidence that vitamin D blood level was associated with RFS, BCSS, and OS in MA.21; the majority of subjects had adequate vitamin D levels at study entry.
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Gilis‐Januszewska A, Trofimiuk‐Müldner M, Jabrocka‐Hybel A, Pach D. Somatostatin Analogues Use in Other than Endocrine Tumor Indications. SOMATOSTATIN ANALOGUES 2015:198-206. [DOI: 10.1002/9781119031659.ch18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Goodwin PJ, Parulekar WR, Gelmon KA, Shepherd LE, Ligibel JA, Hershman DL, Rastogi P, Mayer IA, Hobday TJ, Lemieux J, Thompson AM, Pritchard KI, Whelan TJ, Mukherjee SD, Chalchal HI, Oja CD, Tonkin KS, Bernstein V, Chen BE, Stambolic V. Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst 2015; 107:djv006. [PMID: 25740979 DOI: 10.1093/jnci/djv006] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Metformin may improve metabolic factors (insulin, glucose, leptin, highly sensitive C-reactive protein [hs-CRP]) associated with poor breast cancer outcomes. The NCIC Clinical Trials Group (NCIC CTG) MA.32 investigates effects of metformin vs placebo on invasive disease-free survival and other outcomes in early breast cancer. Maintaining blinding of investigators to outcomes, we conducted a planned, Data Safety Monitoring Committee-approved, analysis of the effect of metformin vs placebo on weight and metabolic factors at six months, including examination of interactions with baseline body mass index (BMI) and insulin, in the first 492 patients with paired blood samples. METHODS Eligible nondiabetic subjects with T1-3, N0-3, M0 breast cancer who had completed surgery and (neo)adjuvant chemotherapy (if given) provided fasting plasma samples at random assignment and at six months. Glucose was measured locally; blood was aliquoted, frozen, and stored at -80°C. Paired plasma aliquots were analyzed for insulin, hs-CRP, and leptin. Spearman correlation coefficients were calculated and comparisons analyzed using Wilcoxon signed rank test. All statistical tests were two-sided. RESULTS Mean age was 52.1±9.5 years in the metformin group and 52.6 ± 9.8 years in the placebo group. Arms were balanced for estrogen/progesterone receptor, BMI, prior (neo)adjuvant chemotherapy, and stage. At six months, decreases in weight and blood variables were statistically significantly greater in the metformin arm (vs placebo) in univariate analyses: weight -3.0%, glucose -3.8%, insulin -11.1%, homeostasis model assessment -17.1%, leptin -20.2%, hs-CRP -6.7%; all P values were less than or equal to .03. There was no statistically significant interaction of change in these variables with baseline BMI or insulin. CONCLUSIONS Metformin statistically significantly improved weight, insulin, glucose, leptin, and CRP at six months. Effects did not vary by baseline BMI or fasting insulin.
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Affiliation(s)
- Pamela J Goodwin
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS).
| | - Wendy R Parulekar
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Karen A Gelmon
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Lois E Shepherd
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Jennifer A Ligibel
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Dawn L Hershman
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Priya Rastogi
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Ingrid A Mayer
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Timothy J Hobday
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Julie Lemieux
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Alastair M Thompson
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Kathleen I Pritchard
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Timothy J Whelan
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Som D Mukherjee
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Haji I Chalchal
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Conrad D Oja
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Katia S Tonkin
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Vanessa Bernstein
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Bingshu E Chen
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
| | - Vuk Stambolic
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (PJG); NCIC Clinical Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (WRP, LES, BEC); NCIC Clinical Trials Group, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada (KAG); Dana Farber Cancer Institute, Harvard Medical School, Boston, MA (JAL); Columbia University Medical Center, New York, NY (DLH); National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA (PR); Vanderbilt-Ingram Medical Center, Vanderbilt University Medical Center, Nashville, TN (IAM); Mayo Clinic College of Medicine, Rochester, MN (TJH); Centre de recherche du CHU de Québec, Unité de recherche en santé des populations Hôpital du Saint-Sacrement, Quebec, Quebec, Canada (JL); National Cancer Research Institute Breast Clinical Studies Group, London, UK (AMT); Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada (KIP); Juravinski Cancer Center at Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada (TJW, SDM); Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (HIC); British Columbia Cancer Agency, Fraser Valley Center, Surrey, British Columbia, Canada (CDO); University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada (KST); British Columbia Cancer Agency - Vancouver Island Center, University of British Columbia, British Columbia, Canada (VB); Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (VS)
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Freedman O, Fletcher G, Gandhi S, Mates M, Dent S, Trudeau M, Eisen A. Adjuvant endocrine therapy for early breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline. Curr Oncol 2015; 22:S95-S113. [PMID: 25848344 PMCID: PMC4381796 DOI: 10.3747/co.22.2326] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Cancer Care Ontario's Program in Evidence-Based Care (pebc) recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question "What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?" The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and her2 (human epidermal growth factor receptor 2)-targeted therapy. METHODS For the systematic review, the literature in the medline and embase databases was searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were "breast cancer" and "systemic therapy" (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (rcts), guidelines, systematic reviews, and meta-analyses. RESULTS Several hundred documents that met the inclusion criteria were retrieved. Meta-analyses from the Early Breast Cancer Trialists' Collaborative Group encompassed many of the rcts found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. SUMMARY The results of the systematic review constitute a comprehensive compilation of high-level evidence, which was the basis for the 2014 pebc guideline on systemic therapy for early breast cancer. The review of the evidence for systemic endocrine therapy (adjuvant tamoxifen, aromatase inhibitors, and ovarian ablation and suppression) is presented here; the evidence for chemotherapy and her2-targeted treatment-and the final clinical practice recommendations-are presented separately in this supplement.
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Affiliation(s)
| | - G.G. Fletcher
- Program in Evidence-Based Care, Cancer Care Ontario; and Department of Oncology, McMaster University, Hamilton, ON
| | - S. Gandhi
- Sunnybrook Health Science Centre, Toronto, ON
| | - M. Mates
- Cancer Centre of Southeastern Ontario, Kinston General Hospital, and Queen’s University, Kingston, ON
| | - S.F. Dent
- The Ottawa Hospital Cancer Centre and University of Ottawa, Ottawa, ON
| | | | - A. Eisen
- Durham Regional Cancer Centre, Oshawa, ON
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Host Factors and Risk of Breast Cancer Recurrence: Genetic, Epigenetic and Biologic Factors and Breast Cancer Outcomes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 862:143-53. [DOI: 10.1007/978-3-319-16366-6_10] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Chapman JAW, Pritchard KI, Goss PE, Ingle JN, Muss HB, Dent SF, Vandenberg TA, Findlay B, Gelmon KA, Wilson CF, Shepherd LE, Pollak MN. Competing risks of death in younger and older postmenopausal breast cancer patients. World J Clin Oncol 2014; 5:1088-1096. [PMID: 25493245 PMCID: PMC4259936 DOI: 10.5306/wjco.v5.i5.1088] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Revised: 04/30/2014] [Accepted: 07/14/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death.
METHODS: MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly. Event-free survival was the primary endpoint of MA.14; at median 7.9 years, the tamoxifen+octreotide and tamoxifen arms had similar event-free survival (P = 0.62). Overall survival was a secondary endpoint, and the two trial arms also had similar overall survival (P = 0.86). We used the median 9.8 years follow-up to examine by intention-to-treat, the multivariate time-to-breast cancer-specific (BrCa) and other cause (OC) mortality with log-normal survival analysis adjusted by treatment and stratification factors. We tested whether baseline factors including Insulin-like growth factor 1 (IGF1), IGF binding protein-3, C-peptide, body mass index, and 25-hydroxy vitamin D were associated with (1) all cause mortality, and if so and (2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models.
RESULTS: The analyses were performed on 329 patients allocated tamoxifen and 329 allocated tamoxifen+octreotide. The median age of MA.14 patients was 60.1 years: 447 (82%) < 70 years and 120 (18%) ≥ 70 years. There were 170 deaths: 106 (62.3%) BrCa; 55 (32.4%) OC, of which 24 were other malignancies, 31 other causes of death; 9 (5.3%) patients with unknown cause of death were excluded from competing risk assessments. BrCa and OC deaths were not significantly different by treatment arm (P = 0.40): tamoxifen patients experienced 50 BrCa and 32 OC deaths, while tamoxifen + octreotide patients experienced 56 BrCa and 23 OC deaths. Proportionately more deaths (P = 0.004) were from BrCa for patients < 70 years, where 70% of deaths were due to BrCa, compared to 54% for those ≥ 70 years of age. The proportion of deaths from OC increased with increasing body mass index (BMI) (P = 0.02). Higher pathologic T and N were associated with more BrCa deaths (P < 0.0001 and 0.002, respectively). The cumulative hazard plot for BrCa and OC mortality indicated the concurrent accrual of both types of death throughout follow-up, that is the existence of competing risks of mortality. MA.14 therapy did not impact mortality (P = 0.77). Three baseline patient and tumor characteristics were differentially associated with cause of death: older patients experienced more OC (P = 0.01) mortality; patients with T1 tumors and hormone receptor positive tumors had less BrCa mortality (respectively, P = 0.01, P = 0.06). Additionally, step-wise cause-specific models indicated that patients with node negative disease experienced less BrCa mortality (P = 0.002); there was weak evidence that, lower C-peptide (P = 0.08) was associated with less BrCa mortality, while higher BMI (P = 0.01) was associated with worse OC mortality.
CONCLUSION: We demonstrate here a new paradigm of simultaneous testing of therapeutics directed at multiple diseases for which postmenopausal women are concurrently at risk. Octreotide LAR did not significantly impact breast cancer or other cause mortality, although different baseline factors influenced type of death.
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Abstract
There is growing appreciation that the current obesity epidemic is associated with increases in cancer incidence at a population level and may lead to poor cancer outcomes; concurrent decreases in cancer mortality at a population level may represent a paradox, i.e., they may also reflect improvements in the diagnosis and treatment of cancer that mask obesity effects. An association of obesity with cancer is biologically plausible because adipose tissue is biologically active, secreting estrogens, adipokines, and cytokines. In obesity, adipose tissue reprogramming may lead to insulin resistance, with or without diabetes, and it may contribute to cancer growth and progression locally or through systemic effects. Obesity-associated changes impact cancer in a complex fashion, potentially acting directly on cells through pathways, such as the phosphoinositide 3-kinase (PI3K) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways, or indirectly via changes in the tumor microenvironment. Approaches to obesity management are discussed, and the potential for pharmacologic interventions that target the obesity-cancer link is addressed.
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Affiliation(s)
- Pamela J Goodwin
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X4, Canada;
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Ali I, Hussain I, Sanagi MM, Ibrahim WAW, Aboul-Enein HY. Analyses of Biguanides and Related Compounds in Biological and Environmental Samples by HPLC. J LIQ CHROMATOGR R T 2014. [DOI: 10.1080/10826076.2014.940803] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Imran Ali
- a Department of Chemistry , Jamia Millia Islamia (Central University) , New Delhi , India
| | - Iqbal Hussain
- b Department of Chemistry, Faculty of Science , Universiti Teknologi Malaysia , Johor Bahru , Johor , Malaysia
- c Ibnu Sina Institute for Fundamental Science Studies, Nanotechnology Reseach Alliance , Universiti Teknologi Malaysia , Johor Bahru , Johor , Malaysia
| | - Mohd Marsin Sanagi
- b Department of Chemistry, Faculty of Science , Universiti Teknologi Malaysia , Johor Bahru , Johor , Malaysia
- c Ibnu Sina Institute for Fundamental Science Studies, Nanotechnology Reseach Alliance , Universiti Teknologi Malaysia , Johor Bahru , Johor , Malaysia
| | - Wan Aini Wan Ibrahim
- b Department of Chemistry, Faculty of Science , Universiti Teknologi Malaysia , Johor Bahru , Johor , Malaysia
- c Ibnu Sina Institute for Fundamental Science Studies, Nanotechnology Reseach Alliance , Universiti Teknologi Malaysia , Johor Bahru , Johor , Malaysia
| | - Hassan Y. Aboul-Enein
- d Department of Pharmaceutical and Medicinal Chemistry , Pharmaceutical and Drug Industries Research Division, National Research Centre , Dokki , Cairo , Egypt
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Moossdorff M, van Roozendaal LM, Schipper RJ, Strobbe LJA, Voogd AC, Tjan-Heijnen VCG, Smidt ML. Inconsistent selection and definition of local and regional endpoints in breast cancer research. Br J Surg 2014; 101:1657-65. [PMID: 25308345 DOI: 10.1002/bjs.9644] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 04/16/2014] [Accepted: 08/07/2014] [Indexed: 11/08/2022]
Abstract
BACKGROUND Results in breast cancer research are reported using study endpoints. Most are composite endpoints (such as locoregional recurrence), consisting of several components (for example local recurrence) that are in turn composed of specific events (such as skin recurrence). Inconsistent endpoint selection and definition might lead to unjustified conclusions when comparing study outcomes. This study aimed to determine which locoregional endpoints are used in breast cancer studies, and how these endpoints and their components are defined. METHODS PubMed was searched for breast cancer studies published in nine leading journals in 2011. Articles using endpoints with a local or regional component were included and definitions were compared. RESULTS Twenty-three different endpoints with a local or regional component were extracted from 44 articles. Most frequently used were disease-free survival (25 articles), recurrence-free survival (7), local control (4), locoregional recurrence-free survival (3) and event-free survival (3). Different endpoints were used for similar outcomes. Of 23 endpoints, five were not defined and 18 were defined only partially. Of these, 16 contained a local and 13 a regional component. Included events were not specified in 33 of 57 (local) and 27 of 50 (regional) cases. Definitions of local components inconsistently included carcinoma in situ and skin and chest wall recurrences. Regional components inconsistently included specific nodal sites and skin and chest wall recurrences. CONCLUSION Breast cancer studies use many different endpoints with a locoregional component. Definitions of endpoints and events are either not provided or vary between trials. To improve transparency, facilitate trial comparison and avoid unjustified conclusions, authors should report detailed definitions of all endpoints.
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Affiliation(s)
- M Moossdorff
- Departments of Surgical Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
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Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, Szabo E. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Breast Cancer Res Treat 2014; 148:81-90. [PMID: 25253174 PMCID: PMC4196136 DOI: 10.1007/s10549-014-3141-1] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 09/17/2014] [Indexed: 12/16/2022]
Abstract
Treatment of diabetics with metformin is associated with decreased breast cancer risk in observational studies, but it remains unclear if this drug has clinical antineoplastic activity. In a recent presurgical trial, we found a heterogeneous effect of metformin on breast cancer proliferation (ki-67) depending upon insulin resistance (HOMA index). Here, we determined the associations of additional serum biomarkers of insulin resistance, tumor subtype, and drug concentration with ki-67 response to metformin. Two-hundred non-diabetic women were randomly allocated to metformin (850 mg/bid) or placebo for 4 weeks prior to breast cancer surgery. The ki-67 response to metformin was assessed comparing data obtained from baseline biopsy (ki-67 and tumor subtype) and serum markers (HOMA index, C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, hs-CRP, adiponectin) with the same measurements at definitive surgery. For patients with a blood sample taken within 24 h from last drug intake, metformin level was measured. Compared with placebo, metformin significantly decreased ki-67 in women with HOMA > 2.8, those in the lowest IGFBP-1 quintile, those in the highest IGFBP-3 quartile, those with low free IGF-I, those in the top hs-CRP tertile, and those with HER2-positive tumors. In women with HOMA index > 2.8, drug levels were positively correlated with the ki-67 decrease, whereas no trend was noted in women with HOMA < 2.8 (p-interaction = 0.07). At conventional antidiabetic doses, the effect of metformin on tumor ki-67 of non-diabetic breast cancer patients varies with host and tumor characteristics. These findings are relevant to design breast cancer prevention and treatment trials with metformin.
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Affiliation(s)
- Sara Gandini
- Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
| | - Matteo Puntoni
- Clinical Trials Office, Office of the Scientific Director, E.O. Ospedali Galliera, Genoa, Italy
| | - Brandy M Heckman-Stoddard
- Breast and Gynecologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Barbara K Dunn
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Leslie Ford
- Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Andrea DeCensi
- Division of Medical Oncology, E.O. Ospedali Galliera, Genoa, Italy
| | - Eva Szabo
- Lung and Upper Aerodigestive Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.
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Goodwin PJ, Segal RJ, Vallis M, Ligibel JA, Pond GR, Robidoux A, Blackburn GL, Findlay B, Gralow JR, Mukherjee S, Levine M, Pritchard KI. Randomized trial of a telephone-based weight loss intervention in postmenopausal women with breast cancer receiving letrozole: the LISA trial. J Clin Oncol 2014; 32:2231-9. [PMID: 24934783 DOI: 10.1200/jco.2013.53.1517] [Citation(s) in RCA: 127] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
PURPOSE Obesity is associated with poor outcomes in women with operable breast cancer. Lifestyle interventions (LIs) that help women reduce their weight may improve outcomes. PATIENTS AND METHODS We conducted a multicenter randomized trial comparing mail-based delivery of general health information alone or combined with a 24-month standardized, telephone-based LI that included diet (500 to 1,000 kcal per day deficit) and physical activity (150 to 200 minutes of moderate-intensity physical activity per week) goals to achieve weight loss (up to 10%). Women receiving adjuvant letrozole for T1-3N0-3M0 breast cancer with a body mass index (BMI) ≥ 24 kg/m(2) were eligible. Weight was measured in the clinic, and self-report physical activity, quality-of-life (QOL), and diet questionnaires were completed. The primary outcome was disease-free survival. Accrual was terminated at 338 of 2,150 planned patients because of loss of funding. RESULTS Mean weight loss was significantly (P < .001) greater in the LI arm versus the comparison arm (4.3 v 0.6 kg or 5.3% v 0.7% at 6 months and 3.1 v 0.3 kg or 3.6% v 0.4% at 24 months) and occurred consistently across strata (BMI 24 to < 30 v ≥ 30 kg/m(2); prior v no prior adjuvant chemotherapy). Weight loss was greatest in those with higher baseline levels of moderate-intensity physical activity or improvement in QOL. Hospitalization rates and medical events were similar. CONCLUSION A telephone-based LI led to significant weight loss that was still evident at 24 months, without adverse effects on QOL, hospitalizations, or medical events. Adequately powered randomized trials with cancer end points are needed.
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Affiliation(s)
- Pamela J Goodwin
- Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Princess Margaret Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Center; Pamela J. Goodwin and Kathleen I. Pritchard, University of Toronto, Toronto; Roanne J. Segal, Ottawa Hospital Regional Cancer Center, University of Ottawa, Ottawa; Gregory R. Pond, Som Mukherjee, and Mark Levine, Juravinski Hospital and Cancer Center; Brian Findlay, Niagara Health System, Walker Family Cancer Center; Gregory R. Pond, Mark Levine, Brian Findlay, and Som Mukherjee, McMaster University, Hamilton, Ontario; Michael Vallis, Dalhousie University, Halifax, Nova Scotia; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Jennifer A. Ligibel, Dana-Farber Cancer Institute; George L. Blackburn, Beth Israel Deaconess Medical Center; Jennifer A. Ligibel and George L. Blackburn, Harvard Medical School, Boston, MA; and Julie R. Gralow, University of Washington, Seattle, WA.
| | - Roanne J Segal
- Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Princess Margaret Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Center; Pamela J. Goodwin and Kathleen I. Pritchard, University of Toronto, Toronto; Roanne J. Segal, Ottawa Hospital Regional Cancer Center, University of Ottawa, Ottawa; Gregory R. Pond, Som Mukherjee, and Mark Levine, Juravinski Hospital and Cancer Center; Brian Findlay, Niagara Health System, Walker Family Cancer Center; Gregory R. Pond, Mark Levine, Brian Findlay, and Som Mukherjee, McMaster University, Hamilton, Ontario; Michael Vallis, Dalhousie University, Halifax, Nova Scotia; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Jennifer A. Ligibel, Dana-Farber Cancer Institute; George L. Blackburn, Beth Israel Deaconess Medical Center; Jennifer A. Ligibel and George L. Blackburn, Harvard Medical School, Boston, MA; and Julie R. Gralow, University of Washington, Seattle, WA
| | - Michael Vallis
- Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Princess Margaret Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Center; Pamela J. Goodwin and Kathleen I. Pritchard, University of Toronto, Toronto; Roanne J. Segal, Ottawa Hospital Regional Cancer Center, University of Ottawa, Ottawa; Gregory R. Pond, Som Mukherjee, and Mark Levine, Juravinski Hospital and Cancer Center; Brian Findlay, Niagara Health System, Walker Family Cancer Center; Gregory R. Pond, Mark Levine, Brian Findlay, and Som Mukherjee, McMaster University, Hamilton, Ontario; Michael Vallis, Dalhousie University, Halifax, Nova Scotia; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Jennifer A. Ligibel, Dana-Farber Cancer Institute; George L. Blackburn, Beth Israel Deaconess Medical Center; Jennifer A. Ligibel and George L. Blackburn, Harvard Medical School, Boston, MA; and Julie R. Gralow, University of Washington, Seattle, WA
| | - Jennifer A Ligibel
- Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Princess Margaret Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Center; Pamela J. Goodwin and Kathleen I. Pritchard, University of Toronto, Toronto; Roanne J. Segal, Ottawa Hospital Regional Cancer Center, University of Ottawa, Ottawa; Gregory R. Pond, Som Mukherjee, and Mark Levine, Juravinski Hospital and Cancer Center; Brian Findlay, Niagara Health System, Walker Family Cancer Center; Gregory R. Pond, Mark Levine, Brian Findlay, and Som Mukherjee, McMaster University, Hamilton, Ontario; Michael Vallis, Dalhousie University, Halifax, Nova Scotia; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Jennifer A. Ligibel, Dana-Farber Cancer Institute; George L. Blackburn, Beth Israel Deaconess Medical Center; Jennifer A. Ligibel and George L. Blackburn, Harvard Medical School, Boston, MA; and Julie R. Gralow, University of Washington, Seattle, WA
| | - Gregory R Pond
- Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Princess Margaret Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Center; Pamela J. Goodwin and Kathleen I. Pritchard, University of Toronto, Toronto; Roanne J. Segal, Ottawa Hospital Regional Cancer Center, University of Ottawa, Ottawa; Gregory R. Pond, Som Mukherjee, and Mark Levine, Juravinski Hospital and Cancer Center; Brian Findlay, Niagara Health System, Walker Family Cancer Center; Gregory R. Pond, Mark Levine, Brian Findlay, and Som Mukherjee, McMaster University, Hamilton, Ontario; Michael Vallis, Dalhousie University, Halifax, Nova Scotia; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Jennifer A. Ligibel, Dana-Farber Cancer Institute; George L. Blackburn, Beth Israel Deaconess Medical Center; Jennifer A. Ligibel and George L. Blackburn, Harvard Medical School, Boston, MA; and Julie R. Gralow, University of Washington, Seattle, WA
| | - André Robidoux
- Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Princess Margaret Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Center; Pamela J. Goodwin and Kathleen I. Pritchard, University of Toronto, Toronto; Roanne J. Segal, Ottawa Hospital Regional Cancer Center, University of Ottawa, Ottawa; Gregory R. Pond, Som Mukherjee, and Mark Levine, Juravinski Hospital and Cancer Center; Brian Findlay, Niagara Health System, Walker Family Cancer Center; Gregory R. Pond, Mark Levine, Brian Findlay, and Som Mukherjee, McMaster University, Hamilton, Ontario; Michael Vallis, Dalhousie University, Halifax, Nova Scotia; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Jennifer A. Ligibel, Dana-Farber Cancer Institute; George L. Blackburn, Beth Israel Deaconess Medical Center; Jennifer A. Ligibel and George L. Blackburn, Harvard Medical School, Boston, MA; and Julie R. Gralow, University of Washington, Seattle, WA
| | - George L Blackburn
- Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Princess Margaret Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Center; Pamela J. Goodwin and Kathleen I. Pritchard, University of Toronto, Toronto; Roanne J. Segal, Ottawa Hospital Regional Cancer Center, University of Ottawa, Ottawa; Gregory R. Pond, Som Mukherjee, and Mark Levine, Juravinski Hospital and Cancer Center; Brian Findlay, Niagara Health System, Walker Family Cancer Center; Gregory R. Pond, Mark Levine, Brian Findlay, and Som Mukherjee, McMaster University, Hamilton, Ontario; Michael Vallis, Dalhousie University, Halifax, Nova Scotia; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Jennifer A. Ligibel, Dana-Farber Cancer Institute; George L. Blackburn, Beth Israel Deaconess Medical Center; Jennifer A. Ligibel and George L. Blackburn, Harvard Medical School, Boston, MA; and Julie R. Gralow, University of Washington, Seattle, WA
| | - Brian Findlay
- Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Princess Margaret Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Center; Pamela J. Goodwin and Kathleen I. Pritchard, University of Toronto, Toronto; Roanne J. Segal, Ottawa Hospital Regional Cancer Center, University of Ottawa, Ottawa; Gregory R. Pond, Som Mukherjee, and Mark Levine, Juravinski Hospital and Cancer Center; Brian Findlay, Niagara Health System, Walker Family Cancer Center; Gregory R. Pond, Mark Levine, Brian Findlay, and Som Mukherjee, McMaster University, Hamilton, Ontario; Michael Vallis, Dalhousie University, Halifax, Nova Scotia; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Jennifer A. Ligibel, Dana-Farber Cancer Institute; George L. Blackburn, Beth Israel Deaconess Medical Center; Jennifer A. Ligibel and George L. Blackburn, Harvard Medical School, Boston, MA; and Julie R. Gralow, University of Washington, Seattle, WA
| | - Julie R Gralow
- Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Princess Margaret Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Center; Pamela J. Goodwin and Kathleen I. Pritchard, University of Toronto, Toronto; Roanne J. Segal, Ottawa Hospital Regional Cancer Center, University of Ottawa, Ottawa; Gregory R. Pond, Som Mukherjee, and Mark Levine, Juravinski Hospital and Cancer Center; Brian Findlay, Niagara Health System, Walker Family Cancer Center; Gregory R. Pond, Mark Levine, Brian Findlay, and Som Mukherjee, McMaster University, Hamilton, Ontario; Michael Vallis, Dalhousie University, Halifax, Nova Scotia; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Jennifer A. Ligibel, Dana-Farber Cancer Institute; George L. Blackburn, Beth Israel Deaconess Medical Center; Jennifer A. Ligibel and George L. Blackburn, Harvard Medical School, Boston, MA; and Julie R. Gralow, University of Washington, Seattle, WA
| | - Som Mukherjee
- Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Princess Margaret Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Center; Pamela J. Goodwin and Kathleen I. Pritchard, University of Toronto, Toronto; Roanne J. Segal, Ottawa Hospital Regional Cancer Center, University of Ottawa, Ottawa; Gregory R. Pond, Som Mukherjee, and Mark Levine, Juravinski Hospital and Cancer Center; Brian Findlay, Niagara Health System, Walker Family Cancer Center; Gregory R. Pond, Mark Levine, Brian Findlay, and Som Mukherjee, McMaster University, Hamilton, Ontario; Michael Vallis, Dalhousie University, Halifax, Nova Scotia; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Jennifer A. Ligibel, Dana-Farber Cancer Institute; George L. Blackburn, Beth Israel Deaconess Medical Center; Jennifer A. Ligibel and George L. Blackburn, Harvard Medical School, Boston, MA; and Julie R. Gralow, University of Washington, Seattle, WA
| | - Mark Levine
- Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Princess Margaret Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Center; Pamela J. Goodwin and Kathleen I. Pritchard, University of Toronto, Toronto; Roanne J. Segal, Ottawa Hospital Regional Cancer Center, University of Ottawa, Ottawa; Gregory R. Pond, Som Mukherjee, and Mark Levine, Juravinski Hospital and Cancer Center; Brian Findlay, Niagara Health System, Walker Family Cancer Center; Gregory R. Pond, Mark Levine, Brian Findlay, and Som Mukherjee, McMaster University, Hamilton, Ontario; Michael Vallis, Dalhousie University, Halifax, Nova Scotia; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Jennifer A. Ligibel, Dana-Farber Cancer Institute; George L. Blackburn, Beth Israel Deaconess Medical Center; Jennifer A. Ligibel and George L. Blackburn, Harvard Medical School, Boston, MA; and Julie R. Gralow, University of Washington, Seattle, WA
| | - Kathleen I Pritchard
- Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Princess Margaret Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Center; Pamela J. Goodwin and Kathleen I. Pritchard, University of Toronto, Toronto; Roanne J. Segal, Ottawa Hospital Regional Cancer Center, University of Ottawa, Ottawa; Gregory R. Pond, Som Mukherjee, and Mark Levine, Juravinski Hospital and Cancer Center; Brian Findlay, Niagara Health System, Walker Family Cancer Center; Gregory R. Pond, Mark Levine, Brian Findlay, and Som Mukherjee, McMaster University, Hamilton, Ontario; Michael Vallis, Dalhousie University, Halifax, Nova Scotia; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Jennifer A. Ligibel, Dana-Farber Cancer Institute; George L. Blackburn, Beth Israel Deaconess Medical Center; Jennifer A. Ligibel and George L. Blackburn, Harvard Medical School, Boston, MA; and Julie R. Gralow, University of Washington, Seattle, WA
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Abstract
INTRODUCTION AND AIMS To provide a current perspective on nutrition and physical activity influence on breast cancer. METHODS AND RESULTS A comprehensive literature review was conducted and selective presentation of findings follows. While some observational studies have associated higher dietary fat intake with higher breast cancer incidence, two full-scale randomized, clinical trials of dietary fat intake reduction programs were negative. However, a lifestyle intervention targeting fat intake reduction in the Women's Intervention Nutrition Study (WINS), resulted in weight loss and also reduced breast cancer recurrences in women with early stage disease. Observational studies evaluating specific nutrient intakes and dietary supplements have provided mixed results. Several observational studies find women with early stage breast cancer with lower 25-hydroxyvitamin D levels at higher recurrence risk, a finding requiring cautious interpretation. The lifestyle factor most strongly and consistently associated with both breast cancer incidence and breast cancer recurrence risk is physical activity. A meta-analyses of observational studies supports the concept that moderate recreational physical activity (about 3-4 h walking per week) may reduce breast cancer incidence and that women with early stage breast cancer who increased or maintain their physical activity may have lower recurrence risk as well. Feasibility of achieving increased physical activity and weight loss in women with early-stage breast cancer has been established. Two full-scale randomized clinical trials are evaluating weight loss/maintenance and increased physical activity in relation to recurrence risk in women with early-stage, resected breast cancer. DISCUSSION/CONCLUSIONS Dietary intake may influence breast cancer but influence is difficult to separate from influence of body weight. A consistent body of observational study evidence suggests higher physical activity has favorable influence on breast cancer incidence and outcome. While awaiting definitive evidence from ongoing randomized trials, breast cancer patients can reasonably be counseled to avoid weight gain and reduce body weight if overweight or obese and increase or maintain a moderate level of physical activity.
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Affiliation(s)
- Rowan T Chlebowski
- Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Building J-3, Torrance, CA 90502, USA.
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Crawford S. Anti-inflammatory/antioxidant use in long-term maintenance cancer therapy: a new therapeutic approach to disease progression and recurrence. Ther Adv Med Oncol 2014; 6:52-68. [PMID: 24587831 PMCID: PMC3932057 DOI: 10.1177/1758834014521111] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The chronic, progressive clinical characteristics of many adult solid tumor malignancies suggest that a more effective therapeutic approach to cancer management may require long-term intervention using nontoxic systemic agents that block critical components of abnormal tumor physiology. Two highly promising systemic targets common to the development, progression and recurrence of many common cancers are dysregulated inflammatory and oxidation/reduction (redox) pathways. Compelling clinical data support the use of anti-inflammatory and antioxidant agents as a therapeutic modality for long-term use in patients diagnosed with several common cancers, including colon cancer and breast cancer. The therapeutic paradigm presented in this paper is the product of a synthesis of what is currently understood about the biological effects of inflammation and oxidative stress that contribute to tumorigenesis, disease progression and recurrence as well as results obtained from research on the use of prophylactics with anti-inflammatory or antioxidant properties in cancer prevention and treatment.
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Affiliation(s)
- Sarah Crawford
- Cancer Biology Research Laboratory, Southern Connecticut State University, New Haven, CT 06515, USA
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Bramwell VHC, Tuck AB, Chapman JAW, Anborgh PH, Postenka CO, Al-Katib W, Shepherd LE, Han L, Wilson CF, Pritchard KI, Pollak MN, Chambers AF. Assessment of osteopontin in early breast cancer: correlative study in a randomised clinical trial. Breast Cancer Res 2014; 16:R8. [PMID: 24451146 PMCID: PMC3978736 DOI: 10.1186/bcr3600] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 01/10/2014] [Indexed: 02/03/2023] Open
Abstract
INTRODUCTION Osteopontin (OPN) is a malignancy-associated glycoprotein that contributes functionally to tumor aggressiveness. In metastatic breast cancer, we previously demonstrated that elevated OPN in primary tumor and blood was associated with poor prognosis. METHODS We measured OPN in plasma by ELISA, and in tumors by immunohistochemistry, in 624 (94%) and 462 (69%), respectively, of 667 postmenopausal women with hormone responsive early breast cancer treated by surgery followed by adjuvant treatment with tamoxifen +/- octreotide in a randomized trial (NCIC CTG MA.14; National Cancer Institute of Canada Clinical Trials Group Mammary.14). RESULTS Plasma OPN was measured in 2,540 samples; 688 at baseline and 1,852 collected during follow-up. Mean baseline plasma OPN was 46 ng/ml (range 22.6 to 290) which did not differ from normal levels. Mean percentage OPN tumor cell positivity was 33.9 (95% CI: 30.2 to 37.9). There was no correlation between plasma and tumor OPN values. In multivariate analysis, neither was associated with event-free survival (EFS), relapse-free survival (RFS), overall survival (OS), bone RFS or non-bone RFS. An exploratory analysis in patients with recurrence showed higher mean OPN plasma levels 60.7 ng/ml (23.9 to 543) in the recurrence period compared with baseline levels. CONCLUSIONS The hypothesis that OPN tumor expression would have independent prognostic value in early breast cancer was not supported by multivariate analysis of this study population. Plasma OPN levels in women with hormone responsive early breast cancer in the MA.14 trial were not elevated and there was no evidence for prognostic value of plasma OPN in this defined group of patients. However, our finding of elevated mean OPN plasma level around the time of recurrence warrants further study. TRIAL REGISTRATION NCT00002864, http://clinicaltrials.gov/show/NCT00002864.
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The insulin–insulin-like growth-factor receptor family as a therapeutic target in oncology. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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Vrieling A, Seibold P, Johnson TS, Heinz J, Obi N, Kaaks R, Flesch-Janys D, Chang-Claude J. Circulating 25-hydroxyvitamin D and postmenopausal breast cancer survival: Influence of tumor characteristics and lifestyle factors? Int J Cancer 2013; 134:2972-83. [PMID: 24272459 DOI: 10.1002/ijc.28628] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 11/06/2013] [Accepted: 11/07/2013] [Indexed: 11/08/2022]
Abstract
We previously reported that lower post-diagnostic circulating 25-hydroxyvitamin D [25(OH)D] concentrations were associated with higher risk of overall mortality and distant disease in stage I-IV postmenopausal breast cancer survivors. This association was now re-examined in an extended dataset to investigate potential effect modification by tumor characteristics and lifestyle factors. A prospective cohort study was conducted in Germany including 2,177 incident stage I-IV postmenopausal breast cancer patients aged 50-74 years. Patients were diagnosed between 2001 and 2005 and median follow-up time was 5.3 years. Cox proportional hazards models were stratified by age at diagnosis, study center and season of blood collection and adjusted for other prognostic factors. A meta-analysis of studies on circulating 25(OH)D and mortality in breast cancer patients was performed to summarize evidence. Lower concentrations of 25(OH)D were significantly associated with higher risk of overall mortality [hazard ratio (HR) lowest vs. highest tertile = 1.86; 95% confidence interval (CI): 1.22, 2.82; p-trend = 0.002] and distant disease (HR = 1.76; 95% CI: 1.24, 2.49; p-trend = 0.003) in stage I-IIIa but not in stage IIIb-IV breast cancer patients. No significant interaction by lifestyle factors was observed (all p-interaction > 0.05). The meta-analysis yielded significant associations with overall and breast cancer-specific mortality (lowest vs. highest quantile: HR = 1.52; 95% CI: 1.22, 1.88 and HR = 1.74; 95% CI: 1.23, 2.40, respectively). In conclusion, post-diagnostic circulating 25(OH)D concentrations were associated with overall mortality and distant disease in stage I-IIIa postmenopausal breast cancer patients. This association was not strongly modified by lifestyle factors.
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Affiliation(s)
- Alina Vrieling
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department for Health Evidence, Radboud university medical center, Nijmegen, The Netherlands
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Hartog H, Boezen H, de Jong M, Schaapveld M, Wesseling J, van der Graaf W. Prognostic value of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 blood levels in breast cancer. Breast 2013; 22:1155-60. [DOI: 10.1016/j.breast.2013.07.038] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 06/20/2013] [Accepted: 07/16/2013] [Indexed: 12/19/2022] Open
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Belardi V, Gallagher EJ, Novosyadlyy R, LeRoith D. Insulin and IGFs in obesity-related breast cancer. J Mammary Gland Biol Neoplasia 2013; 18:277-89. [PMID: 24154546 DOI: 10.1007/s10911-013-9303-7] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 10/02/2013] [Indexed: 02/07/2023] Open
Abstract
Obesity and the Metabolic Syndrome are associated with multiple factors that may cause an increased risk for cancer and cancer-related mortality. Factors involved include hyperinsulinemia, hyperglycemia, hyperlipidemia and IGFs. Insulin resistance is also associated with alterations in the levels of proinflammatory cytokines, chemokines, adipokines (leptin, adiponectin) that may also be contributing factors. The insulin family of proteins is ubiquitously expressed and has pleiotropic effects on metabolism and growth. However insulin, IGF-1 and particularly IGF-2 have been identified as tumor promoters in multiple studies. Mouse models have focused on insulin and IGF-1 and their receptors as being involved in tumor progression and metastases. The role of the insulin receptor as either mediating the effects on tumors or as compensating for the insulin-like growth factor receptor has arisen. Its role has been supported by preclinical studies and the importance of insulin resistance and hyperinsulinemia in obesity and early diabetes. Since the focus of this review is the insulin-family we will focus on insulin, IGF-1 and IGF-2.
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Affiliation(s)
- Valentina Belardi
- Department of Endocrinology, University of Pisa, Via Paradisa 2, 50124, Pisa, Italy
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Breast cancer follow-up strategies in randomized phase III adjuvant clinical trials: a systematic review. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2013; 32:89. [PMID: 24438135 PMCID: PMC3828573 DOI: 10.1186/1756-9966-32-89] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 11/07/2013] [Indexed: 01/02/2023]
Abstract
The effectiveness of different breast cancer follow-up procedures to decrease breast cancer mortality are still an object of debate, even if intensive follow-up by imaging modalities is not recommended by international guidelines since 1997. We conducted a systematic review of surveillance procedures utilized, in the last ten years, in phase III randomized trials (RCTs) of adjuvant treatments in early stage breast cancer with disease free survival as primary endpoint of the study, in order to verify if a similar variance exists in the scientific world. Follow-up modalities were reported in 66 RCTs, and among them, minimal and intensive approaches were equally represented, each being followed by 33 (50%) trials. The minimal surveillance regimen is preferred by international and North American RCTs (P = 0.001) and by trials involving more than one country (P = 0.004), with no relationship with the number of participating centers (P = 0.173), with pharmaceutical industry sponsorship (P = 0.80) and with trials enrolling > 1000 patients (P = 0.14). At multivariate regression analysis, only geographic location of the trial was predictive for a distinct follow-up methodology (P = 0.008): Western European (P = 0.004) and East Asian studies (P = 0.010) use intensive follow-up procedures with a significantly higher frequency than international RCTs, while no differences have been detected between North American and international RCTs. Stratifying the studies according to the date of beginning of patients enrollment, before or after 1998, in more recent RCTs the minimal approach is more frequently followed by international and North American RCTs (P = 0.01), by trials involving more than one country (P = 0.01) and with more than 50 participating centers (P = 0.02). It would be highly desirable that in the near future breast cancer follow-up procedures will be homogeneous in RCTs and everyday clinical settings.
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Hawsawi Y, El-Gendy R, Twelves C, Speirs V, Beattie J. Insulin-like growth factor - oestradiol crosstalk and mammary gland tumourigenesis. Biochim Biophys Acta Rev Cancer 2013; 1836:345-53. [PMID: 24189571 DOI: 10.1016/j.bbcan.2013.10.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 10/15/2013] [Accepted: 10/24/2013] [Indexed: 12/22/2022]
Abstract
Development and differentiation of the mammary gland are dependent on the appropriate temporal expression of both systemically acting hormones and locally produced growth factors. A large body of evidence suggests that molecular crosstalk between these hormonal and growth factor axes is crucial for appropriate cell and tissue function. Two of the most important trophic factors involved in this process are the oestrogen (E) and insulin-like growth factor (IGF) molecular axes. The reciprocal crosstalk that exists between these pathways occurs at transcriptional/post-transcriptional and translational/post-translational levels regulate the expression and activity of genes involved in this process. In a clinical context an important consequence of such crosstalk in the mammary gland is the role which it may play in the aetiology, maintenance and development of breast tumours. Although oestradiol (E2) acting through oestrogen receptors α and β (ERα/β) is important for normal mammary gland function it can also provide a mitogenic drive to ER+ breast tumours. Therefore over several years anti-oestrogen therapeutic regimens in the form of selective oestrogen receptor modulators (SERMs - e.g. tamoxifen), aromatase inhibitors (AI e.g. anastrozole) or selective oestrogen receptor down regulators (SERDs - e.g. fulvestrant) have been used in an adjuvant setting to control tumour growth. Although initial response is usually encouraging, large cohorts of patients eventually develop resistance to these treatments leading to tumour recurrence and poor prognosis. There are potentially many routes by which breast cancer (BC) cells could escape anti-oestrogen based therapeutic strategies and one of the most studied is the possible growth factor mediated activation of ER(s). Because of this, growth factor modulation of ER activity has been an intensively studied route of molecular crosstalk in the mammary gland. The insulin-like growth factors (IGF-1 and -2) are amongst the most potent mitogens for mammary epithelial cells and there is accumulating evidence that they interact with the E2 axis to regulate mitogenesis, apoptosis, adhesion, migration and differentiation of mammary epithelial cells. Such interactions are bi-directional and E2 has been shown to regulate the expression and activity of IGF axis genes with the general effect of sensitising breast epithelial cells to the actions of IGFs and insulin. In this short review we discuss the evidence for the involvement of crosstalk between the insulin-like growth factor (IGF) and oestrogen axes in the mammary gland and comment on the relevance of such studies in the aetiology and treatment of BC.
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Jayakrishnan TT, Groeschl RT, George B, Thomas JP, Clark Gamblin T, Turaga KK. Review of the impact of antineoplastic therapies on the risk for cholelithiasis and acute cholecystitis. Ann Surg Oncol 2013; 21:240-7. [PMID: 24114054 DOI: 10.1245/s10434-013-3300-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Development of cholecystitis in patients with malignancies can potentially disrupt their treatment and alter prognosis. This review aims to identify antineoplastic interventions associated with increased risk of cholecystitis in cancer patients. METHODS A comprehensive search strategy was developed to identify articles pertaining to risk factors and complications of cholecystitis in cancer patients. FDA-issued labels of novel antineoplastic drugs released after 2010 were hand-searched to identify more therapies associated with cholecystitis in nonpublished studies. RESULTS Of an initial 2,932 articles, 124 were reviewed in the study. Postgastrectomy patients have a high (5-30 %) incidence of gallstone disease, and 1-7 % develop symptomatic disease. One randomized trial addressing the role of cholecystectomy concurrent with gastrectomy is currently underway. Among other risk groups, patients with neuroendocrine tumors treated with somatostatin analogs have a 15 % risk of cholelithiasis, and most are symptomatic. Hepatic artery based therapies carry a risk of cholecystitis (0.02-24 %), although the risk is reduced with selective catheterization. Myelosuppression related to chemotherapeutic agents (0.4 %), bone marrow transplantation, and treatment with novel multikinase inhibitors are associated with high risk of cholecystitis. CONCLUSIONS There are several risk factors for gallbladder-related surgical emergencies in patients with advanced malignancies. Incidental cholecystectomy at index operation should be considered in patients planned for gastrectomy, and candidates for regional therapies to the liver or somatostatin analogs. While prophylactic cholecystectomy is currently recommended for patients with cholelithiasis receiving myeloablative therapy, this strategy may have value in patients treated with multikinase inhibitors, immunotherapy, and oncolytic viral therapy based on evolving evidence.
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Affiliation(s)
- Thejus T Jayakrishnan
- Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
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Post-surgical highly sensitive C-reactive protein and prognosis in early-stage breast cancer. Breast Cancer Res Treat 2013; 141:485-93. [DOI: 10.1007/s10549-013-2694-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 08/30/2013] [Indexed: 12/26/2022]
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Abstract
Metformin is widely prescribed for the treatment of type II diabetes. Recently, it has been proposed that this compound or related biguanides may have antineoplastic activity. Biguanides may exploit specific metabolic vulnerabilities of transformed cells by acting on them directly, or may act by indirect mechanisms that involve alterations of the host environment. Preclinical data suggest that drug exposure levels are a key determinant of proposed direct actions. With respect to indirect mechanisms, it will be important to determine whether recently demonstrated metformin-induced changes in levels of candidate systemic mediators such as insulin or inflammatory cytokines are of sufficient magnitude to achieve therapeutic benefit. Results of the first generation of clinical trials now in progress are eagerly anticipated. Ongoing investigations may justify a second generation of trials that explore pharmacokinetic optimization, rational drug combinations, synthetic lethality strategies, novel biguanides, and the use of predictive biomarkers.
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Affiliation(s)
- Michael Pollak
- Department of Oncology, McGill University, Montreal, Quebec, Canada.
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Gallagher EJ, LeRoith D. Epidemiology and molecular mechanisms tying obesity, diabetes, and the metabolic syndrome with cancer. Diabetes Care 2013; 36 Suppl 2:S233-9. [PMID: 23882051 PMCID: PMC3920794 DOI: 10.2337/dcs13-2001] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Emily J Gallagher
- Division of Endocrinology, Diabetes and Bone Disease, Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA
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Theodoropoulou M, Stalla GK. Somatostatin receptors: from signaling to clinical practice. Front Neuroendocrinol 2013; 34:228-52. [PMID: 23872332 DOI: 10.1016/j.yfrne.2013.07.005] [Citation(s) in RCA: 281] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 06/13/2013] [Accepted: 07/12/2013] [Indexed: 02/08/2023]
Abstract
Somatostatin is a peptide with a potent and broad antisecretory action, which makes it an invaluable drug target for the pharmacological management of pituitary adenomas and neuroendocrine tumors. Somatostatin receptors (SSTR1, 2A and B, 3, 4 and 5) belong to the G protein coupled receptor family and have a wide expression pattern in both normal tissues and solid tumors. Investigating the function of each SSTR in several tumor types has provided a wealth of information about the common but also distinct signaling cascades that suppress tumor cell proliferation, survival and angiogenesis. This provided the rationale for developing multireceptor-targeted somatostatin analogs and combination therapies with signaling-targeted agents such as inhibitors of the mammalian (or mechanistic) target of rapamycin (mTOR). The ability of SSTR to internalize and the development of rabiolabeled somatostatin analogs have improved the diagnosis and treatment of neuroendocrine tumors.
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Affiliation(s)
- Marily Theodoropoulou
- Department of Endocrinology, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany.
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