MammaPrint

Sampling technique

There are two specimen types that can be submitted:

Formalin-fixed paraffin-embedded tissue block or 10 unstained slides with a 5 micron section on each slide

Must contain at least 30% invasive tumor

or

Fresh specimen

Core needle biopsies or tissue taken from a surgical specimen. If submitting a fresh specimen, the sample must be at least 3x3mm (tic-tac size) preserved in RNARetain®. Maximum side dimension should not exceed 5 mm to allow adequate penetration of RNARetain

Ordering criteria

USA-

Breast Cancer Stage 1 or Stage 2

Invasive carcinoma (infiltrating carcinoma)

Tumor size <5.0 cm

Lymph node negative

Estrogen receptor positive (ER+) or Estrogen receptor negative (ER-)

Women of all ages

International-

Breast Cancer Stage 1 or Stage 2

Invasive carcinoma (infiltrating carcinoma)

Tumor size <5.0 cm

Lymph node status: negative or positive (up to 3 nodes)

ER+ or ER-

Clinical trials

Agendia’s extensive clinical trials and research collaborations have produced numerous retrospective and prospective validation studies over the past decade which have enabled the successful commercialization of genomic microarray assays, such as the FDA-cleared 70-gene MammaPrint profile. Large, multi-institutional clinical trials, such as MINDACT and ISPY-2, are assessing MammaPrint.

PROMIS

Study Design:

Prospective Registry Of MammaPrint in breast cancer patients with an Intermediate recurrence Score (PROMIS). This will be a prospective observational, case-only, study of MammaPrint in patients with an Oncotype DX intermediate score (18-30). The clinical data is to be entered online. There will be two Case Report Forms (CRF). The first CRF must be completed before receiving the MammaPrint result. This CRF will capture baseline patient characteristics, pathology information, Oncotype DX score and the recommended treatment plan without knowing the MammaPrint result. The second CRF will be completed within 4 weeks after receiving the MammaPrint result and will capture the recommended treatment based on MammaPrint. It is expected that approximately 20-30 institutions in the US will participate. Around 300 patients will be enrolled in 2 years.

Objectives:

This registry study has the following objectives:

Describe the frequency of chemotherapy + endocrine versus endocrine alone decisions in Oncotype DX intermediate score patients

Assess the impact of MammaPrint on chemotherapy + endocrine versus endocrine alone treatment decisions

Assess the distribution of MammaPrint Low and High Risk in patients with an intermediate recurrence score

Assess concordance of TargetPrint ER, PR and Her2 results with Oncotype DX ER, PR and Her2 and with locally assessed IHC/FISH ER, PR and Her2

Compare clinical subtype based on IHC/FISH ER, PR, Her2 and Ki-67 (if available) with BluePrint molecular subtype

I-SPY I and I-SPY II

(CALGB 150007/150012 & ACRIN 6657)

Agendia’s MammaPrint signature and its microarray technology are integral components of biomarker analysis and molecular prediction in the landmark National Cancer Institute supported I-SPY I and I-SPY II breast cancer clinical trials which focus on the prediction of therapeutic response in the neoadjuvant setting. The utilization of MammaPrint and Agendia’s whole-genome, microarray platform are anticipated to assist in rapid, focused development of oncologic therapies paired with biomarkers.

Key Objectives of I-SPY breast cancer trials for which the MammaPrint whole-genome microarray is utilized:

I-SPY I evaluated biomarkers and imaging for predicting response to standard neoadjuvant chemotherapy

I-SPY II will evaluate Phase 2 drugs in combination with standard chemotherapy in a neoadjuvant setting

I-SPY II will use biomarkers to stratify patients based on their predicted likelihood of response to treatment

MINDACT

The MINDACT (Microarray In Node negative and 1-3 positive lymph node Disease may Avoid ChemoTherapy) clinical trial is a multi-center, prospective, phase III randomized study comparing the MammaPrint 70-gene expression signature with a common clinical-pathological prognostic tool (Adjuvant! Online) in selecting patients with negative or 1-3 positive nodes for adjuvant chemotherapy in breast cancer.

To date, over 5,942 breast cancer patients have been registered and over 3,142 patients enrolled from 93 participating institutions in 9 European Countries. The goal was to complete enrollment of 6,000 breast cancer patients by late 2011.

In the MINDACT trial, women with breast cancer who are assessed as “High Risk” by both MammaPrint and clinical-pathologic guidelines are advised to have chemotherapy whereas for women with “Low Risk” concordance, hormonal therapy alone is recommended. However, discordant cases are randomized to receive either chemotherapy or hormonal therapy based on clinical-pathological risk assessment or MammaPrint and the patients are followed. It is anticipated by Agendia that the results of MINDACT will validate MammaPrint as an important prognostic and predictive tool in cancer treatment.

Primary objectives of the MINDACT trial are:

To confirm that breast cancer patients with a “low risk” molecular prognosis by MammaPrint and “high risk” clinical prognosis can be safely spared chemotherapy without affecting Distant Metastases Free Survival (DMFS).

To compare Anthracycline-based chemotherapy regimens to a Docetaxel-Capecitabine regimen which may be associated with increased efficacy and reduced long-term toxicities for women with breast cancer.

To compare the efficacy and safety of 7 years of single agent Letrozole to the sequential strategy of 2 years of Tamoxifen followed by 5 years of Letrozole (Randomization Endocrine therapy).

MINT

Study Design:

Multi Institutional Neo Adjuvant Therapy Mammaprint Project (MINT). Patients with locally advanced breast cancer (LABC) are often treated with neoadjuvant chemotherapy to shrink the tumor before definitive surgery is performed. This allows oncologists to measure a patients response to a given chemotherapy regimen in vivo. Achievement of a complete pathologic response (pCR) to neoadjuvant chemotherapy allows for a better prediction of the prospect for a favorable outcome.

Genomics assays that measure specific gene expression patterns in a patient's primary tumor have become important prognostic tools for breast cancer patients. This study is designed to test the ability of MammaPrint® in combination with TargetPrint®, BluePrint®, and TheraPrint®, as well as traditional pathologic and clinical prognostic factors, to predict responsiveness to neo-adjuvant chemotherapy in patients with LABC.

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 chemoresponsiveness.

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.

NBRST

Study Design: Prospective neo-adjuvant REGISTRY trial linking MammaPrint, Subtyping and treatment response: Neoadjuvant Breast Registry - Symphony™ Trial (NBRST) (pronounced “in breast”.) This is a prospective observational, case-only, study linking MammaPrint, BluePrint, TargetPrint, TheraPrint and possible additional profiles of interest to treatment response, Recurrence Free Survival (RFS) and Distant Metastases Free Survival (DMFS). Only patients who receive neo-adjuvant therapy can participate. For this project, approximately 20-30 institutions in the US will be invited to contribute clinical patient data from enrolled patients after a MammaPrint, TargetPrint, BluePrint and TheraPrint test has been successfully performed and the patient has started neo-adjuvant therapy. Treatment is at the discretion of the physician, adhering to NCCN approved regimens or a recognized alternative.

The clinical data is to be entered online at 4 time points; amounting to four Case Report Forms (CRFs). Data will be collected on an ongoing basis, the first CRF must be completed within 6 weeks after the MammaPrint, BluePrint, TargetPrint, and TheraPrint result was provided. The second CRF should be completed by 4 weeks after definitive surgery. CRF 3 and CRF4 will be completed 2-3 and 5 years after surgery. It is expected that we will enroll around 500 patients in 4 years.

Objectives:

Measure chemosensitivity (as defined by pCR) or endocrine sensitivity (as defined by decrease in longest tumor diameter or RCB1) in the molecular subgroups as determined by combining MammaPrint and BluePrint results.

Correlate chemosensitivity (as defined by pCR) to TheraPrint Therapy Gene Assay results.

Compare local IHC and FISH results (if available) with TargetPrint results.

Compare the three BluePrint molecular subgroups with IHC-based subtype classification.

Document impact of MammaPrint, TargetPrint and BluePrint result on treatment decision.

Assess the 2-3 and 5 years DMFS and RFS for the different molecular subgroups.

Measure chemosensitivity or endocrine sensitivity correlation with novel expression profiles.