<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/NCT04476485</url>
  </required_header>
  <id_info>
    <org_study_id>ShengjingH 3</org_study_id>
    <nct_id>NCT04476485</nct_id>
  </id_info>
  <brief_title>Sj-subway, a Predictor for the Recurrence of High-risk Hormone Receptor-positive Breast That is Sensitive to Extended Endocrine Therapy</brief_title>
  <official_title>A Newly Discovered Clinical Recurrence Predictor for High-risk Hormone Receptor-positive Breast Cancer: a Real Word Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Shengjing Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Shengjing Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hormone receptor-positive breast cancer accounts for about 70% of all breast cancers.&#xD;
      Extended endocrine therapy with aromatase inhibitor is the current main treatment for hormone&#xD;
      receptor-positive breast cancer. However, previous studies have shown a long-lasting risk of&#xD;
      the recurrence of hormone receptor-positive breast cancer at early stage, and disease&#xD;
      recurrence is considered inevitable only depending on a 5-year of adjuvant endocrine therapy.&#xD;
      Therefore, extended endocrine therapy is considered as a possible measure to reduce the risk&#xD;
      of recurrence.&#xD;
&#xD;
      Numerous clinical studies have focused on extended endocrine therapy in patients with&#xD;
      specific types of breast cancer. In 2017, the National Comprehensive Cancer Network (NCCN)&#xD;
      updated the recommends for extended endocrine therapy with aromatase inhibitor, where&#xD;
      postmenopausal early-stage breast cancer patients wo have high risk factors may be considered&#xD;
      to be given an extended 5-year endocrine treatment with aromatase inhibitor after the initial&#xD;
      5-year treatment. In 2019, the Chinese Society of Clinical Oncology also suggested that&#xD;
      postmenopausal hormone receptor-positive patients who have been well tolerated to the initial&#xD;
      5 years of adjuvant endocrine therapy can be given the extended endocrine therapy under some&#xD;
      restrictions.&#xD;
&#xD;
      However, extended endocrine therapy may also cause other risks in patients. Long-term&#xD;
      tamoxifen treatment can significantly increase the incidence of adverse reactions such as&#xD;
      endometrial cancer, thrombotic disease, and dyslipidemia, and long-term aromatase inhibitor&#xD;
      treatment can also increase the incidence of osteoporosis, fractures, dyslipidemia, and&#xD;
      hypertension. Although anti-cancer treatment can reduce cancer deaths, it may increase deaths&#xD;
      due to cardiovascular diseases.&#xD;
&#xD;
      An attempt has been proposed to find out an indicator that can effectively determine the&#xD;
      necessity of extended endocrine therapy in such patients, not only improving the prognosis of&#xD;
      breast cancer patients, but also reducing treatment-related side effects. The author's team&#xD;
      recently discovered sj-subway, a possible factor with a long tubular structure in breast&#xD;
      cancer lesions. The authors found that the higher expression of sj-subway indicates the worse&#xD;
      patient's prognosis. So the positive expression of sj-subway may be a predictor of recurrence&#xD;
      and metastasis in high-risk hormone receptor-positive patients. However, whether this&#xD;
      predictor can be used clinically remains to be studied.&#xD;
&#xD;
      This real-world study intends to analyze the difference in the clinical efficacy of extended&#xD;
      endocrine therapy under different sj-subway expression in high-risk hormone receptor-positive&#xD;
      breast cancer patients, and to explore whether sj-subway can screen out the patients who can&#xD;
      benefit from extended endocrine therapy, thus providing a therapeutic help for hormone&#xD;
      receptor-positive breast cancer patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Breast cancer has been one of the most common malignant tumors in women, accounting for 23%&#xD;
      of all the malignancies. There are estimated 1,300,000 new cases of breast cancers and&#xD;
      400,000 deaths due to breast cancers every year in the world. Hormone receptor-positive&#xD;
      breast cancer accounts for about 70% of all breast cancers.&#xD;
&#xD;
      Since ovarian resection was first used in the treatment of advanced breast cancer in the late&#xD;
      19th century, with more than a century of development, endocrine therapy has become the most&#xD;
      important adjuvant therapy for hormone receptor-positive breast cancers, especially for&#xD;
      advanced breast cancers. Increasing clinical trials of adjuvant endocrine therapy such as&#xD;
      ATAC, BIG1-98, and IES, which have been implemented since 2002, have ascertained the effect&#xD;
      of adjuvant endocrine therapy with aromatase inhibitor, and the guidelines for the diagnosis&#xD;
      and treatment of breast cancer have been also changed accordingly.&#xD;
&#xD;
      Although early-stage hormone receptor-positive breast cancer patients have a better prognosis&#xD;
      than HER-2 positive and triple-negative patients, there is still a long-lasting risk of&#xD;
      postoperative recurrence, which has been confirmed in two large-scale meta-analyses reported&#xD;
      by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG). A meta-analysis released&#xD;
      by the EBCTCG in 1998 indicated that early-stage hormone receptor-positive breast cancer&#xD;
      patients, especially lymph node-positive patients, experienced the second recurrence peak at&#xD;
      2-3 years and 7-9 years after completion of endocrine therapy. In 2016, the EBCTCG released&#xD;
      another relevant study at the annual meeting of the American Society of Clinical Oncology&#xD;
      (ASCO), in which the long-term recurrence rate within 5-20 years was up to 14% in T1N0 breast&#xD;
      cancer patients who had undergone 5 years of adjuvant endocrine therapy. Therefore, the 5&#xD;
      years of standard adjuvant endocrine therapy cannot eliminate the risk of recurrence. Most&#xD;
      scholars have suggested that the duration of endocrine therapy should be extended to reduce&#xD;
      the recurrence risk of breast cancer.&#xD;
&#xD;
      Numerous clinical trials have focused on the use of extended endocrine therapy in patients&#xD;
      with specific types of breast cancer. In the MA17R trial, patients received 3-5 years of&#xD;
      tamoxifen or 5 years of aromatase inhibitor treatment, followed by another 5 years of&#xD;
      aromatase inhibitor treatment. The extended aromatase inhibitor treatment was found to&#xD;
      significantly improve the disease-free survival time of hormone receptor-positive early&#xD;
      breast cancer patients, while also reducing the risk of contralateral breast cancer and&#xD;
      distant relapse. In the NSABP B42 trial, patients who had received initial 5 years of&#xD;
      aromatase inhibitor treatment or initial 5 years of tamoxifen + aromatase inhibitor treatment&#xD;
      were all treated with extended aromatase inhibitor. Although the primary endpoint (P = 0.048)&#xD;
      did not reach the expected value, extended treatment with aromatase inhibitors significantly&#xD;
      reduced the secondary endpoints - breast cancer-free interval and distant relapse, confirming&#xD;
      the conclusion of the MA17R study. In the DATA trial, although extended treatment with&#xD;
      aromatase inhibitor did not benefit in general, subgroup analysis showed that some high-risk&#xD;
      patients, such as patients with positive lymph nodes, tumors larger than 2 cm in diameter, or&#xD;
      receiving chemotherapy, could benefit from 6 years of anastrozole treatment. The IDEAL trial&#xD;
      showed that there is a trend of benefit in patients with positive lymph nodes. With the&#xD;
      support of many large-scale clinical studies published in succession, the NCCN practice&#xD;
      guidelines for breast cancer released in 2017 recommends an additional 5 years of aromatase&#xD;
      inhibitor treatment following the initial 5-year treatment in postmenopausal patients with&#xD;
      early-stage breast cancer at high risk for relapse. As per the Chinese Society of Clinical&#xD;
      Oncology guidelines published in 2019, the extended endocrine therapy is also recommended for&#xD;
      postmenopausal hormone receptor-positive patients who have been well tolerated to the initial&#xD;
      5-year adjuvant treatment. However, there are some restrictions, such as positive lymph&#xD;
      nodes, G3 or other risk factors that require adjuvant chemotherapy. For premenopausal hormone&#xD;
      receptor-positive patients who have been well tolerated to the initial 5 years of endocrine&#xD;
      treatment, extended endocrine therapy is also recommended in some situations, such as the&#xD;
      presence of positive lymph nodes, G3, less than 35 years old at diagnosis, high-level Ki-67&#xD;
      or pT2 and above.&#xD;
&#xD;
      However, the extended endocrine therapy also has some adverse events. Multiple studies have&#xD;
      shown that long-term use of tamoxifen can significantly increase the incidence of adverse&#xD;
      reactions such as endometrial cancer, thrombotic disease, and dyslipidemia. Similarly,&#xD;
      long-term treatment with aromatase inhibitors can also increase the incidence of adverse&#xD;
      reactions such as osteoporosis, fractures, dyslipidemia, and hypertension. In the ATLAS&#xD;
      trial, the incidence of endometrial cancer in patients treated with 10 years of tamoxifen was&#xD;
      higher than that in patients treated with 5 years of tamoxifen. Similar results are&#xD;
      discovered in the aTTom trial. In the IDEAL trial, the incidence rates of osteoarthritis and&#xD;
      osteoporosis in patients treated with 5 years of letrozole was increased by 14% and 10% of&#xD;
      that in patients undergoing 2.5 years of treatment. A study involving nearly 100,000 breast&#xD;
      cancer patients showed that only 49.9% of breast cancer patients died of breast cancer, 16.3%&#xD;
      died of cardiovascular disease, and 33.8% died of other causes. Among them, breast cancer and&#xD;
      cardiovascular disease were the main causes of death in well- and poor-tolerated patients,&#xD;
      respectively. This suggests that although anti-cancer treatment can reduce cancer deaths, it&#xD;
      may increase the death due to cardiovascular disease. Such deaths are often offset, which&#xD;
      often improves the BCFI, but does not benefit the overall survival.&#xD;
&#xD;
      Therefore, an effective predictor for relapse risks that can accurately determine the&#xD;
      necessity of extended endocrine therapy is expected to be discovered. The use of this&#xD;
      predictor will both improve patient's prognosis and reduce treatment-related side effects.&#xD;
      The author's team recently discovered a possible factor with a long tubular structure in&#xD;
      breast cancer lesions using immunofluorescence staining, which was named as sj-subway. The&#xD;
      authors conducted a retrospective analysis based on the specimen library and case follow-up&#xD;
      library of the Breast Center of Shengjing Hospital Affiliated to China Medical University.&#xD;
      They found that sj-subway was positively expressed in various subtypes of breast cancer&#xD;
      tissues, and mostly expressed in the hormone receptor-positive subtype. The group with more&#xD;
      sj-subway expression had a higher positive expression of hormone receptor/ progesterone&#xD;
      receptor. Further survival analysis also revealed the worse prognosis of patients with the&#xD;
      existence of higher sj-subway expression. Therefore, the authors speculate that positively&#xD;
      expressed sj-subway may become a predictor of recurrence and metastasis in high-risk patients&#xD;
      with hormone receptor positive. However, the clinical use of this factor to screen the&#xD;
      population benefiting from extended endocrine therapy remains to be studied.&#xD;
&#xD;
      This real-world study intends to observe the difference in the clinical efficacy of extended&#xD;
      endocrine therapy under different sj-subway expression in high-risk hormone receptor-positive&#xD;
      breast cancer patients, and to analyze whether the use of sj-subway can further screen out&#xD;
      the population with benefit from extended endocrine therapy, thus further improving the&#xD;
      survival of such patients without additional adverse events.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Anticipated">July 19, 2021</start_date>
  <completion_date type="Anticipated">December 31, 2026</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2021</primary_completion_date>
  <study_type>Observational [Patient Registry]</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>
  <target_duration>10 Years</target_duration>
  <primary_outcome>
    <measure>disease-free survival</measure>
    <time_frame>5 years after enrollment</time_frame>
    <description>the time from enrollment to relapse or death due to any reason.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>5 years after enrollment</time_frame>
    <description>the time from enrollment to death due to any reason</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of contralateral breast cancer</measure>
    <time_frame>1, 2, 3, 4, and 5 years after enrollment</time_frame>
    <description>the proportion of contralateral breast cancer. Evaluations will be made at 1, 2, 3, 4, and 5 years after enrollment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>1, 2, 3, 4, and 5 years after enrollment</time_frame>
    <description>the proportion of adverse events, including osteoporosis, bone pain, fractures, dyslipidemia, endometrial lesions. Evaluations will be made 1, 2, 3, 4, and 5 years after enrollment</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">1000</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>experimental group</arm_group_label>
    <description>If the expression of sj-subway in the surgical wax block is eligible, it is recommended but not mandatory that patients follow the guidelines to choose the appropriate extended endocrine therapy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>endocrine therapy</intervention_name>
    <description>If the expression of sj-subway in the surgical wax block is eligible, it is recommended but not mandatory that patients follow the guidelines to choose the appropriate extended endocrine therapy. 1. For postmenopausal patients: Extend treatment with aromatase inhibitors 10 years: letrozole or anastrozole or exemestane. 2. For premenopausal patients: An initial 5 years tamoxifen treatment followed by additional 5 years extended tamoxifen treatment. Postmenopausals are treated with aromatase inhibitors 5 years. 3. For patients have completed ovarian function suppression plus initial 5-year aromatase inhibitor treatment: Menopausals: Aromatase inhibitors; Non-menopausals: 5 years of tamoxifen treatment or ovarian function suppression plus 5 years of aromatase inhibitor treatment. 4. For patients have completed ovarian function suppression plus initial 5-year tamoxifen treatment: Menopausals: Aromatase inhibitors for additional 5 years; Non-menopausals: Tamoxifen for additional 5 years.</description>
    <arm_group_label>experimental group</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        The early-stage invasive breast cancer positive for estrogen receptor and / or progesterone&#xD;
        receptor and have completed standard endocrine therapy for 5 years.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  early-stage invasive breast cancer positive for estrogen receptor and / or&#xD;
             progesterone receptor is pathologically confirmed;&#xD;
&#xD;
          -  patients who have completed standard endocrine therapy for 5 years without recurrence&#xD;
             and metastasis;&#xD;
&#xD;
          -  18-70 years old;&#xD;
&#xD;
          -  patients with one of the following six manifestations: KI67 ≥ 30%; tumor size &gt; 2 cm;&#xD;
             positive lymph nodes; histological grade III; vascular cancer thrombus; HER-2 gene&#xD;
             overexpression or amplification.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  with a history of other malignancies;&#xD;
&#xD;
          -  patients who have severe abnormalities in important organs, such as the heart, liver,&#xD;
             and kidney or who cannot be tolerant to extended treatment due to poor constitution;&#xD;
&#xD;
          -  patients with severe osteoporosis or dyslipidemia, or those who cannot tolerate&#xD;
             endocrine therapy ;&#xD;
&#xD;
          -  patients who have participated in other clinical trials.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jin-Qi Xue</last_name>
    <role>Principal Investigator</role>
    <affiliation>Shengjing hospital affiliated to China Medical University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Xi Gu</last_name>
    <role>Principal Investigator</role>
    <affiliation>Shengjing hospital affiliated to China Medical University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Nan Niu</last_name>
    <role>Principal Investigator</role>
    <affiliation>Shengjing hospital affiliated to China Medical University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Tian-Hui Xia</last_name>
    <role>Principal Investigator</role>
    <affiliation>Shengjing hospital affiliated to China Medical University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Wei Tu</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fourth Affiliated Hospital of China Medical University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hong Xu</last_name>
    <role>Principal Investigator</role>
    <affiliation>Liaoning Cancer Hospital &amp; Institute</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hao Zhang</last_name>
    <role>Principal Investigator</role>
    <affiliation>Liaoning Cancer Hospital &amp; Institute</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Yuan-Xi Huang</last_name>
    <role>Principal Investigator</role>
    <affiliation>Heilongjiang Cancer Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Shao-Qiang Cheng</last_name>
    <role>Principal Investigator</role>
    <affiliation>Heilongjiang Cancer Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Bing-Shu Xia</last_name>
    <role>Principal Investigator</role>
    <affiliation>Heilongjiang Cancer Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Wen-Bin Guo</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dalian Municipal Central Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Xue Jiang</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dalian Municipal Central Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Cai-Gang Liu, MD</last_name>
    <phone>18940254967</phone>
    <email>angel-s205@163.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Cancer Hospital Affiliated to Harbin Medical University</name>
      <address>
        <city>Harbin</city>
        <state>Heilongjiang</state>
        <zip>150081</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Xuesong Chen</last_name>
      <phone>+8615804500816</phone>
      <email>cxs1978@163.com</email>
    </contact>
    <investigator>
      <last_name>Xuesong Chen</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The Second Hospital of Jilin University</name>
      <address>
        <city>Changchun</city>
        <state>Jilin</state>
        <zip>130041</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yingchao Zhang</last_name>
      <email>zhang_yc@jlu.edu.cn</email>
    </contact>
    <investigator>
      <last_name>Yingchao Zhang</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Dalian Municipal Central Hospital</name>
      <address>
        <city>Dalian</city>
        <state>Liaoning</state>
        <zip>116033</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Wenbin Guo</last_name>
      <phone>+8613079850586</phone>
      <email>drguowb@hotmail.com</email>
    </contact>
    <investigator>
      <last_name>Wenbin Guo</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Panjin Liaohe Oilfield Gem Flower Hospital</name>
      <address>
        <city>Panjin</city>
        <state>Liaoning</state>
        <zip>124010</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hongbin Han</last_name>
      <phone>+8613704236001</phone>
      <email>rose_030201@163.com</email>
    </contact>
    <investigator>
      <last_name>Hongbin Han</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Shengjing Hospital affiliated to China Medical University</name>
      <address>
        <city>Shenyang</city>
        <state>Liaoning</state>
        <zip>110004</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Nan Niu, MD</last_name>
    </contact>
    <investigator>
      <last_name>Cai-Gang Liu, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Shengjing Hospital of China Medical University</name>
      <address>
        <city>Shenyang</city>
        <state>Liaoning</state>
        <zip>110004</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Xi Gu</last_name>
      <phone>+86 18940255116</phone>
      <email>jadegx@163.com</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Shengjing Hospital of China Medical University</name>
      <address>
        <city>Shenyang</city>
        <state>Liaoning</state>
        <zip>110004</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Caigang Liu</last_name>
      <phone>+86 18940254967</phone>
      <email>liucg@sj-hospital.org</email>
    </contact>
    <contact_backup>
      <last_name>Rong Wu</last_name>
      <phone>+86 18940251156</phone>
      <email>wur@sj-hospital.com</email>
    </contact_backup>
    <investigator>
      <last_name>Caigang Liu</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Rong Wu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Shengjing Hospital of China Medical University</name>
      <address>
        <city>Shenyang</city>
        <state>Liaoning</state>
        <zip>110004</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Nan Niu, MD</last_name>
      <phone>+8618940256668</phone>
      <email>niunannancy@163.com</email>
    </contact>
    <investigator>
      <last_name>Cai-Gang Liu, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The Fourth Affiliated Hospital of China Medical University</name>
      <address>
        <city>Shenyang</city>
        <state>Liaoning</state>
        <zip>110032</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Wei Tu</last_name>
      <phone>+8618900913000</phone>
      <email>cmu4htw@126.com</email>
    </contact>
    <investigator>
      <last_name>Wei Tu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Liaoning Cancer Hospital &amp; Institute</name>
      <address>
        <city>Shenyang</city>
        <state>Liaoning</state>
        <zip>110042</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hong Xu</last_name>
      <phone>+8618900917779</phone>
      <email>xh4015@163.com</email>
    </contact>
    <investigator>
      <last_name>Hong Xu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Liaoning Tumor Hospital &amp; Institute</name>
      <address>
        <city>Shenyang</city>
        <state>Liaoning</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hong Xu</last_name>
      <phone>+86-18900917779</phone>
      <email>xh4015@163.com</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>People's Hospital of Liaoning Province</name>
      <address>
        <city>Shenyang</city>
        <state>Liaoning</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Qingfeng Liu</last_name>
      <phone>+86-17702486789</phone>
      <email>drliuqf1970@126.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>July 15, 2020</study_first_submitted>
  <study_first_submitted_qc>July 17, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 20, 2020</study_first_posted>
  <last_update_submitted>July 18, 2021</last_update_submitted>
  <last_update_submitted_qc>July 18, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 20, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Shengjing Hospital</investigator_affiliation>
    <investigator_full_name>Caigang Liu</investigator_full_name>
    <investigator_title>Director</investigator_title>
  </responsible_party>
  <keyword>receptor, estrogen</keyword>
  <keyword>endocrine therapy</keyword>
  <keyword>aromatase inhibitor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Recurrence</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/NCT04476485
org study id: ShengjingH 3
nct id: NCT04476485
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Hormone receptor-positive breast cancer accounts for about 70% of all breast cancers.
      Extended endocrine therapy with aromatase inhibitor is the current main treatment for hormone
      receptor-positive breast cancer. However, previous studies have shown a long-lasting risk of
      the recurrence of hormone receptor-positive breast cancer at early stage, and disease
      recurrence is considered inevitable only depending on a 5-year of adjuvant endocrine therapy.
      Therefore, extended endocrine therapy is considered as a possible measure to reduce the risk
      of recurrence.

      Numerous clinical studies have focused on extended endocrine therapy in patients with
      specific types of breast cancer. In 2017, the National Comprehensive Cancer Network (NCCN)
      updated the recommends for extended endocrine therapy with aromatase inhibitor, where
      postmenopausal early-stage breast cancer patients wo have high risk factors may be considered
      to be given an extended 5-year endocrine treatment with aromatase inhibitor after the initial
      5-year treatment. In 2019, the Chinese Society of Clinical Oncology also suggested that
      postmenopausal hormone receptor-positive patients who have been well tolerated to the initial
      5 years of adjuvant endocrine therapy can be given the extended endocrine therapy under some
      restrictions.

      However, extended endocrine therapy may also cause other risks in patients. Long-term
      tamoxifen treatment can significantly increase the incidence of adverse reactions such as
      endometrial cancer, thrombotic disease, and dyslipidemia, and long-term aromatase inhibitor
      treatment can also increase the incidence of osteoporosis, fractures, dyslipidemia, and
      hypertension. Although anti-cancer treatment can reduce cancer deaths, it may increase deaths
      due to cardiovascular diseases.

      An attempt has been proposed to find out an indicator that can effectively determine the
      necessity of extended endocrine therapy in such patients, not only improving the prognosis of
      breast cancer patients, but also reducing treatment-related side effects. The author's team
      recently discovered sj-subway, a possible factor with a long tubular structure in breast
      cancer lesions. The authors found that the higher expression of sj-subway indicates the worse
      patient's prognosis. So the positive expression of sj-subway may be a predictor of recurrence
      and metastasis in high-risk hormone receptor-positive patients. However, whether this
      predictor can be used clinically remains to be studied.

      This real-world study intends to analyze the difference in the clinical efficacy of extended
      endocrine therapy under different sj-subway expression in high-risk hormone receptor-positive
      breast cancer patients, and to explore whether sj-subway can screen out the patients who can
      benefit from extended endocrine therapy, thus providing a therapeutic help for hormone
      receptor-positive breast cancer patients.
Breast cancer has been one of the most common malignant tumors in women, accounting for 23%
      of all the malignancies. There are estimated 1,300,000 new cases of breast cancers and
      400,000 deaths due to breast cancers every year in the world. Hormone receptor-positive
      breast cancer accounts for about 70% of all breast cancers.

      Since ovarian resection was first used in the treatment of advanced breast cancer in the late
      19th century, with more than a century of development, endocrine therapy has become the most
      important adjuvant therapy for hormone receptor-positive breast cancers, especially for
      advanced breast cancers. Increasing clinical trials of adjuvant endocrine therapy such as
      ATAC, BIG1-98, and IES, which have been implemented since 2002, have ascertained the effect
      of adjuvant endocrine therapy with aromatase inhibitor, and the guidelines for the diagnosis
      and treatment of breast cancer have been also changed accordingly.

      Although early-stage hormone receptor-positive breast cancer patients have a better prognosis
      than HER-2 positive and triple-negative patients, there is still a long-lasting risk of
      postoperative recurrence, which has been confirmed in two large-scale meta-analyses reported
      by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG). A meta-analysis released
      by the EBCTCG in 1998 indicated that early-stage hormone receptor-positive breast cancer
      patients, especially lymph node-positive patients, experienced the second recurrence peak at
      2-3 years and 7-9 years after completion of endocrine therapy. In 2016, the EBCTCG released
      another relevant study at the annual meeting of the American Society of Clinical Oncology
      (ASCO), in which the long-term recurrence rate within 5-20 years was up to 14% in T1N0 breast
      cancer patients who had undergone 5 years of adjuvant endocrine therapy. Therefore, the 5
      years of standard adjuvant endocrine therapy cannot eliminate the risk of recurrence. Most
      scholars have suggested that the duration of endocrine therapy should be extended to reduce
      the recurrence risk of breast cancer.

      Numerous clinical trials have focused on the use of extended endocrine therapy in patients
      with specific types of breast cancer. In the MA17R trial, patients received 3-5 years of
      tamoxifen or 5 years of aromatase inhibitor treatment, followed by another 5 years of
      aromatase inhibitor treatment. The extended aromatase inhibitor treatment was found to
      significantly improve the disease-free survival time of hormone receptor-positive early
      breast cancer patients, while also reducing the risk of contralateral breast cancer and
      distant relapse. In the NSABP B42 trial, patients who had received initial 5 years of
      aromatase inhibitor treatment or initial 5 years of tamoxifen + aromatase inhibitor treatment
      were all treated with extended aromatase inhibitor. Although the primary endpoint (P = 0.048)
      did not reach the expected value, extended treatment with aromatase inhibitors significantly
      reduced the secondary endpoints - breast cancer-free interval and distant relapse, confirming
      the conclusion of the MA17R study. In the DATA trial, although extended treatment with
      aromatase inhibitor did not benefit in general, subgroup analysis showed that some high-risk
      patients, such as patients with positive lymph nodes, tumors larger than 2 cm in diameter, or
      receiving chemotherapy, could benefit from 6 years of anastrozole treatment. The IDEAL trial
      showed that there is a trend of benefit in patients with positive lymph nodes. With the
      support of many large-scale clinical studies published in succession, the NCCN practice
      guidelines for breast cancer released in 2017 recommends an additional 5 years of aromatase
      inhibitor treatment following the initial 5-year treatment in postmenopausal patients with
      early-stage breast cancer at high risk for relapse. As per the Chinese Society of Clinical
      Oncology guidelines published in 2019, the extended endocrine therapy is also recommended for
      postmenopausal hormone receptor-positive patients who have been well tolerated to the initial
      5-year adjuvant treatment. However, there are some restrictions, such as positive lymph
      nodes, G3 or other risk factors that require adjuvant chemotherapy. For premenopausal hormone
      receptor-positive patients who have been well tolerated to the initial 5 years of endocrine
      treatment, extended endocrine therapy is also recommended in some situations, such as the
      presence of positive lymph nodes, G3, less than 35 years old at diagnosis, high-level Ki-67
      or pT2 and above.

      However, the extended endocrine therapy also has some adverse events. Multiple studies have
      shown that long-term use of tamoxifen can significantly increase the incidence of adverse
      reactions such as endometrial cancer, thrombotic disease, and dyslipidemia. Similarly,
      long-term treatment with aromatase inhibitors can also increase the incidence of adverse
      reactions such as osteoporosis, fractures, dyslipidemia, and hypertension. In the ATLAS
      trial, the incidence of endometrial cancer in patients treated with 10 years of tamoxifen was
      higher than that in patients treated with 5 years of tamoxifen. Similar results are
      discovered in the aTTom trial. In the IDEAL trial, the incidence rates of osteoarthritis and
      osteoporosis in patients treated with 5 years of letrozole was increased by 14% and 10% of
      that in patients undergoing 2.5 years of treatment. A study involving nearly 100,000 breast
      cancer patients showed that only 49.9% of breast cancer patients died of breast cancer, 16.3%
      died of cardiovascular disease, and 33.8% died of other causes. Among them, breast cancer and
      cardiovascular disease were the main causes of death in well- and poor-tolerated patients,
      respectively. This suggests that although anti-cancer treatment can reduce cancer deaths, it
      may increase the death due to cardiovascular disease. Such deaths are often offset, which
      often improves the BCFI, but does not benefit the overall survival.

      Therefore, an effective predictor for relapse risks that can accurately determine the
      necessity of extended endocrine therapy is expected to be discovered. The use of this
      predictor will both improve patient's prognosis and reduce treatment-related side effects.
      The author's team recently discovered a possible factor with a long tubular structure in
      breast cancer lesions using immunofluorescence staining, which was named as sj-subway. The
      authors conducted a retrospective analysis based on the specimen library and case follow-up
      library of the Breast Center of Shengjing Hospital Affiliated to China Medical University.
      They found that sj-subway was positively expressed in various subtypes of breast cancer
      tissues, and mostly expressed in the hormone receptor-positive subtype. The group with more
      sj-subway expression had a higher positive expression of hormone receptor/ progesterone
      receptor. Further survival analysis also revealed the worse prognosis of patients with the
      existence of higher sj-subway expression. Therefore, the authors speculate that positively
      expressed sj-subway may become a predictor of recurrence and metastasis in high-risk patients
      with hormone receptor positive. However, the clinical use of this factor to screen the
      population benefiting from extended endocrine therapy remains to be studied.

      This real-world study intends to observe the difference in the clinical efficacy of extended
      endocrine therapy under different sj-subway expression in high-risk hormone receptor-positive
      breast cancer patients, and to analyze whether the use of sj-subway can further screen out
      the population with benefit from extended endocrine therapy, thus further improving the
      survival of such patients without additional adverse events.
observational model: Cohort
time perspective: Prospective
measure: disease-free survival
time frame: 5 years after enrollment
description: the time from enrollment to relapse or death due to any reason.
measure: Overall survival
time frame: 5 years after enrollment
description: the time from enrollment to death due to any reason
measure: Incidence of contralateral breast cancer
time frame: 1, 2, 3, 4, and 5 years after enrollment
description: the proportion of contralateral breast cancer. Evaluations will be made at 1, 2, 3, 4, and 5 years after enrollment
measure: Incidence of adverse events
time frame: 1, 2, 3, 4, and 5 years after enrollment
description: the proportion of adverse events, including osteoporosis, bone pain, fractures, dyslipidemia, endometrial lesions. Evaluations will be made 1, 2, 3, 4, and 5 years after enrollment
arm group label: experimental group
description: If the expression of sj-subway in the surgical wax block is eligible, it is recommended but not mandatory that patients follow the guidelines to choose the appropriate extended endocrine therapy.
intervention type: Other
intervention name: endocrine therapy
description: If the expression of sj-subway in the surgical wax block is eligible, it is recommended but not mandatory that patients follow the guidelines to choose the appropriate extended endocrine therapy. 1. For postmenopausal patients: Extend treatment with aromatase inhibitors 10 years: letrozole or anastrozole or exemestane. 2. For premenopausal patients: An initial 5 years tamoxifen treatment followed by additional 5 years extended tamoxifen treatment. Postmenopausals are treated with aromatase inhibitors 5 years. 3. For patients have completed ovarian function suppression plus initial 5-year aromatase inhibitor treatment: Menopausals: Aromatase inhibitors; Non-menopausals: 5 years of tamoxifen treatment or ovarian function suppression plus 5 years of aromatase inhibitor treatment. 4. For patients have completed ovarian function suppression plus initial 5-year tamoxifen treatment: Menopausals: Aromatase inhibitors for additional 5 years; Non-menopausals: Tamoxifen for additional 5 years.
arm group label: experimental group
study pop: 
sampling method: Probability Sample
criteria: 
gender: Female
gender based: Yes
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Jin-Qi Xue
role: Principal Investigator
affiliation: Shengjing hospital affiliated to China Medical University
last name: Xi Gu
role: Principal Investigator
affiliation: Shengjing hospital affiliated to China Medical University
last name: Nan Niu
role: Principal Investigator
affiliation: Shengjing hospital affiliated to China Medical University
last name: Tian-Hui Xia
role: Principal Investigator
affiliation: Shengjing hospital affiliated to China Medical University
last name: Wei Tu
role: Principal Investigator
affiliation: Fourth Affiliated Hospital of China Medical University
last name: Hong Xu
role: Principal Investigator
affiliation: Liaoning Cancer Hospital & Institute
last name: Hao Zhang
role: Principal Investigator
affiliation: Liaoning Cancer Hospital & Institute
last name: Yuan-Xi Huang
role: Principal Investigator
affiliation: Heilongjiang Cancer Hospital
last name: Shao-Qiang Cheng
role: Principal Investigator
affiliation: Heilongjiang Cancer Hospital
last name: Bing-Shu Xia
role: Principal Investigator
affiliation: Heilongjiang Cancer Hospital
last name: Wen-Bin Guo
role: Principal Investigator
affiliation: Dalian Municipal Central Hospital
last name: Xue Jiang
role: Principal Investigator
affiliation: Dalian Municipal Central Hospital
last name: Cai-Gang Liu, MD
phone: 18940254967
email: angel-s205@163.com
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Shengjing Hospital
investigator full name: Caigang Liu
investigator title: Director
mesh term: Breast Neoplasms
mesh term: Recurrence
sharing ipd: Undecided