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



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:

Contacts:Contacts:

Jessica Gibson, Clinical Research

Manager (619)316-1416

[email protected]

Principal Investigator: Charles E. Cox, M.D. Co Investigators: Stefan Glück, M.D.

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