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

Study Overview
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Brief Summary
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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.

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

Conditions
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Triple Negative Breast Cancer, Chemotherapy Effect, Simvastatin Adverse Reaction

Intervention / Treatment
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* Drug: Simvastatin 40mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients with advanced breast cancer (locally advanced and distantly advanced) with triple-negative molecular type confirmed by biopsy and immunohistochemical examination. The patient planned to receive 8 cycles of AC-T chemotherapy. Patient age > 18 years. Willing to participate in research by signing informed consent. Exclusion Criteria: The patient is pregnant or breastfeeding. Patients who have received chemotherapy or are on simvastatin therapy. Allergy to statins.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Simvastatin<br>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<br>* The administration of Simvastatin 40 mg in addition to ACT regiment of neoadjuvant chemotherapy<br>* Other names: Simvastatin;|
| Placebo Comparator: Placebo<br>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<br>* The administration of Placebo capsule 40 mg in addition to ACT regiment of neoadjuvant chemotherapy<br>* Other names: Placebo oral capsule 40 mg;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vimentin, Simvastatin, Epithelial-Mesenchymal Transition, Neoadjuvant Chemotherapy, Clinical Response, Pathological Response