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Principal Investigator: Charles E. Cox, M.D. Co Investigators: Stefan Glück, M.D.
MINTMINT• Title: MINT I Multi-Institutional Neo-
adjuvant Therapy MammaPrint Project I Principal Investigator: Charles E. Cox, M.D.
University of South Florida, Tampa FL
Co Investigators: Stefan Glück, M.D. and Alberto Montero
M.D. University of Miami/Sylvester Comprehensive Cancer
Center University of Miami, Miller School of Medicine FL
• Total of 226 patients; up to 10 institutes in the USA• 44K gene expression profiling Agendia Inc
• Central pathology review at Moffitt Cancer Center FL
• Timelines; Oct 2011- Oct 2013
MammaPrint: 70-gene profile prognostic and predictive tumor analysis
Will patient benefit from chemotherapy?
TargetPrint: Gene expression of ER/PR/HER2 Centralized lab confirmation of receptor
statusWill patient benefit from hormonal treatment?BluePrint: 80-gene molecular subtyping profile
Basal, Luminal, and HER2 subtypesWhich therapy works best?
TheraPrint: Gene expression of 56 genes Potential markers for prognosis and therapeutic
responsePotential therapy options saved for the future
Breast Cancer Symphony SuiteBreast Cancer Symphony Suite
BluePrint - Identifies molecular BluePrint - Identifies molecular subtypes of breast cancersubtypes of breast cancer
Analysis of Entire Human Genome ~25,000 Genes
Prognostic & Predictive Breast
Cancer Genes Identified
Breast Cancer
Basal, Luminal, and HER2-type
classification
Luminal-TypeBasal-Type HER2-Type
TargetPrint: quantification of TargetPrint: quantification of ER/PR/HER2ER/PR/HER2
mRNA levelsmRNA levels Analysis of Entire Human Genome ~25,000 Genes
Prognostic & Predictive Breast Cancer Genes
Identified
Breast Cancer
Centralized lab confirmation of receptors
IHC
microarray
Microarray based readout of ER, PR Microarray based readout of ER, PR
and HER2and HER2
TheraPrint - Suggests alternative TheraPrint - Suggests alternative treatment options in advanced diseasetreatment options in advanced disease
Analysis of Entire Human Genome ~25,000 Genes
Prognostic & Predictive Breast Cancer Genes
Identified
Breast Cancer
Gene expression analysis for drug sensitivity
TheraPrint: quantitates 56 genes TheraPrint: quantitates 56 genes linked to specific drug responseslinked to specific drug responses
Offers read-out of gene expression for 56 genes Genes might have relevance in breast cancer therapy and
prognosis No claims about mRNA level and response can be made
Genes Included:
The response to chemotherapy The response to chemotherapy varies in the different molecular varies in the different molecular subtypessubtypes
Straver1 Somlo2 Hess3 Total
n pCR n pCR n pCR n pCR %
Luminal-type/MP Low Risk21 0 14 1 29 1 64 2 3%
Luminal-type/MP High Risk 67 3 16 0 53 6 136 9 7%
HER2-type 41 13 18 10 24 12 83 35 42%
Basal-type 38 13 20 4 27 15 85 44 52%
1. Straver et al. Breast Cancer Res Treat, 20092. Somlo et al. ASCO, 20093. Hess study as part of Krijgsman et al. In press, 2011
MINT; Study ObjectivesMINT; Study Objectives To determine the predictive power of chemosensitivity of
the combination of MammaPrint and BluePrint as measured
by pCR.
To compare TargetPrint single gene read out of ER, PR and
HER2 with local and centralized IHC and/or CISH/FISH
assessment of ER, PR and HER2.
To identify possible correlations between the TheraPrint
Research Gene Panel outcomes and chemo-
responsiveness.
To identify and/or validate predictive gene expression
profiles of clinical response/resistance to chemotherapy.
To compare the three BluePrint molecular subtype
categories with IHC-based subtype classification.
MINT; Eligibility CriteriaMINT; Eligibility Criteria
Inclusion criteria: Women with histologically proven invasive breast cancer; T2(≥3.5cm)-
T4, N0,M0 or T2-4N1M0 DCIS or LCIS are allowed in addition to invasive cancer at T2 or T3
level. Age ≥ 18 years. Measurable disease in two dimensions Adequate bone marrow reserves, adequate renal function, and hepatic
function Signed informed consent
Exclusion criteria Patients with inflammatory breast cancer. Tumor sample shipped to Agendia with ≤ 30% tumor cells or that fails
QA or QC criteria. Patients who have had any prior chemotherapy, radiotherapy, or
endocrine therapy for the treatment of breast cancer. Any serious uncontrolled inter current infections, or other serious
uncontrolled concomitant disease.
MINT; Nodal stagingMINT; Nodal staging
Study Design Flowchart Study Design Flowchart Core
Needle Biopsies
Sample placed in
RNA Retain, send to
Agendia*
Breast Cancer
Symphony Suite
successful
Breast Cancer
Symphony Suite
not successfu
l
Patient ineligible
Patient informati
on & informed consent
Neo- adjuvant
treatment
CRF 1
baseline
Surgery
CRF 2
surgery
* (Diagnostic commercial testing for Symphony Breast cancer Suite)Suite
FFPE Slides and
microscopic worksheets
to USF Pathology
FFPE Slides and
microscopic worksheets
to USF Pathology
Neo-adjuvant therapyNeo-adjuvant therapyFor HER2 negative patients:
TAC chemotherapy
TC chemotherapy
Dose Dense AC or FEC100 followed by paclitaxel or docetaxel
chemotherapy
For HER2 positive patients:
TCH chemotherapy
Dose adjustments
Hematological and non-hematological toxicities should be
managed by treating oncologist as per routine clinical practice.
Tissue CollectionTissue Collection Tissue should be collected by incisional biopsy (when
placing port) or via core needle biopsy.
If the tissue is obtained by incisional biopsy then the tissue sample should be no greater than 3 to 4 mm in thickness and between 8 to 10 mm in diameter.
Core needle biopsies should be obtained with a 14 gauge or larger needle.
◦ If a 14 gauge needle is used: 5 cores
◦ If a 11 gauge needle is used: 4 cores
◦ If a 9 gauge needle is used: 3 cores
Sending Sample to Sending Sample to AgendiaAgendia
A. Remove large specimen tube from kit and open it.
B. Place large screw cap with small specimen vial on table and open small specimen vial.
C. Place a barcode label from the completed requisition form on to the vial.
D. Place the small specimen vial into the large specimen tube and place the tube into the specimen safety bag.
E. Place the sealed specimen bag into the shipping kit along with the requisition form. IMPORTANT: ensure that the study sticker is affixed to the requisition form.
F. Package the kit into the FedEx shipping pack and attach the pre printed label for shipment to Agendia Inc.
G. Please call Fed Ex for pickup.
Central Pathology Review Central Pathology Review Initial core/incisional biopsy specimens
Cold ischemic time (time from collection of specimen to
fixation solution) should be restricted to < 1 hour
Tissue submitted for histopathological analysis will be fixed in
10% buffered formalin for 6 to 48 hours
Send 1 H&E, original ER, PR, and HER2 IHC stains, and 10
unstained sections of representative tumor on positive-
charged glass slides for central review (Appendix III).
If receptor studies are not available, an additional 10
unstained sections on positive-charged glass slides of
representative tumor will be required.
Central Pathology Review Central Pathology Review Gross specimen processing
1. Lumpectomy/partial mastectomy
The specimen is oriented, inked in 6 colors, and sectioned at 0.3-0.4 cm intervals.
If gross residual tumor is identified:
◦ Dimensions (width, length, height) are recorded
◦ Distance from all margins if < 0.2 cm is noted, otherwise the closest margin is
recorded
◦ The gross residual tumor is entirely submitted in sequential sections (Appendix IV)
◦ Sampling of margins is performed
If no-grossly identifiable residual tumor is present:
◦ The dimensions of the biopsy site and surrounding fibrosis/ induration is recorded
◦ The specimen is entirely submitted sequentially (Appendix IV)
◦ Description of margin status is recorded as noted above
Central Pathology Review Central Pathology Review 2. Total mastectomy/modified radical mastectomy
The specimen is oriented and inked accordingly
If gross residual tumor is identified:
◦ Dimensions (width, length, height) are recorded
◦ Distance from all margins if < 0.2 cm is noted, otherwise the closest margin is
recorded
◦ The gross residual tumor is entirely submitted in sequential sections (Appendix IV)
◦ Sampling of margins is performed
If no-grossly identifiable residual tumor is present:
◦ The dimensions of the biopsy site and surrounding fibrosis/ induration is recorded
◦ The area of fibrosis (“tumor bed”), to include biopsy site, is entirely submitted
sequentially (Appendix IV)
◦ Description of margin status is recorded as noted above
Central Pathology Review Central Pathology Review Sentinel lymph node processing
Sentinel lymph nodes will be serially sectioned along the long axis at
2-mm intervals. If the lymph node measures 0.5 cm in greatest
dimension, it may be bivalve. Specimens are then entirely submitted
(Appendix IV).
Clinical Report FormClinical Report FormWeb based data collection/electronic
CRF◦ CRF1; Baseline information◦ CRF2; After surgery
Relatively easy to complete compared to drug trial
15-20 minutes for CRF1 and 2
Accessing the DatabaseAccessing the Database◦ There is one hyperlink to access all the electronic Case Report Forms (CRFs)
https://trials.agendia.com/MINT
◦ You will receive an institution specific site number and password from your
Agendia Clinical Research Manager.
Institution:
Detailed Data Entry Instructions will be sent to site.
Samples will appear in the database if they are found to be eligible.
CRF Overview Administrative pageCRF Overview Administrative page
CRF 1: QuestionsCRF 1: QuestionsBaseline Patient characteristics Age at diagnosis Ethnicity/ origin Menopausal status Date of biopsy Specimen type
Tumor measurements Kind of imaging used Primary tumor size Size largest metastatic lymph node
Pathology Date of histologic diagnosis Histopathologic tumor type
Histological grade ER, PR and Her2-neu status Vascular invasion TNM Nodal staging Date nodal staging If sentinel lymph node
Number of sentinel nodes removed
Number of counts Blue dye Histology of SLN: Concordance of nodal
histology to primary tumor
CRF 2: QuestionsCRF 2: QuestionsNeo-adjuvant treatment
Regimen given
Was specified number of cycles completed?
Any grade 4 or 5 CTC for Adverse Events observed?
Surgery information
Date breast carcinoma surgery
Type of surgery
Lymph node assessments
Pathology
Nodal status
ypTN
Tumor measurements
What kind of imaging has been used ?
Primary tumor size
Size largest metastatic lymph node
Treatment response
Lymph node assessments
Sentinel Lymph Node Procedure (SLNP)
If yes
•Number of sentinel nodes examined
•Number of positive sentinel nodes
•Number of negative sentinel nodes
•Blue dye
•Concordance of nodal histology to
primary tumor
Axillary Lymph Node Dissection
(ALND) If yes
•Number of axillary nodes examined
•Number of positive axillary nodes
•Number of negative axillary nodes
SLNP and ALND if yes: