MammaPrint is a
prognostic
Prognosis (Ancient Greek, Greek: πρόγνωσις "fore-knowing, foreseeing") is a medicine, medical term for predicting the likely or expected development of a disease, including whether the sign (medicine), signs and symptoms will improve or ...
and
predictive
A prediction ( Latin ''præ-'', "before," and ''dicere'', "to say"), or forecast, is a statement about a future event or data. They are often, but not always, based upon experience or knowledge. There is no universal agreement about the exa ...
diagnostic
Diagnosis is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in many different disciplines, with variations in the use of logic, analytics, and experience, to determine " cause and effect". In systems engine ...
test for early stage
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...
patients that assess the risk that a tumor will
metastasize
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
to other parts of the body. It gives a binary result, high-risk or low-risk
classification Classification is a process related to categorization, the process in which ideas and objects are recognized, differentiated and understood.
Classification is the grouping of related facts into classes.
It may also refer to:
Business, organizat ...
, and helps physicians determine whether or not a patient will benefit from
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
. Women with a low risk result can safely forego chemotherapy without decreasing likelihood of disease free survival. MammaPrint is part of the
personalized medicine
Personalized medicine, also referred to as precision medicine, is a medical model that separates people into different groups—with medical decisions, practices, interventions and/or products being tailored to the individual patient based on the ...
portfolio marketed by Agendia.
MammaPrint is based on the Amsterdam 70-gene breast cancer gene signature and uses formalin-fixed-paraffin-embedded (FFPE) or fresh tissue for
microarray
A microarray is a multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of genes from a sample (e.g. from a tissue). It is a two-dimensional array on a solid substrate—usually a glass slide or silic ...
analysis.
It is a
laboratory developed test (LDT) which falls into the class of ''In Vitro'' Diagnostic Multivariate Index Assays (IVDMIA). MammaPrint was the first (2007) IVDMIA to be cleared by the
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA) in a ''De Novo'' Classification Process (Evaluation of Automatic Class III Designation) and is the only molecular diagnostic test with a randomized prospective clinical trial validating clinical utility. The test uses
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
isolated from tumor samples and run on custom glass microarray slides in order to determine the expression of a 70-gene signature. The expression profile is then used in a proprietary algorithm to categorically classify the patient as being at either high or low risk of breast cancer recurrence.
MammaPrint has been prospectively, clinically validated for use in early stage (I and II) breast cancer patients regardless of
estrogen receptor
Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors ( ERα and ERβ), which are members of th ...
(ER) or
Human Epidermal Growth Factor Receptor 2
Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
(HER2) status, with a tumor size ≤ 5.0 cm, and 0-3 positive lymph nodes (LN0-1), with no special specifications for N1mi pathology. This differentiates MammaPrint from other multi-gene assays in use today that have only shown predictive value in ER positive, HER2 negative, lymph node (LN) negative patients. MammaPrint is also indicated for patients with ER negative tumors (15% of tumors). There are no exclusion criteria based on histopathologic tumor type (i.e. ductal, lobular, mixed, etc.) or age. MammaPrint is predictive for pre- and post-menopausal women.
Development
The
Human Genome Project
The Human Genome Project (HGP) was an international scientific research project with the goal of determining the base pairs that make up human DNA, and of identifying, mapping and sequencing all of the genes of the human genome from both a ...
identified approximately 25,000 genes in the human genome and created the possibility for personalized medicine. The
Netherlands Cancer Institute
The Netherlands Cancer Institute (NKI) in Amsterdam was founded in 1913 by, among others, the surgeon Jacob Rotgans.
The NKI, together with the Antoni van Leeuwenhoekziekenhuis, is formed into the NKI-AVL, which combines a scientific research i ...
(NKI) in Amsterdam utilized this information and applied it specifically to breast cancer, creating the Amsterdam 70-gene signature (70-GS). MammaPrint is the commercialized assay that measures the 70-GS.
The NKI hypothesized that breast cancer is a genetic, heterogeneous disease, where gene expression would be different in aggressive breast tumors that develop recurrences following surgery than from those that are less aggressive and do not recur or spread throughout the body. To identify a novel and independent predictor of breast cancer recurrence, DNA microarray technology was used to interrogate all 25,000 genes in untreated tumor samples from women where follow-up categorized them as being disease free or having distant metastases within five years.
Supervised classification
Supervised learning (SL) is a machine learning paradigm for problems where the available data consists of labelled examples, meaning that each data point contains features (covariates) and an associated label. The goal of supervised learning alg ...
identified significantly different expression patterns in 70 genes that were strongly predictive of a short interval to distant metastases.
Implications for utility
The paradigm used to development the 70-GS makes it unique in molecular breast cancer diagnostics because it allowed the tumor biology itself to show the genes most predictive of known patient outcomes. Rather than pre-selecting a few genes based on literature and known information at a given time, supervised learning from the entire expressed genome gives it farsighted utility as the knowledge of cancer biology evolves. Furthermore, development using ''untreated'' tumors allows physicians to know their patient's risk of recurrence, without any treatment bias or assumptions, before making a patient's treatment plan.
Clinical Utility
Molecular diagnostics are used in combination with traditional clinicopathologic factors to decide on a treatment plan. MammaPrint provides a binary result, either high risk or low risk. Patients with a low risk result are unlikely to develop distant metastases and are therefore unlikely to benefit from chemotherapy. Since many breast cancers are considered genomically low-risk independent from clinicopathology, a significant number of patients can be saved from overtreatment with chemotherapy.
Guideline Inclusion
MammaPrint is included as standard of care with the highest medical level of evidence in the following guidelines
* Dutch Institute CBO Guidelines for treatment of primary breast cancer
* St. Gallen's International Oncology Guidelines for the treatment of early stage breast cancer
* German Gynecological Oncology Group (AGO) guidelines for breast cancer management
* European Group on Tumour Markers (EGTM)
Ordering indications
In February 2007, the
U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
(FDA) cleared the MammaPrint test for use in the U.S. for lymph node negative breast cancer patients of all ages,
ER negative
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a ...
or
ER positive A hormone-receptor-positive (HR+) tumor is a tumor which consists of cells that express receptors for certain hormones. The term most commonly refers to estrogen receptor positive tumors (i.e. tumors that contain estrogen receptor positive cells), ...
, with tumors of less than 5 cm. MammaPrint can be considered as a part of
standard of care
In tort law, the standard of care is the only degree of prudence and caution required of an individual who is under a duty of care.
The requirements of the standard are closely dependent on circumstances. Whether the standard of care has been b ...
disease management for early stage breast cancer and has significant
insurance
Insurance is a means of protection from financial loss in which, in exchange for a fee, a party agrees to compensate another party in the event of a certain loss, damage, or injury. It is a form of risk management, primarily used to hedge ...
coverage in the US, including coverage through
Medicare and
Medicaid
Medicaid in the United States is a federal and state program that helps with healthcare
Health care or healthcare is the improvement of health via the prevention, diagnosis, treatment, amelioration or cure of disease, illness, injury, and ...
. The American Medical Association has granted a Category 1, MAAA
Current Procedural Terminology
The Current Procedural Terminology (CPT) code set is a procedural code set developed by the American Medical Association (AMA). It is maintained by the CPT Editorial Panel. The CPT code set describes medical, surgical, and diagnostic services and ...
(CPT) code for MammaPrint.
Indications for ordering MammaPrint include:
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
Samples from the United States and North America are processed and run in
CLIA certified lab in
Irvine Irvine may refer to:
Places On Earth Antarctica
*Irvine Glacier
* Mount Irvine (Antarctica)
Australia
* Irvine Island
*Mount Irvine, New South Wales
Canada
* Irvine, Alberta
*Irvine Inlet, Nunavut
United Kingdom
*Irvine, North Ayrshire, Scot ...
, CA.
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-
Samples from outside North America are processed and run in
Amsterdam
Amsterdam ( , , , lit. ''The Dam on the River Amstel'') is the Capital of the Netherlands, capital and Municipalities of the Netherlands, most populous city of the Netherlands, with The Hague being the seat of government. It has a population ...
, Netherlands.
Pakistan-
Mammaprint is now exclusively available in Pakistan through Precision Diagnostic Laboratory
Tissue sampling technique
Tumor samples may be submitted as core needle biopsies or surgical specimen. MammaPrint is FDA cleared to accept fresh, frozen, and formalin fixed paraffin embedded (FFPE) specimen types. 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. Quality measures require invasive tumor cellularity of ≥30%.
or
* Fresh specimens are currently accepted for research purposes. Samples 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. Invasive tumor cellularity of ≥30% is required.
Cost and Cost-Effectiveness
The cost of the assay in the U.S. is $4,200. In Europe, the test costs EUR 2675.
Several studies show that the use of the MammaPrint is cost-effective for patients in the United States, Europe, Canada and Japan by providing additional information to help doctors tailor treatment to the individual patient.
MammaPrint provides definitive results and does not have an intermediate category, making it more cost-effective than other breast cancer risk assays available.
Key Clinical trials
MammaPrint is the only commercially available breast cancer molecular diagnostic assay to achieve level 1A evidence. Other extensive
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s 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.
MINDACT
The MINDACT trial provides the highest
medical level of evidence, level 1A, for the use of MammaPrint in early stage breast cancer. 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
Adjuvant therapy, also known as adjunct therapy, adjuvant care, or augmentation therapy, is a therapy that is given in addition to the primary or initial therapy to maximize its effectiveness. The surgeries and complex treatment regimens used in ...
in breast cancer.
Publication in the
New England Journal of Medicine
''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one.
His ...
showed 6,693 breast cancer patients enrolled from 112 participating institutions in 9 European Countries.
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
Hormone therapy or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also be referred to as hormonal therapy or antihormone therapy. The most general classes of hormone therapy are oncologic horm ...
alone is recommended. However, discordant cases are
randomized
In common usage, randomness is the apparent or actual lack of pattern or predictability in events. A random sequence of events, symbols or steps often has no order and does not follow an intelligible pattern or combination. Individual rand ...
to receive either chemotherapy or hormonal therapy based on clinical-pathological risk assessment or MammaPrint and the patients are followed. The results of MINDACT validate MammaPrint as an important prognostic and predictive tool in cancer treatment.
Primary findings of the MINDACT trial are:
* 46% of patients identified as high risk for recurrence according to clinical-pathological factors as described in the publication, and who therefore would be usual candidates for adjuvant chemotherapy, were reclassified as Low Risk by MammaPrint and MINDACT shows could safely forgo chemotherapy.
* MammaPrint can change clinical practice by providing critical prognostic information to aid in assessing patients’ risk for distant metastasis and potentially sparing over one hundred thousand women annually with early-stage breast cancer worldwide from unnecessary toxicities and side effects from chemotherapy and creating considerable cost savingsr.
* As demonstrated in the MINDACT trial, MammaPrint is now the only FDA-cleared breast cancer prognostic test with the highest level of evidence (1A) for its clinical utility to aid correctly identifying Low Risk patients
PROMIS
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.
This 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
A microarray is a multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of genes from a sample (e.g. from a tissue). It is a two-dimensional array on a solid substrate—usually a glass slide or silicon ...
are integral components of
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...
analysis and molecular prediction in the landmark
National Cancer Institute
The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. T ...
supported I-SPY I an
II I-SPY IIbreast 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
Neoadjuvant therapy is the administration of therapeutic agents before a main treatment. One example is neoadjuvant hormone therapy prior to radical radiotherapy for adenocarcinoma of the prostate. Neoadjuvant therapy aims to reduce the size or ...
* 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
MINT
Multi Institutional Neo Adjuvant Therapy Mammaprint Projec
(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.
This study has the following 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
Prospective neo-adjuvant REGISTRY trial linking MammaPrint, Subtyping and treatment response: Neoadjuvant Breast Registry - Symphony™ Tria
(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.
This registry study has the following 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.
See also
*
Breast cancer classification
Breast cancer classification divides breast cancer into categories according to different schemes criteria and serving a different purpose. The major categories are the histopathological type, the grade of the tumor, the stage of the tumor, and ...
*
Personalized Medicine
Personalized medicine, also referred to as precision medicine, is a medical model that separates people into different groups—with medical decisions, practices, interventions and/or products being tailored to the individual patient based on the ...
*
Personal genomics
Personal genomics or consumer genetics is the branch of genomics concerned with the sequencing, analysis and interpretation of the genome of an individual. The genotyping stage employs different techniques, including single-nucleotide polymorphi ...
*
Cancer genomics
Oncogenomics is a sub-field of genomics that characterizes cancer-associated genes. It focuses on genomic, epigenomic and transcript alterations in cancer.
Cancer is a genetic disease caused by accumulation of DNA mutations and epigenetic alterati ...
(
Oncogenomics
Oncogenomics is a sub-field of genomics that characterizes cancer-associated genes. It focuses on genomic, epigenomic and transcript alterations in cancer.
Cancer is a genetic disease caused by accumulation of DNA mutations and epigenetic alter ...
)
External links
AgendiaKnowYourBreastCancer.com
References
*
*{{cite journal , pmid = 23371464 , doi=10.1002/ijc.28082 , volume=133 , title=A prospective evaluation of a breast cancer prognosis signature in the observational RASTER study , pmc=3734625 , year=2013 , journal=Int. J. Cancer , pages=929–36 , author=Drukker CA, Bueno-de-Mesquita JM, Retèl VP, van Harten WH, van Tinteren H, Wesseling J, Roumen RM, Knauer M, Veer LJ, Sonke GS, Rutgers EJ, van de Vijver MJ, Linn SC , issue=4
Microarrays