Study of Breast Cancer Shrinkage Modes After Neoadjuvant Chemotherapy With Whole-mount Serial Sections and Three-dimensional Pathological and MRI Reconstruction (BCSMANC)

Phase III Trail of Breast Cancer Shrinkage Modes After Neoadjuvant Chemotherapy With Whole-mount Serial Sections and Three-dimensional Pathological and MRI Reconstruction

The main clinical goal of NAC is to down-stage the primary tumor for BCS,yet BCS after NAC has been associated with significantly higher ipsilateral breast tumor recurrences.The accuracy of breast tumor excision in BCS can dramatically reduce IBTR.The main reseason of IBTR might be the uncertain shrinkage modes of the breast cancer after NAC.This clinical trial is firstly carried out to make clear the shrinkage modes of the primary tumor after 3 cycles and whole cycles of NAC,respectively,with whole-mount serial section(WMSS) and three-dimensional(3D) pathological reconstruction of the residual tumor.The second objective is to investigate the predictive value of 3D MRI reconstruction for the shrinkage modes of the primary tumor after NAC.

Study Overview

• Status: Unknown
• Conditions: Breast Cancer
• Intervention / Treatment: Device: Ultrasound; Procedure: CNB; Procedure: BCS, Modified Radical Mastectomy; Device: Pathologic Large Tissue Selected Table; Device: Leica TP1020; Device: Pathologic Large Tissue Embedded Table; Device: Leica SM2000 R; Procedure: HE Stain; Device: CX22; Device: Epson V600; Procedure: Three-Dimensional Reconstruction; Device: Mammography; Drug: TAC,TC,TA,CAF,CEF; Device: MRI; Drug: AC-P,TEC,AC,TC,TCH,CEF,TAC,CAF

• Study Type: Interventional
• Enrollment (Anticipated): 4
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China, 250117
      • Recruiting
      • Shandong Cancer Hospital
      • Principal Investigator: Yong-sheng Wang, MD
      • Contact: Tao Yang, MD; Phone Number: +8618264190568; Email: yangtao133252@aliyun.com
      • Principal Investigator: Tao Yang, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Female patients,locally advanced breast cancer,age ≥18 years.
2. Histologically confirmed invasive adenocarcinoma of the breast.
3. Primary palpable disease confined to a breast and axilla on physical examination. For patients without clinically suspicious axillary adenopathy, the primary tumor must be larger than 2 cm in diameter by physical exam or imaging studies (clinical T2-T3, N0-N1, M0). For patients with clinically suspicious axillary adenopathy, the primary breast tumor can be any size (clinical T1-3, N1-2, M0). (T1N0M0 lesions are excluded.)
4. Patients without clearly defined palpable breast mass or axillary lymph nodes but radiographically measurable tumor masses are acceptable. Accepted procedures for measuring breast disease are mammography, MRI, and breast ultrasound. This will need to be re-evaluated after 3 cycles and prior to surgery.
5. ECOG 0 or 2
6. No distant metastasis, as documented by complete staging workup ≤6 weeks prior to initiation of study treatment.
7. No previous treatment for breast cancer.

8. Adequate hematologic function with:

   Absolute neutrophil count (ANC) >1500/μL. Platelets ≥100,000/μL. Hemoglobin ≥10 g/dL.

9. Adequate hepatic function with:

   Serum bilirubin ≤ the institutional upper limit of normal (ULN). Aspartate aminotransferase (AST) ≤2.5 x institutional ULN. Alanine aminotransferase (ALT) ≤2.5 x institutional ULN.

10. Adequate renal function with serum creatinine ≤1.5 x ULN.
11. Planned primary systemic (neoadjuvant) chemotherapy and surgical resection of residual primary tumor (mastectomy or lumpectomy/breast conservation) following completion of neoadjuvant chemotherapy

Exclusion Criteria:

1. inflammatory breast cancer
2. Pregnancy or breast-feeding.A negative serum pregnancy test within 7 days prior to first study treatment (Day 1, Cycle 1) for all women of childbearing potential is required. Patients of childbearing potential must agree to use a birth control method that is approved by their study physician while receiving study treatment and for 3 weeks after their last dose of study treatment. Patients must agree to not breast-feed while receiving study treatment.
3. Concurrent treatment with an ovarian hormonal replacement therapy or with hormonal agents such as raloxifene, tamoxifen or other selective estrogen receptor modulator (SERM). Patients must have discontinued use of such agents prior to beginning study treatment.
4. Uncontrolled intercurrent illness including (but not limited to) ongoing or active infection.
5. Concurrent treatment with any anti-cancer therapy other than those agents used in this study.
6. Mental condition or psychiatric disorder that would prevent patient comprehension of the nature, scope, and possible consequences of the study or that would limit compliance with study requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Half Cycles Group; Patients complete half of the whole cycles of neoadjuvant chemotherapy.	Device: Ultrasound; Evaluation of the tumor size by sonography is performed before neoadjuvant chemotherapy and prior to surgery.; Measurement of tumor size refers to WHO standards.; Other Names: GE LOGIQ C5; Procedure: CNB; Typically, the pretreatment tumor specimen will be a core needle biopsy. Because 15% to 28% of patients will have no residual tumor after NAT, it is important to have an adequate pretreatment sample in which an unequivocal diagnosis of invasive carcinoma is established and evaluation of hormone receptors and HER2/ neu status is completed before treatment.; Other Names: core needle biopsy; Procedure: BCS, Modified Radical Mastectomy; All patients after neoadjuvant chemotherapy are performed BCS and modified radical mastectomy.; Other Names: BCS: breast conservative surgery; Device: Pathologic Large Tissue Selected Table; Pathologic large tissue selected table has obtained Chinese patent.Its license ID is CN101261200.; Each piece of breast tissues by cutting with the table has 3mm thickness.; Device: Leica TP1020; Procedure: Alcohol 70 % 1h; Alcohol 80 % 1h; Alcohol 85 % 1h; Alcohol 90 % 1h; Alcohol 95 % 1h; Alcohol Ⅰ 100 % 1h; Alcohol Ⅱ 100 % 1h; Xylene Ⅰ 2h; Xylene Ⅱ 2h; Xylene Ⅲ 2h; Paraffin 6h; Paraffin 6h; Other Names: Semi-enclosed Benchtop Tissue Processor Leica TP1020; Device: Pathologic Large Tissue Embedded Table; The table is made of brass .It is applying for a chinese patent.; The table can simultaneously embed 8 piece of breast tissues.; Device: Leica SM2000 R; Each of paraffin section has 4 um thickness.; Other Names: Sliding microtome Leica SM2000 R; Procedure: HE Stain; Procedure: Xylene Ⅰ 60℃ 15-20 minutes; Xylene Ⅱ 60℃ 15-20 minutes; Alcohol 100% Ⅰ 3-5 minutes; Alcohol 100% Ⅱ 3-5 minutes; Alcohol 95% Ⅱ 3-5 minutes; Alcohol 90% Ⅱ 3-5 minutes; Wash in running tap water for 3 minutes; Hematoxylin 5-10 minutes; Wash in running tap water for 3 minutes; Differentiate in 1% acid alcohol for 30 seconds; Wash in running tap water for 1 minute; Bluing in 0.2% ammonia water for 30-60 seconds; Wash in running tap water for 3 minutes; Counterstain in eosin Y solution for 30-60 seconds; Wash in running tap water for 1 minute; Alcohol 90% Ⅱ 2-3 minutes; Alcohol 95% Ⅱ 2-3 minutes; Alcohol 100% Ⅱ 3-5 minutes; Alcohol 100% Ⅱ 3-5 minutes; Xylene Ⅲ 5-10 minutes; Xylene Ⅳ 5-10 minutes; Mounting with neutral resin; Device: CX22; The residual tumor areas are microscopically outlined on each slice by pathologist.; Other Names: Biological Microscope CX22（Olympus）; Device: Epson V600; Each slice that has been microscopically outlined is scanned by Epson V600.; Every image by scanning should be saved as JPG.; Other Names: Epson Perfection V600 Photo Scanner; Procedure: Three-Dimensional Reconstruction; A.Pathological images three-dimensional reconstruction: Pathological images registration is based on skin and shear mark by Photoshop 13.0 software.; Residual tumor boundary on Pathological images after registration are outlined and taken three-dimensional reconstruction by 3D-doctor 4.0 software.; Observe the shrinkage modes in three-dimensional space.; According to WHO standard,the boundaries of all residual tumor images are displayed in one plane and the longest diameter and its longest perpendicular diameter of boundaries are measured in one-dimensional space.; According to RECIST standard,the longest diameter of boundaries of residual tumor images in three-dimensional space. B.MRI images three-dimensional reconstruction:the procedure is similar to Pathological images three-dimensional reconstruction; Device: Mammography; Evaluation of the tumor size by mammography is performed before neoadjuvant chemotherapy and prior to surgery.; Measurement of tumor size and calcification extent refers to WHO standards.; Calcification extent is not only measured in mammography image but also under microscope.; Other Names: GE Mammography; Drug: TAC,TC,TA,CAF,CEF; TAC:Docetaxel 75 mg/㎡ iv day 1 + Doxorubicin 50 mg/㎡ in day 1 + Cyclophosphamide 500 mg/㎡ iv day 1(Cycled every 21 days for 3 cycles); TC:Docetaxel 75 mg/㎡ iv day 1 + Cyclophosphamide 600 mg/㎡in day 1(Cycled every 21 days for 2 cycles); TA:Docetaxel 75 mg/㎡ iv day 1 + Doxorubicin 50 mg/㎡ in day 1(Cycled every 21 days for 2 cycles); CAF:Cyclophosphamide 100 mg/㎡ po days 1-14 + Doxorubicin 30 mg/㎡ iv days 1,8 +5-fluorouracil 500 mg/㎡ iv days 1,8(cycled every 28 days for 3 cycles); CEF:Cyclophosphamide 75 mg/㎡ po day 1-14 + Epirubicin 60 mg/㎡ iv days 1,8 + 5-fluorouracil 500mg/㎡ iv days 1,8(cycled every 28 days for 3 cycles); Other Names: 1.TAC(docetaxel/doxorubicin/cyclophosphamide); 2.TC(docetaxel/cyclophosphamide); 3.TA(paclitaxel/doxorubicin); 4.CAF(fluorouracil/doxorubicin/cyclophosphamide); 5.CEF(cyclophosphamide/epirubicin//fluorouracil)
Experimental: Whole Cycles Group; Patients complete whole cycles of neoadjuvant chemotherapy.	Device: Ultrasound; Evaluation of the tumor size by sonography is performed before neoadjuvant chemotherapy and prior to surgery.; Measurement of tumor size refers to WHO standards.; Other Names: GE LOGIQ C5; Procedure: CNB; Typically, the pretreatment tumor specimen will be a core needle biopsy. Because 15% to 28% of patients will have no residual tumor after NAT, it is important to have an adequate pretreatment sample in which an unequivocal diagnosis of invasive carcinoma is established and evaluation of hormone receptors and HER2/ neu status is completed before treatment.; Other Names: core needle biopsy; Procedure: BCS, Modified Radical Mastectomy; All patients after neoadjuvant chemotherapy are performed BCS and modified radical mastectomy.; Other Names: BCS: breast conservative surgery; Device: Pathologic Large Tissue Selected Table; Pathologic large tissue selected table has obtained Chinese patent.Its license ID is CN101261200.; Each piece of breast tissues by cutting with the table has 3mm thickness.; Device: Leica TP1020; Procedure: Alcohol 70 % 1h; Alcohol 80 % 1h; Alcohol 85 % 1h; Alcohol 90 % 1h; Alcohol 95 % 1h; Alcohol Ⅰ 100 % 1h; Alcohol Ⅱ 100 % 1h; Xylene Ⅰ 2h; Xylene Ⅱ 2h; Xylene Ⅲ 2h; Paraffin 6h; Paraffin 6h; Other Names: Semi-enclosed Benchtop Tissue Processor Leica TP1020; Device: Pathologic Large Tissue Embedded Table; The table is made of brass .It is applying for a chinese patent.; The table can simultaneously embed 8 piece of breast tissues.; Device: Leica SM2000 R; Each of paraffin section has 4 um thickness.; Other Names: Sliding microtome Leica SM2000 R; Procedure: HE Stain; Procedure: Xylene Ⅰ 60℃ 15-20 minutes; Xylene Ⅱ 60℃ 15-20 minutes; Alcohol 100% Ⅰ 3-5 minutes; Alcohol 100% Ⅱ 3-5 minutes; Alcohol 95% Ⅱ 3-5 minutes; Alcohol 90% Ⅱ 3-5 minutes; Wash in running tap water for 3 minutes; Hematoxylin 5-10 minutes; Wash in running tap water for 3 minutes; Differentiate in 1% acid alcohol for 30 seconds; Wash in running tap water for 1 minute; Bluing in 0.2% ammonia water for 30-60 seconds; Wash in running tap water for 3 minutes; Counterstain in eosin Y solution for 30-60 seconds; Wash in running tap water for 1 minute; Alcohol 90% Ⅱ 2-3 minutes; Alcohol 95% Ⅱ 2-3 minutes; Alcohol 100% Ⅱ 3-5 minutes; Alcohol 100% Ⅱ 3-5 minutes; Xylene Ⅲ 5-10 minutes; Xylene Ⅳ 5-10 minutes; Mounting with neutral resin; Device: CX22; The residual tumor areas are microscopically outlined on each slice by pathologist.; Other Names: Biological Microscope CX22（Olympus）; Device: Epson V600; Each slice that has been microscopically outlined is scanned by Epson V600.; Every image by scanning should be saved as JPG.; Other Names: Epson Perfection V600 Photo Scanner; Procedure: Three-Dimensional Reconstruction; A.Pathological images three-dimensional reconstruction: Pathological images registration is based on skin and shear mark by Photoshop 13.0 software.; Residual tumor boundary on Pathological images after registration are outlined and taken three-dimensional reconstruction by 3D-doctor 4.0 software.; Observe the shrinkage modes in three-dimensional space.; According to WHO standard,the boundaries of all residual tumor images are displayed in one plane and the longest diameter and its longest perpendicular diameter of boundaries are measured in one-dimensional space.; According to RECIST standard,the longest diameter of boundaries of residual tumor images in three-dimensional space. B.MRI images three-dimensional reconstruction:the procedure is similar to Pathological images three-dimensional reconstruction; Device: Mammography; Evaluation of the tumor size by mammography is performed before neoadjuvant chemotherapy and prior to surgery.; Measurement of tumor size and calcification extent refers to WHO standards.; Calcification extent is not only measured in mammography image but also under microscope.; Other Names: GE Mammography; Device: MRI; Evaluation of the tumor size by MRI was performed before neoadjuvant chemotherapy and prior to surgery.; Measurement of tumor size refers to WHO standards.; The images of patients which were scanned by MRI should be burned onto disc for 3d reconstruction.; Other Names: Philips Achieva 3.0T MRI System; Drug: AC-P,TEC,AC,TC,TCH,CEF,TAC,CAF; AC-P:Doxorubicin 60 mg/㎡ iv day 1 +Cyclophosphamide 600 mg/㎡ iv day 1(Cycled every 14 days for 4 cycles)→ Paclitaxel 175mg/㎡ by 3h iv infusion day 1(Cycled every 14 days for 4 cycles) or Paclitaxel 80mg/㎡ by 1h iv infusion weekly for 12 wks.; TEC:Docetaxel 75 mg/㎡ iv day 1 + Epirubicin 75 mg/㎡ in day 1 + Cyclophosphamide 500 mg/㎡ iv day 1(Cycled every 21 days for 6 cycles); AC:Doxorubicin 60 mg/㎡ in day 1 + Cyclophosphamide 600 mg/㎡ iv day 1(Cycled every 21 days for 4 cycles); TC:Docetaxel 75 mg/㎡ iv day 1 + Cyclophosphamide 600 mg/㎡in day 1(Cycled every 21 days for 4 cycles); TCH:Docetaxel 75 mg/㎡ iv day 1 + Carboplatin AUC 6 iv day1(Cycled every 21 days for 6 cycles) + Trastuzumab 4 mg/kg iv wk 1 → Trastuzumab 2 mg/kg iv for 17 wks → Trastuzumab 6 mg/kg iv every 3 wks to complete 1 year.; CEF:Cyclophosphamide 75 mg/㎡ po day 1-14 + Epirubicin 60 mg/㎡ iv days 1,8 + 5-fluorouracil 500mg/㎡ iv days 1,8(cycled every 28 days for 6 cycles); Other Names: 1.AC(doxorubicin/cyclophosphamide)-P(paclitaxel); 2.TEC(docetaxel/epirubicin/cyclophosphamide); 3.AC(doxorubicin/cyclophosphamide)-T(docetaxel); 4.TC(docetaxel/cyclophosphamide); 5.TCH(docetaxel/carboplatin/trastuzumab); 6.CEF(cyclophosphamide/epirubicin/fluorouracil); 7.TAC(docetaxel/doxorubicin/cyclophosphamide); 8.CAF(fluorouracil/doxorubicin/cyclophosphamide)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The shrinkage modes of breast tumor after NAC.	The tumor shrinkage modes of the primary tumor in patients with locally advanced breast cancer after 3 cycles and whole cycles of neoadjuvant chemotherapy(NAC).	6 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The WMSS and 3D pathological reconstruction of the residual tumors after NAC.	The whole-mount serial section(WMSS) and three-dimensional(3D) pathological reconstruction of the residual tumors after NAC.	6 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The predictive value of 3D MRI reconstruction for the shrinkage modes of primary tumor after NAC.	The predictive value of 3D MRI reconstruction for the shrinkage modes of the primary tumor after whole cycles of NAC.	4 year

Collaborators and Investigators

• Sponsor: Shandong Cancer Hospital and Institute
• Investigators: Principal Investigator: Tao Yang, MD, Shandong Cancer Hospital and Institute

Publications and helpful links

General Publications

• Y-S Wang, Z-P Zhang, G Liu, D-B Mu, and X-Y Sun.Study of Breast Cancer Shrinkage Modes After Neoadjuvant Chemotherapy With Whole-mount Serial Sections and Three-dimensional Pathological and MRI Reconstruction. Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-17.

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Anticipated): March 1, 2014
• Study Completion (Anticipated): July 1, 2014

Study Registration Dates

• First Submitted: August 4, 2013
• First Submitted That Met QC Criteria: August 4, 2013
• First Posted (Estimate): August 6, 2013

Study Record Updates

• Last Update Posted (Estimate): August 6, 2013
• Last Update Submitted That Met QC Criteria: August 4, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: Breast Cancer; neoadjuvant chemotherapy; Magnetic Resonance Imaging; three-dimensional reconstruction; shrinkage modes
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Docetaxel; Cyclophosphamide; Carboplatin; Paclitaxel; Trastuzumab; Fluorouracil; Epirubicin; Albumin-Bound Paclitaxel; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: BCSMANC001