MINT study

Principal Investigator: Charles E. Cox, M.D.

Co Investigators: Stefan Glück, M.D.

MINT

• MINT I: Multi-Institutional Neo-adjuvant Therapy MammaPrint Project I

• Principal Investigator: Charles E. Cox, M.D. USF, Tampa FL• Co Investigator: Stefan Glück, M.D. UM/Sylvester

Comprehensive Cancer Center University of Miami, Miller School of Medicine FL

• Total of 226 patients; up to 10 institutes in the US• Full genome gene expression profiling Agendia Inc• Central pathology review at USF pathology FL• Timelines; Oct 2011- Oct 2013

MammaPrint: 70-gene profile prognostic and predictive tumor

analysisWill 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 Suite

pCR rate of MammaPrint and BluePrint in previous neo-adjuvant studies

MINT; 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 and/or validate predictive gene expression profiles of clinical response/resistance to chemotherapy.

• To identify possible correlations between the TheraPrint Research Gene Panel outcomes and chemoresponsiveness.

• To compare the three BluePrint molecular subtype categories with IHC-based subtype classification.

MINT; 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 staging

Study Design Flowchart

Core Needle Biopsies

Sample placed in

RNA Retain, send to Agendia

Full Genome Array*

not successfu

l

Patient ineligible

Patient informati

on & informed consent

TAC

CRF 1

baseline

Surgery including nodal staging

CRF 2

surgery

* (Including diagnostic commercial testing for Symphony Breast cancer Suite)

Central slide

pathology review

Central slide

pathology review

TC

ddAC/FEC100, paclitaxel or

docetaxel

TCH

Full Genome Array*

successful

HER

2-

HER

2-

HER

2-

HER

2+

T H/FEC HH

ER

2+

Neo-adjuvant therapy

For HER2 negative patients:• TAC chemotherapy• TC chemotherapy• Dose Dense AC or FEC100 followed by paclitaxel or

docetaxel chemotherapyFor HER2 positive patients:• TCH chemotherapy• T H followed by FEC H

Dose adjustments• Hematological and non-hematological toxicities should be

managed by treating oncologist as per routine clinical practice.

• Agendia will store remaining tissue from patient samples

• This tissue can be used for future scientific research

• Patients are asked in the patient consent form to provide consent for storage and future research

• Please note: If a patient does not wish to allow their tissue to be used for future research, it is the responsibility of the site to communicate this with Agendia

Future Research – Remaining Tissue

Tissue 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 Agendia

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 for RCB score will be done at USF Pathology FL

• Representative slides of core needle biopsy, sentinel lymph node biopsies and surgical sample should be send to:

USF PathologyAttn: MINT Trial12901 Bruce B. Downs Blvd MDC 11Tampa, FL 33612

Procedures for Sending SlidesAPPENDIX III Pathology Worksheet for Core/Incisional Biopsy

Please send the following, and complete the form below: • One H&E section of tumor • ER immunohistochemical stain • PR immunohistochemical stain • HER2 immunohistochemical stain or FISH/CISH/SISH report • 10 unstained sections on positively-charged glass slides (If ER, PR, and/or HER2 studies not available, please send an additional 10 unstained sections on

positively-charged glass slides)

Questions to be completed on worksheet:1. Laterality

a. Left breast b. Right breast

2. Location a. UOQ b. LOQ c. UIQ d. LIQ

3. Time in formalin a. ≥ 6 to ≤ 48 hours b. Other

Procedures for Sending SlidesAPPENDIX IV Pathology Worksheet for Post-Neoadjuvant Specimens

Please send the following, and complete the form below: • Two representative blocks of tumor, or 15 unstained slides on positively

charged glass slides • Copy of final pathology report (including gross description) 1. Specimen

a. Lumpectomy/partial mastectomy b. Total mastectomy c. Skin-sparing, nipple-sparing total mastectomy d. Nipple-sparing total mastectomy e. Modified radical mastectomy f. Other

2. Residual tumor a. Grossly identified

i. Dimensions: ____ x ____ x ____ cm ii. Percent gross necrosis:

b. Not grossly identified *i. Fibrotic tumor bed dimensions: ____ x ____ x ____ cm

c. Distance from closest margin: ____

*NOTE: If no definitive tumor grossly identified, please submit entire tumor bed sequentially

Pathology Guidelines

• Note: additional guidelines for your pathology are outlined in Appendix II of the protocol.

Clinical Report Form

• Web 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 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 page

CRF 1: Questions

Baseline 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: 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:

Contacts:

• Jessica Gibson, Clinical Research

Manager (619)316-1416

jessica.gibson@agendia.com