<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03784651</url>
  </required_header>
  <id_info>
    <org_study_id>H-18016600</org_study_id>
    <nct_id>NCT03784651</nct_id>
  </id_info>
  <brief_title>Metabolic and Bone Changes After Adjuvant Cancer Treatments in Early Non-metastatic Breast Cancer</brief_title>
  <official_title>Metabolic and Bone Changes After Adjuvant Cancer Treatments in Early Non-metastatic Breast Cancer - a 5-year Follow-up Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rigshospitalet, Denmark</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rigshospitalet, Denmark</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Breast cancer is the most common cancer type in European women. Patients treated for early&#xD;
      non-metastatic breast cancer comprise a growing group of survivors due to early diagnosis and&#xD;
      improved treatment. Many of these survivors experience adverse effects such as decreased bone&#xD;
      mineral density, derangement of metabolic markers (fat, glucose, insulin) and increased blood&#xD;
      pressure. Increasing risk of bone fracture and cardiometabolic disease (eg. diabetes mellitus&#xD;
      type 2).&#xD;
&#xD;
      The purpose of this study is to identify mechanisms behind cardiometabolic changes that may&#xD;
      be connected to the (neo-)adjuvant treatment. On top of this we hope to indentify potential&#xD;
      biological markers that can help prevent development of metabolic disease.&#xD;
&#xD;
      We will be recruiting 120 post-menopausal women age 50-70 with early breast cancer and 1-2&#xD;
      times a year for 5 years examine bone mineral density, body composition, glucose and fat&#xD;
      metabolism and nerve damage. A questionnaire will be used to collect information on diet,&#xD;
      physical activity and quality of life. Derudover anvendes spørgeskemaer til at indsamle&#xD;
      information vedrørende. This new knowledge will help clinicians start adequate preventive&#xD;
      measures to help patients avoid cardiometabolic disease secondary to cancer treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Purpose and background Breast cancer is the most common cancer in Danish women, and has an&#xD;
      average of 4,750 new cases a year (1). Patients treated for early (non-metastatic) breast&#xD;
      cancer (EBC) comprise, due to earlier diagnosis and improved treatment, a large and growing&#xD;
      group of cancer survivors. However, many patients experience treatment-related endocrine&#xD;
      side-effects such as reduced bone mineral density (BMD), dyslipidemia, insulin resistance and&#xD;
      hypertension increasing the risk of bone fractures as well risk of development of&#xD;
      cardiometabolic disease including Type 2 diabetes (T2D).&#xD;
&#xD;
      The purpose of the study is to understand the underlying physiological and molecular&#xD;
      mechanisms responsible for the chemotherapy-induced bone and cardiometabolic derangements to&#xD;
      identify novel disease mechanisms as well as to identify potential biomarkers to be used for&#xD;
      better prediction and prevention of metabolic disease.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      In a cohort of women (n=120) with EBC to assess (WP1):&#xD;
&#xD;
      • Bone metabolism, body composition, insulin resistance, neuropathy, bone mineral density&#xD;
      (BMD) and lung function before chemotherapy, after chemotherapy and during five years&#xD;
      follow-up.&#xD;
&#xD;
      Background Patients treated for EBC comprise, due to earlier diagnosis and improved&#xD;
      treatment, a large and growing group of cancer survivors. However, there might be unintended&#xD;
      complications associated with the treatment, since patients experience treatment-related&#xD;
      endocrine side-effects including an average weight gain of approximately 5 kg primarily&#xD;
      reflected by an increase in fat mass and a decrease in muscle mass and thus change in body&#xD;
      composition (2, 3). Besides less physical activity contributing to weight gain,&#xD;
      (neo-)adjuvant chemotherapy and anti-estrogen treatment administered to prevent disease&#xD;
      recurrence, may cause sarcopenia, increased appetite, reduced basal metabolic rate and&#xD;
      altered whole-body metabolism (4, 5). Obesity is not only a risk factor for breast cancer&#xD;
      development but also a risk factor for recurrence of breast cancer (6, 7). In addition to&#xD;
      increased weight, several studies have reported increased fasting glucose, insulin and&#xD;
      adipokine levels, increased lipids, increased insulin resistance (homeostatic model&#xD;
      assessment (HOMA-IR)) as well as hypertension in response to chemotherapy (3, 5, 8, 9). All&#xD;
      together these metabolic changes may induce a prediabetic phenotype associated with increased&#xD;
      risk of developing cardiometabolic disease including Type 2 diabetes as well as cancer&#xD;
      recurrence (10).&#xD;
&#xD;
      Patients with estrogen receptor positive early breast cancer may be sensitive to antihormonal&#xD;
      therapy. For postmenopausal women, a common adjuvant hormonal therapy is with an aromatase&#xD;
      inhibitor (AI) for five years (11). However, treatment with AIs is associated with reduction&#xD;
      in BMD and increase in fracture risk due to accelerated bone resorption from estrogen&#xD;
      suppression (12-16). Previous studies reported the highest rates of bone loss during the&#xD;
      first year of AI treatment (17). Additionally, it has been shown that the increased bone&#xD;
      resorption and bone loss with regard to AI can be prevented and managed with lifestyle&#xD;
      changes, calcium and vitamin-D supplementation and the use of anti-resorptive medication&#xD;
      (18-22).&#xD;
&#xD;
      Women with hormone receptor-positive breast cancer (BC) have an 88% 5-year survival, and if&#xD;
      hormone-receptor-positive EBC, this is even higher and underscores the importance of ensuring&#xD;
      that therapeutic interventions do not confer long-term morbidity.&#xD;
&#xD;
      The underlying cause for the changes in body composition during chemotherapy has not been&#xD;
      well described and likewise has the underlying physiological and molecular mechanisms&#xD;
      responsible for the cardio-metabolic derangements not been described either. Understanding&#xD;
      the underlying causes and impact of treatment-related metabolic disease, will allow&#xD;
      clinicians to initiate interventions to prevent, that these otherwise healthy women develop&#xD;
      metabolic disease secondary to cancer treatment. This will in turn improve quality of life&#xD;
      and reduced morbidity and mortality.&#xD;
&#xD;
      Methods Subjects Postmenopausal women age 50-75 years diagnosed with EBC stage I-III eligible&#xD;
      to receive (neo-)adjuvant chemotherapy or other adjuvant antineoplastic treatments Exclusion&#xD;
      criteria include prior malignancy, preexisting T2D or other metabolic disease. The women will&#xD;
      be recruited via the Department of Oncology at Rigshospitalet, Denmark.&#xD;
&#xD;
      Examinations&#xD;
&#xD;
      A cohort of 120 EBC women (WP1) will be followed from time of diagnosis through treatment and&#xD;
      five years follow-up during AI treatment. Examinations will be performed either every six&#xD;
      months or once a year, alongside routine visits and include:&#xD;
&#xD;
      WP1 (n=120)&#xD;
&#xD;
        -  Blood samples (safety biochemistry, buffy coat (DNA), calcium homeostasis, bone markers,&#xD;
           glucose, insulin and lipid levels, adipokines and inflammation markers&#xD;
&#xD;
        -  Anthropometry (height, weight, waist/hip ratio)&#xD;
&#xD;
        -  Neuropathy test by RR-interval-variation-analysis and vibration test&#xD;
&#xD;
        -  Spirometry&#xD;
&#xD;
        -  Questionnaires: food frequency (FFQ), physical activity (IPAQ)&#xD;
&#xD;
        -  DXA scanning of body composition (GE Electric) and bone mass (Hologic)&#xD;
&#xD;
        -  Urine&#xD;
&#xD;
        -  App &quot;Bone@BC&quot;&#xD;
&#xD;
      Bone mineral density (BMD)/trabecular bone score (TBS) BMD is measured at the lumbar spine&#xD;
      (mean of L2-L4), femoral neck and total hip on both sides using DXA (Hologic DiscoveryTM QDR&#xD;
      Series scanner). DXA accurately determines 2 dimensional BMD (g/cm2) and detects patients at&#xD;
      a heightened risk for osteoporotic fracture (23). The (unitless) calculated TBS is a novel,&#xD;
      readily available, non-invasive clinical technique based on DXA images of the LS that&#xD;
      provides a surrogate measure of the 3 dimensional microarchitecture of the skeleton (24). A&#xD;
      high correlation between the TBS and CT42addressed microarchitecture has been observed (25),&#xD;
      and the TBS is less influenced by the presence of osteoarthritis than BMD (26).&#xD;
&#xD;
      The same laboratory technician will perform all analyses. According to the manufacturer, the&#xD;
      CV (coefficient of variation) of the total BMD is approximately 1% (Europe H. Hologic&#xD;
      Osteoporosis Assesment. Reference Manual. 2006; Document No. Man-00214Revision 006).&#xD;
&#xD;
      Bone@BC app A newly developed app &quot;Bone@BC&quot; from RegionH that will be used by all women, is a&#xD;
      guide and data collection app addressed to women with breast cancer receiving adjuvant&#xD;
      anti-estrogen treatment. The app collects data on patient experiences (1. quality of life&#xD;
      measures i.e. mobility, power/energy, mood, social contact and 2. measures of possible&#xD;
      side-effects i.e. pain, dizziness, sleep) and from i.e. DXA-scanning, blood markers of bone&#xD;
      turn-over and other biochemical measures. The specific data collection is for patient use,&#xD;
      and can if approved by the patient, be part of the patient-caretaker-MD collaboration within&#xD;
      the confines of this research study. The Bone@BC app will, with regard to patients in the&#xD;
      study, only collect data for use in the study. The Bone@BC app has approved integration of&#xD;
      app data with Region Security Requirements and is an official RegionH App legally approved at&#xD;
      all levels (Nem-ID login, informed consent, approved by Datatilsynet).&#xD;
&#xD;
      Biological material Blood samples: Blood samples are obtained via venipuncture and processed&#xD;
      at the central laboratory following routine procedures at Rigshospitalet.&#xD;
&#xD;
      Five ml urine will be stored in the biobank for metabolomics analysis.&#xD;
&#xD;
      Research biobank The biological material will be used for molecular analyses as described in&#xD;
      the present protocol. These analyses including statistics will take place in a 10-year period&#xD;
      after initiation of the project. After 10 years the biological material will be transferred&#xD;
      to a research biobank at Rigshospitalet for future metabolic research. Participants will be&#xD;
      made aware of this in the information material. The use of these samples would require&#xD;
      re-approval of the Research Ethics Committee of the Capital Region. The establishment of a&#xD;
      biobank has been approved by the Data Protection Agency.&#xD;
&#xD;
      Statistical considerations Based on literature studies the large cohort is estimated to&#xD;
      include 120 enrolled EBC patients based on a power calculation of 80 finalizing the study&#xD;
      (drop-out rate ~33% at year 5).&#xD;
&#xD;
      Side effects, risks and inconveniences During the examinations, there will be a temporary&#xD;
      discomfort when applying peripheral venous catheters (venflon). In addition, blood tests are&#xD;
      always associated with a risk of infection. All tissue samples will be excised by a trained&#xD;
      professional, and the research team has comprehensive experience with blood and tissue&#xD;
      sampling.&#xD;
&#xD;
      The total blood loss at each examination will not exceed 20 ml. Radiation from the DXA scan&#xD;
      (DXA, TBS and Vertebral Fracture Assessment) is equivalent to 0.06 mRem and considered quite&#xD;
      harmless. In comparison, a conventional X-ray image of the heart and lungs has a beam volume&#xD;
      of approx. 30 mRem (0.3 mSv), and the annual background radiation in Denmark is about 300&#xD;
      mRem (3 mSv), corresponding to 0.8 mRem (0.008 mSv) daily.&#xD;
&#xD;
      If for any unforeseen reason, doubt arises about the health and security of the subject the&#xD;
      study will be terminated immediately.&#xD;
&#xD;
      G. Data security All personal information regarding the participants will be protected by the&#xD;
      &quot;Lov om behandling af personlige oplysninger og Sundhedsloven&quot;. The protocol will be&#xD;
      performed in accordance with the Declaration of Helsinki II, and has been approved by the&#xD;
      Data Protection Agency. Analysis of biological material can possibly take place in Europe&#xD;
      and/or in the United States. In such cases, the analyses will be conducted under the&#xD;
      receiving country's laws and regulations, and in accordance with &quot;Lov om behandling af&#xD;
      personoplysninger&quot;.&#xD;
&#xD;
      Patient files will be used to check standard biochemistry tests. In addition due to the long&#xD;
      observation period and the potential for relapse due to the underlying condition, it will be&#xD;
      necessary to check patient files to maintain the security of the patients. Therefore consent&#xD;
      from the patient will give the involved researchers access to the electronic patient files.&#xD;
&#xD;
      H. Financing Senior scientist, PhD. Charlotte Brøns and professor, dr.med. Peter Schwarz are&#xD;
      responsible for initiating the research project. Neither have any conflicts of interest to&#xD;
      declare.&#xD;
&#xD;
      Compensation There will not be given any compensation to patients participating in the study.&#xD;
&#xD;
      Recruitment All subjects will be recruited consecutively from the Department of Oncology, the&#xD;
      breast cancer section, at Rigshospitalet, Denmark until 120 EBC patients have been included.&#xD;
      All information given before consent is signed, will be to a researcher.&#xD;
&#xD;
      Publication and dissemination strategy The scientific results obtained from the study,&#xD;
      whether positive, negative or inconclusive, will be written up in original manuscripts to&#xD;
      become submitted to peer-reviewed international journals in the field. The results will&#xD;
      furthermore be disseminated in oral presentations as well as in poster forms at relevant&#xD;
      national and international meetings.&#xD;
&#xD;
      Ethical considerations Before entering the study, all individuals will receive oral and&#xD;
      written information, and there will be a written consent to participate in the study. A&#xD;
      unique subject ID number will be subscribed to all participants to anonymize data. The&#xD;
      identification key (ID to personal information) will be encrypted and stored securely and&#xD;
      separately from the unique ID number on a secure database, to ensure that no information on&#xD;
      the participant can be assigned to the ID number. All data will automatically be backed up on&#xD;
      a secure server. Only the research team will have access to the data. Neither the absolute&#xD;
      nor the relative risk will be of unjustifiable size or of irresponsible character considering&#xD;
      the impact of the study. The participants will gain information about personal health status.&#xD;
      The current study provides an innovative and highly promising study approach to understanding&#xD;
      metabolic and bone changes after adjuvant cancer treatments in early non-metastatic breast&#xD;
      cancer.&#xD;
&#xD;
      If necessary, participants are covered by the insurance of Rigshospitalet.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 17, 2018</start_date>
  <completion_date type="Anticipated">November 2026</completion_date>
  <primary_completion_date type="Anticipated">November 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Bone Mineral Density</measure>
    <time_frame>1-5 years</time_frame>
    <description>Change in bone mineral density</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Metabolic syndrome</measure>
    <time_frame>1-5 years</time_frame>
    <description>Change in number of patients with the metabolic syndrome</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Bone fracture</measure>
    <time_frame>1-5 years</time_frame>
    <description>Change in number of fractures</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Insulin resistance</measure>
    <time_frame>1-5 years</time_frame>
    <description>Change in insulin resistance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glucose</measure>
    <time_frame>1-5 years</time_frame>
    <description>Change in blood glucose</description>
  </secondary_outcome>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Bone Fracture</condition>
  <condition>Glucose, High Blood</condition>
  <condition>Insulin Resistance</condition>
  <condition>Blood Pressure, High</condition>
  <condition>Cholesterolemia</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood samples&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Postmenopausal women age 50-70 years diagnosed with breast cancer stage I-III eligible to&#xD;
        receive (neo-)adjuvant chemotherapy or other adjuvant antineoplastic treatments including&#xD;
        trastuzumab and CKK4-6 inhibitors, AI and bisphosphonate. Exclusion criteria include prior&#xD;
        malignancy, preexisting T2D or other metabolic disease. The women will be recruited via the&#xD;
        Department of Oncology at Rigshospitalet, Denmark.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Postmenopausal&#xD;
&#xD;
          -  Breast cancer stage I-III&#xD;
&#xD;
          -  Eligible to receive (neo-)adjuvant chemotherapy/other antineoplastic treatment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior malignancy&#xD;
&#xD;
          -  Metabolic disease (diabetes mellitus etc)&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Peter Schwarz, Prof, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rigshospitalet, Denmark</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Kristian Buch, cand.med.</last_name>
    <phone>29434376</phone>
    <phone_ext>+45</phone_ext>
    <email>buch.kristian@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Rigshospitalet</name>
      <address>
        <city>Copenhagen</city>
        <state>Danmark</state>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kristian Buch, MD</last_name>
      <phone>29434376</phone>
      <email>kristian.buch@regionh.dk</email>
    </contact>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
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  </reference>
  <reference>
    <citation>Winters-Stone KM, Dobek J, Nail L, Bennett JA, Leo MC, Naik A, Schwartz A. Strength training stops bone loss and builds muscle in postmenopausal breast cancer survivors: a randomized, controlled trial. Breast Cancer Res Treat. 2011 Jun;127(2):447-56. doi: 10.1007/s10549-011-1444-z. Epub 2011 Mar 19. Erratum In: Breast Cancer Res Treat. 2011 Jun;127(2):457.</citation>
    <PMID>21424279</PMID>
  </reference>
  <reference>
    <citation>Saarto T, Sievanen H, Kellokumpu-Lehtinen P, Nikander R, Vehmanen L, Huovinen R, Kautiainen H, Jarvenpaa S, Penttinen HM, Utriainen M, Jaaskelainen AS, Elme A, Ruohola J, Palva T, Vertio H, Rautalahti M, Fogelholm M, Luoto R, Blomqvist C. Effect of supervised and home exercise training on bone mineral density among breast cancer patients. A 12-month randomised controlled trial. Osteoporos Int. 2012 May;23(5):1601-12. doi: 10.1007/s00198-011-1761-4. Epub 2011 Sep 3.</citation>
    <PMID>21892676</PMID>
  </reference>
  <reference>
    <citation>Theodorou DJ, Theodorou SJ, Sartoris DJ. Dual-energy X-ray absorptiometry in diagnosis of osteoporosis: basic principles, indications, and scan interpretation. Compr Ther. 2002 Fall;28(3):190-200. doi: 10.1007/s12019-002-0028-6.</citation>
    <PMID>12360631</PMID>
  </reference>
  <reference>
    <citation>Silva BC, Bilezikian JP. Trabecular bone score: perspectives of an imaging technology coming of age. Arq Bras Endocrinol Metabol. 2014 Jul;58(5):493-503. doi: 10.1590/0004-2730000003456.</citation>
    <PMID>25166040</PMID>
  </reference>
  <reference>
    <citation>Dufour R, Winzenrieth R, Heraud A, Hans D, Mehsen N. Generation and validation of a normative, age-specific reference curve for lumbar spine trabecular bone score (TBS) in French women. Osteoporos Int. 2013 Nov;24(11):2837-46. doi: 10.1007/s00198-013-2384-8. Epub 2013 May 17.</citation>
    <PMID>23681084</PMID>
  </reference>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>June 29, 2018</study_first_submitted>
  <study_first_submitted_qc>December 21, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 24, 2018</study_first_posted>
  <last_update_submitted>September 14, 2021</last_update_submitted>
  <last_update_submitted_qc>September 14, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 16, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Rigshospitalet, Denmark</investigator_affiliation>
    <investigator_full_name>Kristian Buch</investigator_full_name>
    <investigator_title>Principal investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Insulin Resistance</mesh_term>
    <mesh_term>Fractures, Bone</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03784651
org study id: H-18016600
nct id: NCT03784651
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Breast cancer is the most common cancer type in European women. Patients treated for early
      non-metastatic breast cancer comprise a growing group of survivors due to early diagnosis and
      improved treatment. Many of these survivors experience adverse effects such as decreased bone
      mineral density, derangement of metabolic markers (fat, glucose, insulin) and increased blood
      pressure. Increasing risk of bone fracture and cardiometabolic disease (eg. diabetes mellitus
      type 2).

      The purpose of this study is to identify mechanisms behind cardiometabolic changes that may
      be connected to the (neo-)adjuvant treatment. On top of this we hope to indentify potential
      biological markers that can help prevent development of metabolic disease.

      We will be recruiting 120 post-menopausal women age 50-70 with early breast cancer and 1-2
      times a year for 5 years examine bone mineral density, body composition, glucose and fat
      metabolism and nerve damage. A questionnaire will be used to collect information on diet,
      physical activity and quality of life. Derudover anvendes spørgeskemaer til at indsamle
      information vedrørende. This new knowledge will help clinicians start adequate preventive
      measures to help patients avoid cardiometabolic disease secondary to cancer treatment.
Purpose and background Breast cancer is the most common cancer in Danish women, and has an
      average of 4,750 new cases a year (1). Patients treated for early (non-metastatic) breast
      cancer (EBC) comprise, due to earlier diagnosis and improved treatment, a large and growing
      group of cancer survivors. However, many patients experience treatment-related endocrine
      side-effects such as reduced bone mineral density (BMD), dyslipidemia, insulin resistance and
      hypertension increasing the risk of bone fractures as well risk of development of
      cardiometabolic disease including Type 2 diabetes (T2D).

      The purpose of the study is to understand the underlying physiological and molecular
      mechanisms responsible for the chemotherapy-induced bone and cardiometabolic derangements to
      identify novel disease mechanisms as well as to identify potential biomarkers to be used for
      better prediction and prevention of metabolic disease.

      Objectives:

      In a cohort of women (n=120) with EBC to assess (WP1):

      • Bone metabolism, body composition, insulin resistance, neuropathy, bone mineral density
      (BMD) and lung function before chemotherapy, after chemotherapy and during five years
      follow-up.

      Background Patients treated for EBC comprise, due to earlier diagnosis and improved
      treatment, a large and growing group of cancer survivors. However, there might be unintended
      complications associated with the treatment, since patients experience treatment-related
      endocrine side-effects including an average weight gain of approximately 5 kg primarily
      reflected by an increase in fat mass and a decrease in muscle mass and thus change in body
      composition (2, 3). Besides less physical activity contributing to weight gain,
      (neo-)adjuvant chemotherapy and anti-estrogen treatment administered to prevent disease
      recurrence, may cause sarcopenia, increased appetite, reduced basal metabolic rate and
      altered whole-body metabolism (4, 5). Obesity is not only a risk factor for breast cancer
      development but also a risk factor for recurrence of breast cancer (6, 7). In addition to
      increased weight, several studies have reported increased fasting glucose, insulin and
      adipokine levels, increased lipids, increased insulin resistance (homeostatic model
      assessment (HOMA-IR)) as well as hypertension in response to chemotherapy (3, 5, 8, 9). All
      together these metabolic changes may induce a prediabetic phenotype associated with increased
      risk of developing cardiometabolic disease including Type 2 diabetes as well as cancer
      recurrence (10).

      Patients with estrogen receptor positive early breast cancer may be sensitive to antihormonal
      therapy. For postmenopausal women, a common adjuvant hormonal therapy is with an aromatase
      inhibitor (AI) for five years (11). However, treatment with AIs is associated with reduction
      in BMD and increase in fracture risk due to accelerated bone resorption from estrogen
      suppression (12-16). Previous studies reported the highest rates of bone loss during the
      first year of AI treatment (17). Additionally, it has been shown that the increased bone
      resorption and bone loss with regard to AI can be prevented and managed with lifestyle
      changes, calcium and vitamin-D supplementation and the use of anti-resorptive medication
      (18-22).

      Women with hormone receptor-positive breast cancer (BC) have an 88% 5-year survival, and if
      hormone-receptor-positive EBC, this is even higher and underscores the importance of ensuring
      that therapeutic interventions do not confer long-term morbidity.

      The underlying cause for the changes in body composition during chemotherapy has not been
      well described and likewise has the underlying physiological and molecular mechanisms
      responsible for the cardio-metabolic derangements not been described either. Understanding
      the underlying causes and impact of treatment-related metabolic disease, will allow
      clinicians to initiate interventions to prevent, that these otherwise healthy women develop
      metabolic disease secondary to cancer treatment. This will in turn improve quality of life
      and reduced morbidity and mortality.

      Methods Subjects Postmenopausal women age 50-75 years diagnosed with EBC stage I-III eligible
      to receive (neo-)adjuvant chemotherapy or other adjuvant antineoplastic treatments Exclusion
      criteria include prior malignancy, preexisting T2D or other metabolic disease. The women will
      be recruited via the Department of Oncology at Rigshospitalet, Denmark.

      Examinations

      A cohort of 120 EBC women (WP1) will be followed from time of diagnosis through treatment and
      five years follow-up during AI treatment. Examinations will be performed either every six
      months or once a year, alongside routine visits and include:

      WP1 (n=120)

        -  Blood samples (safety biochemistry, buffy coat (DNA), calcium homeostasis, bone markers,
           glucose, insulin and lipid levels, adipokines and inflammation markers

        -  Anthropometry (height, weight, waist/hip ratio)

        -  Neuropathy test by RR-interval-variation-analysis and vibration test

        -  Spirometry

        -  Questionnaires: food frequency (FFQ), physical activity (IPAQ)

        -  DXA scanning of body composition (GE Electric) and bone mass (Hologic)

        -  Urine

        -  App "Bone@BC"

      Bone mineral density (BMD)/trabecular bone score (TBS) BMD is measured at the lumbar spine
      (mean of L2-L4), femoral neck and total hip on both sides using DXA (Hologic DiscoveryTM QDR
      Series scanner). DXA accurately determines 2 dimensional BMD (g/cm2) and detects patients at
      a heightened risk for osteoporotic fracture (23). The (unitless) calculated TBS is a novel,
      readily available, non-invasive clinical technique based on DXA images of the LS that
      provides a surrogate measure of the 3 dimensional microarchitecture of the skeleton (24). A
      high correlation between the TBS and CT42addressed microarchitecture has been observed (25),
      and the TBS is less influenced by the presence of osteoarthritis than BMD (26).

      The same laboratory technician will perform all analyses. According to the manufacturer, the
      CV (coefficient of variation) of the total BMD is approximately 1% (Europe H. Hologic
      Osteoporosis Assesment. Reference Manual. 2006; Document No. Man-00214Revision 006).

      Bone@BC app A newly developed app "Bone@BC" from RegionH that will be used by all women, is a
      guide and data collection app addressed to women with breast cancer receiving adjuvant
      anti-estrogen treatment. The app collects data on patient experiences (1. quality of life
      measures i.e. mobility, power/energy, mood, social contact and 2. measures of possible
      side-effects i.e. pain, dizziness, sleep) and from i.e. DXA-scanning, blood markers of bone
      turn-over and other biochemical measures. The specific data collection is for patient use,
      and can if approved by the patient, be part of the patient-caretaker-MD collaboration within
      the confines of this research study. The Bone@BC app will, with regard to patients in the
      study, only collect data for use in the study. The Bone@BC app has approved integration of
      app data with Region Security Requirements and is an official RegionH App legally approved at
      all levels (Nem-ID login, informed consent, approved by Datatilsynet).

      Biological material Blood samples: Blood samples are obtained via venipuncture and processed
      at the central laboratory following routine procedures at Rigshospitalet.

      Five ml urine will be stored in the biobank for metabolomics analysis.

      Research biobank The biological material will be used for molecular analyses as described in
      the present protocol. These analyses including statistics will take place in a 10-year period
      after initiation of the project. After 10 years the biological material will be transferred
      to a research biobank at Rigshospitalet for future metabolic research. Participants will be
      made aware of this in the information material. The use of these samples would require
      re-approval of the Research Ethics Committee of the Capital Region. The establishment of a
      biobank has been approved by the Data Protection Agency.

      Statistical considerations Based on literature studies the large cohort is estimated to
      include 120 enrolled EBC patients based on a power calculation of 80 finalizing the study
      (drop-out rate ~33% at year 5).

      Side effects, risks and inconveniences During the examinations, there will be a temporary
      discomfort when applying peripheral venous catheters (venflon). In addition, blood tests are
      always associated with a risk of infection. All tissue samples will be excised by a trained
      professional, and the research team has comprehensive experience with blood and tissue
      sampling.

      The total blood loss at each examination will not exceed 20 ml. Radiation from the DXA scan
      (DXA, TBS and Vertebral Fracture Assessment) is equivalent to 0.06 mRem and considered quite
      harmless. In comparison, a conventional X-ray image of the heart and lungs has a beam volume
      of approx. 30 mRem (0.3 mSv), and the annual background radiation in Denmark is about 300
      mRem (3 mSv), corresponding to 0.8 mRem (0.008 mSv) daily.

      If for any unforeseen reason, doubt arises about the health and security of the subject the
      study will be terminated immediately.

      G. Data security All personal information regarding the participants will be protected by the
      "Lov om behandling af personlige oplysninger og Sundhedsloven". The protocol will be
      performed in accordance with the Declaration of Helsinki II, and has been approved by the
      Data Protection Agency. Analysis of biological material can possibly take place in Europe
      and/or in the United States. In such cases, the analyses will be conducted under the
      receiving country's laws and regulations, and in accordance with "Lov om behandling af
      personoplysninger".

      Patient files will be used to check standard biochemistry tests. In addition due to the long
      observation period and the potential for relapse due to the underlying condition, it will be
      necessary to check patient files to maintain the security of the patients. Therefore consent
      from the patient will give the involved researchers access to the electronic patient files.

      H. Financing Senior scientist, PhD. Charlotte Brøns and professor, dr.med. Peter Schwarz are
      responsible for initiating the research project. Neither have any conflicts of interest to
      declare.

      Compensation There will not be given any compensation to patients participating in the study.

      Recruitment All subjects will be recruited consecutively from the Department of Oncology, the
      breast cancer section, at Rigshospitalet, Denmark until 120 EBC patients have been included.
      All information given before consent is signed, will be to a researcher.

      Publication and dissemination strategy The scientific results obtained from the study,
      whether positive, negative or inconclusive, will be written up in original manuscripts to
      become submitted to peer-reviewed international journals in the field. The results will
      furthermore be disseminated in oral presentations as well as in poster forms at relevant
      national and international meetings.

      Ethical considerations Before entering the study, all individuals will receive oral and
      written information, and there will be a written consent to participate in the study. A
      unique subject ID number will be subscribed to all participants to anonymize data. The
      identification key (ID to personal information) will be encrypted and stored securely and
      separately from the unique ID number on a secure database, to ensure that no information on
      the participant can be assigned to the ID number. All data will automatically be backed up on
      a secure server. Only the research team will have access to the data. Neither the absolute
      nor the relative risk will be of unjustifiable size or of irresponsible character considering
      the impact of the study. The participants will gain information about personal health status.
      The current study provides an innovative and highly promising study approach to understanding
      metabolic and bone changes after adjuvant cancer treatments in early non-metastatic breast
      cancer.

      If necessary, participants are covered by the insurance of Rigshospitalet.
observational model: Cohort
time perspective: Prospective
measure: Bone Mineral Density
time frame: 1-5 years
description: Change in bone mineral density
measure: Metabolic syndrome
time frame: 1-5 years
description: Change in number of patients with the metabolic syndrome
measure: Bone fracture
time frame: 1-5 years
description: Change in number of fractures
measure: Insulin resistance
time frame: 1-5 years
description: Change in insulin resistance
measure: Glucose
time frame: 1-5 years
description: Change in blood glucose
Blood samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 50 Years
maximum age: 70 Years
healthy volunteers: No
last name: Peter Schwarz, Prof, MD
role: Principal Investigator
affiliation: Rigshospitalet, Denmark
last name: Kristian Buch, cand.med.
phone: 29434376
phone ext: +45
email: buch.kristian@gmail.com
facility: 
status: Recruiting
contact: 
country: Denmark
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PMID: 21421523
citation: Dieli-Conwright CM, Wong L, Waliany S, Bernstein L, Salehian B, Mortimer JE. An observational study to examine changes in metabolic syndrome components in patients with breast cancer receiving neoadjuvant or adjuvant chemotherapy. Cancer. 2016 Sep 1;122(17):2646-53. doi: 10.1002/cncr.30104. Epub 2016 May 24.
PMID: 27219902
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PMID: 8315439
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PMID: 24088604
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citation: Goodwin PJ, Ennis M, Bahl M, Fantus IG, Pritchard KI, Trudeau ME, Koo J, Hood N. High insulin levels in newly diagnosed breast cancer patients reflect underlying insulin resistance and are associated with components of the insulin resistance syndrome. Breast Cancer Res Treat. 2009 Apr;114(3):517-25. doi: 10.1007/s10549-008-0019-0. Epub 2008 Apr 25.
PMID: 18437560
citation: Coskun T, Kosova F, Ari Z, Sakarya A, Kaya Y. Effect of oncological treatment on serum adipocytokine levels in patients with stage II-III breast cancer. Mol Clin Oncol. 2016 May;4(5):893-897. doi: 10.3892/mco.2016.815. Epub 2016 Mar 10.
PMID: 27123303
citation: Gadea E, Thivat E, Planchat E, Morio B, Durando X. Importance of metabolic changes induced by chemotherapy on prognosis of early-stage breast cancer patients: a review of potential mechanisms. Obes Rev. 2012 Apr;13(4):368-80. doi: 10.1111/j.1467-789X.2011.00957.x. Epub 2011 Dec 1.
PMID: 22133030
citation: Reid DM, Doughty J, Eastell R, Heys SD, Howell A, McCloskey EV, Powles T, Selby P, Coleman RE. Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group. Cancer Treat Rev. 2008;34 Suppl 1:S3-18. doi: 10.1016/j.ctrv.2008.03.007. Epub 2008 Jun 2.
PMID: 18515009
citation: Chien AJ, Goss PE. Aromatase inhibitors and bone health in women with breast cancer. J Clin Oncol. 2006 Nov 20;24(33):5305-12. doi: 10.1200/JCO.2006.07.5382. No abstract available.
PMID: 17114665
citation: Amir E, Seruga B, Niraula S, Carlsson L, Ocana A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst. 2011 Sep 7;103(17):1299-309. doi: 10.1093/jnci/djr242. Epub 2011 Jul 9.
PMID: 21743022
citation: Becker T, Lipscombe L, Narod S, Simmons C, Anderson GM, Rochon PA. Systematic review of bone health in older women treated with aromatase inhibitors for early-stage breast cancer. J Am Geriatr Soc. 2012 Sep;60(9):1761-7. doi: 10.1111/j.1532-5415.2012.04107.x.
PMID: 22985145
citation: Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol. 2001 Jul 15;19(14):3306-11. doi: 10.1200/JCO.2001.19.14.3306.
PMID: 11454877
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PMID: 17267326
citation: Brufsky AM et al, Cancer 118, 398, 2012
citation: Coleman R, de Boer R, Eidtmann H, Llombart A, Davidson N, Neven P, von Minckwitz G, Sleeboom HP, Forbes J, Barrios C, Frassoldati A, Campbell I, Paija O, Martin N, Modi A, Bundred N. Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol. 2013 Feb;24(2):398-405. doi: 10.1093/annonc/mds277. Epub 2012 Oct 9.
PMID: 23047045
citation: Griggs JJ, Liu Y, Sorbero ME, Jagielski CH, Maly RC. Adjuvant chemotherapy dosing in low-income women: the impact of Hispanic ethnicity and patient self-efficacy. Breast Cancer Res Treat. 2014 Apr;144(3):665-72. doi: 10.1007/s10549-014-2869-y. Epub 2014 Mar 5.
PMID: 24596046
citation: Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J, Fan M, Jun S. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008 Oct 20;26(30):4875-82. doi: 10.1200/JCO.2008.16.3832. Epub 2008 Aug 25.
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citation: Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Fan M, Kim D. Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study. Breast Cancer Res Treat. 2009 Nov;118(1):81-7. doi: 10.1007/s10549-009-0352-y. Epub 2009 Mar 24.
PMID: 19308727
citation: Winters-Stone KM, Dobek J, Nail L, Bennett JA, Leo MC, Naik A, Schwartz A. Strength training stops bone loss and builds muscle in postmenopausal breast cancer survivors: a randomized, controlled trial. Breast Cancer Res Treat. 2011 Jun;127(2):447-56. doi: 10.1007/s10549-011-1444-z. Epub 2011 Mar 19. Erratum In: Breast Cancer Res Treat. 2011 Jun;127(2):457.
PMID: 21424279
citation: Saarto T, Sievanen H, Kellokumpu-Lehtinen P, Nikander R, Vehmanen L, Huovinen R, Kautiainen H, Jarvenpaa S, Penttinen HM, Utriainen M, Jaaskelainen AS, Elme A, Ruohola J, Palva T, Vertio H, Rautalahti M, Fogelholm M, Luoto R, Blomqvist C. Effect of supervised and home exercise training on bone mineral density among breast cancer patients. A 12-month randomised controlled trial. Osteoporos Int. 2012 May;23(5):1601-12. doi: 10.1007/s00198-011-1761-4. Epub 2011 Sep 3.
PMID: 21892676
citation: Theodorou DJ, Theodorou SJ, Sartoris DJ. Dual-energy X-ray absorptiometry in diagnosis of osteoporosis: basic principles, indications, and scan interpretation. Compr Ther. 2002 Fall;28(3):190-200. doi: 10.1007/s12019-002-0028-6.
PMID: 12360631
citation: Silva BC, Bilezikian JP. Trabecular bone score: perspectives of an imaging technology coming of age. Arq Bras Endocrinol Metabol. 2014 Jul;58(5):493-503. doi: 10.1590/0004-2730000003456.
PMID: 25166040
citation: Dufour R, Winzenrieth R, Heraud A, Hans D, Mehsen N. Generation and validation of a normative, age-specific reference curve for lumbar spine trabecular bone score (TBS) in French women. Osteoporos Int. 2013 Nov;24(11):2837-46. doi: 10.1007/s00198-013-2384-8. Epub 2013 May 17.
PMID: 23681084
responsible party type: Principal Investigator
investigator affiliation: Rigshospitalet, Denmark
investigator full name: Kristian Buch
investigator title: Principal investigator
mesh term: Hypertension
mesh term: Insulin Resistance
mesh term: Fractures, Bone
sharing ipd: Undecided