Prognostic and Predictive: MammaPrint answers your Clinical Questions
MammaPrint can help you answer the most important clinical questions for the care and management of breast cancer patients:
Who is at risk for recurrence?
Does MammaPrint help identify which patients may safely forego chemotherapy?
What is the optimal treatment for each patient?
See the Validation and Clinical Utility sections below for more information
MammaPrint is the only breast cancer assay backed by peer-reviewed, prospective outcome data1
In the first ever prospective clinical study for a breast cancer recurrence assay, RASTER (MicroarRAy PrognoSTics in Breast CancER) confirmed the utility of the MammaPrint 70-gene signature to identify those breast cancer patients that may safely forgo chemotherapy. As compared to standard clincopathological classification, MammaPrint re-stratified 20% of Clinical High Risk patients to Low risk. 97% of this Low Risk patient group which primarily chose to forgo chemotherapy, were disease free at 5 years.
With binary Low Risk or High Risk classifications, MammaPrint eliminates the ambiguity of an intermediate risk result. The TRANSBIG study showed that patients classified as Low Risk had a 10% chance of recurrence and those classified as High Risk had a 29% chance of recurrence, without adjuvant treatment at 10 years.
MammaPrint changes up to 37% of adjuvant treatment decisions4
In a study by Cusumano PG et al. using MammaPrint, chemotherapy treatment advice for ER+ / HER2- breast cancer patients was changed in 37% of patients. It was also noted that MammaPrint increased inter-institutional treatment advice agreement by 22%.
MammaPrint developed using unbiased gene selection based on patient outcomes5
Cancer researchers Professors Rene Bernards Ph.D and Laura van’t Veer Ph.D of the Netherlands Cancer Institute in Amsterdam (NKI) sought to answer one of the most important clinical questions in breast cancer management, who is at risk for recurrence? Adjuvant treatment recommendations for chemotherapy are primarily based on this question. They hypothesized that since breast cancer is a heterogeneous disease, gene expression should be different in High Risk breast tumors that may benefit from adjuvant chemotherapy vs. those that are Low Risk and would likely not see any benefit from adjuvant chemotherapy.
Tumor specimens from 78 untreated breast cancer patients with known outcomes were analyzed. The entire human genome was interrogated to determine which genes were most predictive of recurrence at five years, since most recurrences occur within the first five years. As a result, the 70 most significant genes predictive of recurrence risk were identified. With this unbiased gene selection method, the tumor biology told them which genes were most predictive.
MammaPrint interrogates all 7 genomic pathways of the metastatic cascade6,13
The pathogenesis of metastatic disease has 7 critical steps. The first step is growth and proliferation of the primary tumor, which is followed by development of blood vessels into the primary tumor (angiogenesis). The third step, local invasion, introduces the cancer cells into the vascular system. The cancer cells then insert themselves into the vascular compartment through the fourth step, intravasation. After continued survival in circulation (fifth step), the cells must exit out of the circulatory system called extravasation, completing the sixth step. The seventh and final step is where they must adapt to the micro-environment starting the cycle again.
The 70 genes that compose the MammaPrint index are clearly identified within the various steps of the metastatic process.
No Intermediates – True Binary Results
MammaPrint provides a numerical index with a range of -1 to +1, that is overlayed with a binary Low Risk / High Risk clinical classification system. The clinical classification threshold was set by the determination of the largest population of Low Risk patients that can safely withhold chemotherapy.
~29% chance (95% CI 22-35) of cancer recurrence within 10 years without any additional adjuvant treatment, either hormonal therapy or chemotherapy
MammaPrint has extensive clinical validation
MammaPrint has been independently validated in studies on over 12,000 breast cancer patients, with results published in hundreds of leading peer reviewed medical and scientific journals internationally.
The first validation for MammaPrint, published in the New England Journal of Medicine, was undertaken in a series of 295 consecutive women with breast cancer. The profile was a statistically independent predictor and added to the power of standard clinico-pathologic parameters; HR = 4.6 (95% CI 2.3 – 9.2).
Confidence in the binary results was proven by the independent validation performed by the TRANSBIG Consortium which conducted a study of 302 adjuvantly untreated patients with at least ten years of follow-up.2 Analysis of this data set in line with FDA standards, (conducted in a study by Delahaye et al.) showed that the proportion of patients who remained free from distant metastases at 10 years was 90% in the Low Risk group and 71% in the High Risk group. MammaPrint was found to provide prognostic information beyond what could be determined from patient age, tumor grade, tumor size, and ER status in a population of lymph node-negative patients, none of whom received any adjuvant chemotherapy.9
Additional studies have been published proving MammaPrint’s additive prognostic ability in:
A study published in 2010 by Knauer et al., demonstrated the predictive value of MammaPrint for adjuvant chemotherapy in early stage breast cancer. Patients allocated to High Risk by MammaPrint resulted in a statistical separation in distant disease free survival (DDFS) with a statistically significant p value (p=0.01). In the High Risk group, the endocrine only treated arm had a 76% DDFS, and the endocrine + chemotherapy arm had a 88% DDFS. This resulted in an overall 12% absolute benefit, and a 50% relative benefit overall for this group. In the MammaPrint Low Risk group, no statistically significant benefit for the chemotherapy + endocrine therapy arm vs endocrine therapy only arm was achieved.
Low Risk= ~10% chance of recurrence = no statistical benefit from chemotherapy
High Risk = ~29% chance of recurrence = statistical benefit from chemotherapy
Published in January of 2013, the RASTER study (microarRAy-prognoSTics-in-breast-cancER) proved the ability of MammaPrint to accurately stratify breast cancer patients as either Low Risk or High Risk better than the available traditional clinical parameters. RASTER is the first and only 5 year prospective outcome-based data for any prognostic breast cancer risk of recurrence assay that has been published. The study consisted of 427 patients, that were enrolled at 16 centers, performed in the community setting.
MammaPrint results were incorporated into the decision making process for patients and physicians with regards to the use of adjuvant chemotherapy
97% of the MammaPrint identified Low Risk patient group, which primarily chose to forego chemotherapy, were disease free after 5 years
MammaPrint identified 20% more Low Risk patients as compared to traditional clinical parameters, and despite this increased allocation in patients, the Low Risk group still had an excellent 97% DRFI
Low Risk MammaPrint result is shown to correlate with excellent outcome
High Risk MammaPrint result is shown to correlate with poorer outcome and higher response to adjuvant chemotherapy
Published in 2006 by Buyse et al., the independent study conducted on behalf of the TRANSBIG consortium which consisted of 302 patients, found that MammaPrint can stratify patients into a binary risk classification of either Low Risk or High Risk, with a statistically significant difference in the probability of metastasis free survival at 10 years.
Low Risk patients have a ∼10% (95%, CI 4-15) chance of cancer recurrence within 10 years without any adjuvant treatment (either hormonal therapy or chemotherapy)
High Risk patients have a ∼29% (95%, CI 22-35) chance of recurrence within 10 years without any adjuvant treatment (either hormonal therapy or chemotherapy)
With FDA clearance, have confidence in your results8
MammaPrint received FDA clearance in 2007 and was the first in vitro diagnostic multivariate index assay (IVDMIA) to be cleared by the regulatory agency. An IVDMIA is a device that combines the values of multiple variables using an interpretative function (bioinformatics algorithm) to provide a single, patient specific result, that is intended for use in the diagnosis of disease and which provides a result whose derivation is non-transparent, and for that reason, cannot be independently derived or verified by the end user.
MammaPrint’s FDA clearance confers confidence in its safety and effectiveness, ensuring that the peer reviewed, published studies used in its development, validation and IVDMIA clearance have been evaluated by the United States Food and Drug Administration. The FDA label indicates that as a diagnostic tool, MammaPrint has a 98.9% degree of accuracy in classifying patients as Low Risk or High Risk and technical reproducibility of 98.5%.
MammaPrint’s FDA indication – patient eligibility in the USA
Breast cancer recurrence and/or metastasis is partly dependent on the activation and suppression of certain genes located within the primary breast tumor. The FDA approved MammaPrint profile is a fresh tissue based genomics test which uses the latest microarray technology to analyze a patient’s breast tumor biology to predict whether existing cancer has the ability to metastasize. This 70-gene profile is validated as an independent indicator for breast cancer prognosis for women with lymph node-negative, estrogen receptor positive breast cancer and estrogen receptor negative disease.
The FDA-cleared MammaPrint (fresh tissue) and MammaPrint FFPE tests are indicated for breast cancer patients that fulfill the following criteria:
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-)
HER2/neu: negative or positive
Women of all ages
Breast cancer is heterogeneous disease
Dr. Rene Bernards, PhD, co-developer of MammaPrint® discusses how breast cancer biology drove the discovery of the 70-Gene Breast Cancer Recurrence Assay