<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/NCT04418089</url>
  </required_header>
  <id_info>
    <org_study_id>18040334</org_study_id>
    <nct_id>NCT04418089</nct_id>
  </id_info>
  <brief_title>Simvastatin Effect in Combination With Neoadjuvant Chemotherapy to Clinical Response and Tumor-Free Margin in Locally Advanced Breast Cancer</brief_title>
  <official_title>Combination of CAF and Simvastatin Improves Response to Neoadjuvant Chemotherapy and Increases Tumor-Free Margin in Locally Advanced Breast Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Indonesia University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Indonesia University</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Introduction: Neoadjuvant chemotherapy (NACT) has been the standard therapy for treating&#xD;
      patients with locally advanced breast cancer (LABC). Doxorubicin-based regimen showed a&#xD;
      clinical response for 70-80%. However, the cardiotoxicity from it was not tolerable.&#xD;
      Simvastatin acts synergistically with doxorubicin against MCF-7 cells, through downregulation&#xD;
      of the cell cycle or induction of apoptosis. Also, it alleviates doxorubicin cardiotoxicity&#xD;
      by attenuating ER stress and activating the Akt pathway. Hmgcris a new pathway mediating&#xD;
      doxorubicin-induced cell death, and cholesterol control drugs combined with doxorubicin could&#xD;
      enhance efficacy and reduce side effects. This study is conducted to see the combination&#xD;
      simvastatin and CAF would increase the NACT response and surgical margin of LABC patients.&#xD;
&#xD;
      Methods: This study was a double-blind, randomized placebo-controlled trial, conducted in dr.&#xD;
      Cipto Mangunkusumo General Hospital and Koja General Hospital. A total of 70 LABC patients&#xD;
      were assessed for eligibility. Patients received either a combination of CAF-Simvastatin (40&#xD;
      mg/day) or CAF-Placebo. The biopsy was taken pre-NACT to make the histopathological diagnosis&#xD;
      and examine the expression of HMG-CoA Reductase (Hmgcr) and P-glycoprotein (P-gp). Patients&#xD;
      were evaluated for the clinical response after 3 cycles. If the response was positive,&#xD;
      patients will proceed to surgery. Then, the post-operative specimen will be reviewed for the&#xD;
      pathological response. However, if it was a negative response, patients will be given 2nd&#xD;
      line NACT.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Backgrounds Neoadjuvant chemotherapy (NACT) which is followed by surgery is now a standard&#xD;
      therapy in the local advanced breast cancer (LABC) since it was introduced 50 years ago,&#xD;
      increasingly being used in early-stage LABC patients. Some NACT studies in RSCM use a&#xD;
      doxorubicin-based regimen, giving a 70-80% partial response, but do not require a complete&#xD;
      response both clinically and pathologically. The NACT response was 80% with a complete&#xD;
      clinical response of 36%. The complete pathological response obtained after NACT is the&#xD;
      prognosis of a replacement marker both overall and disease-free survival in the LABC. The&#xD;
      purpose of giving NACTis to increase tumor resectability and de-escalation surgery and kill&#xD;
      micrometastasis which will increase the length of disease-free and life expectancy of the&#xD;
      patient. New tumor margins causing post-NACT tumor shrinkage can be used as surgical margins.&#xD;
&#xD;
      Doxorubicin-based chemotherapy is the most commonly given chemotherapy for NACT as well as&#xD;
      entering the first line of the National Formulary. However, side effects are limited from&#xD;
      drug resistance side effects that can cause cardiomyopathy and heart failure. One of the&#xD;
      factors that influence doxorubicin resistance is the presence of efflux pumps such as&#xD;
      P-glycoprotein (P-gp) on the cell surface. While the effects of toxicity arise due to the&#xD;
      formation of reactive oxygen species (ROS) and the presence of free radicals. Efforts to&#xD;
      improve the efficacy of the combination of chemotherapy currently being used with targeted&#xD;
      therapies such as anti-HER-2 and bevacizumab, but have a high enough toxicity and are&#xD;
      expensive and not included in ForNas. Likewise, some drugs that have been tested in vitro as&#xD;
      P-gp inhibitors/modifiers, but failed in clinical trials because of ineffectiveness and&#xD;
      greater side effects on the kidneys and heart. Some previous studies have confirmed that&#xD;
      simvastatin is a potential ABCB1 / P-gp inhibitor.&#xD;
&#xD;
      Statins are the most widely used anti-hypercholesterolemia in the world, through inhibition&#xD;
      of 3-hydroxy-3-methylglutaryl coenzyme-A reductase (Hmgcr) which is an enzyme that limits the&#xD;
      use of the mevalonate pathway that can be used as intracellular cholesterol. Besides having&#xD;
      pleiotropic effects, statins also have anti-tumor effects. At this time, statins have&#xD;
      received approval as a potential anti-tumor agent because several epidemiological studies&#xD;
      have agreed on the relationship between statin use and reducing the risk of recurrence of&#xD;
      LABC after adjuvant therapy. Some preclinical studies show that statins can decrease breast&#xD;
      cancer cell proliferation and induce apoptosis in various experimental models. results from&#xD;
      pre-operative &quot;window-of-opportunity&quot; clinical trials on LABC so that statins can reduce&#xD;
      tumor proliferation and induce apoptosis. Reports in the RSCM get simvastatin 40 mg for 4&#xD;
      weeks for neoadjuvant reduce the proliferation index in the LABC by 53.3% and inhibit the&#xD;
      increase in LABC cells through the Rho / Rock pathway. Although several studios of statin&#xD;
      antitumor activity have been carried out, the role of statins in oncology has not yielded&#xD;
      satisfactory results or controversies and provides heterogeneous responses depending on the&#xD;
      molecular identity and tumor type malignancy. The results of a clinical preliminary study&#xD;
      indicate that giving a single statin is not as effective as an anti-cancer because it&#xD;
      requires large effects and large side effects.&#xD;
&#xD;
      Several in vitro studies and animal models show that the combination of statins can increase&#xD;
      the accumulation of intra-cell chemotherapy so that the effects of potentiation of&#xD;
      chemotherapy arise. The administration of a combination of doxorubicin statins increases the&#xD;
      potential for anti-cancer effects through the accumulation of doxorubicin in cancer cells,&#xD;
      causing the potential for DNA damage, inhibition of proliferation, and induction of&#xD;
      apoptosis. statins can also protect cardiotoxic induced by doxorubicin if it is given&#xD;
      pre-therapy in mice. With a variety of anti-tumor mechanisms as well as the enormous benefits&#xD;
      and potential addition of statins that can be well-tolerated, safe, and inexpensive. However,&#xD;
      until now the effects of antiproliferation synergy and induction of apoptosis combination of&#xD;
      simvastatin and doxorubicin in LABC patients are not well known. This study aims to determine&#xD;
      the efficacy, tolerability, and safety of simvastatin combination and CAF chemotherapy as&#xD;
      neo-advanced therapy in LABC patients. The use of this combination is expected to improve&#xD;
      clinical and pathological responses as well as surgical margins while providing&#xD;
      cardioprotection effects, so as to provide the best service with high oncological value.&#xD;
&#xD;
      Methods&#xD;
&#xD;
        1. Subject and study design This research is a double-blind, placebo-controlled clinical&#xD;
           trial conducted at Dr. Cipto Mangunkusumo General Hospital and Koja General Hospital&#xD;
           from January 2018 to September 2019. Eligible patients are patients with grade IIIA to&#xD;
           IIIC invasive breast cancer that is histologically proven. A total of 60 LABC patients&#xD;
           were included in this study. Participants received a combination of NACT CAF and&#xD;
           Simvastatin (40 mg / day) (n = 30) or placebo (n = 30). Besides being used to make a&#xD;
           histopathological diagnosis, samples were taken by biopsy before NACT, examined for the&#xD;
           expression of HMG-CoA Reductase (HMGCR) and P-glycoprotein (P-gp). Participants were&#xD;
           evaluated for the clinical response after 3 NACT cycles. If it gives a complete or&#xD;
           partial response, then the patient will proceed to surgery. Then, the postoperative&#xD;
           specimen will be reviewed for a pathological response. However, if it is stable or&#xD;
           progressive, the patient will be given a 2nd line NACT.&#xD;
&#xD;
        2. Tumor assessment The primary outcome was clinical response while the secondary outcome&#xD;
           was the pathological response, incision boundary, P-gp expression, Hmgcr expression and&#xD;
           side effects. The analysis was performed on the population per protocol. Clinical&#xD;
           response assessment uses WHO 1979 criteria. Pathological responses of tumors are&#xD;
           evaluated according to the Miller-Payne scoring system. MPG classification is used to&#xD;
           evaluate the relevance between pathological response and clinical response. The incision&#xD;
           boundary assessment is performed using histopathological tissue incisions depending on&#xD;
           the surgical margins of the tumor on the medial, lateral, cranial, caudal, and baseline&#xD;
           sides of the tumor; based on the size of the new tumor. Histopathological results will&#xD;
           determine whether the level is free from the tumor or not based on the size of the new&#xD;
           tumor. Disease assessment is carried out by investigation after 3 NACT cycles. Side&#xD;
           effects were assessed during treatment and for 7 days after the last treatment dose and&#xD;
           assessed using CTCAE 3.0.&#xD;
&#xD;
        3. Biomarker assessment Estimation of P-glycoprotein (Pgp) and Hmgcr expression was seen&#xD;
           under a microscope from a sample after a core biopsy was performed before starting&#xD;
           chemotherapy. P-gp expression was interpreted based on the percentage of p-glycoprotein&#xD;
           positive cells in the total cell population (low = 0%, 1+ = 1-19%, and 2 + = 20-100%&#xD;
           positive cells). Hmgcr expression is interpreted based on the percentage of Hmgcr&#xD;
           positive cells in the total cell population (negative = 0%, 1+ = 1-10%, 2+ = 11-50%, 3+&#xD;
           =&gt; 51-100% positive cells)..&#xD;
&#xD;
        4. Statistical analysis The main results in this study were clinical responses based on WHO&#xD;
           1970 criteria. ORR values in this study were calculated from the ratio of the number of&#xD;
           patients who showed a response (complete and partial) to the total number of patients&#xD;
           and were analyzed using the Pearson Chi-Square Test. Secondary outcomes in the form of&#xD;
           pathological responses based on GMP and incision boundaries were analyzed using Fisher's&#xD;
           Exact Test. Bivariate analysis of clinicopathological variables and molecular biology&#xD;
           with the therapeutic response using the Continuity Correction Test and the Fischer's&#xD;
           Exact Test. The results of the bivariate analysis with p&gt; 0.25 were performed&#xD;
           multivariate analysis using the Logistic Regression Test. The analysis was performed&#xD;
           with the help of a computer using the SPSS 23 program. Differences were stated to be&#xD;
           meaningful and obtained p values &lt;0.05.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 15, 2018</start_date>
  <completion_date type="Actual">September 5, 2019</completion_date>
  <primary_completion_date type="Actual">May 20, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical Response as WHO 1979</measure>
    <time_frame>3 months</time_frame>
    <description>Clinical Response is measured using WHO 1979 criteria.&#xD;
Complete Response (CR): Disappearance; confirmed at 3 months&#xD;
Partial Response (PR): 50% decrease; confirmed at 3 months&#xD;
Stable Disease(SD): Neither PR nor PD criteria met&#xD;
Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pathological Response as Measured by Miller-Payne system</measure>
    <time_frame>3 months</time_frame>
    <description>Evaluation of the MP system is based on the reduction of tumor cellularity before and after chemotherapy, divided into:&#xD;
Grade 1 ie there is no change or reduction in cancer cells.&#xD;
Grade 2: reduction of &lt;30% cancer cells&#xD;
Grade 3: reduction of cancer cells between 30-90%&#xD;
Grade 4: reduction of &gt; 90% cancer cells&#xD;
Grade 5 is that there are no residual cancer cells. Grade 4 is categorized as partial pathology response. Grade 5 is categorized as a complete pathology response</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Surgical margin as measured by histopathological</measure>
    <time_frame>3 months</time_frame>
    <description>histopathologically the tissue to the tumor incision limit on the medial, lateral, cranial, and caudal sides along with the tumor base; based on the size of the new tumor. Hisopathologically assesses the extent of incision free or not tumor based on the size of the new tumor.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association of P-gp expression with response by WHO criteria</measure>
    <time_frame>3 months</time_frame>
    <description>Clinical Response is measured using WHO 1979 criteria.&#xD;
Complete Response (CR): Disappearance; confirmed at 3 months&#xD;
Partial Response (PR): 50% decrease; confirmed at 3 months&#xD;
Stable Disease(SD): Neither PR nor PD criteria met&#xD;
Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association of Hmgcr expression with response by WHO criteria</measure>
    <time_frame>3 months</time_frame>
    <description>Clinical Response is measured using WHO 1979 criteria.&#xD;
Complete Response (CR): Disappearance; confirmed at 3 months&#xD;
Partial Response (PR): 50% decrease; confirmed at 3 months&#xD;
Stable Disease(SD): Neither PR nor PD criteria met&#xD;
Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Breast Cancer</condition>
  <condition>Chemotherapy Effect</condition>
  <arm_group>
    <arm_group_label>Simvastatin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The group received standard treatment with the oral administration of Simvastatin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The group received standard treatment with the oral administration of Placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Simvastatin 40mg</intervention_name>
    <description>The administration of Simvastatin 40 mg in addition to neoadjuvant chemoterapy CAF</description>
    <arm_group_label>Simvastatin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo oral capsule</intervention_name>
    <description>The administration of Placebo capsule 40 mg in addition to neoadjuvant chemoterapy CAF</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  LABC IIIA-IIIC TNM / AJCC 2018 with histopathological examination.&#xD;
&#xD;
          -  Patients are planned to get NACT&#xD;
&#xD;
          -  Performance status of Eastern Cooperative Oncology Group (ECOG) 0-2.&#xD;
&#xD;
          -  LABC patients who have not received surgery, radiation or systemic therapy and&#xD;
             previous statin therapy.&#xD;
&#xD;
          -  Normal kidney organ function (serum creatinine ≤ 1.5 upper limit normal).&#xD;
&#xD;
          -  Normal liver organ function (ALT ≤ 2 times the normal limit, or total bilirubin level&#xD;
             ≤ 1.5 times the normal upper limit)&#xD;
&#xD;
          -  Heart function (E / F)&gt; 55%&#xD;
&#xD;
          -  Willing to participate in this study by signing an informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  LABC patients are both residual and recurrent.&#xD;
&#xD;
          -  Allergy to tattoo ink&#xD;
&#xD;
          -  Allergy to statins&#xD;
&#xD;
          -  Patients are pregnant or breastfeeding&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nurjati Chairani Siregar, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Department of Pathology, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Baju Adji</last_name>
    <role>Study Chair</role>
    <affiliation>Department of Surgery, Koja General Hospital, Jakarta, Indonesia</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Filipus Dasawala, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hanifah Hasan, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Internship Program as Research Assistant, Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Muhammad Rizki Kamil, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Internship Program as Research Assistant, Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Faculty of Medicine, Universitas Indonesia</name>
      <address>
        <city>Jakarta Pusat</city>
        <state>DKI Jakarta</state>
        <zip>10430</zip>
        <country>Indonesia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Indonesia</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>May 27, 2020</study_first_submitted>
  <study_first_submitted_qc>June 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 5, 2020</study_first_posted>
  <last_update_submitted>June 4, 2020</last_update_submitted>
  <last_update_submitted_qc>June 4, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 5, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Indonesia University</investigator_affiliation>
    <investigator_full_name>Dr. dr. Erwin Danil Yulian, Sp.B (K) Onk</investigator_full_name>
    <investigator_title>Lecturer, Staff of Oncology Division of Department of Surgery, Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Simvastatin</keyword>
  <keyword>Local Advanced Breast Cancer</keyword>
  <keyword>Clinical Response</keyword>
  <keyword>Pathological Response</keyword>
  <keyword>Surgical Margins</keyword>
  <keyword>Neoadjuvant Chemoterapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Simvastatin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT04418089
org study id: 18040334
nct id: NCT04418089
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Introduction: Neoadjuvant chemotherapy (NACT) has been the standard therapy for treating
      patients with locally advanced breast cancer (LABC). Doxorubicin-based regimen showed a
      clinical response for 70-80%. However, the cardiotoxicity from it was not tolerable.
      Simvastatin acts synergistically with doxorubicin against MCF-7 cells, through downregulation
      of the cell cycle or induction of apoptosis. Also, it alleviates doxorubicin cardiotoxicity
      by attenuating ER stress and activating the Akt pathway. Hmgcris a new pathway mediating
      doxorubicin-induced cell death, and cholesterol control drugs combined with doxorubicin could
      enhance efficacy and reduce side effects. This study is conducted to see the combination
      simvastatin and CAF would increase the NACT response and surgical margin of LABC patients.

      Methods: This study was a double-blind, randomized placebo-controlled trial, conducted in dr.
      Cipto Mangunkusumo General Hospital and Koja General Hospital. A total of 70 LABC patients
      were assessed for eligibility. Patients received either a combination of CAF-Simvastatin (40
      mg/day) or CAF-Placebo. The biopsy was taken pre-NACT to make the histopathological diagnosis
      and examine the expression of HMG-CoA Reductase (Hmgcr) and P-glycoprotein (P-gp). Patients
      were evaluated for the clinical response after 3 cycles. If the response was positive,
      patients will proceed to surgery. Then, the post-operative specimen will be reviewed for the
      pathological response. However, if it was a negative response, patients will be given 2nd
      line NACT.
Backgrounds Neoadjuvant chemotherapy (NACT) which is followed by surgery is now a standard
      therapy in the local advanced breast cancer (LABC) since it was introduced 50 years ago,
      increasingly being used in early-stage LABC patients. Some NACT studies in RSCM use a
      doxorubicin-based regimen, giving a 70-80% partial response, but do not require a complete
      response both clinically and pathologically. The NACT response was 80% with a complete
      clinical response of 36%. The complete pathological response obtained after NACT is the
      prognosis of a replacement marker both overall and disease-free survival in the LABC. The
      purpose of giving NACTis to increase tumor resectability and de-escalation surgery and kill
      micrometastasis which will increase the length of disease-free and life expectancy of the
      patient. New tumor margins causing post-NACT tumor shrinkage can be used as surgical margins.

      Doxorubicin-based chemotherapy is the most commonly given chemotherapy for NACT as well as
      entering the first line of the National Formulary. However, side effects are limited from
      drug resistance side effects that can cause cardiomyopathy and heart failure. One of the
      factors that influence doxorubicin resistance is the presence of efflux pumps such as
      P-glycoprotein (P-gp) on the cell surface. While the effects of toxicity arise due to the
      formation of reactive oxygen species (ROS) and the presence of free radicals. Efforts to
      improve the efficacy of the combination of chemotherapy currently being used with targeted
      therapies such as anti-HER-2 and bevacizumab, but have a high enough toxicity and are
      expensive and not included in ForNas. Likewise, some drugs that have been tested in vitro as
      P-gp inhibitors/modifiers, but failed in clinical trials because of ineffectiveness and
      greater side effects on the kidneys and heart. Some previous studies have confirmed that
      simvastatin is a potential ABCB1 / P-gp inhibitor.

      Statins are the most widely used anti-hypercholesterolemia in the world, through inhibition
      of 3-hydroxy-3-methylglutaryl coenzyme-A reductase (Hmgcr) which is an enzyme that limits the
      use of the mevalonate pathway that can be used as intracellular cholesterol. Besides having
      pleiotropic effects, statins also have anti-tumor effects. At this time, statins have
      received approval as a potential anti-tumor agent because several epidemiological studies
      have agreed on the relationship between statin use and reducing the risk of recurrence of
      LABC after adjuvant therapy. Some preclinical studies show that statins can decrease breast
      cancer cell proliferation and induce apoptosis in various experimental models. results from
      pre-operative "window-of-opportunity" clinical trials on LABC so that statins can reduce
      tumor proliferation and induce apoptosis. Reports in the RSCM get simvastatin 40 mg for 4
      weeks for neoadjuvant reduce the proliferation index in the LABC by 53.3% and inhibit the
      increase in LABC cells through the Rho / Rock pathway. Although several studios of statin
      antitumor activity have been carried out, the role of statins in oncology has not yielded
      satisfactory results or controversies and provides heterogeneous responses depending on the
      molecular identity and tumor type malignancy. The results of a clinical preliminary study
      indicate that giving a single statin is not as effective as an anti-cancer because it
      requires large effects and large side effects.

      Several in vitro studies and animal models show that the combination of statins can increase
      the accumulation of intra-cell chemotherapy so that the effects of potentiation of
      chemotherapy arise. The administration of a combination of doxorubicin statins increases the
      potential for anti-cancer effects through the accumulation of doxorubicin in cancer cells,
      causing the potential for DNA damage, inhibition of proliferation, and induction of
      apoptosis. statins can also protect cardiotoxic induced by doxorubicin if it is given
      pre-therapy in mice. With a variety of anti-tumor mechanisms as well as the enormous benefits
      and potential addition of statins that can be well-tolerated, safe, and inexpensive. However,
      until now the effects of antiproliferation synergy and induction of apoptosis combination of
      simvastatin and doxorubicin in LABC patients are not well known. This study aims to determine
      the efficacy, tolerability, and safety of simvastatin combination and CAF chemotherapy as
      neo-advanced therapy in LABC patients. The use of this combination is expected to improve
      clinical and pathological responses as well as surgical margins while providing
      cardioprotection effects, so as to provide the best service with high oncological value.

      Methods

        1. Subject and study design This research is a double-blind, placebo-controlled clinical
           trial conducted at Dr. Cipto Mangunkusumo General Hospital and Koja General Hospital
           from January 2018 to September 2019. Eligible patients are patients with grade IIIA to
           IIIC invasive breast cancer that is histologically proven. A total of 60 LABC patients
           were included in this study. Participants received a combination of NACT CAF and
           Simvastatin (40 mg / day) (n = 30) or placebo (n = 30). Besides being used to make a
           histopathological diagnosis, samples were taken by biopsy before NACT, examined for the
           expression of HMG-CoA Reductase (HMGCR) and P-glycoprotein (P-gp). Participants were
           evaluated for the clinical response after 3 NACT cycles. If it gives a complete or
           partial response, then the patient will proceed to surgery. Then, the postoperative
           specimen will be reviewed for a pathological response. However, if it is stable or
           progressive, the patient will be given a 2nd line NACT.

        2. Tumor assessment The primary outcome was clinical response while the secondary outcome
           was the pathological response, incision boundary, P-gp expression, Hmgcr expression and
           side effects. The analysis was performed on the population per protocol. Clinical
           response assessment uses WHO 1979 criteria. Pathological responses of tumors are
           evaluated according to the Miller-Payne scoring system. MPG classification is used to
           evaluate the relevance between pathological response and clinical response. The incision
           boundary assessment is performed using histopathological tissue incisions depending on
           the surgical margins of the tumor on the medial, lateral, cranial, caudal, and baseline
           sides of the tumor; based on the size of the new tumor. Histopathological results will
           determine whether the level is free from the tumor or not based on the size of the new
           tumor. Disease assessment is carried out by investigation after 3 NACT cycles. Side
           effects were assessed during treatment and for 7 days after the last treatment dose and
           assessed using CTCAE 3.0.

        3. Biomarker assessment Estimation of P-glycoprotein (Pgp) and Hmgcr expression was seen
           under a microscope from a sample after a core biopsy was performed before starting
           chemotherapy. P-gp expression was interpreted based on the percentage of p-glycoprotein
           positive cells in the total cell population (low = 0%, 1+ = 1-19%, and 2 + = 20-100%
           positive cells). Hmgcr expression is interpreted based on the percentage of Hmgcr
           positive cells in the total cell population (negative = 0%, 1+ = 1-10%, 2+ = 11-50%, 3+
           => 51-100% positive cells)..

        4. Statistical analysis The main results in this study were clinical responses based on WHO
           1970 criteria. ORR values in this study were calculated from the ratio of the number of
           patients who showed a response (complete and partial) to the total number of patients
           and were analyzed using the Pearson Chi-Square Test. Secondary outcomes in the form of
           pathological responses based on GMP and incision boundaries were analyzed using Fisher's
           Exact Test. Bivariate analysis of clinicopathological variables and molecular biology
           with the therapeutic response using the Continuity Correction Test and the Fischer's
           Exact Test. The results of the bivariate analysis with p> 0.25 were performed
           multivariate analysis using the Logistic Regression Test. The analysis was performed
           with the help of a computer using the SPSS 23 program. Differences were stated to be
           meaningful and obtained p values <0.05.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Supportive Care
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Clinical Response as WHO 1979
time frame: 3 months
description: Clinical Response is measured using WHO 1979 criteria.
Complete Response (CR): Disappearance; confirmed at 3 months
Partial Response (PR): 50% decrease; confirmed at 3 months
Stable Disease(SD): Neither PR nor PD criteria met
Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease
measure: Pathological Response as Measured by Miller-Payne system
time frame: 3 months
description: Evaluation of the MP system is based on the reduction of tumor cellularity before and after chemotherapy, divided into:
Grade 1 ie there is no change or reduction in cancer cells.
Grade 2: reduction of <30% cancer cells
Grade 3: reduction of cancer cells between 30-90%
Grade 4: reduction of > 90% cancer cells
Grade 5 is that there are no residual cancer cells. Grade 4 is categorized as partial pathology response. Grade 5 is categorized as a complete pathology response
measure: Surgical margin as measured by histopathological
time frame: 3 months
description: histopathologically the tissue to the tumor incision limit on the medial, lateral, cranial, and caudal sides along with the tumor base; based on the size of the new tumor. Hisopathologically assesses the extent of incision free or not tumor based on the size of the new tumor.
measure: Association of P-gp expression with response by WHO criteria
time frame: 3 months
description: Clinical Response is measured using WHO 1979 criteria.
Complete Response (CR): Disappearance; confirmed at 3 months
Partial Response (PR): 50% decrease; confirmed at 3 months
Stable Disease(SD): Neither PR nor PD criteria met
Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease
measure: Association of Hmgcr expression with response by WHO criteria
time frame: 3 months
description: Clinical Response is measured using WHO 1979 criteria.
Complete Response (CR): Disappearance; confirmed at 3 months
Partial Response (PR): 50% decrease; confirmed at 3 months
Stable Disease(SD): Neither PR nor PD criteria met
Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease
arm group label: Simvastatin
arm group type: Experimental
description: The group received standard treatment with the oral administration of Simvastatin
arm group label: Placebo
arm group type: Experimental
description: The group received standard treatment with the oral administration of Placebo
intervention type: Drug
intervention name: Simvastatin 40mg
description: The administration of Simvastatin 40 mg in addition to neoadjuvant chemoterapy CAF
arm group label: Simvastatin
intervention type: Drug
intervention name: Placebo oral capsule
description: The administration of Placebo capsule 40 mg in addition to neoadjuvant chemoterapy CAF
arm group label: Placebo
criteria: 
gender: Female
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Nurjati Chairani Siregar, MD
role: Study Chair
affiliation: Department of Pathology, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
last name: Baju Adji
role: Study Chair
affiliation: Department of Surgery, Koja General Hospital, Jakarta, Indonesia
last name: Filipus Dasawala, MD
role: Study Chair
affiliation: Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
last name: Hanifah Hasan, MD
role: Study Chair
affiliation: Internship Program as Research Assistant, Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
last name: Muhammad Rizki Kamil, MD
role: Study Chair
affiliation: Internship Program as Research Assistant, Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
facility: 
country: Indonesia
responsible party type: Principal Investigator
investigator affiliation: Indonesia University
investigator full name: Dr. dr. Erwin Danil Yulian, Sp.B (K) Onk
investigator title: Lecturer, Staff of Oncology Division of Department of Surgery, Principal Investigator
mesh term: Breast Neoplasms
mesh term: Simvastatin
sharing ipd: No