The Role of Simvastatin in The Epithelial-Mesenchymal Transition Process of Breast Cancer

Vimentin Expression-based Therapeutic Response in Triple Negative Breast Cancer Receiving Combination of Simvastatin and NAC: A Randomized, Double-Blind, Placebo-Controlled Trial

Introduction: Most cases of Triple Negative Breast Cancer (TNBC) have a high proliferation rate. TNBC is associated with a poor prognosis, a high recurrence rate, and a high incidence of distant metastases. The Epithelial-Mesenchymal Transition process (EMT) plays an essential role in the metastatic process. EMT markers were also more abundant in TNBC and contributed to a poorer TNBC prognosis. As an important EMT marker, the increased expression of vimentin also contributed to the increase in TNBC aggressiveness and resistance to chemotherapeutic agents. Through the mechanism of action in inhibiting the mevalonate pathway, statins can help inhibit the EMT process in metastases. Notably, simvastatin promotes the down-regulation of vimentin in breast cancer cells. The combination of statins and neoadjuvant chemotherapy (NAC) improves the cancer patient's response. This study is expected to evaluate the role of a combination between NAC and simvastatin on therapeutic response in TNBC patients through vimentin expression.

Methods: This study is a double-blind, randomized, placebo-controlled trial conducted in Dr. Cipto Mangunkusumo National Central General Hospital. An expected total of 26 TNBC patients will be assessed for eligibility and asked for informed consent. Patients with the plan to have ACT (Doxorubicin hydrochloride, Cyclophosphamide, Paclitaxel) chemotherapy regimen will receive either a combination of ACT-Simvastatin (40 mg/day) or ACT-Placebo. The biopsy will be taken pre-NAC to make the histopathological diagnosis and examine the expression of vimentin. Patients will be evaluated for adverse effects reaction every cycle and the clinical response after 8 cycles. The post-intervention biopsy will be conducted after the cycle finish. The pathological response and vimentin expression will be reviewed from the obtained samples.

Study Overview

• Status: Recruiting
• Conditions: Triple Negative Breast Cancer; Chemotherapy Effect; Simvastatin Adverse Reaction
• Intervention / Treatment: Drug: Simvastatin 40mg; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 26
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Erwin D Yulian, MD; Phone Number: +6281315249627; Email: erwin.yulian@ui.ac.id

Study Locations

• Indonesia
  • DKI Jakarta
    • Jakarta Pusat, DKI Jakarta, Indonesia, 10430
      • Recruiting
      • Dr. Cipto Mangunkusumo National Central General Hospital
      • Contact: Erwin D Yulian, MD; Phone Number: +6281315249627

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Female patients with advanced breast cancer (locally advanced and distantly advanced) with triple-negative molecular type confirmed by biopsy and immunohistochemical examination.
2. The patient planned to receive 8 cycles of AC-T chemotherapy.
3. Patient age > 18 years.
4. Willing to participate in research by signing informed consent.

Exclusion Criteria:

1. The patient is pregnant or breastfeeding.
2. Patients who have received chemotherapy or are on simvastatin therapy.
3. Allergy to statins.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Simvastatin; The group received standard treatment with simvastatin 40mg in capsule by oral route, once a day, for 21 days (every cycle of the chemotherapy regiment)	Drug: Simvastatin 40mg; The administration of Simvastatin 40 mg in addition to ACT regiment of neoadjuvant chemotherapy; Other Names: Simvastatin
Placebo Comparator: Placebo; The group received standard treatment with placebo 40mg in capsule by oral route, once a day, for 21 days (every cycle of the chemotherapy regiment)	Drug: Placebo; The administration of Placebo capsule 40 mg in addition to ACT regiment of neoadjuvant chemotherapy; Other Names: Placebo oral capsule 40 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vimentin Expression	Vimentin expression is measured based on Histoscore (H-Score) with immunohistochemistry examination: 0-50 : negative (0); 51-100 : weak positive (1+); 101-200 : moderate positive (2+); 201-300 : strong positive (3+)	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Response	Pathological Response as Measured by Miller-Payne system Evaluation before and after chemotherapy, divided into: Grade 1: There is no significant 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 : There are no residual cancer cells. DCIS (Ductal Carcinoma In Situ) might be detected.	6 months
Clinical Response	Clinical response based on WHO (World Health Organization) criteria: Complete Response (CR): Disappearance; Partial Response (PR): 50% decrease; Stable Disease(SD): Neither PR nor PD criteria met; Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease	6 months

Collaborators and Investigators

• Sponsor: Indonesia University
• Investigators: Principal Investigator: Erwin D Yulian, MD, Surgical Oncology Division, Department of Surgery, Universitas Indonesia; Study Director: Tantri Hellyanti, MD, Department of Pathological Anatomy, Universitas Indonesia; Study Chair: Shabrina Adzania, MD, Research Assistant, Department of Surgery, Universitas Indonesia

Study record dates

Study Major Dates

• Study Start (Actual): August 19, 2022
• Primary Completion (Anticipated): August 1, 2024
• Study Completion (Anticipated): February 1, 2025

Study Registration Dates

• First Submitted: September 19, 2022
• First Submitted That Met QC Criteria: September 19, 2022
• First Posted (Actual): September 22, 2022

Study Record Updates

• Last Update Posted (Actual): September 26, 2022
• Last Update Submitted That Met QC Criteria: September 22, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Simvastatin; Neoadjuvant Chemotherapy; Clinical Response; Epithelial-Mesenchymal Transition; Pathological Response; Vimentin
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: IndonesiaU2022

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No