MicroRNA Profiles in Triple Negative Breast Cancer

Study Overview
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Brief Summary
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Triple negative breast cancer (TNBC) is an aggressive disease with higher proportion of Blacks affected and in younger age groups. There is no targeted therapy unlike other types of breast cancer such as hormone positive and Human Epidermal Growth factor 2 (HER2) positive subtypes. Chemotherapy is therefore the main choice of systemic treatment with rapid development of resistance in most cases. At present, there is no blood test to monitor treatment response and disease relapse. This one-stage phase II study with a single arm design will determine the response rate of standard chemotherapy using Epirubicin (60mg/m2), Cyclophosphamide (600mg/m2) , Paclitaxel (120mg/m2) and Carboplatin (6AUC) in TNBC patients. We will measure the blood level of microRNA molecules and circulating tumor DNA during and after treatment to test if changes can be used to indicate drug failure in these patients. Disease status and tumor response will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines while toxicity will be assessed using CTCAE v5). The trial will be conducted as per the International Council on Harmonisation Good Clinical Practice (ICH GCP) Guidelines E6 (R1) and other applicable guidelines

Detailed Description
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Triple negative subtype of breast cancer (TNBC), accounts for about 55% of all breast cancer among indigenous blacks, such as Nigerians, and younger women are more susceptible Patients with TNBC generally experience a more aggressive clinical course with faster disease progression and poorer overall survival. There is no targeted treatment available beyond conventional cytotoxic chemotherapy . Unfortunately, standard chemotherapy is only effective in about 40% of patients with pathological complete response (pCR) achieved only in 20%-30% . Local relapse occurs early. Therefore, chemo-resistance is the main cause of chemotherapeutic failure and leads to suboptimal response rates . There are no biomarkers of response for close monitoring of TNBC patients to identify chemotherapy failure early. This one-stage phase II study with a single arm is designed to assess the response rate and toxicity of Epirubicin-Cyclophosphamide with Paclitaxel-Carboplatin (ECPC) and examine the potential of using circulating microRNa and circulating tumor cells as a surrogate marker of chemotherapy resistance in Nigerian women with triple negative breast cancer. A total of 42 patients will be enrolled into the trial. Each participant will receive Epirubicin (60mg/m2), Cyclophosphamide (600mg/m2) , Paclitaxel (120mg/m2) and Carboplatin (6AUC) . Blood microRNA and circulating tumor DNA will be determined before and after therapy. Tumor response will be measured by breast ultrasound and described using RECIST criteria while toxicity will be graded using CTCAE criteria. Quality of life (QoL) of participants while on chemotherapy will also be assessed using EORTC quality of life questionnaire - (General and Breast cancer specific).

Official Title
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Treatment Response and microRNA Profiles in Triple Negative Breast Cancer Patients Receiving Standard Chemotherapy

Conditions
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Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: Epirubicin
* Drug: Cyclophosphamide
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women ages of 18 to 70 years old Women who give informed consent for the study Biopsy-accessible breast tumor of significant size for core needle biopsy/ultrasound measurable (≥ 2cm) Patients with histologically confirmed carcinoma of the female breast with triple negative status by immuno-histochemistry (IHC) Clinical stages IIA -IIIC (AJCC 2009) Chemotherapy-naïve patients (for this malignancy) Performance status: Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Non-pregnant and not nursing. Women of childbearing potential must take the pregnancy test and must commit to receive Leuteinizing Hormone Realising Hormone (LHRH) agonist Zoladex (goserelin) for two years starting from the commencement of the study medications Required Initial Laboratory Data. Adequate hematologic, renal and hepatic function, as defined by each of the following: 1. Granulocyte ≥ 1,500/μL 2. Platelet count ≥ 100,000/μL 3. Absolute neutrophil count (ANC) ≥ l500/μL 4. Hemoglobin ≥ 10g/dL 5. Bilirubin ≤ 1.5 x upper limit of normal 6. SGOT and SGPT < 2.5 x upper limit of normal 7. Creatinine within institutional normal limits or glomerular filtration rate ≥ 30 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (CKD EPI) equation (see http://mdrd.com/ for calculator) 10. Echocardiogram (ECHO): Baseline left ventricular ejection fraction of ≥ 55% Exclusion Criteria: Pregnant or lactating women. Women of childbearing potential not using a reliable and appropriate contraceptive method. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Patients with distant metastasis (brain and/or visceral metastasis) Serious, uncontrolled, concurrent infection(s). Treatment for other carcinomas within the last 5 years, except non-melanoma skin cancer and treated cervical carcinoma in-situ (CCIS) Participation in any investigational drug study within 4 weeks preceding the start of study treatment Other serious uncontrolled medical conditions that the investigator feels might compromise study participation including but not limited to chronic or active infection, HIV-positive patient, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled Diabetes mellitus, or psychiatric illness/social situations that would limit compliance with study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Intervention Model: Single Group Assignment
Interventional Model Description: This is a one-stage phase II study with a single arm design. All patients will receive 4 cycles of epirubicin + cyclophosphamide followed by paclitaxel +carboplatin for four cycles in the neo-adjuvant setting. Those with clinical response (assessed via breast ultrasound), will undergo surgery. After surgery, all patients who achieve pCR will undergo radiotherapy. Patients with pathological incomplete response or stable disease may have additional chemotherapy at the discretion of the managing physician.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epirubicin-Cyclophosphamide plus Paclitaxel- Carboplatin<br>Epirubicin 60mg/m2 with cyclophosphamide 600/m2 every three weeks for four courses followed by paclitaxel 120mg/m2 and carboplatin 6 AUC every three weeks for four courses | Drug: Epirubicin<br>* Epirubicin is an antitumor antibiotics with good activity on breast cancer. It has less cardiotoxic effect than doxorubicin<br>* Other names: Cytoxan;Drug: Cyclophosphamide<br>* Cyclophosphamide is a cytoxic drug indicated for the treatment of many malignancies including breast cancer<br>* Other names: Cytoxan;Drug: Paclitaxel<br>* Paclitaxel is a taxane chemotherapy agent indicated for the treatment of many cancers including breast cancer. It can be used alone or in combination with other drugs<br>* Other names: Taxol;Drug: Carboplatin<br>* Carboplatin is a platinum compound indicated for the treatment of many types of malignancies including breast cancer<br>* Other names: Paraplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants achieving pathological complete response (pCR) at surgery following neoadjuvant treatment with epirubicin + cyclophosphamide every three weeks for four cycles followed by paclitaxel + carboplatin every three weeks for four cycles | Percentage of participants achieving pathological complete response (pCR) at surgery | 4 - 6 months from commencement of chemotherapy. (Surgery will be performed within 4-6 weeks after completion of chemotherapy | 
| Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0 | Percentage of participants experiencing grades 3 and 4 hematological, gastro-intestinal, neurological and cardiovascular toxicities. | From the date of commencement of chemotherapy till date of first documentation of adverse event up to 60 months or withdrawal or death from any cause or which ever occurs first. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants without disease for 2 , 5 and 10 years respectively | Invasive Disease Free Survival (iDFS ) | From date of first dose of study drug treatment up to a maximum of 120 months years. | 
| Change in quality of life (QoL) score of patients from baseline using the EORTC quality of life questionnaire during chemotherapy and at study completion | The various domains of QoL over time and the changes from baseline using the validated European Organization for Research and Treatment of Cancer (EORTC)) QoL instrument (global and breast module). | From date of commencement of study medications up to 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, neoadjuvant treatment, microRNA, circulating tumor cells