Biomarkers Investigation of Neoadjuvant Chemotherapy for Breast Cancer

Study Overview
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Brief Summary
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The BINC-B trial is a diagnostic and interventional study in which various function imaging methods as Magnetic Resonance Imaging (PWI, DWI and DCE-MRI) and will be compared with common imaging methods (mammography and/or ultrasound) to investigate if an early response to a combined neoadjuvant chemotherapy in operable or potentially operable breast cancer. For breast cancer patients with positive HER-2, additional Herceptin could improve the response further. In this study the efficacy of combined neoadjuvant therapy with or without Herceptin should be evaluated and the role in predicting the tumor response with different imaging should be estimated.

Detailed Description
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Firstly, the investigators aim to show that the results of functional imaging including dynamic enhanced, diffuse weighted, and perfusion MR imaging biomarkers as well the ultrasonic outcome could be used to predict the response to the neoadjuvant chemotherapy for operable and potentially operable breast cancer (luminal B, HER-2 positive and triple negative). Secondly, the investigators will study the role of peripheral blood biomarker including circulating tumor DNA (ctDNA), circulating endothelial cells (CECs) and subsets, myeloid-derived suppressor cells (MDSCs), and lymph cell subsets and their combinations could predict the response of the tumor measured with imaging. Thirdly, the investigators will establish a mode with these multiple imaging and serum biomarker panel as well as their changes during the treatment course establish to predict the response to neoadjuvant chemotherapy.

Official Title
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The Role of Multimodal Imaging and Circulating Biomarkers in Predicting the Response of Neoadjuvant Chemotherapy for Breast Cancer

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age ≥18 years and ≤70 years Female Operable or potentially operable primary breast cancer (≥ cT2, N0 or N+, M0); Confirmed by core biopsy Histological confirmed unilateral, solitaire breast cancer Baseline LVEF ≥55% (measured by echocardiography) according to institution specific norm Informed consent for clinical trial including analysis of predictive imaging tests and biomarkers Clinically or by imaging (mammogram, MRI or US) assessed breast cancer ≥2 cm with bi-dimensional measurable lesion independent of nodal status Negative pregnancy test (urine or serum) within 7 days prior to registration if patient is premenopausal with intact reproductive organs and if patient is less than one year after menopause ECOG Performance status 0-2 Adequate organ function for cytotoxic chemotherapy Adequate renal function including Serum creatinine ≤ ULN, Measured or calculated creatinine clearance > 60 ml per min Absolute neutrophil count ≤ 1500/µL, platelet count ≥ 100,000/µL Bilirubin ≤ ULN; ALT or AST ≤ 1.5 x ULN, and alkaline phosphatase ≤2.5 x ULN Patients must be available and compliant for treatment and follow-up Exclusion Criteria Evidence of distant metastases by clinical or imaging diagnosis Multifocal primary tumor, defined as histologically confirmed tumor-manifestations within different quadrants; distance ≥ 4 cm Pre-existing motor or sensory neuropathy of a severity ≥ grade 2 NCI criteria Previous breast cancer Prior malignancy with a disease-free survival of < 5 year Prior malignancy which has not been curatively treated Inflammatory breast cancer Prior systemic therapy for cancer Patients with immunosuppressive therapy Pregnant or lactating women Women of childbearing potential not using highly effective birth control Patients with known hypersensitivity reactions to the compounds or incorporated substances of trastuzumab or its constituents (for HER2+ tumors) Invasive malignancy which could affect compliance with the protocol or interpretation of results Other serious illness or medical condition including: Known or suspected congestive heart failure (>NYHA I) and/or coronary heart disease, Angina pectoris requiring antianginal medication; Previous history of myocardial infarction, Evidence of transmural infarction on ECG, Un- or poorly controlled arterial hypertension (i.e. BP >150/100 mmHg under treatment with two antihypertensive drugs), Rhythm abnormalities requiring permanent treatment; Clinically significant valvular heart disease, Patients with dyspnea at rest due to malignant or other disease or who require supportive oxygen therapy, Active serious uncontrolled infections, Poorly controlled diabetes, History of hypertensive crisis or hypertensive encephalopathy; History of TIA or CVA Neutrophil count of < 1500, platelet count of < 100,000/µL, Haemoglobin < 10 g/dL Inadequate bone marrow, hepatic and renal functions as evidenced by the following: Serum total bilirubin > ULN, ALT or AST > 1.5 x ULN, Alkaline phosphatase > 2.5 x ULN, serum creatinine > ULN Concurrent treatment with any other anti-cancer therapy No informed consent for analysis of predictive imaging tests and biomarkers Contraindications against MRI: Cardiac pacemakers, other forms of medical or biostimulation implants, ferromagnetic foreign bodies or metallic implants (e.g. surgical protheses, aneurysm clips), implanted insulin pumps, valvular implants, allergy to contrast agent, renal insufficiency, claustrophobia Active peptic ulcer, incomplete wound healing or unhealed bone fracture Disease significantly affecting gastrointestinal function, e.g. malabsorption syndrome, resection of the stomach or small bowel, ulcerative colitis, abdominal fistula, intra-abdominal abscess within 6 months of enrolment or gastrointestinal perforation Concurrent treatment with other experimental drugs; participation in another clinical trial with any investigational drug within 30 days prior to study entry Chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids)

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: Sequential Assignment
Interventional Model Description: epirubicin, paclitaxol, cyclophosphamide, trastuzumab
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant chemotherapy<br>Epirubicin 100mg/m2 and cyclophosphamine 600mg/m2 for four cycles followed by paclitaxol 175mg/m2 for four cycles with (for patients with positive HER-2) or without Trastuzumab (loading dose of 6 mg/kg followed by 4 mg/kg every 2 weeks for four cycles), each cycle is 14 days. | Drug: Chemotherapy<br>* AC followed by T Chemotherapy with or without trastuzumab, i.e. Epirubicin 100mg/m2 and cyclophosphamine 600mg/m2 for four cycles followed by paclitaxol 175mg/m2 for four cycles with (for patients with positive HER-2) or without Trastuzumab (loading dose of 6 mg/kg followed by 4 mg/kg every 2 weeks for four cycles), each cycle is 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pathological complete response (pCR) | Rate of pathological complete response (pCR) following neoadjuvant therapy and to determine efficacy of neoadjuvant therapy in primary breast cancer using pCR (According to National Surgical Adjuvant Breast and Bowel Project guideline) | from the first day of the the first cycle (each cycle is 14 days) of neoadjuvant chemotherapy to the date that breast and axillary sugery will be performed | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | the summary of clinical complete response and partial response (RESICIST 1.1 criteria) | from the first day of the the first cycle (each cycle is 14 days) of neoadjuvant chemotherapy to the date that breast and axillary sugery will be performed | 
| Disease free survival | from the beginning of neoadjuvant chemotherapy to the confirmed time of recurrence or metastatic disease, or death due to any other cause. | from the first day of the the first cycle of neoadjuvant chemotherapy (each cycle is 14 days) to the date of first documented progression or date of death from breast cancer, whichever came first, assessed up to 60 months | 
| Overall survival | from the beginning of neoadjuvant chemotherapy to the death with any causes | from the first day of the the first cycle (each cycle is 14 days) of neoadjuvant chemotherapy to the date of death from any cause, whichever came first, assessed up to 60 months |